Cognitive-behavioral therapy for psychogenic nonepileptic seizures: a pilot RCT.

OBJECTIVE: To compare cognitive-behavioral therapy (CBT) and standard medical care (SMC) as treatments for psychogenic nonepileptic seizures (PNES). METHODS: Our randomized controlled trial (RCT) compared CBT with SMC in an outpatient neuropsychiatric setting. Sixty-six PNES patients were randomized to either CBT (plus SMC) or SMC alone, scheduled to occur over 4 months. PNES diagnosis was established by video-EEG telemetry for most patients. Exclusion criteria included comorbid history of epilepsy, <2 PNES/month, and IQ <70. The primary outcome was seizure frequency at end of treatment and at 6-month follow-up. Secondary outcomes included 3 months of seizure freedom at 6-month follow-up, measures of psychosocial functioning, health service use, and employment. RESULTS: In an intention-to-treat analysis, seizure reduction following CBT was superior at treatment end (group x time interaction p < 0.0001; large to medium effect sizes). At follow-up, the CBT group tended to be more likely to have experienced 3 months of seizure freedom (odds ratio 3.125, p = 0.086). Both groups improved in some health service use measures and on the Work and Social Adjustment Scale. Mood and employment status showed no change. CONCLUSIONS: Our findings suggest that cognitive-behavioral therapy is more effective than standard medical care alone in reducing seizure frequency in PNES patients. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that CBT in addition to SMC, as compared to SMC alone, significantly reduces seizure frequency in patients with PNES (change in median monthly seizure frequency: baseline to 6 months follow-up, CBT group, 12 to 1.5; SMC alone group, 8 to 5).

Schizophrenia-like psychosis arising de novo following a temporal lobectomy: timing and risk factors.

OBJECTIVES: To clarify risk factors for the development of schizophrenia-like psychotic disorders following temporal lobectomy, and to explore the possibility that the early postoperative period is a time of high risk for the onset of such chronic psychotic disorders. METHODS: Patients who developed schizophrenia-like psychosis were identified from a series of 320 patients who had a temporal lobectomy for medically intractable epilepsy. The relationship of their disorders to both the operation and subsequent seizure activity was examined. Using a retrospective case-control design, risk factors for the development of schizophrenia-like psychosis were established. RESULTS: Eleven patients who developed schizophrenia-like psychosis postoperatively were identified and compared with 33 control subjects who remained free of psychosis postoperatively. The onset of de novo psychotic symptoms was typically in the first year following the operation. No clear relationship between postoperative seizure activity and fluctuations in psychotic symptoms emerged. Compared with the controls, patients who become psychotic had more preoperative bilateral electroencephalogram (EEG) abnormalities, pathologies other than mesial temporal sclerosis in the excised lobe and a smaller amygdala on the unoperated side. CONCLUSIONS: Temporal lobectomy for medically intractable epilepsy may precipitate a schizophrenia-like psychosis. Patients with bilateral functional and structural abnormalities, particularly of the amygdala, may be at particular risk for the development of such psychoses.

Pseudoseizures and asthma.

BACKGROUND: Sexual abuse and head injury are important risk factors of pseudoseizures, reported in about a third of patients. Clinical experience suggests that asthma is another possible risk factor. OBJECTIVES: To determine the relative prevalence of asthma in patients with pseudoseizures. METHODS: A retrospective record review was undertaken of reported asthma in 102 patients with pseudoseizures and 70 psychotic controls. The pseudoseizure patients were subgrouped according to method of diagnosis: 47 in whom epilepsy was excluded by capturing a typical attack on video-electroencephalographic monitoring (VEEM), and 55 not diagnostically confirmed with VEEM. RESULTS: Asthma was reported in 26.5% of pseudoseizure patients, compared with 8.6% of the psychotic controls (chi(2) = 8.6; p = 0.003). Asthma was reported at similar rates in the VEEM confirmed (29.8%) and non-VEEM confirmed (23.6%) pseudoseizure subgroups. The significant excess of reported asthma held for both the VEEM confirmed subjects (Pearson's chi(2) = 5.4, p = 0.02) and non-VEEM confirmed subjects (Pearson's chi(2) = 8.9, p = 0.003). CONCLUSIONS: There is an association between pseudoseizures and reported asthma. Various models are proposed whereby somatisation, anxiety hyperventilation, and dissociative elaboration may account for the observed association. Both asthma and anxiety hyperventilation may be important risk factors for the development of pseudoseizures. The reported asthma may itself be psychogenic in origin in a proportion of patients. Confirmatory prospective studies are indicated.

Cognitive behaviour therapy with adults with intractable epilepsy and psychiatric co-morbidity: preliminary observations on changes in psychological state and seizure frequency.

