Epilepsy: A Comprehensive Textbook
2nd Edition

Chapter 204
Schizophrenia and Other Psychoses
Michael R. Trimble
Bettina Schmitz
Introduction
Because the brain is the central organ that regulates behavior, a change of behavior may come about with disturbances of the brain, either through alteration of its structure or via functional change, functional here being used in its original meaning to emphasize disturbance of brain function.92 Neurologists interested in behavioral disorders have mainly concerned themselves with patients with lesions that cause structural changes, whereas psychiatrists have dealt more with the consequences of disturbed function, where underlying structural lesions have been more difficult to discern. Epilepsy is one of a number of conditions in which there is often an underlying structural abnormality to be found if the appropriate technique is used (e.g., neuropathology, magnetic resonance imaging), but profound functional changes also occur, either as a consequence or independently. These may be reflected in the seizure, one manifestation of the epilepsy process, but may also be associated with some of the less dramatic but nonetheless clinically significant behavioral manifestations of epilepsy.
Definitions and Phenomenology
Psychosis, as used in the International Classification of Diseases (ICD)-10,25 defines a disorder with the presence of “hallucinations, delusions, or a limited number of severe abnormalities of behavior, such as gross excitement and overactivity, marked psychomotor retardation, and catatonic behavior.” In the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV), the term psychotic refers to delusions, any prominent hallucinations, disorganized speech, or disorganized or catatonic behavior.7
Hallucinations and delusions, the hallmark of psychosis, suggest some deviant neurologic processing, underlying which are usually structural but sometimes solely functional alterations of activity. Although in epilepsy hallucinations and delusions may be experienced in certain settings for which patients have clear insight, in the majority of cases insight is lacking, and the condition is truly psychotic.
Historical Background
In the middle of the 19th century, European psychiatrists noted the high incidence of psychotic episodes in institutionalized patients with epilepsy. Several authors described the specific psychopathology of psychiatric complications occurring in the context of epilepsy using such terms as “épilepsie lavvée,”50 “grand mal intellectual,”9 “epileptoid states,”18 and “epileptic equivalents.”24 Samt62 put forward the idea that the pathophysiology of certain psychoses occurring in the context of epilepsy, especially episodic twilight states, was identical to the pathophysiology of motor seizures. He suggested that in the absence of epileptic seizures, such epileptic equivalents could be sufficient for a diagnosis of epilepsy.
Some authors in the 19th century explicitly noted the rarity of chronic paranoia or true madness in patients with epilepsy. These observations resulted in intensive discussions on the nature of the relationship between epilepsy and schizophrenia, a subject frequently chosen in theoretical disputes on definitions of terms such as disease and symptom complex in psychiatry at the beginning of the 20th century.20,30
Combined seizures and schizophrenialike symptoms have generally been interpreted either as symptomatic seizures secondary to cerebral sequelae of insanity—for example, brain edema in catatonia—or as symptomatic psychoses caused by seizures or the underlying epileptic process.32,36 In cases with no obvious temporal relationship between epileptic seizures and psychotic symptoms, it was speculated that both were not directly linked but were caused by the same underlying brain pathology.54,73 Ganter,13 Krapf,32 and Glaus16 published clinical case series with prevalence rates of combinations lower than expected. These studies, together with observations of alternating periods with seizures and seizure-free periods with psychosis in some patients and the improvement of psychotic symptoms after spontaneous seizures in others, led to the theory of functional dependency and biologic antagonism of schizophrenic and epileptic symptoms, a concept that influenced von Meduna46 to introduce iatrogenic convulsions into the treatment of schizophrenia.
With progress in diagnosis and treatment in epilepsy, epileptology shifted conceptually to the realm of neurologists in many countries. Psychiatric aspects were neglected until they were “rediscovered” in the 1950s and 1960s.14,38,82 American and English authors reported an excess of schizophrenialike psychoses in epilepsy patients, especially in those suffering from temporal lobe epilepsy.15,55,70
Slater et al. published a detailed analysis of 69 patients from two London hospitals who suffered from epilepsy and interictal psychoses. On the basis of this case series, the authors challenged the antagonism theory and postulated a positive link between epilepsy and schizophrenia. Although Slater was criticized for drawing conclusions on the basis of insufficient statistics,77 the temporal lobe hypothesis soon became broadly accepted and stimulated extensive research into the role of temporal lobe pathology in schizophrenia. The use of epileptic psychoses as a biologic model or “mockup” of schizophrenia59 is largely based on Gibbs and Slater’s work.
