Epilepsy, psychosis,

and schizophrenia:
Clinical and neuropathologic correlations
C.J. Bruton, MD; Janice R. Stevens, MD; and C.D. Frith, PhD
Article abstract-This study examines the relationship between epilepsy and psychosis. It compares clinical, EEG,
and neuropathologic data from a group of subjects who had both epilepsy and psychosis with similar information from
another group of patients who had epilepsy but no evidence of psychotic illness. We examined, blind to clinical diagno-
sis, gross and microscopic material from whole-brain specimens from 10 patients diagnosed with epilepsy plus
schizophrenia-like psychosis, nine subjects diagnosed with epilepsy plus epileptic psychosis, and 36 individuals with
epilepsy (21 from an epileptic colony and 15 from the community at large) who had no history of psychosis (n = 10 + 9 +
21 + 15 = 55). We abstracted case histories without knowledge of pathologic findings. Epileptic colony patients had an
earlier age at onset of seizures, while epileptic colony and epileptic psychosis patients had more frequent seizures.
Epileptic individuals in the community died at a younger age than did epileptic patients in long-stay hospital care.
Psychotic epileptic patients had larger cerebral ventricles, excess periventricular gliosis, and more focaI cerebral dam-
age compared with epileptic patients who had no psychotic illness. Epileptic patients with schizophrenia-like psychosis
were distinguished from all other groups by a significant excess of pinpoint perivascular white-matter softenings. We
found that mesial temporal sclerosis and temporal lobe epilepsy occurred with equal frequency in the psychotic and
nonpsychotic groups; generalized seizures occurred more frequently in the psychotic epileptics and the epileptic colony
epileptics than in the community epileptic controls.
NEUROLOGY 1994;44:34-42
Despite many attempts to investigate the subject,
the relationship between epilepsy and psychosis is
unclear. The frequency of major psychopathology
found i n individuals with epilepsy has varied
greatly from one study t o the next; it is very high in
epileptic patients from mental institutions and
high in subjects referred t o special epilepsy clinics,
but it is only slightly greater than that of the gen-
eral population in epileptics who are treated by
general medical practitioners or who receive no
regular medical care at all.S2 Nevertheless, since
the influential papers of Gibbs et al,3 Hill,4 and
Slater and Beard,5 temporal lobe epilepsy (TLE)
has been thought to carry a particularly high risk
for psychosis, including schizophrenia.6-10 Other
clinical rep~rt sl -~ have not substantiated the in-
creased risk, however, and the matter remains con-
troversial. Even after 30 years of debate, few prop-
erly controlled studies of large epilepsy populations
have been published.
In contrast t o the widespread clinical interest,
neuropathologists have seldom considered a link
between psychosis and epilepsy because, although
the pathology of epilepsy is well documented,18-22
for many years there has been considerable doubt
t hat neuropathologic lesions occur at all i n the
brains of patients who have schizophrenia. How-
ever, during the last decade, well-controlled neu-
roimaging and postmortem studies have convinc-
ingly demonstrated the presence of structural ab-
normalities in the brains of a significant number of
schizophrenic patients. These abnormalities in-
clude enlargement of the lateral ventricles, en-
largement of the third ventricle, and reduction in
the area or the volume of several limbic structures,
notably the parahippocampal gyrus, the hippocam-
pus, and the amygdaloid n ~ c l e u s . ~ ~ - ~ ~ Histologic
studies have also suggested the presence of exces-
sive focal damage26 and g l i o ~ i s ~ ~ , ~ ~ and a significant
reduction in the number of nerve cells in the hip-
poc a mpu~, ~~ the nucleus accumbens, and the dorso-
medial nucleus of the thalamus.30 In addition, an
examination of temporal lobe tissue resected from
patients who had both intractable TLE and psy-
chosis demonstrated a greater incidence of medial
temporal abnormalities that had occurred during
From the MRC Department of Neuropathology (Dr. Bruton), Runwell Hospital, Wickford, and the Division of Psychiatry (Drs. Bruton and Frith), CRC,
Harrow, UK the National Institute of Mental Health (Dr. Stevens), St. Elizabeths Hospital, Washington, DC; and Oregon Health Sciences University
(Dr. Stevens), Portland, OR.
Supported by a grant from the Stanley Foundation.
Received April 28, 1993. Accepted for publication i n final form July 19, 1993.
Address correspondence and reprint requests to Dr. C.J. Bruton, Neuropathology Department, Runwell Hospital, Wickford, Essex, SS11 7QE, UK.
34 NEUROLOGY 44 January 1994
Epilepsy, psychosis,
and schizophrenia:
Clinical and neuropathologic correlations
C.J. Bruton, MD; Janice R. Stevens, MD; and C.D. Frith, PhD
Article abstract-This study examines the relationship between epilepsy and psychosis. It compares clinical, EEG,
and neuropathologic data from a group of subjects who had both epilepsy and psychosis with similar information from
another group of patients who had epilepsy but no evidence of psychotic illness. We examined, blind to clinical diagno-
sis, gross and microscopic material from whole-brain specimens from 10 patients diagnosed with epilepsy plus
schizophrenia-like psychosis, nine subjects diagnosed with epilepsy plus "epileptic psychosis," and 36 individuals with
epilepsy (21 from an epileptic colony and 15 from the community at large) who had no history of psychosis (n = 10 + 9 +
21 + 15 = 55). We abstracted case histories without knowledge of pathologic findings. Epileptic colony patients had an
earlier age at onset of seizures, while epileptic colony and epileptic psychosis patients had more frequent seizures.
Epileptic individuals in the community died at a younger age than did epileptic patients in long-stay hospital care.
Psychotic epileptic patients had larger cerebral ventricles, excess periventricular gliosis, and more focal cerebral dam-
age compared with epileptic patients who had no psychotic illness. Epileptic patients with schizophrenia-like psychosis
were distinguished from all other groups by a significant excess of pinpoint perivascular white-matter softenings. We
found that mesial temporal sclerosis and temporal lobe epilepsy occurred with equal frequency in the psychotic and
non psychotic groups; generalized seizures occurred more frequently in the psychotic epileptics and the epileptic colony
epileptics than in the community epileptic controls.
Despite many attempts to investigate the subject,
the relationship between epilepsy and psychosis is
unclear. The frequency of major psychopathology
found in individuals with epilepsy has varied
greatly from one study to the next; it is very high in
epileptic patients from mental institutions and
high in subjects referred to special epilepsy clinics,
but it is only slightly greater than that of the gen-
eral population in epileptics who are treated by
general medical practitioners or who receive no
regular medical care at all.
1
,2 Nevertheless, since
the influential papers of Gibbs et al,3 Hill,4 and
Slater and Beard,5 temporal lobe epilepsy (TLE)
has been thought to carry a particularly high risk
for psychosis, including schizophrenia.
6
.
1o
Other
clinical reports
l1
.
17
have not substantiated the in-
creased risk, however, and the matter remains con-
troversial. Even after 30 years of debate, few prop-
erly controlled studies of large epilepsy populations
have been published.
In contrast to the widespread clinical interest,
neuropathologists have seldom considered a link
between psychosis and epilepsy because, although
NEUROLOGY 1994;44:34-42
the pathology of epilepsy is well documented,18.22
for many years there has been considerable doubt
that neuropathologic lesions occur at all in the
brains of patients who have schizophrenia. How-
ever, during the last decade, well-controlled neu-
roimaging and postmortem studies have convinc-
ingly demonstrated the presence of structural ab-
normalities in the brains of a significant number of
schizophrenic patients. These abnormalities in-
clude enlargement of the lateral ventritles, en-
largement of the third ventricle, and reduction in
the area or the volume of several limbic structures,
notably the parahippocampal gyrus, the hippocam-
pus, and the amygdaloid nucleus.
23
.
25
Histologic
studies have also suggested the presence of exces-
sive focal damage
26
and gliosis
27
,28 and a significant
reduction in the number of nerve cells in the hip-
pocampus,29 the nucleus accumbens, and the dorso-
medial nucleus of the thalamus. 30 In addition, an
examination of temporal lobe tissue resected from
patients who had both intractable TLE and psy-
chosis demonstrated a greater incidence of medial
temporal abnormalities that had occurred during
From the MRC Department of Neuropathology (Dr, Bruton), Runwell Hospital, Wickford, and the Division of Psychiatry (Drs, Bruton and Frith), CRC,
Harrow, UK; the National Institute of Mental Health (Dr, Stevens), St, Elizabeth's Hospital, Washington, DC; and Oregon Health Sciences University
(Dr, Stevens), Portland, OR.
Supported by a grant from the Stanley Foundation,
Received April 28, 1993, Accepted for publication in final form July 19, 1993,
Address correspondence and reprint requests to Dr, C.J, Bruton, Neuropathology Department, Runwell Hospital, Wickford, Essex, SSll 7QE, UK
34 NEUROLOGY 44 January 1994
the fetal period or ear l y infancy among such pa-
tients than among appar ent l y similar t empor al
lobectomy pat i ent s who did not have a psychotic ill-
ness.31,32
In this st udy, we investigated the relationship
bet ween epilepsy and psychosis from a new per-
spective, namel y that of a macroscopic and histo-
logic assessment of postmortem whole-brain speci-
mens from patients with a history of epilepsy who
had been hospi t al i zed wi t h psychosis compared
wi t h a similar assessment of whol e-brai n speci-
mens f r om a no t he r gr oup of i ndi vi dual s wi t h
epilepsy who had no evidence of psychosis. After we
had examined the case notes in detail, we under-
took a neuropathologic investigation, blind to the
clinical status of each patient. This had two objec-
tives: t he first was t o assess the nat ur e, degree,
and distribution of brain damage seen in the psy-
chotic and the nonpsychotic patients with epilepsy;
the second was t o examine further those st ruct ural
and neurohistologic abnor mal i t i es that have re-
cently become the focus of great i nt erest in the in-
vestigation of schizophrenic patients.
Methods. Whole brains from 661 subjects with epilepsy
were available for study. These form part of an archive of
8,000 psychiatric and neurologic brain specimens (t he
Corsellis collection) accumulated over a period of 40
years (1950 t o 1990) in the Department of Neuropathol-
ogy at Runwell Hospital, Essex, UK.
