Download Seizures and Schizophrenia

Seizures and Schizophrenia
by Thomas M. Hyde and Daniel R. Weinberger
articulated by Gibbs (1951) and Rodin et al. (1957) four
decades ago.
For the practitioner, dealing with a single seizure or a
seizure disorder in a schizophrenia patient can be a diagnostic and therapeutic challenge. In the sections to follow,
the relationship between epilepsy and schizophrenia will
be reexamined. The approach to both a single seizure and
recurrent seizures in the schizophrenia patient will also be
discussed. In addition, the role of neuroleptics and other
psychoactive medications will be reviewed. Finally, the
role of diagnostic testing in evaluating unusual episodes
and seizures in the schizophrenia patient will be discussed. The aim of this review is to provide a useful perspective for addressing the overall issue of seizures in the
schizophrenia patient.
Abstract
Patients with epilepsy develop psychosis or schizophrenia at a rate exceeding that expected if the two
disorders were independent. Similarly, patients with
schizophrenia are more prone to seizures than the general population. This excess vulnerability may be conferred by the neuropathological substrate of schizophrenia itself or by the secondary effects of the illness,
including exposure to psychotropic medications that
lower the seizure threshold. Neuropathological investigations into the anatomic substrate of seizures in
patients with psychosis or schizophrenia are consistent
with the notion that there are neurodevelopmental
abnormalities involving the mesial temporal lobe.
Finally, clinical recommendations for the evaluation
and pharmacological management of patients with
schizophrenia who have one or more seizures are
described.
Is There an Association Between
Schizophrenia and Epilepsy?
Schizophrenia Bulletin, 23(4):611-622,1997.
A fundamental controversy in the schizophrenia-epilepsy
literature is the frequency of the coexistence of these conditions. Many studies purporting to address this issue are
limited by both their methodology and their imprecise terminology. First, many studies have failed to discriminate
between a single seizure and a seizure disorder. In the
course of treatment for a wide variety of medical, neurological, and psychiatric problems, many patients will suffer a single seizure. This is distinctly different from a
seizure disorder, in which there is substantial long-term
risk for recurrent seizures. In the literature, there is a tendency for the terms seizure disorder and epilepsy to be
used interchangeably. Epilepsy refers to a condition characterized by recurrent seizures; seizure disorder does not
necessarily imply this. Additionally, when considering
The interaction between schizophrenia and seizures has
been a subject of considerable curiosity in neuropsychiatry for at least 40 years, stimulated by the reports of Gibbs
(Gibbs et al. 1948; Gibbs 1951) of an increased frequency
of interictal psychoses in patients with complex partial
seizure disorders. Recent neuroimaging and neuropathology studies in schizophrenia have identified structural and
neurochemical abnormalities in the mesial temporal lobe,
including volume loss, cytoarchitectural disorganization,
and neurochemical changes (as reviewed by Knable and
Weinberger 1995). The mesial temporal lobe also is often
the site of origin for epileptiform potentials, which underlie complex partial-seizure disorders. It would not be surprising, therefore, that damage to the mesial temporal lobe
might produce both seizures and a chronic psychotic disorder, such as schizophrenia, as alternate manifestations
of a single site of pathology. In fact, this perspective was
Reprint requests should be sent to Dr. T.M. Hyde, Clinical Brain
Disorders Branch, NIMH Neuroscience Ctr., St. Elizabeths Hospital,
2700 Martin Luther King, Jr. Ave., SE, Washington, DC 20032.
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T.M. Hyde and D.R.Weinberger
reported that among 678 patients with complex partial
seizures, 7.2 percent had unclassified psychoses and 0.2
percent had schizophrenia, while among 1,806 patients
with both complex partial and generalized motor seizures,
9.4 percent had unclassified psychoses and 0.8 percent
had schizophrenia. In a short report, Hill (1953) mentioned that 25 percent of patients with complex partial
seizures suffered some form of psychotic episode. Small
and Small (1967) found the prevalence of psychosis
among patients with epilepsy to be 4.4 percent. Currie et
al. (1971) studied a series of 666 patients with welldefined complex partial seizure disorders and found that,
while 6 percent (40 of 666) had florid psychiatric disorders, only 1.8 percent (12 of 666) had schizophrenia.