Table 1 Clinical Characteristics of Psychoses in Relation to Seizure Activity
  Ictal Postictal Parictal Alternative Interictal
Relative frequency ∼10% ∼50% ∼10% ∼10% ∼20%
Consciousness Impaired Impaired or normal Impaired Normal Normal
Typical features Mild motor symptoms Lucid interval Occurs often during presurgical evaluation Initial symptom insomnia Schizophrenialike psychopathology
Duration Hours to days Days to weeks Days to weeks Weeks Months
EEG Status epilepticus Increased slowing, increased epileptic Increased slowing, increased epileptic Normalized Unchanged
Treatment Antiepileptic drugs IV Spontaneous recovery, benzodiazepines, seizure control Seizure control Sleep regulation, reduction of antiepileptic drugs Antipsychotics
EEG, electroencephalogram.
The possible impact of research into epileptic psychosis on the understanding of the pathophysiology of endogenous psychoses explains the bias in the literature toward study of interictal schizophrenialike psychoses. The spectrum of psychotic syndromes in epilepsy is, however, much more complex, and psychotic complications are not restricted to patients with temporal lobe epilepsy.
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Epidemiology
Some of the earlier studies were reviewed in the first edition of this textbook (Chapter 197). The more recent studies have employed an improved methodology. Bredkjaer2 in a record linkage study looked for associations between epilepsy from the national patient register of Denmark and the equivalent psychiatric register. The incidence of nonorganic, nonaffective psychoses, which included schizophrenia and schizophrenia spectrum disorders, was significantly increased in epilepsy, even when patients with learning disability or substance misuse were excluded.
Stefansson et al.76 in a case-control study compared the prevalence of nonorganic psychiatric disorders in patients with epilepsy to those with other somatic diseases, the groups being taken from a disability register in Iceland. Although the difference in psychiatric diagnoses overall was not significant, there was a higher rate of psychoses, particularly schizophrenia and paranoid states, among males with epilepsy.
Qin et al.56 in another study from Denmark have confirmed the increased risk of schizophrenia and schizophrenialike psychoses in epilepsy, and in this study a family history of psychoses and a family history of epilepsy were significant risk factors for psychosis.
Studies from Japan examining new referrals for epilepsy quote a 6% prevalence of psychoses in those with normal intelligence (in contrast to 24% in those with learning disability).44
There are several studies of much more selected populations, such as hospital case series. Thus, Gureje,19 in patients attending a neurologic clinic, quoted that 37% of patients were psychiatric cases and that 29% of these were psychotic. Mendez et al.48 in a retrospective investigation reported that interictal psychotic disorders were found in over 9% of a large cohort of patients with epilepsy in contrast to just over 1% in patients with migraine. The epilepsy sample had more complex partial seizures, more auras, and less generalized epilepsy.
None of the above studies has been able to examine issues related to epilepsy classification in any detail, cohorts being derived from case registers lacking detailed information from, for example, brain imaging. Certain risk factors have been defined, but not from these data, and are noted below.
Classification
There is no internationally accepted syndromic classification of psychoses in epilepsy. Most of the previously proposed classification systems for these psychoses3,10,29,85 are based on a combination of psychopathologic, etiologic, longitudinal, and electroencephalographic (EEG) parameters. Unfortunately, because of a lack of taxonomic studies, our knowledge about regular syndromic associations is still limited.
“Atypical” syndromes are not unusual, and presentations such as those associated with forced normalization (see below) and postictal psychoses make simple divisions between what is ictal and what is interictal difficult to discern. In other words, the above two examples are of psychotic states closely tied to the biology of the ictus but which are interictal in their timing. A new multiaxial approach to the classification of psychoses in epilepsy can be found in the proposal by Krishnamoorthy.33
It is suggested that patients with epilepsy and psychoses receive two separate diagnoses according to either ICD-10 or DSM-IV,7 but in addition, the relationships between onset of psychosis and seizure activity, antiepileptic therapy, and changes of EEG findings should be noted.
For pragmatic reasons, however, it remains convenient to group psychoses in epilepsy according to their temporal relationship to seizures.
Syndromes of Psychoses in Relation to Seizure Activity
The various syndromes are described in Table 1. The ictal psychoses are more likely to be linked to complex partial seizure status but have never been examined in any detail. In clinical practice they are not uncommon in seizures of temporal origin, but some of them are secondary to frontal lobe seizures. Simple focal status or aura continua may cause complex hallucinations, thought disorders, and affective symptoms. The continuous epileptic activity is restricted and may escape scalp EEG recordings. Insight usually is maintained, and true psychoses emerging from such a state have not been described. Nonconvulsive status epilepticus requires immediate treatment with intravenous antiepileptic drugs.