Runwell Hospital is a large institution for the men-
tally ill. The Neuropathology Department receives brains
for study from deceased patients with various psychiatric
disorders, particularly schizophrenia and the senile psy-
choses. In addition, under the direction of Professor
J.A.N. Corsellis, the laboratory has for many years had a
special interest in the study of epilepsy. As a result,
brains from patients with epilepsy were received not only
from Runwell Hospital but also from general hospitals,
coroners departments, neurosurgical units, and long-
stay epilepsy institutions (epileptic colonies) in the
Greater London area.
Clinical. The case records of all 661 patients were first
screened, without knowledge of the neuropathologic diag-
nosis, for evidence of epilepsy and psychosis. Cases were
excluded from further study if the clinical data were in-
complete or if only a part of the brain were available for
study (ie, following temporal lobectomy). All patients
under age 18 at death and all patients who were men-
tally retarded were similarly excluded. Of the original
sample of 661 patients with epilepsy, 75 individuals met
the study criteria: age 218 years at death, availability of
the entire brain specimen, satisfactory clinical notes, and
evidence of both psychosis and epilepsy. For nonpsy-
chotic epileptic controls, two groups were available: indi-
viduals who had been inpatients at long-stay epileptic
colonies and whose case notes showed no evidence of a
psychotic illness (n = 21) and individuals with epilepsy
who had lived in the community at large until death and
who had no history of psychiatric disease ( n = 15).
The case notes of these subjects (n = 75 + 21 + 15 =
111) were examined in detail by J.R.S. and C.J.B. Psy-
chiatric symptoms were assessed according t o DSM 111-
R33 criteria. Of the 75 patients whose clinical notes men-
tioned both psychosis and epilepsy, only 27 (4% of the
original sample of 661) had fully documented evidence of
a long-standing interictal psychotic illness in addition t o
long-standing epilepsy, Forty-eight of the 75 patients
were excluded, most often because seizures had occurred
for the first time a few months before death (13 individu-
als). Schizophrenic patients whose epilepsy began shortly
after prefrontal leukotomy were also removed from the
study, as were all cases of dementia, mental retardation,
and inadequate clinical history. Of the remaining 27 pa-
tients who had both psychosis and epilepsy, 10 individu-
als (1.5% of the original sample) had psychotic symptoms
that were indistinguishable from DSM 111-R schizophre-
nia apart from the additional diagnosis of epilepsy (group
1, the schizophrenia-psychosis group). A further nine pa-
tients had been considered by their attending physicians
t o be suffering from an epileptic psychosis. Many of
these patients did not meet the DSM 111-R criteria for
schizophrenia and would currently be classified as hav-
ing organic psychoses (group 2, the epileptic-organic psy-
chosis group). The remaining eight subjects conformed t o
criteria for other major psychoses-ie, depression (three
patients), manic depression (two patients), or paranoid
state (three patients). As noted above, there were two
groups of patients who had epilepsy without psychosis-
21 long-stay inpatients from an epileptic colony (group 3,
t he epileptic colony group) and 15 individuals with
epilepsy who had lived and often worked in the commu-
nity and had no recorded history of mental illness (group
4, the community epilepsy group). Brains from this last
cohort of patients were sent to Runwell from general hos-
pitals or were coroners cases.
The diagnosis of epilepsy was made on the case note
history, which frequently included descriptions of
seizures given by hospital staff or family members.
Seizures had been classified as grand mal, petit mal,
minor, or psychomotor in accordance with criteria at the
time of hospitalization or medical care. EEGs had been
recorded on 4-, 5-, or 8-channel electroencephalographs.
EEG data were obtained from factual reports written at
the time of recording; original EEG recordings were not
available for examination.
Neuropathology. The brains of all 661 patients had
been reported as part of routine departmental procedure;
some epileptic colony cases had also formed part of the
epilepsy study by Margerison and Corsellis.20 For the
purposes of t he present investigation, we coded the
brains, macroscopic reports, photographs, and histologic
slides and then reassessed them without knowledge of
the clinical history. Extensive bilateral blocks for cel-
loidin and paraffin embedding had been taken in many
cases; where necessary, we took further blocks so that
representative bilateral histology would be available
from the frontal, occipital, and temporal lobes and the
cerebellum and midbrain. We stained microscopic sec-
tions using histologic techniques including Nissls
method using cresyl violet, hematoxylin and eosin, van
Gieson, Heidenhain-Woelcke for myelin, and Holzers
method for fibrous glia. Frozen sections from the frontal,
parietal, and temporal lobes were stained by von Braun-
miihls method for plaques and tangles.
We carefully identified both the type and the lateral-
ity of any visible abnormality. On naked-eye examina-
tion, we paid particular attention t o cortical atrophy,
ventricular size, and the degree and distribution of focal
pathology. Microscopic assessment took special account
of nerve cell loss and gliosis in the cortex and basal gan-
glia; gliosis and focal damage in the white matter, the
periventricular regions, the temporal lobes, and the cere-
bellum; and the degree of vascular and senile change.
January 1994 NEUROLOGY 44 35
the fetal period or early infancy among such pa-
tients than among apparently similar temporal
lobectomy patients who did not have a psychotic ilJ-
ness.
31
,32
In this study, we investigated the relationship
between epilepsy and psychosis from a new per-
spective, namely that of a macroscopic and histo-
logic assessment of postmortem whole-brain speci-
mens from patients with a history of epilepsy who
had been hospitalized with psychosis compared
with a similar assessment of whole-brain speci-
mens from another group of individuals with
epilepsy who had no evidence of psychosis. After we
had examined the case notes in detail, we under-
took a neuropathologic inv!,stigation, blind to the
clinical status of each patient. This had two objec-
tives: the first was to assess the nature, degree,
and distribution of brain damage seen in the psy-
chotic and the nonpsychotic patients with epilepsy;
the second was to examine further those structural
and neurohistologic abnormalities that have re-
cently become the focus of great interest in the in-
vestigation of schizophrenic patients.
Methods. Whole brains from 661 subjects with epilepsy
were available for study. These form part of an archive of
8,000 psychiatric and neurologic brain specimens (the
Corsellis collection) accumulated over a period of 40
years (1950 to 1990} in the Department of Neuropathol-
ogy at Runwell Hospital, UK.
Runwell Hospital is a large institution for the men-
tally ill. The Neuropathology Department receives brains
for study from deceased patients with various psychiatric
disorders, particularly schizophrenia and the senile psy-
choses. In addition, under the direction of Professor
J.A.N. Corsellis, the laboratory has for many years had a
special interest in the study of epilepsy. As a result,
brains from patients with epilepsy were received not only
from Runwell Hospital but also from genera] hospitals,
coroners' departments, neurosurgical units, and long-
stay epilepsy institutions ("epileptic colonies") in the
Greater London area.
Clinical. The case records of all 661 patients were first
screened, without knowledge of the neuropathologic diag-
nosis, for evidence of epilepsy and psychosis. Cases were
excluded from further study if the clinical data were in-
complete or if only a part of the brain were available for
study (ie, following temporal lobectomy). All patients
under age 18 at death and all patients who were men-
tally retarded were similarly excluded. Of the original
sample of 661 patients with epilepsy, 75 individuals met
the study criteria: age :2:18 years at death, availability of
the entire brain specimen, satisfactory clinical notes, and
evidence of both psychosis and epilepsy. For nonpsy-
chotic epileptic controls, two groups were available: indi-
viduals who had been inpatients at long-stay epileptic
colonies and whose case notes showed no evidence of a
psychotic illness (n = 21) and individuals with epilepsy
who had lived in the community at large until death and
who had no history of psychiatric disease (n = 15).
The case notes of these subjects (n = 75 + 21 + 15 =
1111 were examined in detail by J.R.S. and C.J.B. Psy-
chiatric symptoms were assessed according to DSM III-
R33 criteria. Of the 75 patients whose clinical notes men-
tioned both psychosis and epilepsy, only 27 (4% of the
original sample of 661) had fully documented evidence of
a long-standing interictal psychotic illness in addition to
long-standing epilepsy. Forty-eight of the 75 patients
were excluded, most often because seizures had occurred
for the first time a few months before death (13 individu-
als). Schizophrenic patients whose epilepsy began shortly
after prefrontal leukotomy were also removed from the
study, as were all cases of dementia, mental retardation,
and inadequate clinical history. Of the remaining 27 pa-
tients who had both psychosis and epilepsy, 10 individu-
als (1.5% of the original sample) had psychotic symptoms
that were indistinguishable from DSM IIl-R schizophre-
nia apart from the additional diagnosis of epilepsy (group
1, the schizophrenia-psychosis group). A further nine pa-
tients had been considered by their attending physicians
to be suffering from an "epileptic" psychosis. Many of
these patients did not meet the DSM III-R criteria for
schizophrenia and would currently be classified as hav-
ing organic psychoses (group 2, the epileptic-organic psy-
chosis group). The remaining eight subjects conformed to
criteria for other major psychoses-ie, depression (three
patients), manic depression (two patients), or paranoid
state (three patients). As noted above, there were two
groups of patients who had epilepsy without psychosis-
21 long-stay inpatients from an epileptic colony (group 3,
the epileptic colony group) and 15 individuals with
epilepsy who had lived and often worked in the commu-
nity and had no recorded history of mental illness (group
4, the community epilepsy group). Brains from this last
cohort of patients were sent to Runwell from general hos-
pitals or were coroners' cases.
The diagnosis of epilepsy was made on the case note
history, which frequently included descriptions of
seizures given by hospital staff or family members.
Seizures had been classified as grand mal, petit mal,
minor, or psychomotor in accordance with criteria at the
time of hospitalization or medical care. EEGs had been
recorded on 4-, 5-, or 8-channel electroencephalographs.
EEG data were obtained from factual reports written at
the time of recording; original EEG recordings were not
available for examination,
Neuropathology. The brains of all 661 patients had
been reported as part of routine departmental procedure;
some epileptic colony cases had also formed part of the
epilepsy study by Margerison and Corsellis.