However, an additional 17 had "gross hysteria," a term
not defined by the authors. Bruens (1971) claimed that 2.4
percent of patients with epilepsy suffer from some form of
psychotic episode. Standage and Fenton (1975) found that
8 percent (3 of 37) of patients with epilepsy also had a
history of psychosis. Lindsay et al. (1979) followed 87
children with "limbic" seizures for over a decade and
found that 9 (10.3%) developed a schizophreniform psychosis. In contrast, in a cohort of 1,073 patients with
epilepsy, Bartlett (1957) found only 12 patients (1.1%)
with a psychosis of more than 1 year's duration, while
Bruens (1971) noted only 1 percent of patients (9 of 900)
who had both epilepsy and psychotic symptoms lasting at
least several weeks. The random chance of schizophrenia
appearing in a large cohort of patients with recurrent
seizures should be similar to general population estimates,
unless there is a biological link between these two entities. The majority of studies suggest that there are more
patients with epilepsy who subsequently develop psychoses than would be expected by pure chance.
patients with seizure disorders and psychoses, postictal
confusional states, brief postictal paranoia, and so-called
"twilight" states of patients in absence or complex partial
status epilepticus must be differentiated from an interictal
thought disorder (Flor-Henry 1972; Belafsky et al. 1978;
Engel et al. 1978).
When epilepsy and psychosis coexist, the psychosis
almost always follows the onset of epilepsy, with an interval ranging from 12 to 27 years (Slater and Beard 1963;
Bruens 1971; Kristensen and Sindrup 1978; Perez et al.
1985). However, there are problems in linking schizophrenia to epilepsy in those individuals who develop seizures
after the onset of psychotic symptoms. Chronic schizophrenia patients may be more prone to closed-head injury,
substance abuse, and other adverse circumstances that
might independently predispose the individual toward
developing a seizure disorder. In other words, having
schizophrenia in and of itself might impose secondary
risks that lead to an increased incidence of seizures, but
such seizures may not be conferred primarily by the intrinsic neuropathological substrate of psychotic behavior.
Seizures arising from these forms of acquired brain injury
may contaminate some studies of epilepsy and psychosis,
obscuring the link between possible developmental neuropathology implicated in both seizures and psychosis.
Another problem with many of the studies of
epilepsy and schizophrenialike psychoses is a lack of uniform psychiatric assessment, as most predate the use of
standardized diagnostic criteria. A notable exception is the
study by Perez and Trimble (1980), which carefully
examined the psychotic symptomatology in 24 patients
with epilepsy and psychosis using the Present State
Examination (Wing et al. 1974). In their cohort, 50 percent of patients had a profile consistent with schizophrenia, while 92 percent had significant first-rank
Schneiderian (Schneider 1959) symptomatology. Slater
and Beard (1963) had noted that 46 of 69 cases of patients
with epilepsy and psychosis had a psychotic disorder typical of chronic paranoid schizophrenia, while 12 of 69 had
symptoms compatible with hebephrenic schizophrenia,
although no precise clinical criteria were used in making
these diagnoses. Just under half of their patients had an
insidious course of psychiatric presentation, as well as a
predisposition toward chronic illness. Those presenting
acutely with psychosis had a better outcome. In this
cohort, about half had chronic psychotic symptoms and
only five patients from the original cohort made a complete psychiatric recovery. In the Slater and Beard (1963)
study, as in many similar studies, the terms psychosis and
schizophrenia are loosely defined by today's standards.
One of the best modern studies addressing the association of schizophrenia and epilepsy was conducted by
Mendez et al. (1993). Interictal psychoses compatible
with DSM-1U-R (American Psychiatric Association 1987)
criteria for schizophrenia occurred in 9.25 percent of
1,611 epilepsy outpatients, but in only 1.06 percent of
2,167 migraine outpatients of a university medical center.
This study overcame the ascertainment bias common at
many university medical centers by using a neurological
disease cohort as a control group. In addition, this study
benefits from the use of standardized psychiatric criteria.
It substantiates previous studies that have reported an
association between psychosis and epilepsy, most of
which suffer from the methodological problems noted
above.
Slater and Beard (1963) set forth one of the more
complete arguments in favor of a greater association of
epilepsy and schizophrenia than one would expect by
Despite the limitations of the earlier studies, their
results were fairly consistent. Gibbs and Gibbs (1952)
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chance coincidence. According to their estimates, in the
general population the prevalence of schizophrenia is 0.8
percent, while that of epilepsy is 0.5 percent. The chance
lifetime association of epilepsy with schizophrenia might
therefore be 40 per million. Limiting their study to those
individuals who develop psychosis after epilepsy, the lifetime prevalence might be 30 per million. At the time of
the study, they estimated that there were 148 individuals
with epilepsy and schizophrenia living in their catchment
area and that new cases should appear at a rate of 3 to 5
per year. They found 69 new cases of psychosis in
patients with history of epilepsy over 11 years in a catchment area of about 10 million, surveying the patients
treated at only two hospitals in this catchment area. While
there may have been some ascertainment bias, this rate of
accrual of new cases greatly exceeded their population
estimates if there were purely a chance association
between epilepsy and schizophrenia. In fact, they felt that,
given the number of neurological and psychiatric facilities
in their catchment area, they were probably not seeing all
the new cases.