Table 2 Differences between Postictal Psychoses (PIP) and Interictal Psychoses (IIP) (Statistically Significant)
  PIP (n = 45) IIP (n = 126)
Reduced intelligence (<70 IQ) 4 39
Complex partial seizures 37 84
Déjà vu auraa 10 of 43 10 of 103
Temporal MRI lesion 16 25
Temporal lobe epilepsy 39 74
Generalized spike-waves 1 21
Age at epilepsy onset (years) 16 11
Age at psychosis onset (years) 35 25
Interval between onset epilepsy and psychosis (years) 18 13
aCalculated for the subgroup of patients with focal epilepsies.
Data from Kanemoto K. Postictal psychosis revisited. In: Trimble MR, Schmitz B, eds. The Neuropsychiatry of Epilepsy. Cambridge: Cambridge University Press; 2002:117–134.
Postictal Psychoses
Most postictal psychoses are precipitated by a series or status of generalized tonic–clonic seizures. More rarely, psychoses occur after single grand mal seizures or following a cluster of complex partial seizures.69 In the elderly, a postictal psychosis may be the first presentation of a new-onset epilepsy disorder.
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Postictal psychoses account for approximately 25% of psychoses in epilepsy.17,64
The relationship to the type of epilepsy is not clear. Dongier8 described a preponderance of generalized epilepsies, and Logsdail and Toone41 noted a higher frequency of postictal psychosis in patients with focal epilepsies and complex focal seizures. One of the more comprehensive studies has been that of Kanemoto, and his distinction between postictal and interictal psychoses is shown in Table 2. Essentially, the postictal psychoses occur with later age of onset of epilepsy and at a later age than the interictal psychoses. They are significantly associated with temporal lobe epilepsy, complex partial seizures, and magnetic resonance imaging (MRI) temporal plus extratemporal structural lesions. Patients are less likely to have learning disability and are less likely to have generalized spike-wave abnormalities on the EEG. He also noted an association with déjà vu auras.27 Others have suggested an association between ictal fear and postictal psychosis.63
A characteristic lucid interval is described in most patients during which time the mental state appears to be normal. This interval can last from 1 to 6 days between the epileptic seizures and onset of psychosis.73 Failure to appreciate the presence of this lucid interval can lead to a misdiagnosis of this condition.
The psychopathology of postictal psychosis is polymorphic, but most patients present with abnormal mood and paranoid delusions.41 Some patients are confused throughout the episode; others present with fluctuating impairment of consciousness and orientation; and sometimes there is no confusion at all. Kanemoto27 suggests that up to 50% have a psychosis in clear consciousness. Dominant are delusions of grandiosity and religiosity often associated with an elevated mood when compared with interictal psychoses. Patients may also be anxious and a typical symptom is fear of impending death. Because patients often have a clear sensorium and may receive command hallucinations if the latter relate to violence or suicide, it is during such states that violent attacks on the self or others may occur.
The EEG during postictal psychosis is usually deteriorated, with increased epileptic as well as slow-wave activity, but there are few reliable studies since people with acute psychoses are difficult to examine.
The psychotic symptoms spontaneously remit within days or weeks, often without need for psychotropic drug treatment. However, in some cases, chronic psychoses develop from recurrent and even a single postictal psychosis41,94; this is estimated to occur in about 25% of cases.
The pathophysiology is not known. Savard et al.63 noted the clinical analogy of psychoses following complex partial seizures to other postictal phenomena such as Todd paresis or postictal memory loss. Logsdail and Toone hypothesized that postictal psychosis results from increased postsynaptic dopamine sensitivity. Ring et al.58 have tested this hypothesis using single-photon emission computed tomography (SPECT) and the D2 ligand [123I] iodobenzamide (IBZM). They noted that patients with epilepsy and psychoses had decreased binding to the ligand, suggesting that there was increased release of endogenous dopamine in the psychotic state. Kanemoto27 suggested that we are dealing with a restricted limbic status epilepticus, but limited functional imaging studies produced contradictory results.39
Parictal Psychosis
Most authors do not distinguish between parictal and postictal psychoses.63 In parictal psychosis,94 psychotic symptoms develop gradually and parallel to increases in seizure frequency. The relationship to seizures is easily overlooked if seizure frequency is not carefully documented over prolonged periods. More rapid development of parictal psychoses can be seen, especially during the presurgical assessment of patients with intractable epilepsy, when series of epileptic seizures may be provoked by withdrawal of antiepileptic drugs. Impairment of consciousness is more frequent than in postictal psychosis.