20
For the
purposes of the present investigation, we coded the
brains, macroscopic reports, photographs, and histologic
slides and then reassessed them without knowledge of
the clinical history. Extensive bilateral blocks for cel-
loidin and paraffin embedding had been taken in many
cases; where necessary, we took further blocks so that
representative bilateral histology would be available
from the frontal, occipital, and temporal lobes and the
cerebellum and midbrain. We stained microscopic sec-
tions using histologic techniques including Nissl's
method using cresyl violet, hematoxylin and eosin, van
Gieson, Heidenhain-Woelcke for myelin, and Holzer's
method for fibrous glia. Frozen sections from the frontal,
parietal, and temporal lobes were stained by von Braun-
mtihl's method for plaques and tangles.
We carefully identified both the type and the lateral-
ity of any visible abnormality. On naked-eye examina-
tion, we paid particular attention to cortical atrophy,
ventricular size, and the degree and distribution of focal
pathology. Microscopic assessment took special account
of nerve cell loss and gliosis in the cortex and basal gan-
glia; gliosis and focal damage in the white matter, the
periventricular regions, the temporal lobes, and the cere-
bellum; and the degree of vascular and senile change.
January 1994 NEUROLOGY 4435
Table 1. Clinical features
Group 1:
Schizophrenia-
psychosis
Number of cases 10
Mean age at death iyr) 60
Average age at onset 15
Sex
of epilepsy (yr)
Male 3
Female 7
Average fit frequency
1 (1-3 per year)
2 (4-12 per year)
3 (2-5 per month)
4 ( 6 per month 1
Duration of epilepsy
before psychosis (yrH
2.1
Mean/Median 21120.5
Range 5-38
Clinical type of epilepsy
Major (grand mall 100%
Psychomotor (TLE) 20%
Minor (petit mall 40%
* Denotes significant differences.
t One patient developed schizophrenia before epilepsy
NS Not significant.
Group 2:
Epilep tic-organic
psychosis
9
67
13
4
5
3.1
17.3115.5
7-42
100%
11%
33%
Group 3:
Epileptic
colony
21
61
7
9
12
3.2*
-
-
95%
15%
43%
Group 4:
Community
epileptics
15
45
23
7
8
2.2
-
-
73%*
138
13%
p Values
p < 0.001*
p < 0.01*
NS
p < 0.05
NS
p < 0.02
NS
NS
Pertinent medical data, clinical and family history, di-
agnosis, details of medical treatment, and details of
physical or neurologic examinations were extracted and
coded. We similarly coded EEG data for subsequent anal-
ysis and correlation with the neuropathologic findings.
Statistical information was processed by C.D.F. using
data analysis packages incorporated in BMDP. We used
analysis of variance for continuous measures and
Fishers exact test for frequencies.
Results. The clinical comparisons between groups
are summarized in table 1. The group 3 epileptic
colony patients had the youngest age at onset of
first seizure (mean age = 7 years; p < 0.01). Age at
death also differed significantly between groups;
the group 4 community epilepsy subjects (average
age at death = 45 years) died at a significantly
younger age ( p < 0.001) than did subjects in groups
1 through 3, who were all long-stay hospital pa-
tients and who had average ages at death of 60,67,
and 61 years. These figures correspond closely to
the national average age at death for community
and hospitalized epileptic patients in England and
Wales (personal communication from the Statistics
Division, Office of Population Censuses and Sur-
veys, UK). Seizure type and frequency also varied;
grand ma1 seizures, present in 73% of community
group patients, were significantly less common in
t he community group t han i n t he ot her t hr ee
groups ( p < 0.02). Furthermore, the seizure fre-
quencies of both the community patients and the
group 1 schizophrenia-psychosis patients were sig-
nificantly lower t han the seizure frequencies re-
ported in the group 3 epileptic colony and the group
36 NEUROLOGY 44 January 1994
2 epileptic-organic psychosis subjects ( p < 0.05 in
both cases).
Blunted affect ( p < 0.05), delusions ( p < 0.08)
and incoherent speech ( p < 0.07) were all more fre-
quent in the schizophrenia-psychosis subjects; irri-
tability and aggression were more common in the
epileptic-organic psychosis group ( p < 0.01 ).
The clinicopathologic correlations are itemized
in table 2. For convenience, the neuropathologic
findings have been subdivided into typical epilep-
tic damage and other, nonepileptic pathologies.
(In our study, typical epileptic pathology includes
cerebellar atrophy or gliosis, cortical scar forma-
tion, Ammons horn [or hippocampall sclerosis [fig-
ure 11, and mesial temporal sclerosis (MTS). MTS34
incorporates both classic Ammons horn sclerosisz0
and end folium sclerosis,2o along with more wide-
spread medial temporal pathology such as nerve
cell loss and gliosis occurring i n t he uncus, the
amygdaloid nucleus, or t he cortex of the medial
temporal gyri. However, table 2 presents the data
for Ammons horn sclerosis and amygdaloid pathol-
ogy separately.)
Our data show that the frequency and the degree
of typical epileptic damage did not differ between
groups apart from the occurrence of cerebellar glio-
sis, which was seen less frequently in the brains of
epileptic subjects who lived in the community ( p <
0.02 1. Major differences in neuropathology were
seen, however, in the presence and the degree of
nonepileptic brain damage. Thus, on naked-eye ex-
amination, a slight, moderate, or severe degree of
ventricular enlargement was recorded in 80% of
Table 1. Clinical features
Group 1: Group 2: Group 3: Group 4:
Schizophrenia- Epileptic-organic Epileptic Community
psychosis psychosis colony epileptics p Values
Number of cases
Mean age at death (yr)
Average age at onset
of epilepsy (yr)
Sex
Male
Female
Average fit frequency
1 0-3 per year)
2 (4-12 per year)
3 (2-5 per month)
4 (6 per month)
Duration of epilepsy
10 9
60 67
15 13
3 4
7 5
2.1 3.1 *
21 15
61 45* P < 0.001*
7* 23 P < 0.01*
9 7
NS
12 8
3.2* 2.2 p < 0.05"
before psychosis (yr)t
Mean/Median
Range
21120.5 17.3/15.5 NS
5-38 7-42
Clinical type of epilepsy
Major (grand mall
Minor (petit mal)
Psychomotor (TLE)
100% 100%
40%
20%
* Denotes significant differences.
t One patient developed schizophrenia before epilepsy.
NS Not significant.
Pertinent medical data, clinical and family history, di-
agnosis, details of medical treatment, and details of
physical or neurologic examinations were extracted and
coded. We similarly coded EEG data for subsequent anal-
ysis and correlation with the neuropathologic findings.
Statistical information was processed by C.D.F. using
data analysis packages incorporated in BMDP. We used
analysis of variance for continuous measures and
Fisher's exact test for frequencies.
Results. The clinical comparisons between groups
are summarized in table 1. The group 3 epileptic
colony patients had the youngest age at onset of
first seizure (mean age = 7 years; p < 0.01). Age at
death also differed significantly between groups;
the group 4 community epilepsy subjects (average
age at death = 45 years) died at a significantly
younger age (p < 0.001) than did subjects in groups
1 through 3, who were all long-stay hospital pa-
tients and who had average ages at death of60, 67,
and 61 years. These figures correspond closely to
the national average age at death for community
and hospitalized epileptic patients in England and
Wales (personal communication from the Statistics
Division, Office of Population Censuses and Sur-
veys, UK). Seizure type and frequency also varied;
grand mal seizures, present in 73% of community
group patients, were significantly less common in
the community group than in the other three
groups (p < 0.02). Furthermore, the seizure fre-
quencies of both the community patients and the
group 1 schizophrenia-psychosis patients were sig-
nificantly lower than the seizure frequencies re-
ported in the group 3 epileptic colony and the group
36 NEUROLOGY 44 January 1994
1191:
33%
95% 73%* P < 0.02"
15% 1391: NS
43% 13<;;( NS
2 epileptic-organic psychosis subjects (p < 0.05 in
both cases).
Blunted affect (p < 0.05), delusions (p < 0.08),
and incoherent speech (p < 0.07) were all more fre-
quent in the schizophrenia-psychosis subjects; irri-
tability and aggression were more common in the
epileptic-organic psychosis group (p < 0.01).
The clinicopathologic correlations are itemized
in table 2. For convenience, the neuropathologic
findings have been subdivided into "typical" epilep-
tic damage and other, "nonepileptic" pathologies.
(In our study, "typical" epileptic pathology includes
cerebellar atrophy or gliosis, cortical scar forma-
tion, Ammon's horn [or hippocampal] sclerosis [fig-
ure 1], and mesial temporal sclerosis (MTS). MTS34
incorporates both classic Ammon's horn sclerosis
20
and end folium sclerosis,20 along with more wide-
spread medial temporal pathology such as nerve
cell loss and gliosis occurring in the uncus, the
amygdaloid nucleus, or the cortex of the medial
temporal gyri. However, table 2 presents the data
for Ammon's horn sclerosis and amygdaloid pathol-
ogy separately.)
Our data show that the frequency and the degree
of typical epileptic damage did not differ between
groups apart from the occurrence of cerebellar glio-
sis, which was seen less frequently in the brains of
epileptic subjects who lived in the community (p <
0.02). Major differences in neuropathology were
seen, however, in the presence and the degree of
nonepileptic brain damage. Thus, on naked-eye ex-
amination, a slight, moderate, or severe degree of
ventricular enlargement was recorded in 80% of
able 2. Pathology: Psychotic groups and controls
Epileptic damage
Ammons horn
sclerosis
Amygdaloid sclerosis
Cortical scars
Cerebellum
Ventricular
Nonepileptic damage
enlargement
Periventricular
gliosis
White-matter disease
(small vessel)
Miscellaneous macroscopic
abnormalities
Congenital
Acquired
None
Group 1:
Schizophrenia-
psychosis
L R
Group 2:
Epileptic-organic
psychosis
L R
30% 20% 33% 33%
NS Not simiticant.
* Denotes significant differences.