of schizophrenia in the temporal lobe epilepsy group (6 of
25 vs. 3 of 25 in the nontemporal lobe epilepsy patients),
there was an increased frequency of schizoid personality
disorder in the nontemporal lobe epilepsy group (5 of 25
vs. 8 of 25); neither of these rates reached significance. In
the latter study, Stevens found a similar rate of residential
psychiatric hospitalization among patients with complex
partial and generalized motor seizure disorders among
100 consecutive adult patients with seizure disorders at a
university clinic. However, that study failed to note that
14 of 17 patients with complex partial seizures and psychiatric hospitalizations received the diagnosis of schizophrenia, versus only 5 of 10 with generalized seizures.
Both studies are limited by small sample sizes and by possible ascertainment biases in the patient population base at
a university clinic.
In a small sample of postmortem cases, Bruton et al.
(1994) did not find an association between complex partial seizures and schizophrenia in comparison to inpatient
or outpatient epilepsy cohorts. This study compared
patients with epilepsy and a schizophreniform psychosis
(n = 10) to patients with epilepsy and an "organic" psychosis (n = 9), an inpatient epilepsy group (n = 21), and
an outpatient epilepsy group (n = 15). This study is limited by both the small cohort size and its reliance on a retrospective review of postmortem records, which may or
may not have included formal psychiatric evaluations of
the nonpsychotic epilepsy groups. It is curious that the
schizophrenia group had a very high incidence of petit
mal seizures, which has not been reported elsewhere in
the literature. Finally, all of these cases were from an
autopsy series. The inpatient epilepsy and outpatient
epilepsy groups may have been skewed toward those
cases with an atypical antemortem history or a suspicious
cause of death, including suicide. None of these issues
were addressed by the authors. Overall, while conflicting,
the literature tends to suggest that patients with complex
partial seizures are at higher risk for developing an interictal psychosis than either the general population or
patients with other forms of seizure disorders.
Electroencephalographic (EEG) data support the role
of the temporal lobe in the psychoses associated with
epilepsy. In a study of patients with focal spikes, Gibbs
(1951) found that anterior temporal lobe foci were most
often associated with psychosis. Hill (1952) found an
increased incidence of anterior temporal spike or focal
slowing and posterior temporal slowing in schizophrenia
patients and "not yet diagnosed" psychotic patients compared to normal controls, although formal statistical
analyses were not performed in this study. While Beard
(1963) found a relatively equal distribution of dominant,
nondominant, and bilateral temporal lobe foci in their
On the basis of these findings, Slater and Beard
(1963) suggested that patients with epilepsy develop
schizophrenialike psychosis at a much greater-thanexpected frequency. However, a review of general population estimates suggests the 1-year and lifetime prevalence
rates for schizophrenia are 1.0 and 1.4 percent, respectively (Karno and Norquist 1995), higher than Slater and
Beard's estimates. If Slater and Beard had underestimated
the prevalence rates of these disorders, then their support
of a linkage between epilepsy and psychosis might be suspect. In addition, there may be a greater element of ascertainment bias in Slater and Beard's study population, that
they did not acknowledge in their statistical analyses
(Stevens 1966). Nevertheless, in addition to Slater and
Beard (1963) there are numerous well-designed studies
that link schizophrenia with seizure disorders (e.g., Currie
et al. 1971; Lindsay et al. 1979; Mendez et al. 1993).
Is There a Preferential Relationship
Between Complex Partial Seizures
and Schizophrenia?
Complex partial seizure disorders, also known as psychomotor or temporal lobe epilepsy, have been more commonly associated with interictal schizophreniform psychoses than have generalized seizures (Dongier 1959;
Beard 1963; Flor-Henry 1969; Bruens 1971; Shukla et al.
1979; Perez and Trimble 1980; Perez et al. 1985). Small
et al. (1962) and Stevens (1966) contested this notion. In
the former study, while there was an increased frequency
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T.M. Hyde and D.R.Weinberger
patients with psychosis and epilepsy, Flor-Henry (1969,
1983) found that epilepsy patients with schizophreniform
psychoses were more likely to have dominant hemisphere
temporal lobe foci. Neither Kristensen and Sindrup (1978)
nor Shukla and Katiyar (1980) found any laterally differences in their patients with complex partial seizures and
psychosis. However, in a series of 666 patients with welldefined complex partial seizures, Currie et al. (1971)
found EEG evidence of a left-sided focus in 52 percent,
right-sided in 29 percent, and bilateral in 19 percent. This
suggests that left temporal foci are more common in the
general population, and any laterality associations with
schizophrenia need to be interpreted cautiously. Taken
together, these findings support the notion that temporal
lobe pathology, the most common etiology of complex
partial seizures, may also play an important role in the
generation of psychosis.