Interictal Psychoses
Interictal psychoses occur between seizures and cannot directly be linked to the ictus. They are less frequent than peri-ictal psychoses, and account for 10% to 30% of diagnoses in unselected case series.8,64 Interictal psychoses are, however, clinically more significant in terms of severity and duration than peri-ictal psychoses, which usually are brief and often self-limiting.
Slater and Beard stated that, in the absence of epilepsy, the psychoses in their study group would have been diagnosed as schizophrenia, and noted the frequent presence of the First Rank Symptoms of Schneider.70 However, there have been persistent arguments as to the exact relationship between the two disorders and the phenomenology of the interictal epileptic psychoses. Slater maintained that there was a distinct difference between schizophrenia and the schizophrenialike psychoses associated with epilepsy, and they highlighted the preservation of affect, a high frequency of delusions and religious mystical experiences, and few motor symptoms.
Other authors have stressed the rarity of negative symptoms and the absence of formal thought disorder and catatonic states.28 McKenna et al.45 pointed out that visual hallucinations were more prominent than auditory hallucinations. Tellenbach82 stated that delusions were less well organized, and Sherwin67 remarked that neuroleptic treatment was less frequently necessary. There have been other authors, however, who denied any clear psychopathologic differences between epileptic psychosis and schizophrenia.21,31
Table 3 Risk Factors Associated with Interictal Psychoses of Epilepsya
Sex Bias to female patients
Age of onset Early adolescence
Interval Onset of seizures to onset of psychosis: Mean 14 years
Epileptic syndrome Temporal lobe epilepsy
Seizure type Complex focal
Seizure frequency Low, diminished
Neurologic findings Sinistrality
Pathology Gangliogliomas, hamartomas
EEG Mediobasal focus, especially left sided
EEG, electroencephalogram.
Using the Present State Examination and the CATEGO computer program, which is a semistandardized and validated method for quantifying psychopathology, it has been possible to compare the presentation of psychosis in epilepsy with process schizophrenia. Very few significant differences emerged from such studies,53,84 which suggests that, assuming the
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patients were representative, a significant number will have a schizophrenialike presentation virtually indistinguishable from schizophrenia in the absence of epilepsy.
Phenomenology apart, Slater argued that long-term prognosis of psychosis in epilepsy was better than that in process schizophrenia. In a follow-up study on his patients, he found that chronic psychotic symptoms tended to remit, and personality deterioration was rare.17 Other authors have also described the outcome to be more favorable and long-term institutionalization to be less frequent than in schizophrenia.28,67 Unfortunately, there have been no longitudinal studies comparing the long-term outcome of psychosis in epilepsy and process schizophrenia.
Risk Factors
The pathogenesis of psychotic episodes in epilepsy is likely to be heterogeneous. In most patients, a multitude of chronic and acute factors can be identified that are potentially responsible for the development of a psychiatric disorder. These factors are difficult to investigate in retrospect, and the interpretation of them as either causally related or simply intercorrelated is arguable.
The literature on risk factors is highly controversial; studies are difficult to compare because of varying definitions of the epilepsy, the psychiatric disorder, and the investigated risk factors. Most studies are restricted to interictal psychoses. Table 3 summarizes factors that have frequently been described to be associated with the interictal psychosis in epilepsy.85
Genetic Predisposition
With few exceptions,26,56 most authors do not find any evidence for an increased rate of psychiatric disorders in relatives of epilepsy patients with psychoses.11,53,69 This was one reason why Slater suggested that these psychoses were truly symptomatic, a representative phenotype of the genotype.
Sex Distribution
There has been a bias toward female sex in several case series,80 but this has not been confirmed in controlled studies.1,34,35
Duration of Epilepsy
The interval between age at onset of epilepsy and age at first manifestation of psychosis has been remarkably homogeneous, in the region of 11 to 15 years, in many series.85 This interval has been used to postulate the etiologic significance of the seizure disorder and a kindlinglike mechanism. However, some authors5,77 have argued that the supposedly specific interval represents an artifact. They have drawn attention to the wide range, with a significantly shorter interval in patients with later onset of epilepsy. They also have pointed out that patients whose psychoses did not succeed their epilepsy were excluded in most series, and that there is a tendency in the general population for the age of onset of epilepsy to have an earlier peak than that of schizophrenia.
Type of Epilepsy
There is a clear excess of temporal lobe epilepsy in almost all case series of patients with epilepsy and psychosis. Among the pooled data of ten studies, 217 (76%) of 287 patients suffered from temporal lobe epilepsy.85 The preponderance of this type of epilepsy is, however, not a uniform finding; in Gudmundsson’s epidemiologic study, for example, only 7% suffered from “psychomotor” epilepsy. However, in many studies, especially the early ones, the classification of seizures and epilepsy is confused, and not supported by neurologic investigations.