30% 40% 44% 33%
0 0 11% 22%
40% 40% 22% 22%
80% 78%
70% 67%
60%* 11%
10%
30%
60%
22%
44%
34%
Group 3 Group 4:
Epileptic Community
colony epileptics
L R L R p Values
14% 19% 20% 13% NS
20% 48% 27% 20% NS
10% 15% 20% 27% NS
25% 35% 7%* 7%* p<o. o2*
45% 33%* p < 0.01*
29%* 20%* p < 0.02*
0 7% p < 0.02*
10% 27% NS
14% 7%* p < 0.04*
76% 66% NS
Figure 1. Coronal slice of brain of case 26 at posterior
hippocampal level. The lower arrow points to a shrunken
sclerotic left hippocampus (H); the upper arrow (F) indicates
atrophy of the left fornk. The left mammillary body was
also shrunken. (Magnification X2 before 41% reduction)
group 1 schizophrenia-psychosis patients and 78%
of group 2 epileptic-organic psychosis patients but
in only 45% of group 3 nonpsychotic epileptic colony
patients and 33% of group 4 community patients.
The differences between t he psychotic and t he
nonpsychotic groups were significant at p < 0.01.
Periventricular and periaqueductal fibrous gliosis,
as assessed by Holzers stain, was found in 70% and
67% of the two groups of psychotic patients but in
only 29% of the group 3 epileptic colony patients
and 20% of group 4 community patients (p < 0.02).
The presence and the degree of various types of
acquired brain damage (eg, focal cystic softenings,
calcification in the basal ganglia, or plaques of de-
myelination in the white matter) also separated the
groups. This acquired focal pathology was more com-
mon in the epileptic individuals who were psychotic
(groups 1 and 2) than in the group 3 epileptic colony
patients and the group 4 community epileptics (p <
0.04). In addition, the group 1 schizophrenia-like
psychosis patients were further separated from all
other groups by the severity with which disease af-
fected the many small vessels in the cerebral white
matter. This form of small-vessel disease, which was
identified on naked-eye examination by the presence
of numerous pinpoint white-matter softenings (fig-
ure 2), was found in 60% of the schizophrenia-psy-
chosis group (group l), 11% of the group 2 epileptic-
organic psychosis patients, 7% of group 4 community
epileptics, and none of the group 3 epileptic colony
subjects ( p < 0.02). Congenital abnormalities (eg,
polymicrogyria, heterotopias, and tuberous sclerosis)
were equally distributed among the groups.
Certain psychiatric symptoms appear t o be more
closely allied to visible brain pathology than others.
Thus, psychotic individuals with hallucinations
had significantly larger ventricles ( p < O. Ol), pa-
tients with cognitive or affective deficit symptoms
had more cortical atrophy (p c 0.05) and more over-
all cerebral damage ( p < 0.04), and subjects with
delusions ( p < 0.02) and with disorganization of
thought or speech (p < 0.02) had more widespread
white-matter damage.
January 1994 NEUROLOGY 44 37
Table 2. Pathology: Psychotic groups and controls
Group 1: Group 2; Group 3: Group (:
Schbwphrenia- Epileptic-organic Epileptic Conununity
I!!Ich08ia )!!;[chosis coloDI el!ile)!!iCfl
L R L
Epileptic damage
Ammon's horn 30% 20% 33%
sclerosis
Amygdaloid IiClerosis 30% 40% 44%
Cortical scars 0 0 11%
Cerebellum 40% 40% 22%
Nonepileptic damage
Ventricular 80% 78%
enlargement
Periventricular 70% 67%
gliosis
White-matter disease 60%* 11%
(small vessel)
Miscellaneous macroscopic
abnormalities
Congenital 10% 22%
Acquired 30% 44%
None 60% 34%
NS Not significant.
Denotes significant differences.
Figure 1. Coronal slice of brain of case 26 at posteriar
hippocampal level. The lower arrow points to a shrunken
sclerotic lR.fl hippocampus (8); the upper arrow (F) indicates
atrophy of the left fornix. The left mammillary body was
also shrunken. (Magnification x2 before 41% reduction)
group 1 schizophrenia-psychosis patients and 78%
of group 2 epileptic-orgamc psychosis patients but
in only 45% of group 3 nonpsychotic epileptic colony
patients and 33% of group 4 community patients.
The differences between the psychotic and the
nonpsychotic groups were significant at p < O.O!.
Periventricular and periaqueductal fibrous gliosis,
as assessed by Holzer's stain, was found in 70% and
67% of the two groups of psychotic patients but in
R L R L R p Values
33% 14% 19% 20% 13% NS
33% 20% 48% 27% 20% NS
22% 10% 15% 20% 27% NS
22% 25% 35% 7%* 7%* P < 0.02*
45% 33%'" P < 0.01*
29%* 20%* P < 0.02*
0 7% p < 0.02*
10% 27% NS
14% 7%* p< 0.04"
76% 66% NS
only 29% of the group 3 epileptic colony patients
and 20% of group 4 community patients (p < 0.02).
The presence and the degree of various types of
"acquired" brain damage (eg, focal cystic softenings,
calcification in the basal ganglia, or plaques of de-
myelination in the white matter) also separated the
groups. This acquired focal pathology was more com-
mon in the epileptic individuals who were psychotic
(groups 1 and 2) than in the group 3 epileptic colony
patients and the group 4 community epileptics (p <
0.04). In addition, the group 1 schizophrenia-like
psychosis patients were further separated from all
other groups by the severity with which disease af-
fected the many small vessels in the cerebral white
matter. This fonn of small-vessel disease, which was
identified on naked-eye examination by the presence
of numerous pinpoint white-matter softenings (fig-
ure 2), was found in 60% of the schizophrenia-psy-
chosis group (group 1), 11% of the group 2 epileptic-
organic psychosis patients, 7% of group 4 community
epileptics, and none of the group 3 epileptic colony
subjects (p < 0.02). Congenital abnonnalities (eg,
palymicrogyria, heterotopias, and tuberous sclerosis)
were equally distributed among the groups.
Certain psychiatric symptoms appear to be more
closely allied to visible brain pathology than others.
Thus, psychotic individuals with hallucinations
had significantly larger ventricles (p < 0.01), pa-
tients with cognitive or affective deficit symptoms
had more cortical atrophy (p < 0.05) and more over-
all cerebral damage (p < 0.04), and subjects with
delusions (p < 0.02) and with disorganization of
thought or speech (p < 0.02) had more widespread
white-matter damage.
January 1994 NEUROLOGY 4-' 87
A summary of the clinical and neuropathologic
data for each individual in the series is contained
in NAPS file no. 05035 (see Note at end of article).
Discussion. This clinicopathologic study examines
the nature, degree, and distribution of brain damage
in psychotic and nonpsychotic epileptic patients and
investigates t he morphologic subst r at e of t he
schizophrenia-like psychoses seen in some patients
who have epilepsy. As part of this investigation, we
consider it pertinent to discuss our results in the
light of the large body of evidence produced by Slater
and Beard5 and to answer two important questions:
1. Given t he widespread belief t ha t t he
schizophrenia-like psychoses of epilepsy are partic-
ularly associated with temporal lobe seizures, is
temporal lobe brain damage found more often in in-
dividuals who have both epilepsy and psychosis
than in individuals with epilepsy who show no evi-
dence of psychotic disease?
2. Is it possible to identify any clinical or neu-
ropathologic characteristic that can distinguish in-
dividuals who have both epilepsy and psychosis
38 NEUROLOGY 44 January 1994
from individuals with epilepsy who have no evi-
dence of a psychotic disorder?
To the first question, the answer provided by our
data is negative. Temporal lobe pathology in general
and MTS, either unilateral or bilateral, occurred
with equal frequency in all four groups studied. Nei-
t her was a history of TLE more common in the
schizophrenic patients, 100% of whom had general-
ized seizures with or without other seizure types.
This last finding is consistent with the 1963 report
of Slater and Beard,5 who noted that although 70%
of their patients with schizophrenia-like psychosis
and epilepsy had temporal lobe seizures, these indi-
viduals also suffered from generalized attacks. The
remaining 30% of their patients had either general-
ized, other focal, or petit ma1 seizures; only five of
their 69 patients had no generalized attacks.
The mean interval between the onset of seizures
and the onset of schizophrenia-like psychosis in
this study was 21 years (17 years between onset of
seizures and development of epileptic psychosis).
Slater and Beard,5 who calculated t he onset of
epilepsy from t he time of onset of established
A
A summary of the clinical and neuropathologic
data for each individual in the series is contained
in NAPS file no. 05035 (see Note at end of article).
Discussion. This clinicopathologic study examines
the nature, degree, and distribution of brain damage
in psychotic and nonpsychotic epileptic patients and
investigates the morphologic substrate of the
schizophrenia-like psychoses seen in some patients
who have epilepsy. As part of this investigation, we
consider it pertinent to discuss our results in the
light of the large body of evidence produced by Slater
and Beards and tAl answer two important questions:
1. Given the widespread belief that the
schizophrenia-like psychoses of epilepsy are partic-
ularly associated with temporal lobe seizures, is
temporal lobe brain damage found more often in in-
dividuals who have both epilepsy and psychosis
than in individuals with epilepsy who show no evi-
dence of psychotic disease?
2. Is it possible to identify any clinical or neu-
ropathologic characteristi.c that can distinguish in-
dividuals who have both epilepsy and psychosis
38 NEUROLOGY 44 January 1994
B
Figure 2. (IV Corolllll sliu of I",un ahowiTlif multipll pinpoinJ
IO/t.eninlJl1 (PIN) in nw/ur. Th.t middle CIIrrbroJ
fAlCAI &hOWI1 thidf1lil\f of it. waJJ.a.
(AlQjfIIifiallilm xl.6 btt{ort 44% reducMn) (8) myelin
dGin of occipital I. 81wwi11ll pillpOinl
)(1.6 bttforr 91% redudicn) fe) High.trpOUJfT of
pinpoinlllO/f.eni"lIt IMwi11ll thi.cJI-wolled Iie'HI.
,U/"POIUIlUd by (MQ61Ii/'icoIioII x20
before 49% redu.ctiortJ (All pGlIIlh dIIpid from CCM 8.)
from individuals with epilepsy who have no evi-
dence of a psychotic disorder?
To the first question, the answer provided by our
data is negative. Temporal lobe pathology in general
and MTS, either unilateral or bilateral, occurred
with equal frequency in all four groups studied. Nei-
ther was a history of TLE more common in the
schizophrenic patients, 100% of whom had general-
ized seizures with or without other seizure types.