Neuroimaging studies also support a role for temporal lobe pathology in psychosis and epilepsy. A positron
emission tomography (PET) study of cerebral blood flow
was conducted on a small cohort of patients with epilepsy
and psychosis, one group on neuroleptics and the second
off (n = 6 for both groups) (Gallhofer et al. 1985). They
were compared with normal and nonpsychotic epileptic
controls matched for age and IQ. Epilepsy patients with
psychosis had abnormalities localized to the frontotemporal regions. A single-photon emission computerized
tomography (SPECT) neuroimaging study revealed
medial temporal lobe abnormalities in patients with schizophrenia and seizures (Marshall et al. 1993). In a sample
of five patients with schizophrenia and seizures, matched
to five epileptic controls by age, age at onset of epilepsy,
type of epilepsy, and side of EEG focus, those with schizophrenia showed significant reductions in the left medial
temporal cerebral blood flow. However, the control group
had higher IQs and more frequent seizures, while the
schizophrenia-with-seizures group had evidence of cerebral atrophy on computerized tomography (CT) scan.
cent of the latter group. In addition, females with alien tissue lesions appeared particularly at risk for the development of psychosis along with epilepsy. The association
between alien tissue lesions and psychosis might be due
to the fetal development of these lesions, as opposed to
mesial temporal sclerosis, which is a perinatal lesion. The
neurodevelopmental hypothesis of schizophrenia holds
that a fixed brain lesion that occurs early in development
is functionally quiescent initially (Weinberger 1996). This
lesion subsequently interacts with normal cerebral maturational events that occur much later, resulting in the onset
of schizophrenia in the second, third, and occasionally
fourth decade of life. The type of temporal lobe lesion and
the age at which it occurs appear to play a critical role in
the propensity of such a lesion to predispose toward the
development of psychosis.
The study by Roberts et al. (1990) offered a partial
replication of Taylor (1975) and supports a role for medial
temporal lobe pathology in schizophrenia in patients with
concurrent seizure disorders. Studying specimens from
249 patients who underwent temporal lobectomy for
intractable seizures, they identified 16 patients with preoperative schizophrenia. Twelve of these patients had
identifiable pathology, and in all cases the lesions were
restricted to the medial temporal lobe. However, only two
of these cases had alien tissue lesions, while eight had
mesial temporal sclerosis, counter to Taylor's (1975) findings. Additionally, Roberts et al. (1990) grouped the different types of pathology by the approximate stage in
development at which the lesion occurred. Ten of their 12
cases with preoperative schizophrenia and identifiable
pathology had lesions that occurred either embryonically
or perinatally. Like Taylor's (1975) work, these findings
support the role of neurodevelopmental abnormalities in
schizophrenia.
Bruton et al. (1994) performed a retrospective neuropathological study of a small cohort of chronically institutionalized patients with schizophrenia and psychosis and
compared them to epilepsy inpatients and outpatients
autopsied at community hospitals or coroners' offices.
They did not find an increased incidence of focal alien tissue lesions in their epilepsy-with-psychosis groups compared to their pure epilepsy cases. Although this study has
serious limitations, as previously noted, the failure to replicate the findings of Taylor (1975) is not easily reconciled.
Is There a Neuropathological
Correlation With Schizophrenia
and Epilepsy?
The type of pathology in the mesial temporal lobe appears
to influence the propensity toward the development of
psychosis in association with epilepsy. Taylor (1975)
examined resected tissue from 255 patients who underwent temporal lobectomy to treat intractable complex partial seizures. Comparing 47 patients with "alien tissue"—
including small tumors, hamartomas, and focal
dysplasia—with 41 patients with mesial temporal sclerosis, 23 percent of the former were psychotic versus 5 per-
Evaluation of the Schizophrenia
Patient Who Suffers a Seizure
In many respects, the evaluation of a schizophrenia
patient with a seizure is the same as the evaluation of anyone who suffers a seizure. As always, the first and imme-
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diate intervention is to check the stability of a patient's
vital signs. If stable, the next step is to evaluate the clinical characteristics of the episode to establish that the
patient did in fact suffer a true seizure. Many events can
simulate a seizure, including acute dystonic reactions and
other paroxysmal movement disorders, acute hypotensive
episodes, syncope of both cardiac and noncardiac origin,
transient ischemic attacks, transient global amnesia,
benign paroxysmal vertigo, migraine, panic attacks, intermittent explosive disorder, sleep disorders (especially narcolepsy), pseudoseizures, and acute intoxication (Morrell
1993). A complete history, including interviews with witnesses of the event, can be the single most helpful strategy in establishing the correct diagnosis. After a generalized tonic-clonic convulsion or complex partial seizure,
the overwhelming majority of patients will have elevated
serum prolactin levels, which can be useful in differentiating seizures from pseudoseizures and other nonepileptic
events (Trimble 1978; Yerby et al. 1987). The rise peaks
within about 20 minutes after the event, returning to baseline after about 60 minutes. An elevation of two to three
times baseline is usually considered indicative of a true
seizure (Yerby et al. 1987). Measuring serum prolactin
levels can be less valuable in the schizophrenia patient
after a possible seizure because neuroleptics can markedly
elevate baseline serum prolactin levels.