The nature of a possible link of psychoses to temporal lobe epilepsy (TLE) is not entirely clear,65 partly because of ambiguities in the definition of TLE in the literature, based on either seizure symptomatology (psychomotor epilepsy), involvement of specific functional systems (limbic epilepsy), or anatomic localization as detected by depth EEG or neuroimaging (amygdalohippocampal epilepsy). Unfortunately, most authors have not sufficiently differentiated frontal and temporal lobe epilepsy.
The temporal lobe hypothesis, although widely accepted, has been criticized for being based on uncontrolled case series, such as in the studies by Gibbs15 and Slater and Beard.70 It was argued that TLE is the most frequent type of epilepsy in the general population and that there is an overrepresentation of this type of epilepsy in patients attending specialized centers. However, there is a general consensus that psychoses are less common in patients with neocortical extratemporal epilepsies.5,15,17,51,64,66,77 Adachi1 suggested that psychoses in patients with frontal lobe epilepsy may be overlooked because of a differing psychopathology, hebephrenic symptoms in particular dominating the presentation.
The findings are less unequivocal regarding TLE and generalized epilepsies. Four studies19,53,66,68 note significant differences in the frequency of psychoses in temporal lobe epilepsy, but several do not.4,14,49,64,72,75,77 However, many patients with generalized epilepsy show pathology of temporal structures, making classification difficult, and again many reports lack the sophisticated brain imaging that is now required for such hypotheses to be tested.
There are several studies showing that psychoses in generalized epilepsies differ from psychoses in TLE.85 The former are more likely to be of short duration and confusional.4,8,77 Alternative psychoses, which are especially common in generalized epilepsy, are usually relatively mild and often remit before any development of paranoid-hallucinatory symptoms. Schneiderian first-rank symptoms and chronicity are more frequent in patients with TLE.64,86 This has considerable significance for psychiatrists attempting to unravel the underlying “neurology” of schizophrenia, and the findings from epilepsy were
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instrumental in altering the view of schizophrenia away from a psychosocial to a biologic model.
Type of Seizures
There is evidence from several studies that focal seizure symptoms that indicate ictal mesial temporal or limbic involvement are overrepresented in patients with psychosis. Hermann and Chabria23 noted a relationship between ictal fear and high scores on paranoia and schizophrenia scales of the Minnesota Multiphasic Personality Inventory (MMPI). Kristensen and Sindrup34,35 found an excess of dysmnesic and epigastric auras in their psychotic group. They also reported a higher rate of ictal amnesia. In another controlled study, ictal impairment of consciousness was related to psychosis, but simple seizure symptoms indicating limbic involvement were not.64
No seizure type is specifically related to psychosis in generalized epilepsies. Most patients with psychosis and generalized epilepsies have absence seizures.64
Severity of Epilepsy
The strongest risk factors for psychosis in epilepsy are those that indicate severity of epilepsy. These are long duration of active epilepsy,70 multiple seizure types,5,22,40,52,60,64,66 history of status epilepticus,64 and poor response to drug treatment.40 Seizure frequency, however, is reported by most authors to be lower in psychotic epilepsy patients than in nonpsychotic patients.11,66,71,74 It has not been clarified whether seizure frequency was low before or during the psychotic episode. This may represent a variant of forced normalization (see below).
Laterality
Left lateralization of temporal lobe dysfunction or temporal lobe pathology as a risk factor for schizophreniform psychosis was originally suggested by Flor-Henry.11 Studies supporting the laterality hypothesis have been made using surface EEG,40 depth electrode recordings,67 computed tomography,6,83 neuropathology,79 neuropsychology,53 and positron emission tomography (PET),91 and more recently with MRI. The earlier literature has been summarized by Trimble.85 In a synopsis of 14 studies with 341 patients, 43% had left, 23% right, and 34% bilateral abnormalities. This is a striking bias toward left lateralization. However, lateralization of epileptogenic foci was not confirmed in all controlled studies.8,34,35,68 Again, it may be that certain symptoms rather than any syndrome are associated with a specific side of focus. Trimble pointed out that a specific group of hallucinations and delusions, defined by Schneider and referred to as first rank symptoms, which usually (but not exclusively) signifies schizophrenia, may be relevant.89,90 He suggested that these may be signifiers of temporal lobe dysfunction, representing disturbances of language and symbolic representation. In this sense, he then equated to a Babinski sign for a neurologist (i.e., pointing to a location and lateralization of an abnormality in the central nervous system).