This last finding is consistent with the 1963 report
of Slater and Beard} who noted that although 70%
of their patients with schizophrenia-like psychosis
and epilepsy had temporal lobe seizures, these indi-
viduals also suffered from generalized attacks. The
remaining 30% of their patients had either general-
ized, other focal. or petit mal seizures; only five of
their 69 patients had no generalized attacks.
The mean interval between the onset of seizures
and the onset of schizophrenia-like psychosis in
this study was 21 years (17 years between onset of
seizures and development of epileptic psychosis).
Slater and who calculated the onset of
epilepsy from the time of onset of established
seizures, reported an average of 14 years to the de-
velopment of a schizophrenia-like psychosis. How-
ever, as Taylor35 has pointed out, this statistic is
relatively meaningless as it represents an average
taken from a wide range of time (in our case, from
5 t o 38 years) and thus does not suggest a direct re-
lationship between the duration of epilepsy and the
onset of psychosis. The seizure frequency, while
equally high in the epileptic-organic psychosis and
the epileptic colony groups ( an average of two to
five seizures per month) was significantly lower in
the schizophrenic psychosis and the community pa-
tients (an average of four t o 12 seizures per year).
As for the second question, while certain clinical
features such as the early age at onset and the fre-
quency of seizures did distinguish the epileptic
colony and the epileptic-organic psychosis patients
from the community controls, neither family his-
tory of psychosis, nor history of birth or head in-
jury, nor an episode of status epilepticus distin-
guished the schizophrenia-like psychosis patients
from the other groups.
Neuropathologically, however, three features
emerged that separated the psychotic patients from
the two nonpsychotic groups: enlarged ventricles,
periventricular gliosis, and an excess of acquired
focal brain damage. These features cannot be at-
tributed solely to the age difference between the
psychotic and nonpsychotic groups, as the nonpsy-
chotic epileptic colony patients of group 3 did not
show a similar degree of ventricular enlargement,
periventricular gliosis, or focal damage despite a
similar age at death. The group 1 schizophrenia-
like psychosis patients were further distinguished
neuropathologically from all other groups by a sig-
nificant excess of minute perivascular white-matter
softenings. These tiny punctate lesions (figure 21,
found around thick-walled small vessels through-
out the white matter, are the result of widespread
small-vessel disease. They would generally be con-
sidered a n age-rel at ed phenomenon; t he
schizophrenia-psychosis patients had a mean age
at death of 60 years. However, similar lesions were
rare or absent in the epileptic-organic psychosis
and the epileptic colony patients (groups 2 and 3),
who were of equal or greater age at death.
Although we know of no previous clinicopatho-
logic comparison of whole-brain specimens of pa-
tients with epilepsy and psychosis, the neuropatho-
logic data from the present study give general sup-
port to the evidence of previous epilepsy-psychosis
investigation^^,^^,^^ that show that psychosis is asso-
ciated with enlargement of the lateral ventricles, an
abnormality that has been attributed to subcortical
brain damage.5.36 Apart from excess fibrous gliosis
in the periventricular and periaqueductal regions,
we found no special relationship between psychosis
and histopathology in any specific subcortical or
cortical structure. In this respect, our findings sup-
port those in separate studies by Stevensz8 and by
Bruton et a1,26 who described excess gliosis of the
periventricular regions in the brains of patients
with true schizophrenia. These authors considered
the various etiologic implications of periventricular
gliosis, including the possibility of a viral pathogen.
Data from the present investigation further sup-
port the findings of Bruton et a1,26 who found signifi-
cantly increased acquired focal pathology in the
brains of a group of schizophrenic patients compared
with an age- and sex-matched group of normal con-
trols. The neuropathologic data from the present
study, although retrospective, are from a totally dif-
ferent cohort of patients yet have the advantage of
including two negative comparison groups (nos. 3
and 4) who were handicapped by epilepsy but had no
evidence of psychotic illness. We assume that our re-
sults are valid and recommend that excess acquired
focal brai n damage now be studied alongside
periventricular fibrous gliosis, ventricular enlarge-
ment, and reduced cerebral size in the search for the
neuropathologic substrate of psychosis.
Two additional findings emerged from our clini-
copathologic study. The first of these, mentioned
above, was the significant increase of widespread
small-vessel disease in the cerebral white matter of
the group 1 schizophrenia-like psychosis patients
when compared with the three other groups. I t
would be easy and perhaps tempting t o dismiss this
apparently specific statistical association as fortu-
itous were it not for the past work of Br u e t ~ c h , ~ ~
van der H o r ~ t , ~ ~ and Bini and Mar ~hi af ava, ~~ who
reported excess widespread small-vessel disease
with enlargement of perivascular spaces and with
small foci of demyelination in the brains of a pro-
portion of patients with schizophrenia. These au-
t hor s at t r i but ed t he small-vessel disease to
rheumatic endarteritis, although this assertion was
later rejected (see C~r s e l l i s ~~ for review). Other evi-
dence that diffuse white-matter pathology may be
associated with psychosis was recently presented by
Hyde et al,42 who suggested that the psychosis com-
monly seen in patients with adult-onset metachro-
matic leukodystrophy may be rel at ed to t he
widespread foci of white-matter demyelination that
characterize this disease. The presence of diffuse
white-matter pathology may, in some cases, also
contribute t o the degree of ventricular enlargement
widely reported in patients with schizophrenia. It is
a matter of debate whether this or other reported
forms of acquired brain damage in patients with
schizophrenia or schizophrenia-like p s y ~hos i s ~, ~~ are
relevant to the clinical symptoms of psychosis, t o
the underlying disease process itself, t o the effects
of treatment, or t o some other confounding factor,
such as the effect of excessive tobacco smoking so
commonly found in patients with s~hi zophr eni a. ~~
In our opinion, however, excess acquired cerebral
pathology has been reported too often in patients
with psychosis t o be dismissed out of hand.
The second additional finding to emerge from our
study was that frequency, degree, and type of tem-
poral lobe damage in the schizophrenic and other
psychotic patients did not differ from that found in
the two nonpsychotic epilepsy groups or from that
January 1994 NEUROLOGY 44 39
seizures, reported an average of 14 years to the de-
velopment of a schizophrenia-like psychosis. How-
ever, as Taylor
35
has pointed out, this statistic is
relatively meaningless as it represents an average
taken from a wide range of time (in our case, from
5 to 38 years) and thus does not suggest a direct re-
lationship between the duration of epilepsy and the
onset of psychosis. The seizure frequency, while
equally high in the epileptic-organic psychosis and
the epileptic colony groups (an average of two to
five seizures per month) was significantly lower in
the schizophrenic psychosis and the community pa-
tients (an average of four to 12 seizures per year).
As for the second question, while certain clinical
features such as the early age at onset and the fre-
quency of seizures did distinguish the epileptic
colony and the epileptic-organic psychosis patients
from the community controls, neither family his-
tory of psychosis, nor history of birth or head in-
jury, nor an episode of status epilepticus distin-
guished the schizophrenia-like psychosis patients
from the other groups.
Neuropathologically, however, three features
emerged that separated the psychotic patients from
the two non psychotic groups: enlarged ventricles,
periventricular gliosis, and an excess of acquired
focal brain damage. These features cannot be at-
tributed solely to the age difference between the
psychotic and nonpsychotic groups, as the nonpsy-
chotic epileptic colony patients of group 3 did not
show a similar degree of ventricular enlargement,
periventricular gliosis, or focal damage despite a
similar age at death. The group 1 schizophrenia-
like psychosis patients were further distinguished
neuropathologically from all other groups by a sig-
nificant excess of minute perivascular white-matter
softenings. These tiny punctate lesions (figure 2),
found around thick-walled small vessels through-
out the white matter, are the result of widespread
small-vessel disease. They would generally be con-
sidered an age-related phenomenon; the
schizophrenia-psychosis patients had a mean age
at death of 60 years. However, similar lesions were
rare or absent in the epileptic-organic psychosis
and the epileptic colony patients (groups 2 and 3),
who were of equal or greater age at death.
Although we know of no previous clinicopatho-
logic comparison of whole-brain specimens of pa-
tients with epilepsy and psychosis, the neuropatho-
logic data from the present study give general sup-
port to the evidence of previous epilepsy-psychosis
investigations
S
,36,37 that show that psychosis is asso-
ciated with enlargement of the lateral ventricles, an
abnormality that has been attributed to subcortical
brain damage.
5
,36 Apart from excess fibrous gliosis
in the peri ventricular and periaqueductal regions,
we found no special relationship between psychosis
and histopathology in any specific subcortical or
cortical structure. In this respect, our findings sup-
port those in separate studies by Stevens
28
and by
Bruton et al,26 who described excess gliosis of the
periventricular regions in the brains of patients
with "true" schizophrenia. These authors considered
the various etiologic implications of periventricular
gliosis, including the possibility of a viral pathogen.
Data from the present investigation further sup-
port the findings of Bruton et al,26 who found signifi-
cantly increased acquired focal pathology in the
brains of a group of schizophrenic patients compared
with an age- and sex-matched group of normal con-
trols. The neuropathologic data from the present
study, although retrospective, are from a totally dif-
ferent cohort of patients yet have the advantage of
including two negative comparison groups (nos. 3
and 4) who were handicapped by epilepsy but had no
evidence of psychotic illness. We assume that our re-
sults are valid and recommend that excess acquired
focal brain damage now be studied alongside
periventricular fibrous gliosis, ventricular enlarge-
ment, and reduced cerebral size in the search for the
neuropathologic substrate of psychosis.
Two additional findings emerged from our clini-
copathologic study. The first of these, mentioned
above, was the significant increase of widespread
small-vessel disease in the cerebral white matter of
the group 1 schizophrenia-like psychosis patients
when compared with the three other groups. It
would be easy and perhaps tempting to dismiss this
apparently specific statistical association as fortu-
itous were it not for the past work of Bruetsch,38
van der Horst,39 and Bini and Marchiafava,40 who
reported excess widespread small-vessel disease
with enlargement of perivascular spaces and with
small foci of demyelination in the brains of a pro-
portion of patients with schizophrenia. These au-
thors attributed the small-vessel disease to
rheumatic endarteritis, although this assertion was
later rejected (see Corsellis
41
for review). Other evi-
dence that diffuse white-matter pathology may be
associated with psychosis was recently presented by
Hyde et al,42 who suggested that the psychosis com-
monly seen in patients with adult-onset metachro-
matic leUkodystrophy may be related to the
widespread foci of white-matter demyelination that
characterize this disease. The presence of diffuse
white-matter pathology may, in some cases, also
contribute to the degree of ventricular enlargement
widely reported in patients with schizophrenia. It is
a matter of debate whether this or other reported
forms of acquired brain damage in patients with
schizophrenia or schizophrenia-like psychosis
2
,43 are
relevant to the clinical symptoms of psychosis, to
the underlying disease process itself, to the effects
of treatment, or to some other confounding factor,
such as the effect of excessive tobacco smoking so
commonly found in patients with schizophrenia.