Several factors peculiar to schizophrenia patients
must be weighed in the event of a seizure (table 1).
Metabolic factors are the first level of consideration.
Hyponatremia is common among a subset of schizophrenia patients, secondary to psychogenic polydipsia (Jose
and Perez-Cruet 1979; Vieweg et al. 1985); therefore,
serum sodium levels must be checked as soon as possible
following a seizure in all schizophrenia patients. Serum
glucose should be obtained if the patient is diabetic, since
hypoglycemia can cause seizures and schizophrenia
patients may not regulate their insulin or diet correctly.
Rarely, either hyperthyroidism or hypothyroidism can
cause seizures. Insofar as schizophrenia patients are
poorly compliant with their medications and may not seek
attention for medical problems, thyroid function tests
should be checked in all schizophrenia patients after a
first-time seizure. Finally, toxin ingestion, including illicit
drugs, can cause seizures and must be considered, especially as the patient may not provide a reliable history.
Schizophrenia patients are at a much higher risk for suicide than the general population, and they may ingest
unusual substances in an attempt to overdose. Appropriate
blood and urine screening studies are essential for diagnostic purposes.
In addition to toxic and metabolic factors, prolonged
sleep deprivation can also lower the seizure threshold.
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Table 1. Differential diagnosis of selzurelike
episodes in schizophrenia
Syncope
Orthostatic hypotension
Cardiac arrhythmias
Valvular heart disease
Coronary artery disease (angina)
Micturition syncope
Vasovagal episodes
Cerebrovascular events
Transient ischemic attacks
Transient global amnesia
Complex migraine headaches
Psychiatric disorders
Pseudoepileptic seizures
Dissociative disorders
Rage attacks
Panic attacks
Hallucinations
Medication side effects
Acute dystonic reactions
Intermittent tremor
Toxic encephalopathies
Toxic/metabolic disorders
Hypoglycemia
Hypocaicemia
Other neurological events
Paroxysmal choreoathetosis or dystonia
Hyperexplexia (enhanced startle reaction)
Tics
Stereotypies
Myoclonus
Trtubation
Sleep disorders
Narcolepsy/cataplexy
Sleepwalking
Night terrors
Sleep automatisms
Sleep apnea
Restless-leg syndrome
While prolonged sleep deprivation is much more common
in the manic phase of bipolar disorder, schizophrenia
patients may have periods in which their sleep cycle is
markedly altered. During these periods, they are vulnerable to seizures, especially when they are on neuroleptics
or other psychoactive medications that further lower the
seizure threshold.
Diagnostic Tests
The most important diagnostic test in evaluating a patient
after a seizure, other than the serological studies reviewed
previously, is the electroencephalogram (EEG). A sleep-
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T.M. Hyde and D.R.Weinberger
deprived study is useful insofar as epileptiform potentials
are most often seen in the transition from wakefulness to
sleep. Nasopharyngeal leads can be helpful in the electrophysiological study of the temporal lobes; however, they
are generally poorly tolerated. In their place, so-called Al
and A2 leads, placed on the scalp over the anterior temporal lobes, may be used. This is an important consideration
since many epileptic foci lie in the temporal lobes. The
presence of an abnormality on the EEG often suggests
that a patient may be at higher than normal risk for
seizures, especially if under treatment with a medication
that lowers the seizure threshold. For example, Logothetis
(1967) studied 859 patients treated with a variety of phenothiazines over a 4^-year period; 10 had seizures, and in
every case, the EEG was abnormal.