These laterality findings have received support from brain imaging studies, especially SPECT and MRI. Mellers,47 using a verbal fluency activation paradigm and HMPAO SPECT, compared patients with schizophrenialike psychoses of epilepsy (n = 12), with schizophrenia (n = 11), and epilepsy and no psychoses (n = 16). The psychotic epilepsy patients showed lower blood flow in the superior temporal gyrus during activation than the other two groups. Using MR spectroscopy, Maier et al.42 were able to compare hippocampal-amygdala volumes and hippocampal N-acetyl aspartate (NAA) levels in patients with temporal lobe epilepsy and schizophrenialike psychoses of epilepsy (n = 12), temporal lobe epilepsy and no psychoses (n = 12), schizophrenia and no epilepsy (n = 26), and matched normal controls (n = 38). The psychotic patients showed significant left-sided reduction of NAA, and this was greater in the psychotic epilepsy group. Regional volume reductions were noted bilaterally in this group, and in the left hippocampus-amygdala in the schizophrenic group.
Flugel et al.12 have recently examined 20 psychotic and 20 nonpsychotic cases with temporal lobe epilepsy using magnetization transfer imaging. They reported significant reductions of the magnetization transfer ratio (an index of signal loss) in the left superior and middle temporal gyri in the psychotic patients; this was unrelated to volume changes and best revealed in the subgroup with no focal MRI lesions.
Structural Lesions
The literature on brain damage and epileptic psychosis is very controversial. Some authors have suggested a higher rate of pathologic neurologic examinations, diffuse slowing on the EEG, and mental retardation,34,35 but others could not find an association with psychosis.11,26 Neuropathologic studies of resected temporal lobes from patients with TLE have suggested a link between psychosis and the presence of cerebral malformations such as hamartomas and gangliogliomas as compared with mesial temporal sclerosis.4,59,80 These findings have been seen as consistent with recent findings of structural abnormalities in the brains of schizophrenic patients without epilepsy that arise during fetal development.
Bruton4 has noted enlarged ventricles, periventricular gliosis, and an excess of acquired focal damage in brains of institutionalized psychotic epileptic patients compared with nonpsychotic controls. Bruton also reported that schizophrenialike psychoses were also distinguished by an excess of perivascular white matter softenings.
In a study specifically looking at hippocampal and amygdala volumes, Tebartz van Elst et al.81 examined 26 patients with epileptic psychoses, 24 with temporal lobe epilepsy and no psychosis, and 20 healthy controls. The psychotic patients had significantly increased amygdala sizes in comparison with the other two groups, which were bilateral, not related to the laterality of the focus or length of epilepsy history. No hippocampal differences were noted in this study. In a complementary study on the same groups, Rusch et al.61 were unable to find any neocortical cortical volumetric differences.
Forced Normalization
A full understanding of the relationships between epilepsy and psychosis requires appreciation of this concept.
Earlier this century, reports appeared that suggested that there was some kind of antagonism between epilepsy and psychosis. This was one of the reasons that led von Meduna to introduce convulsive therapy for the treatment of schizophrenia. In the 1950s, Landolt37,38 published a series of papers on patients who had epilepsy who became psychotic when their seizures were under control. He defined forced normalization as follows: “Forced normalisation is the phenomenon characterised by the fact that, with the recurrence of psychotic states, the EEG becomes more normal, or entirely normal, as compared with previous and subsequent EEG findings.”
Forced normalization was thus essentially an EEG phenomenon. The clinical counterpart of patients becoming psychotic when their seizures became under control and their
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psychosis resolving with return of seizures was referred to as alternative psychoses by Tellenbach.82
These phenomena have now been well documented clinically. The following are important to note, however. First, the EEG does not need to become “normal,” but the interictal disturbances decrease and in some cases disappear. Second, the clinical presentation need not necessarily be a psychosis but sometimes is. In childhood or in the mentally handicapped, aggression and agitation are common. Other manifestations include pseudoseizures or other conversion symptoms, depression, mania, and anxiety states. Third, the disturbed behavior may last days or weeks. They may be terminated by a seizure, and the EEG abnormalities then return. Fourthly, Landolt originally associated this phenomenon with focal epilepsies, but with the introduction of the succinimide drugs, he noted an association with the generalized epilepsies. Certainly, forced normalization may be provoked by the administration of anticonvulsants and has been reported with barbiturates, benzodiazepines, ethosuximide, tiagabine, topiramate, vigabatrin, levetiracetam, and more recently lamotrigine5,85 (see Chapter 208).