44
In our opinion, however, excess acquired cerebral
pathology has been reported too often in patients
with psychosis to be dismissed out of hand.
The second additional finding to emerge from our
study was that frequency, degree, and type of tem-
poral lobe damage in the schizophrenic and other
psychotic patients did not differ from that found in
the two nonpsychotic epilepsy groups or from that
January 1994 NEUROLOGY 44 39
described in patients with epilepsy since the time of
Sommer18 and of S~i e1meyer. l ~ This information,
combined with the absence of pathologic lesions lo-
calized t o the frontal or other specific areas, sug-
gests that neither MTS nor macroscopic frontal lobe
pathology is critical t o the development of psychosis
in epilepsy. This is not so surprising, however, for in
schizophrenia, despite the presence of a small-sized
or dysplastic hippocampus or parahippocampal
gyrus in a percentage of the patients studied, both
MTS and frontal lobe lesions are ~ n c o m m o n ~ ~ , ~ ~ , ~ ~
and the cause of the lateral ventricular enlargement
remains unknown. We found MTS in 40% to 50% of
all four epileptic groups; t hi s figure compares
closely with the findings of other epilepsy studies by
Falconer,jG Veith,47 Margerison and Corsellis,20 and
BrutomZz There are other ways in which our find-
ings do not support the widely accepted belief that
TLE particularly predisposes t o schizophrenia. Par-
tial (including temporal lobe) seizures were no more
common in our schizophrenia-like psychosis pa-
tients than in our most (normal group of epileptics,
ie, those who lived in the community. Furthermore,
although Taylor et a148 and B r u t ~ n ~ ~ found that con-
genital malformations, especially gangliogliomas
and hamartomas, were overrepresented in the tem-
poral lobes removed at surgery from patients with
epilepsy and psychosis, we found no similar lesions
among the 27 patients with psychosis (including 10
with schizophrenia-like psychosis) in the present
study. Possible reasons for this discrepancy may be
due t o selection bias; the cases of both Taylor et a1
and Bruton were selected for temporal lobe surgery
because of intractability of TLE and thus, in con-
trast to the earlier Slater and Beard study,5 did not
include patients who had other types of epilepsy. A
particularly forceful case for relationship between
TLE and psychosis was also made by Perez and
Trimble.*Jo The schizophrenia-like psychoses they
reported differed greatly from those of the chronic,
hospitalized patients in our study. Diagnosed by the
Present St at e Examination as having nuclear
schizophrenia,8 most of their patients were outpa-
tients who lived and often worked in the commu-
nity, many without long-term neuroleptic medica-
tion. In contrast, our patients were chronic, often
deteriorated schizophrenics, confined to a mental
hospital and generally receiving antipsychotic as
well as anticonvulsant medication. The absence of a
significant increase in temporal lobe pathology in
our pat i ent s appears t o be powerful evidence
against a discrete connection between TLE, tempo-
ral lobe pathology, and schizophrenia as Kraepelin
defined the disorder. Several investigators have re-
ported evidence for a preponderance of left-sided
anatomic abnormality in and in
the schizophrenia-like psychoses of e p i l e p ~ y . ~ ~ , ~ ~
However, no evidence of lateralization of pathology
appeared in this pathologic study of whole brains.
Our findings are compatible with those of Kris-
tensen and S i n d r ~ p , ~ ~ who compared pneumoen-
cephalograms from nearly 200 TLE patients, one-
40 NEUROLOGY 44 January 1994
half with and one-half without psychosis, and re-
ported diffuse ventricular enlargement without lat-
eralization of pathology as t he distinguishing
anatomic feature of patients with psychosis.
Aggressive, violent, and impulsive behavior was
generally considered t o be characteristic of patients
diagnosed with epileptic psychosis.54 However, in
contrast t o the anecdotal reports of links between
aggressive personality disorders and TLE , 55, 56 we
found that a separate analysis of aggression as a be-
havioral trait did not correlate with type of epilepsy
or medial temporal pathology. Moreover, the rela-
tive independence of epilepsy and psychosis is fur-
ther emphasized by our study in that among 661
brain specimens from individuals with epilepsy in
the Runwell Hospital collection, only 75 patients
(11%) had a diagnosis of epilepsy and psychosis. Of
these, we excluded two-thirds as the onset of their
seizures had occurred either in late life, after leukot-
omy, following insulin therapy, or in association
with other organic disease. This leaves the coinci-
dence of epilepsy followed by psychosis at around
4% in this highly selected population of mentally ill
individuals. We therefore conclude that, under mod-
ern conditions of treatment, clinical epilepsy-in-
cluding TLE-is a n uncommon ant ecedent of
schizophrenia or psychosis. The mean age at onset
of epilepsy for patients who subsequently developed
an epileptic or a schizophrenic psychosis was 13 and
15 years, compared with 7 years for epileptic colony
patients and 23 years for community patients. This
finding is in keeping with observations by Taylor57
and Ounsted and Li nd~ay~ that epilepsy beginning
in or enduring through puberty is more likely to be
associated with subsequent psychosis.
Conclusions. The results of our neuropathologic
investigation were unexpected yet clear-cut. Indi-
viduals with psychosis in this study were character-
ized by their pubertal age at onset of seizures and a
preponderance of generalized (grand mal) epilepsy.
They were not characterized by degree, type, later-
ality, or bilaterality of MTS. The brains of psychotic
individuals were distinguished by larger ventricles
and more focal pathology, including periventricular
gliosis. In patients with schizophrenia-like psy-
chosis, the brains also contained a significant excess
of punctate white-matter lesions. Our findings show
that epileptic patients with psychosis have more se-
vere and widespread brain damage than do epilep-
tic patients with no evidence of psychotic illness.
The results also suggest that the additional pathol-
ogy is unrelated t o the cerebral lesions commonly
associated with epilepsy but resembles both the
structural abnormalities and the acquired pathol-
ogy recently described in patients with schizophre-
nia. White-matter lesions similar to those reported
here are common in elderly patients who are not
psychotic, but such lesions were significantly less
frequent in the similarly aged epileptic colony and
epileptic psychosis groups in this study. We con-
clude that psychoses associated with epilepsy are
not the result of classic epileptic pathology of the
described in patients with epilepsy since the time of
Sommer
18
and of Spielmeyer,19 This information,
combined with the absence of pathologic lesions lo-
calized to the frontal or other specific areas, sug-
gests that neither MTS nor macroscopic frontal lobe
pathology is critical to the development of psychosis
in epilepsy. This is not so surprising, however, for in
schizophrenia, despite the presence of a small-sized
or "dysplastic" hippocampus or parahippocampal
gyrus in a percentage of the patients studied, both
MTS and frontal lobe lesions are uncommon
24
.
2
6.45
and the cause of the lateral ventricular enlargement
remains unknown. We found MTS in 40% to 50% of
all four epileptic groups; this figure compares
closely with the findings of other epilepsy studies by
Veith,47 Margerison and Corsellis,20 and
Bruton.
32
There are other ways in which our find-
ings do not support the widely accepted belief that
TLE particul arly predisposes to schizophrenia. Par-
tial (including temporal lobe) seizures were no more
common in our schizophrenia-like psychosis pa-
tients than in our most "normal" group of epileptics,
ie, those who lived in the community. Furthermore,
although Taylor et al
4
1:l and Bruton
32
found that con-
genital malformations, especially gangliogliomas
and hamartomas, were overrepresented in the tem-
poral lobes removed at surgery from patients with
epilepsy and psychosis, we found no similar lesions
among the 27 patients with psychosis (including 10
with schizophrenia-like psychosis) in the present
study. Possible reasons for this discrepancy may be
due to selection bias; the cases of both Taylor et al
and Bruton were selected for temporal lobe surgery
because of intractability of TLE and thus, in con-
trast to the earlier Slater and Beard study,
5
did not
include patients who had other types of epilepsy. A
particularly forceful case for relationship between
TLE and psychosis was also made by Perez and
Trimble.
8
.
10
The schizophrenia-like psychoses they
reported differed greatly from those of the chronic,
hospitalized patients in our study. Diagnosed by the
Present State Examination as having "nuclear
schizophrenia,"8 most of their patients were outpa-
tients who lived and often worked in the commu-
nity, many without long-term neuroleptic medica-
tion. In contrast, our patients were chronic, often
deteriorated schizophrenics, confined to a mental
hospital and generally receiving antipsychotic as
well as anticonvulsant medication. The absence of a
significant increase in temporal lobe pathology in
our patients appears to be powerful evidence
against a discrete connection between TLE, tempo-
rallobe pathology, and schizophrenia as Kraepelin
defined the disorder. Several investigators have re-
ported evidence for a preponderance of left-sided
anatomic abnormality in schizophrenia
49
.
51
and in
the schizophrenia-like psychoses of epilepsy.''i2,53
However, no evidence of lateralization of pathology
appeared in this pathologic study of whole brains.
Our findings are compatible with those of Kris-
tensen and Sindrup,36 who compared pneumoen-
cephalograrns from nearly 200 TLE patients, one-
40 NEUROLOGY 44 January 1994
half with and one-half without psychosis, and re-
ported diffuse ventricular enlargement without lat-
eralization of pathology as the distinguishing
anatomic feature of patients with psychosis.
Aggressive, violent, and impulsive behavior was
generally considered to be characteristic of patients
diagnosed with epileptic psychosis.