In addition to the sleep-deprived EEG, ambulatory
EEG monitoring or video-EEG telemetry may be useful,
especially when trying to differentiate between complex
partial seizures and other phenomena. Ambulatory monitoring involves continuous recording for 24 to 48 hours,
using 8 to 16 scalp leads attached to a self-contained
recording device. During the test, the patient presses a
marker button each time a possible clinical seizurelike
episode occurs so that the diagnostician reviews that part
of the tape with special care. Although the technical apparatus has become more sophisticated and compact over
the years, ambulatory EEG monitoring may be intolerable
for many schizophrenia patients. Inpatient video-EEG
telemetry monitoring may be a better choice for the schizophrenia patient with unusual episodes that need additional diagnostic clarification. A continuous 16-channel
EEG is recorded, with a nurse or technician nearby to
make sure that the scalp leads remain in place. A video
camera records all motor activity, allowing a direct correlation between the clinical event and the EEG. This form
of monitoring, which is highly definitive but expensive,
may be more practical for the poorly compliant or uncooperative schizophrenia patient.
The EEG can have predictive value regarding the
degree of risk for recurrent seizures. Adult patients with
an initial seizure of unknown etiology who have epileptiform discharges on EEG face an 81 percent risk of a
recurrent seizure within 2 years. However, those with a
normal EEG have only a 12 percent risk (Van Donselaar
et al. 1991). Hauser et al. (1990) found that the only EEG
associated with an increased risk of recurrent seizures following an initial event was a generalized spike and wave
pattern, whereas others have reported that a focal EEG
abnormality (Camfield et al. 1985) or an EEG abnormality of any type (Annegers et al. 1986; Shinnar et al. 1990)
confers significant risk. Such predictions in the schizophrenia patient are complicated because psychotropic
medications can produce a variety of abnormal EEG patterns. However, unequivocal focal abnormalities, focal
sharp waves or spikes, or generalized spike and wave patterns should be viewed with great suspicion.
Neuroimaging studies play an important role in
assessing the etiology and risk of recurrent seizures after a
single seizure; they also dictate some forms of treatment.
Magnetic resonance imaging (MRI) is the most sensitive
test for lesion detection (Sperling 1993).While CT is less
sensitive, it is still valuable in patients who cannot have
an MRI (Ramirez-Lassepas et al. 1984). A CT scan is also
valuable if an intracranial hemorrhage is suspected. It
should be noted that there is a high degree of agreement
between focal findings on neurological examination and
lesions on neuroimaging studies. If a patient has an nonfocal neurological examination 48 hours after a seizure
(by which time any postictal transient neurological abnormality, "Todd's paresis," should have remitted), a neuroimaging study is probably going to be much less valuable
(Russo and Goldstein 1983). Sperling (1993) recommends
that all patients have an MRI scan of the brain at initial
evaluation. Certainly, those patients with focal findings on
neurological examination or abnormalities on EEG should
have a neuroimaging study to screen for structural lesions.
Role of Neuroleptics and Other
Psychotropic Medications in Seizure
Induction
Neuroleptics and other psychotropic medications may
play a role in the induction of a seizure. In fact, psychotropic agents are the class of medications most commonly associated with a drug-induced generalized convulsion (Messing et al. 1984). Most of the literature
regarding psychotropics and seizures are case reports.
Seizures attributable to a medication usually occur within
several weeks of the initiation of therapy or after a change
in medication dosage. Many of the case reports involve
very high doses of medication; for example, Messing et
al. (1984) reported a case of a seizure after 2,000 mg of
amitriptyline. Toone and Fenton (1977) reported that
polypharmacy, changes in medication dosage, and postnatal brain damage predisposed individuals to drug-induced
seizures.
Not all neuroleptics are equally epileptogenic. Both
animal and human studies have been used to assess the
relative risk of seizure induction from neuroleptics. One
animal study suggested that haloperidol is most potent in
the induction of spike activity. Chlorpromazine, thioridazine, and pimozide had inverted U-shaped dose-risk
curves. Molindone, pimozide, and fluphenazine produced
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the least amount of spike activity in a study of in vitro tissue slices (Oliver et al. 1982). Chen and colleagues
(1968) found that chlorpromazine and haloperidol lowered the seizure threshold at low doses and actually raised
it at higher doses. However, the clinical experience with
neuroleptics often does not mirror in vitro and animal
studies. In humans, clozapine and chlorpromazine are
thought to have the highest propensity toward seizure
induction. About 9 percent of patients on doses of chlorpromazine over 1 gram per day may experience seizures
(Logothetis 1967). Perphenazine, thiothixene, loxapine,
and haloperidol are intermediate. Thioridazine, fluphenazine, and molindone are considered the safest (Logothetis
1967; Itil and Soldatos 1980; Peterson 1981). Logothetis
(1967), in a study of 859 patients treated with a variety of
phenothiazines over a 4!4-year period, found that 1.2 percent suffered seizures. While additional evidence is necessary, initial clinical experience with risperidone, olanzapine, and sertindole suggests that they carry a low risk of
seizure induction (Casey 1996). Itil and Soldatos (1980)
proposed that highly sedating neuroleptics with a low
incidence of extrapyramidal side effects are more likely to
induce seizures. As newer neuroleptics with low
extrapyramidal side-effect profiles become available, this
hypothesis may need revision.