The literature on antagonism between epilepsy and psychosis has been held to be incompatible with the suggestions outlined above that there is an increased association between epilepsy and psychosis. This has been resolved by more careful understanding of the original literature.93 Thus, within the association or link between psychosis and epilepsy, there may be an antagonism of symptoms between seizures and the symptoms of psychosis (i.e., the hallucinations and delusions). It is the longitudinal course of the disorders that has to be followed, and forced normalization, as opposed to alternative psychosis, requires serial EEG recordings before the diagnosis can be made.
It is often denied that forced normalization occurs, probably with good reason. Thus, it is certainly rarer than made out by Landolt, and studies are few and far between. It is difficult to document cases precisely, EEG recordings being difficult to obtain at the right times. However, other less enlightened reasons to ignore such findings relate to the fact that the concept brings psychiatry uncomfortably close to neurology, revealing a close biologic link between seizures and psychosis. It also affects treatment. Thus, if in some patients suppression of seizures provokes psychopathology, it reinforces the fact, often ignored or misunderstood, that seizures and epilepsy are not synonymous, and that an understanding of the epileptic process and its treatment goes far beyond the control of seizures. In clinical practice, to ignore the fact that some patients manifest these problems as their seizures come under control can lead to the continuation of severe behavior disturbances, with all of the social disruption that then emerges, and a failure to manage the epilepsy appropriately.
Psychosis Following Surgery
Temporal lobectomy is an ever-increasing treatment for patients with intractable epilepsy. Ever since the early series, the possibility that surgery itself may be associated with the development of psychiatric disturbance, in particular psychosis, has been discussed. Some of the best evidence comes from the Maudsley series, initially described by Taylor78 and more recently by Bruton.4 Most centers have stopped operating on floridly psychotic patients, based on the observation that psychoses generally do not improve with the operation. A few centers, however, regularly include psychiatric screening as part of their preoperative assessment, but postoperative psychiatric follow-up is often nonexistent. Assessment of psychosocial adjustment is rarely performed, in contrast to the often scrupulous recording of neuropsychological deficits.
The Maudsley series show that some patients develop new psychosis postoperatively, and there is an increased reporting of depression. Bruton4 has suggested that the development of postoperative psychoses may be more common with certain pathologies (gangliogliomas). Patients with right-sided temporal lobectomies may be more prone to these psychiatric disturbances.85 In some cases, the sudden relief of seizures that occurs following surgery may suggest a mechanism similar to forced normalization, although no persistent clear relationship emerges between success of operation and the development of psychotic postoperative states. In recent times, there have been several small series reported of patients with psychoses who have been successfully operated on, without worsening of their seizures but with marked improvement in seizure control. This topic is discussed in much more detail in Chapter 209.57
Diagnosis
The principles of diagnosis of psychiatric problems in epilepsy are essentially the same as when a patient does not have epilepsy. However, as noted, it is not possible to apply the strict DSM-IV classifications,7 and in many patients there are subtle aspects to the clinical picture that may suggest the underlying neurologic flavor of the phenomenology. These include in the schizophrenialike psychoses the retention of affective responses, lack of chronic personality and lifestyle deterioration, and development of some of the personality features noted in the interictal personality syndrome. An inclination to mysticism with developing religiosity is one of the most common.
Close attention to the relationship of the development of the psychoses to the seizure pattern is essential if the peri-ictal disorders are to be distinguished from the interictal, although in many patients this is not always clear, and the pattern may change with time. In particular, there are reports of ictally driven psychoses evolving to a chronic interictal syndrome, subtle at first but then more enduring. In other cases, the acute psychoses may erupt in the absence of an obvious cluster of seizures, even though on previous occasions the relationship has been obvious. The EEG in some cases is very important in clarifying the diagnoses, especially for nonconvulsive status and states of forced normalization.
Because many patients with psychoses of epilepsy display prominent affective symptoms, it is important to identify those patients with an affective disorder, as opposed to a schizophrenialike state or a paranoid illness, that may respond initially to effective antidepressant therapy.
Treatment
Essentially, management of psychiatric problems in patients with epilepsy is similar to that in patients without epilepsy, with a few caveats. Certainly, a number of nonmedical treatments are available. These should always be thought of in individual cases.
Patients with psychoses should be treated with neuroleptic medications, although these, like most antidepressants, can lower the seizure threshold. To date, all known neuroleptics have this potential, although some more than others; this is covered in more detail in Chapter 214.
Postictal psychoses may occasionally need neuroleptic drugs, although they usually settle rapidly. It is more important to prevent patients from damaging themselves or causing harm to others, but a drug such as haloperidol or one of the newer atypical antipsychotics at regular intervals may control behavior satisfactorily. Interictally, the paranoid or schizophrenialike states need to be evaluated in terms of their relationship to seizure frequency. Thus, in patients who stop having seizures
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in association with the onset of psychosis, a neuroleptic that increases the seizure threshold (e.g., chlorpromazine or even clozapine) may be the most logical prescription.