54
However, in
contrast to the anecdotal reports of links between
aggressive personality disorders and TLE,55,s6 we
found that a separate analysis of aggression as a be-
havioral trait did not correlate with type of epilepsy
or medial temporal pathology. Moreover, the rela-
tive independence of epilepsy and psychosis is fur-
ther emphasized by our study in that among 661
brain specimens from individuals with epilepsy in
the Runwell Hospital collection, only 75 patients
(11 %) had a diagnosis of epilepsy and psychosis. Of
these, we excluded two-thirds as the onset of their
seizures had occurred either in late life, after leukot-
omy, following insulin therapy, or in association
with other organk disease. This leaves the coinci-
dence of epilepsy followed by psychosis at around
4% in this highly selected population of mentally ill
individuals. We therefore conclude that, under mod-
ern conditions of treatment, clinical epilepsy-in-
cluding TLE-is an uncommon antecedent of
schizophrenia or psychosis. The mean age at onset
of epilepsy for patients who subsequently developed
an epileptic or a schizophrenic psychosis was 13 and
15 years, compared with 7 years for epileptic colony
patients and 23 years for community patients. This
finding is in keeping with observations by Taylor
5
?
and Ounsted and Lindsay58 that epilepsy beginning
in or enduring through puberty is more likely to be
associated with subsequent psychosis.
Conclusions. The results of our neuropathologic
investigation were unexpected yet clear-cut. Indi-
viduals with psychosis in this study were character-
ized by their pubertal age at onset of seizures and a
preponderance of generalized (grand mal) epilepsy.
They were not characterized by degree, type, later-
ality, or bilaterality of MTS. The brains of psychotic
individuals were distinguished by larger ventricles
and more focal pathology, including peri ventricular
gliosis. In patients with schizophrenia-like psy-
chosis, the brains also contained a significant excess
of punctate white-matter lesions. Our findings show
that epileptic patients with psychosis have more se-
vere and widespread brain damage than do epilep-
tic patients with no evidence of psychotic illness.
The results also suggest that the additional pathol-
ogy is unrelated to the cerebral lesions commonly
associated with epilepsy but resembles both the
structural abnormalities and the acquired pathol-
ogy recently described in patients with schizophre-
nia. White-matter lesions similar to those reported
here are common in elderly patients who are not
psychotic, but such lesions were significantly less
frequent in the similarly aged epileptic colony and
epileptic psychosis groups in this study. We con-
clude that psychoses associated with epilepsy are
not the result of classic epileptic pathology of the
temporal lobe or of TLE but may arise as a result of
other degenerative or regenerative changes in the
brain. The nature of this pathologic response may
be found using neurotransmitter or neuroreceptor
techniques beyond those of classic neuropath~logy. ~~
Note. Readers can obtain 8 pages of supplementary material from the
National Auxiliary Publications Service, do Microfiche Publications, PO
Box 3513, Grand Central Station, New York, NY 10163-3513. Request
document no. 05035. Remit with your order (not under separate cover), i n
US funds only, $7.75 for photocopies or $4.00 for microfiche. Outside the
United States and Canada, add postage of $4.50 for the first 20 pages and
$1.00 for each 10 pages of material thereafter, or $1.75 for the first mi-
crofiche and $.50 for each fiche thereafter. There is a $15.00 invoicing
charge on all orders filled before payment.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Zielinski JJ. Epilepsy and mortality rate and cause of death.
Epilepsia 1974;15:191-201.
Toone BK, Garralda ME, Ron MA. The psychoses of epilepsy
and the functional psychoses: a clinical and phenomenologi-
cal comparison. Br J Psychiatry 1982;141:256-261.
Gibbs EL, Gibbs FA, Fuster B. Psychomotor epilepsy. Arch
Neurol Psychiatry 1948;60:331-339.
Hill D. Psychiatric disorders of epilepsy. Medical Press
Slater E, Beard AW. The schizophrenia-like psychoses of
epilepsy. Br J Psychiatry 1963;109:95-150.
Flor-Henry P. Psychosis and temporal lobe epilepsy: a con-
trolled investigation. Epilepsia 1969;10:363-395.
Taylor DC. Factors influencing the occurrence of schizophre-
nia-like psychosis in patients with temporal lobe epilepsy.
Psychol Med 1975;5:249-254.
Perez NM, Trimble MR. Epileptic psychosis-diagnostic
comparison with process schizophrenia. Br J Psychiatry
Shukla GD, Srivastava ON, Katiyar BC, Joshi V, Mohan
PK. Psychiatric manifestations in temporal lobe epilepsy: a
controlled study. Br J Psychiatry 1979;135:411-417.
Trimble MR. Interictal psychoses of epilepsy. Acta Psychiatr
Scand [Suppll 1984;313:9-20.
Bartlet JEA. Chronic psychosis following epilepsy. Am J
Psychiatry 1957;114:338-343.
St evens JR. Psychiatric implications of psychomotor
epilepsy. Arch Gen Psychiatry 1966;14:461-471.
Betts TA. A follow-up study of a cohort of patients with
epilepsy admitted t o psychiatric care in an English city. In:
Harris P, Mawdsley C, eds. Epilepsy: proceedings of the
Hans Berger Cent enar y Symposium. Edinburgh, UK:
Churchill Livingstone, 1974:326-336.
Parnas J, Korsgaard S, Krautwald 0, Stigaard Jensen P.
Chronic psychosis in epilepsy: a clinical investigation of 29
patients. Acta Psychiatr Scand 1982;66:282-293.
Hermann BP, Whitman S. Behavioral and personality corre-
lates of epilepsy: a review, methodological critique, and con-
ceptual model. Psychol Bull 1984;95:451-497.
Rodin EA, Katz M, Lennox K. Differences between patients
with temporal lobe seizures and those with other forms of
epileptic attacks. Epilepsia 1976;17:313-320.
Standage KF, Fenton GW. Psychiatric symptom profiles of
patients with epilepsy: a controlled investigation. Psychol
Med 1975:5:152-160.
1953;229:473-475.
1980;137:245-249.
18. Sommer W. Erkrankung des Ammonshornes als aetolog-
isches Moment der Epilepsie. Arch Psychiatr Nervenkr
19. Spielmeyer W. Die pathogenese des epileptischen Krampfes.
Histopathologischer Teil. Z Dtsch Ges Neurol Psychiatr
20. Margerison JH, Corsellis JAN. Epilepsy and the temporal
lobes. Brain 1966;89:499-530.
21. Dam AM. Hippocampal neuron loss in epilepsy and after ex-
perimental seizures. Acta Neurol Scand 1982;66:601-642.
22. Meldrum BS, Bruton CJ. Epilepsy. In: Adams JH, Duchen
LW, eds. Greenfields neuropathology. 5th ed. London: Ed-
1880;10:631-675.
1927;109:501-520.
ward Arnold, 1992:1246-1283.
23. Johnstone EC, Crow TJ, Frith CD, Husband J , Kreel L.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
Cerebral ventricular size and cognitive impairment in
chronic schizophrenia. Lancet 1976;2:924-926.
Bogerts B, Meertz E, Schonfeldt-Bausch R. Basal ganglia
and limbic system pathology i n schizophrenia: a morpho-
metric study of brain volume and shrinkage. Arch Gen Psy-
chiatry 1985;42:784-791.
Brown R, Colter N, Corsellis JAN, Crow TJ, Frith CD. Post-
mortem evidence of structural brain changes in schizophre-
nia. Arch Gen Psychiatry 1986;43:36-42.
Bruton CJ, Crow TJ, Frith CD, Johnstone EC, Owens DGC,
Roberts GW. Schizophrenia and the brain: a prospective clin-
ico-neuropathologica1 study. Psychol Med 1990;20:285-304.
Nieto D, Escobar A. Major psychoses. In: Minckler J, ed.
Pathology of the nervous system, vol3. New York: McGraw-
Hill, 1972:2654-2665.
Stevens JR. Neuropathology of schizophrenia. Arch Gen
Psychiatry 1982;39:1131-1139.
Falkai P, Bogerts B. Cell loss in hippocampus of schizo-
phrenics. Eur Arch Psychiatry Neurol Sci 1986;236:154-161.
Pakkenberg B. Pronounced reduction of total neuron num-
ber in mediodorsal thalamic nucleus and nucleus accumbens
in schizophrenics. Arch Gen Psychiatry 1990;47:1023-1028.
Taylor DC. Mental state and temporal lobe epilepsy: a cor-
relative account of 100 patients treated suracally. Epilepsia
Bruton CJ. The neuropathology of temporal lobe epilepsy.
Maudsley Monograph No. 31. Oxford, U K Oxford University
Press, 1988.
American Psychiatric Association. Diagnostic and statistical
manual of mental disorders. 3rd ed, rev. Washington, DC:
APA Press, 1987.
Falconer MA, Serafetinides EA, Corsellis JAN. Etiology and
pathogenesis of temporal lobe epilepsy. Arch Neurol 1964;
Taylor DC. Epileptic experience, schizophrenia and the tem-
poral lobe. In: Blumerd, Levin K, eds. Psychiatric complica-
tions i n t he epilepsy: cur r ent research and treatment.
McLean Hosp J 1977;suppl:22-39.
Kristensen 0, Sindrup EH. Psychomotor epilepsy and psy-
chosis. I. Physical aspects. Acta Neurol Scand 1978;57:361-379.
Stevens JR. Epilepsy and psychosis: neuropathologic studies
of six cases. In: Bolwig T, Trimble M, eds. Aspects of epilepsy
and psychiatry. London: John Wiley & Sons, 1986:117-146.
Bruetsch WL. Specific structural neuropathology of the cen-
tral nervous system (rheumatic, demyelinating, vasofunc-
tional etc.) in schizophrenia. In: First International Con-
gress of Neuropathology. Turin, Italy: Rosenberg & Sellier,
1952:487-499.
van der Horst L. Histopathology of clinically diagnosed
schizophrenic psychoses or schizophrenia-like psychoses of
unknown origin. In: First International Congress of Neu-
ropathology. Turin, Italy: Rosenberg & Sellier, 1952:501-513.
Bini L, Marchiafava G. Schizophrenia. In: First Interna-
tional Congress of Neuropathology. Turin, Italy: Rosenberg
& Sellier, 1952:670-672.
Corsellis JAN. Psychoses of obscure pathology. In: Black-
wood W, Corsellis JAN, eds. Greenfields neuropathology.
3rd ed. London: Edward Arnold, 1976:903-915.