Cognitive behaviour therapy (CBT) was undertaken with six adults with chronic, poorly controlled seizures and co-existing psychiatric and/or psychosocial difficulties. During 12 sessions of CBT from an experienced CBT Nurse Specialist, treatment focused concurrently on epilepsy-related problems, associated psychopathology and on the development of psychological strategies to reduce seizure occurrence. At the end of treatment participants rated their initial epilepsy-related problem as having less impact on their daily lives and at one-month follow-up reported less deleterious impact on everyday life in terms of their psychological difficulties. In addition participants demonstrated significant improvements in terms of their self-rated work and social adjustment, and in their decreased use of escape-avoidance coping strategies. These positive findings occurred despite the absence of a significant decrease in seizure frequency. Issues raised by the complexity and severity, both of these patients' psychological/psychosocial difficulties and their epilepsy, are discussed in relation to the optimal length of treatment that may be required when adopting a CBT model in this patient group.

VNS in patients with previous unsuccessful resective epilepsy surgery: antiepileptic and psychotropic effects.

OBJECTIVES: To assess the efficacy of vagus nerve stimulation (VNS) in patients with medically and surgically intractable complex partial seizures (CPS). PATIENTS AND METHODS: Sixteen patients with previous temporal [15] and frontal [one] resections were treated with VNS between 1994 and 1999 at King's College Hospital, London, UK. Post-operative video-electroencephalogram telemetry had shown that CPS started from the operated side in 12 patients, contralaterally in three and bilaterally independently in one. RESULTS: Three patients (18.75%) had 50% or more reduction in seizure frequency, but one showed severe worsening of epilepsy, which remitted upon VNS discontinuation. The antiepileptic effect of VNS was not different with respect to the type of operation (anterior temporal lobectomy vs amygdalohippocampectomy), the side of operation, or the side of seizure onset. We observed psychotropic effects in two patients with post-ictal psychosis, in two others with depression, and in a child with severe behavioral disorder. CONCLUSIONS: VNS may have a rather limited antiepileptic role to play in patients with persistent seizures following epilepsy surgery, but may independently possess useful antipsychotic and mood-stabilizing properties.

Postictal psychosis after temporal lobectomy.

Three of 282 consecutive patients who had temporal resections for intractable epilepsy developed postoperative postictal psychosis. These three patients had seizure recurrence contralateral to the resection, whereas none of the patients with ipsilateral seizure recurrence developed any psychiatric symptoms after surgery. Two had left amygdalo-hippocampectomy and one right temporal lobectomy. The de novo occurrence of postoperative postictal psychosis is a well-defined complication of surgery for temporal lobe epilepsy, and may relate to contralateral epileptogenesis.

Changes in regional cerebral blood flow due to cognitive activation among patients with schizophrenia.

BACKGROUND: The regional cerebral blood flow (rCBF) response to the Wisconsin Card Sort Test (WCST) has been used to assess the functional integrity of the prefrontal cortex in patients with schizophrenia. AIMS: In this study, patients were divided into two groups according to whether they had made few or many perseverative errors on a modified version of the WCST. A control group consisted of normal volunteers. The groups were then compared with respect to rCBF response to WCST activation. METHOD: rCBF was measured during administration of a modified version of the WCST and during a card sorting control task, using single photon emission computerised tomography (SPECT). RESULTS: Performance of the modified WCST was associated with a widespread and substantial increase in rCBF, particularly in the frontal region. The poorly performing group of patients with schizophrenia showed only a modest increase in rCBF in the left anterior cingulate region. CONCLUSION: Subjects with schizophrenia are able to respond to specific neuropsychological challenge with activation of the frontal regions.

Homocysteine, folate, methylation, and monoamine metabolism in depression.

OBJECTIVES: Previous studies suggest that folate deficiency may occur in up to one third of patients with severe depression, and that treatment with the vitamin may enhance recovery of the mental state. There are, however, difficulties in interpreting serum and red cell folate assays in some patients, and it has been suggested that total plasma homocysteine is a more sensitive measure of functional folate (and vitamin B12) deficiency. Other studies suggest a link between folate deficiency and impaired metabolism of serotonin, dopamine, and noradrenaline (norepinephrine), which have been implicated in mood disorders. A study of homocysteine, folate, and monoamine metabolism has, therefore, been undertaken in patients with severe depression. METHODS: In 46 inpatients with severe DSM III depression, blood counts, serum and red cell folate, serum vitamin B12, total plasma homocysteine, and, in 28 patients, CSF folate, S-adenosylmethionine, and the monoamine neurotransmitter metabolites 5HIAA, HVA, and MHPG were examined. Two control groups comprised 18 healthy volunteers and 20 patients with neurological disorders, the second group undergoing CSF examination for diagnostic purposes. RESULTS: Twenty four depressed patients (52%) had raised total plasma homocysteine. Depressed patients with raised total plasma homocysteine had significant lowering of serum, red cell, and CSF folate, CSF S-adenosylmethionine and all three CSF monoamine metabolites. Total plasma homocysteine was significantly negatively correlated with red cell folate in depressed patients, but not controls. CONCLUSIONS: Utilising total plasma homocysteine as a sensitive measure of functional folate deficiency, a biological subgroup of depression with folate deficiency, impaired methylation, and monoamine neurotransmitter metabolism has been identified. Detection of this subgroup, which will not be achieved by routine blood counts, is important in view of the potential benefit of vitamin replacement.