Clozapine merits special comment. According to premarketing studies by the manufacturer, 3.5 percent of
patients treated with clozapine had a seizure, although
rates up to 10 percent have subsequently been reported
(Povlsen et al. 1985; Wilson and Claussen 1994; McEvoy
1996a). The risk appears to be dose-related (Honigfeld
and Patin 1990). Patients with a previous history of
seizures are at higher risk for a clozapine-induced seizure
(Wilson and Claussen 1994). If a patient suffers a seizure
while on clozapine, the dose should be lowered, and a
broad-spectrum anticonvulsant, such as valproate or
phenytoin, should be added (Haller and Binder 1990).
Once a therapeutic trough serum level of the anticonvulsant has been reached, the dose of clozapine may be
slowly increased. Doses above 600 mg per day are generally to be avoided following a clozapine-induced seizure.
A final caveat: Other causes of seizures in schizophrenia
patients must be considered and ruled out, even when a
seizure occurs in a patient who is receiving clozapine.
Among nonneuroleptics, tricyclic antidepressants—
especially imipramine, amitriptyline, and protriptyline
(Betts et al. 1968: Dallos and Heathfield 1969; Itil and
Soldatos 1980)—are fairly epileptogenic. About 1 percent
of patients on tricyclic therapy for more than 1 week will
have a medication-related seizure (Lowry and Dunner
1980). In an in vitro study of seizure induction in tissue
slices with tricyclic antidepressants, imipramine was the
most potent at therapeutic serum levels, while amitriptyline, nortriptyline, maprotiline, and desipramine were less
effective (listed in descending order of epileptogenic
potency). Doxepin and nomifensine increased spike activity at low doses but reduced it at higher levels. Protriptyline and trimipamine actually suppressed spike activity
with increasing doses (Luchins et al. 1984). However, the
validity of extrapolating epileptogenic potential from
slices of tissue in a laboratory to humans is not well established for psychoactive drugs (Trimble 1980). From clinical experience, bupropion and lithium also are fairly
epileptogenic, particularly at higher clinical doses and
more frequently, following overdose (Ghadirian and
Lehmann 1980; Itil and Soldatos 1980; Davidson 1989;
Johnston et al. 1991; Spiller et al. 1994). The risk of
seizure on bupropion is greatest at daily doses of 450 mg
or more (Davidson 1989). However, lithium has also been
demonstrated to have anticonvulsant properties at therapeutic serum levels in patients with preexisting seizure
disorders (Erwin et al. 1973). Selective serotonin-uptake
inhibitors and monoamine oxidase inhibitors are comparatively safe with respect to seizures. Benzodiazepines and
barbiturates are anticonvulsants, but rapid withdrawal or
abrupt cessation of therapy with these medications can
result in withdrawal seizures or even status epilepticus.
The possibility that certain individuals may be more
vulnerable to medication-induced seizures should be considered. Patients with a history of serious closed-head
injury—especially if associated with amnesia, coma, or
intracranial hemorrhage—may, for the rest of their lives,
be more vulnerable to seizures from a wide variety of
provocations, including medications. Focal findings on a
neurological examination may indicate a focal central nervous system lesion, which may, in tum, predispose toward
seizures. Finally, a childhood history of febrile convulsions might suggest a developmental predisposition
toward seizures. In such individuals, careful consideration
should be given to the type of neuroleptic therapy. If
clozapine is to be used, concurrent therapy with a broad
spectrum anticonvulsant might be advisable.
Risk Factors for Recurrent Seizures
Several historical factors place an individual at increased
risk for recurrent seizures following a single event. A history of febrile convulsions in childhood places children
(and probably adults) at increased risk of recurrent
seizures after a non-febrile-associated event (Hirtz et al.
1984; Shinnar et al. 1990). Age at onset of seizures is also
important. Adolescent onset has a worse prognosis than
childhood onset, whereas adult onset has a nominally
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T.M. Hyde and D.R.Weinberger
higher risk of relapse than childhood onset (Shinnar and
Berg 1995). A partial seizure is a positive predictor of
recurrence in studies of children (Hirtz et al. 1984;
Camfield et al. 1985; Shinnar et al. 1990) and in one study
of adults (Annegers et al. 1986). In these studies, any
form of partial seizure is a positive predictor, not just
complex partial seizures. However, Callaghan et al.