Hyde TM, Ziegler JC, Weinberger DR. Psychiatric distur-
bances in metachromatic leukodystrophy. Arch Neurol
Davison K, Bagley CR. Schizophrenia-like psychoses associ-
ated with organic disorders of the central nervous system: a
review of the literature. In: Herrington RN, ed. Current
problems in neuropsychiatry, schizophrenia, epilepsy, the
temporal lobe. Kent, UK Headley Brothers, 1969: 113-184.
Lohr JB, Flynn K. Smoking and schizophrenia. Schizophr
Res 1992;8:93-102.
Jakob H, Beckmann H. Prenatal developmental distur-
bances in the limbic allocortex in schizophrenics. J Neural
Transm 1986;65:303-326.
Falconer MA. Mesial temporal (Ammons horn) sclerosis as a
common cause of epilepsy: aetiology, treatment, and preven-
tion. Lancet 1974;2:767-770.
1972;13:727-765.
10:233-248.
1992;49:401-406.
January 1994 NEUROLOGY 44 41
temporal lobe or of TLE but may arise as a result of
other degenerative or regenerative changes in the
brain. The nature of this pathologic response may
be found using neurotransmitter or neuroreceptor
techniques beyond those of classic neuropathology. 59
Note. Readers can obtain 8 pages of supplementary material from the
National Auxiliary Publications Service, c/o Microfiche Publications, PO
Box 3513, Grand Central Station, New York, NY 10163-3513. Request
document no. 05035. Remit with your order (not under separate cover), in
US funds only, $7.75 for photocopies or $4.00 for microfiche. Outside the
United States and Canada, add postage of $4.50 for the first 20 pages and
$1.00 for each 10 pages of material thereafter, or $1.75 for the first mi-
crofiche and $.50 for each fiche thereafter. There is a $15.00 invoicing
charge on all orders filled before payment.
References
1. Zielinski JJ. Epilepsy and mortality rate and cause of death.
Epilepsia 1974;15:191-201.
2. Toone BK, Garralda ME, Ron MA. The psychoses of epilepsy
and the functional psychoses: a clinical and phenomenologi-
cal comparison. Br J Psychiatry 1982;141:256-261.
3. Gibbs EL, Gibbs FA, Fuster B. Psychomotor epilepsy. Arch
Neurol Psychiatry 1948;60:331-339.
4. Hill D. Psychiatric disorders of epilepsy. Medical Press
1953;229:473-475.
5. Slater E, Beard AW. The schizophrenia-like psychoses of
epilepsy. Br J Psychiatry 1963;109:95-150.
6. Flor-Henry P. Psychosis and temporal lobe epilepsy: a con-
trolled investigation. Epilepsia 1969;10:363-395.
7. Taylor DC. Factors influencing the occurrence of schizophre-
nia-like psychosis in patients with temporal lobe epilepsy.
Psychol Med 1975;5:249-254.
8. Perez NM, Trimble MR. Epileptic psychosis-diagnostic
comparison with process schizophrenia. Br J Psychiatry
1980;137:245-249.
9. Shukla GD, Srivastava ON, Katiyar BC, Joshi V, Mohan
PK. Psychiatric manifestations in temporal lobe epilepsy: a
controlled study. Br J Psychiatry 1979;135:411-417.
10. Trimble MR. Interictal psychoses of epilepsy. Acta Psychiatr
Scand [Suppl] 1984;313:9-20.
11. Bartlet JEA. Chronic psychosis following epilepsy. Am J
Psychiatry 1957;114:338-343.
12. Stevens JR. Psychiatric implications of psychomotor
epilepsy. Arch Gen Psychiatry 1966;14:461-471.
13. Betts TA. A follow-up study of a cohort of patients with
epilepsy admitted to psychiatric care in an English city. In:
Harris P, Mawdsley C, eds. Epilepsy: proceedings of the
Hans Berger Centenary Symposium. Edinburgh, UK:
Churchill Livingstone, 1974:326-336.
14. Parnas J, Korsgaard S, Krautwald 0, Stigaard Jensen P.
Chronic psychosis in epilepsy: a clinical investigation of 29
patients. Acta Psychiatr Scand 1982;66:282-293.
15. Hermann BP, Whitman S. Behavioral and personality corre-
lates of epilepsy: a review, methodological critique, and con-
ceptual model. Psychol Bull 1984;95:451-497.
16. Rodin EA, Katz M, Lennox K. Differences between patients
with temporal lobe seizures and those with other forms of
epileptic attacks. Epilepsia 1976;17:313-320.
17. Standage KF, Fenton GW. Psychiatric symptom profiles of
patients with epilepsy: a controlled investigation. Psychol
Med 1975;5:152-160.
18. Sommer W. Erkrankung des Ammonshornes als aetolog-
isches Moment del' Epilepsie. Arch Psychiatr Nervenkr
1880;10:631-675.
19. Spielmeyer W. Die pathogenese des epileptischen Krampfes.
Histopathologischer Teil. Z Dtsch Ges Neurol Psychiatr
1927;109:501-520.
20. Margerison JH, Corsellis JAN. Epilepsy and the temporal
lobes. Brain 1966;89:499-530.
21. Dam AM. Hippocampal neuron loss in epilepsy and after ex-
perimental seizures. Acta Neurol Scand 1982;66:601-642.
22. Meldrum BS, Bruton CJ. Epilepsy. In: Adains JH, Duchen
LW, eds. Greenfield's neuropathology. 5th ed. London: Ed-
ward Arnold, 1992:1246-1283.
23. Johnstone EC, Crow TJ, Frith CD, Husband J, Kreel L.
Cerebral ventricular size and cognitive impairment in
chronic schizophrenia. Lancet 1976;2:924-926.
24. Bogerts B, Meertz E, Schonfeldt-Bausch R. Basal ganglia
and limbic system pathology in schizophrenia: a morpho-
metric study of brain volume and shrinkage. Arch Gen Psy-
chiatry 1985;42:784-791.
25. Brown R, Colter N, Corsellis JAN, Crow TJ, Frith CD. Post-
mortem evidence of structural brain changes in schizophre-
nia. Arch Gen Psychiatry 1986;43:36-42.
26. Bruton CJ, Crow TJ, Frith CD, Johnstone EC, Owens DGC,
Roberts GW. Schizophrenia and the brain: a prospective clin-
ico-neuropathological study. Psychol Med 1990;20:285-304.
27. Nieto D, Escobar A. Major psychoses. In: Minckler J, ed.
Pathology of the nervous system, vol 3. New York: McGraw-
Hill, 1972:2654-2665.
28. Stevens JR. Neuropathology of schizophrenia. Arch Gen
Psychiatry 1982;39:1131-1139.
29. Falkai P, Bogerts B. Cell loss in hippocampus of schizo-
phrenics. Eur Arch Psychiatry Neurol Sci 1986;236:154-161.
30. Pakkenberg B. Pronounced reduction of total neuron num-
ber in mediodorsal thalamic nucleus and nucleus accumbens
in schizophrenics. Arch Gen Psychiatry 1990;47: 1023-1028.
31. Taylor DC. Mental state and temporal lobe epilepsy: a cor-
relative account of 100 patients treated surgically. Epilepsia
1972;13:727 -765.
32. Bruton CJ. The neuropathology of temporal lobe epilepsy.
Maudsley Monograph No. 31. Oxford, UK: Oxford University
Press, 1988.
33. American Psychiatric Association. Diagnostic and statistical
manual of mental disorders. 3rd ed, rev. Washington, DC:
APA Press, 1987.
34. Falconer MA, Serafetinides EA, Corsellis JAN. Etiology and
pathogenesis of temporal lobe epilepsy. Arch Neurol 1964;
10:233-248.
35. Taylor DC. Epileptic experience, schizophrenia and the tem-
poral lobe. In: Blumerd, Levin K, eds. Psychiatric complica-
tions in the epilepsy: current research and treatment.
McLean Hosp J 1977;suppl:22-39.
36. Kristensen 0, Sindrup EH. Psychomotor epilepsy and psy-
chosis. 1. Physical aspects. Acta Neurol Scand 1978;57:361-379.
37. Stevens JR. Epilepsy and psychosis: neuropathologic studies
of six cases. In: Bolwig T, Trimble M, eds. Aspects of epilepsy
and psychiatry. London: John Wiley & Sons, 1986:117-146.
38. Bruetsch WL. Specific structural neuropathology of the cen-
tral nervous system (rheumatic, demyelinating, vasofunc-
tional etc.) in schizophrenia. In: First International Con-
gress of Neuropathology. Turin, Italy: Rosenberg & Sellier,
1952:487 -499.
39. van der Horst L. Histopathology of clinically diagnosed
schizophrenic psychoses or schizophrenia-like psychoses of
unknown origin. In: First International Congress of Neu-
ropathology. Turin, Italy: Rosenberg & Sellier, 1952:501-513.
40. Bini L, Marchiafava G. Schizophrenia. In: First Interna-
tional Congress of Neuropathology. Turin, Italy: Rosenberg
& Sellier, 1952:670-672.
41. Corsellis JAN. Psychoses of obscure pathology. In: Black-
wood W, CorseIlis JAN, eds. Greenfield's neuropathology.
3rd ed. London: Edward Arnold, 1976:903-915.
42. Hyde TM, Ziegler JC, Weinberger DR. Psychiatric distur-
bances in metachromatic leukodystrophy. Arch Neurol
1992;49:401-406.
43. Davison K, Bagley CR. Schizophrenia-like psychoses associ-
ated with organic disorders of the central nervous system: a
review of the literature. In: Herrington RN, ed. Current
problems in neuropsychiatry, schizophrenia, epilepsy, the
temporal lobe. Kent, UK: Headley Brothers, 1969:113-184.
44. Lohr JB, Flynn K. Smoking and schizophrenia. Schizophr
Res 1992;8:93-102.
45. Jakob H, Beckmann H. Prenatal developmental distur-
bances in the limbic allocortex in schizophrenics. J Neural
Transm 1986;65:303-326.
46. Falconer MA. Mesial temporal (Ammon's horn) sclerosis as a
common cause of epilepsy: aetiology, treatment, and preven-
tion. Lancet 1974;2:767-770.
January 1994 NEUROLOGY 44 41