Where patients with epilepsy have no alteration of the seizure frequency or the psychosis is occurring in the setting of increased seizure frequency, a neuroleptic less likely to precipitate seizures, such as risperidone, an atypical antipsychotic, is logical. It should be recalled that patients taking anticonvulsants that increase hepatic metabolism will show lower serum levels of neuroleptics and may therefore require somewhat higher doses than patients not on these medications to achieve a similar clinical effect. Occasionally, the addition of an antidepressant or a neuroleptic to a patient’s prescription may lead to increases in serum anticonvulsant levels.
Postictal psychoses often do not require psychotropic medication, resolving over a few hours. However, it is important to stress how dangerous these cases can be, and it is essential to take note of any command hallucinations or delusions of harm to the self or others and protect accordingly. In the first instance, treatment with a benzodiazepine is helpful, since there is a risk, especially with some of the antipsychotics, of precipitating further seizures and exacerbating the psychosis. Regular benzodiazepines for perhaps 48 hours are often sufficient. In the longer-term management it is important to realize that postictal psychoses have a tendency to recur. It is therefore important to warn about this, and to try with effective antiepileptic drug therapy to try to prevent clusters of seizures. It is sometimes possible to prevent such a cluster and hence the later psychosis by telling patients to take their benzodiazepine at the onset of any cluster and continue then for about 48 hours. Sometimes all these measures fail, and so intermittent or even continuous antipsychotic treatment becomes important.
As with all psychiatric problems, psychopharmacologic management alone is not sufficient. Although the role of psychotherapy in the management of psychotic conditions has not proven of any substantial value, it is important to acknowledge that epileptic patients with psychosis bear the burden of epilepsy in addition to their psychosis. Patients with intermittent psychotic states are often perplexed and embarrassed about what has happened to them while psychotic and fear further continuing bouts with a descent into insanity. Patients with continuous psychosis require the skills of paramedical intervention, and the full resources of community care may be needed to help them rehabilitate and to assist their families in coping with their difficulties. In many patients with chronic psychoses of epilepsy, the preservation of affect and lack of personality disintegration over years sustains them well in their communities and may enable them to live with their families or even marry. Maintaining them and bringing such support to them is important, sustaining them in the community and preventing their recurrent admission to the hospital. Further, in a good family environment with adequate medical facilities and follow-up care, patient compliance will tend to be good. Deterioration of an otherwise delicate situation induced by poor compliance, leading to more seizures and exacerbation of psychopathology with loss of control by the family and the physician, may thereby be avoided.
Summary and Conclusions
There is evidence that psychoses are overrepresented in patients with epilepsy, and few physicians who manage epilepsy have not seen patients with either an ictal, postictal, or interictal psychosis. The link to temporal lobe epilepsy is strong, both clinically and theoretically, because there is an acknowledged link between the limbic system and the modulation of emotional and social behaviors.88 It has to be of profound interest that epilepsy, which is so often associated with lesions in medial temporal structures that tend to be present from an early phase in life, is linked to psychoses, which often resemble paranoid and schizophreniform states found in the absence of epilepsy. Thus, the latter can also be shown to have pathology in the same areas of the brain,87 and schizophrenia is now viewed as a developmental disorder associated with anomalous central nervous system development in the fetal or perinatal era of life.
Although the underlying pathology may be different, the absence of gliosis in the hippocampus and related structures characterizing schizophrenia, the site of the pathology, the timing of the lesions, and the consequent functional changes in the brain may all be crucial to the later development of any behavior changes in both epilepsy and schizophrenia. Thus, the behavior changes should be viewed as an integral part of the process of epilepsy that are manifest in some patients. However, the recent evidence, especially from brain imaging studies, suggests that Slater’s original hypothesis was part right but part wrong. Thus, the interictal psychoses seem different from schizophrenia, especially with regard to the admixture with affective symptoms and the long-term prognosis. While hippocampal changes may relate to both disorders, the increased amygdala size, bilateral and around 17% to 20%, and the lesser volumetric changes in the hippocampus suggest that the two psychopathologic states are biologically quite different. While the laterality findings with regard to the functioning of the left hemisphere seem to hold up, the data point away from fundamentally cortical abnormalities in these psychoses, and bring the amygdala and related structures as central in pathogenesis. Finally, it has to be repeated that epilepsy is not synonymous with seizures, and the latter are but one manifestation of the disordered cerebral function of patients with epilepsy.
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