(1988) found that patients with a history of complex partial seizures with secondary generalization are more likely
to relapse following discontinuation of anticonvulsant
therapy after a 2-year seizure-free period than patients
with generalized seizures and complex or simple partial
seizures without secondary generalization. Children with
Jacksonian seizures, complex partial seizures, or multiple
seizure types are more likely to relapse when off of anticonvulsants than children with generalized motor or
absence seizures (Thurston et al. 1982).
Abnormalities on EEG may be important in predicting the risk of recurrent seizures after a single event, as
well as after a long seizure-free interval when under anticonvulsant treatment. EEG abnormalities present before
the initiation of anticonvulsant therapy and that persist
despite treatment are associated with a higher risk of
seizure recurrence when off anticonvulsants (Callaghan
et al. 1988; Shinnar and Berg 1995). Another study
reported that the presence of spikes on the EEG increases
the risk of seizure recurrence (Tennison et al. 1994). In
contrast, Thurston et al. (1972, 1982) found no predictive
value for the risk of seizure relapse in the type of EEG
abnormality.
The clinical characteristics of a brain injury have predictive value in assessing the risk of recurrent seizures. A
history of mental retardation or motor dysfunction is positively correlated with an increased risk of seizure relapse
in children and adolescents (Thurston et al. 1972, 1982;
Tennison et al. 1994). Following head trauma, seizures
within the first week of injury and those that occur months
later are associated with posttraumatic epilepsy. Patients
with persistent focal neurological deficits following
closed-head injury have an increased risk of recurrent
seizures. Penetrating head trauma produces an even
higher risk of recurrent seizures (Caveness 1976), and
head injuries with an intracerebral hematoma are particularly associated with the subsequent development of a
seizure disorder (Jennett 1975; Feeney and Walker 1979).
Although a single seizure does not necessarily require
chronic anticonvulsant therapy, evaluation after an initial
seizure may identify specific unremediable factors that
make recurrent seizures likely. In such a setting, chronic
anticonvulsant therapy may be prudent.
Anticonvulsant Choice in a Patient
With Schizophrenia
If a patient is felt to be at risk for recurrent seizures, then
anticonvulsant therapy should be initiated. The choice of
anticonvulsant depends in part on the type of seizure.
Valproate is the drug of choice for generalized seizures,
including motor, absence, and myoclonic forms; phenytoin and phenobarbital are secondary choices. Carbamazepine is the drug of choice for complex partial seizures;
gabapentin, lamotrigine, and even valproate can also be
used. The addition of an anticonvulsant can alter the
metabolism and distribution of antipsychotic medication,
lowering serum concentrations and diminishing efficacy,
so adjustments in the antipsychotic dosage may be necessary. Furthermore, antipsychotic medications can increase
the serum levels of anticonvulsants, precipitating toxic
effects (Mendez et al. 1984, 1986). Anticonvulsant levels
must be monitored carefully in a patient receiving
antipsychotic medications, especially if there is a change
in clinical state. Since both clozapine and carbamazepine
can depress white blood cell counts and even produce
agranulocytosis, combination therapy with these two
medications should be avoided if possible. Clonazepam
and valproate should not be combined as they can precipitate absence status in some individuals (McEvoy 19966).
Finally, epilepsy surgery, with resection of the epileptic
focus, is an option in refractory patients, that is, those
with persistent seizures despite multiple trials of single
and combination anticonvulsants at therapeutic doses or
those who suffer from intolerable medication side effects
(Devinsky and Pacia 1993). Unfortunately, temporal
lobectomy has little or no effect on preexisting psychoses
(Roberts et al. 1990).
Conclusions
Schizophrenia patients probably are more prone to
seizures than the general population. This vulnerability
may be conferred by the neuropathological substrate of
schizophrenia itself, as well as by the secondary effects of
the illness and by exposure to medications that lower the
seizure threshold. For the schizophrenia researcher, the
increased incidence of seizures in patients with schizophrenia may offer important insights into the neurobiology of schizophrenia. Complex partial seizures are the
most common type of seizure in schizophrenia. In addition, focal temporal lobe abnormalities are commonly
seen in patients with schizophrenia and seizure disorders.
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Seizures and Schizophrenia
These findings support the contention that a lesion in the
mesial temporal lobe may underlie both schizophrenia
and a seizure disorder. For the clinician, seizures in schizophrenia require careful evaluation and selection of medications, both anticonvulsants and antipsychotics. Patients
with schizophrenia and seizure disorders offer useful
insights into the biology of schizophrenia and pose special
challenges for the clinicians who care for them.
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