A neuropsychological comparison of schizophrenia and schizophrenia-like psychosis of epilepsy.

BACKGROUND: The schizophrenia-like psychoses of epilepsy (SLPE) might represent a secondary form of schizophrenia in which the pathology is relatively confined to the temporal lobe. To test this possibility we have compared the neuropsychological profile of schizophrenia and SLPE. Our main hypothesis was that both psychotic groups would show deficits of temporal lobe function but that prefrontal impairment, as measured by tests of executive function, would be found only in the primary schi ophrenic group. METHODS: Four groups were studied: (1) patients with SLPE (N = 25); (2) patients with epilepsy but not psychiatric history (N = 24); (3) patients with schizophrenia (N = 22); and (4) healthy volunteers (N = 24). Neuropsychological testing comprised measures of pre-morbid IQ, current verbal and performance IQ, information processing, digit span, motor speed, verbal and visual learning and memory, verbal fluency, the Wisconsin Card Sorting Task, the Stroop test and the trail making task. RESULTS: Patients with schizophrenia and those with SLPE had almost identical neuropsychological profiles, with impairments of attention, episodic memory (verbal > visual) and executive function. The epileptic controls showed similar though less severe impairments of memory and of some tests of executive function. CONCLUSIONS: Our results do not support the hypothesis that the pathophysiology of SLPE and schizophrenia are distinct. While our findings suggest an important role for dominant temporal lobe abnormality in schizophrenia, both in its primary form and in that occurring in patients with epilepsy, they also implicate generalized cognitive impairment, manifest in particular as attentional deficits, in both forms of the disorder.

Effects of d-amphetamine and haloperidol on latent inhibition in healthy male volunteers.

Latent inhibition (LI) refers to a retardation of learning about the consequences of a stimulus when that stimulus has been passively presented a number of times without reinforcement. Acute positive-symptom schizophrenics, normal volunteers who score high on questionnaire measures of schizotypy and non-patients or animals treated with dopamine agonists show reduced LI. Neuroleptic drugs, such as haloperidol, administered at low doses, potentiate LI and effectively reverse disruption of LI induced by dopamine agonists in animals. However, a high dose of haloperidol, administered on its own, has been found to reduce LI. We examined the effects on LI of acute oral administration of an indirect dopamine-agonist, d-amphetamine (5 mg), and a nonselective dopamine receptor antagonist, haloperidol (5 mg), in normal male volunteers, using an associative learning task. Replicating previous reports, we found that d-amphetamine reduced LI; haloperidol also reduced LI, but only in subjects who scored low on the Psychoticism scale of the Eysenck Personality Questionnaire. In a subsequent study, no effect was found of 2 mg oral haloperidol administration on LI. The effect of 5 mg haloperidol on LI is interpreted as similar to that observed with a high dose of haloperidol in rats.

Effects of single oral administrations of haloperidol and d-amphetamine on prepulse inhibition of the acoustic startle reflex in healthy male volunteers.

The effects of acute administration of an indirect dopamine-agonist, d-amphetamine, and a non-selective dopamine receptor antagonist, haloperidol, were investigated in normal male volunteers on habituation and prepulse inhibition (PPI) of the acoustic startle reflex in two experiments. In Experiment 1, 40 male non-smoker volunteers were tested for habituation and PPI (defined as percentage reduction of the pulse-alone amplitude; prepulses 9 dB above background) before and after double-blind administration of either 2 mg haloperidol or placebo. No influence of haloperidol was observed on either habituation or PPI of the startle reflex in this experiment. In Experiment 2, 60 male volunteers underwent startle testing before and after double-blind administration of a single oral dose of 5 mg haloperidol, 5 mg d-amphetamine or placebo. Habituation and PPI (prepulses 15 dB above background) for the placebo group did not differ significantly from that observed for the d-amphetamine or for the haloperidol group. However, in a subgroup of smoking subjects, both d-amphetamine and haloperidol reduced PPI as compared to that observed prior to drug administration. The implications of these findings in relation to animal pharmacological studies and observed sensorimotor gating deficits in schizophrenia are discussed.

SPET study of verbal fluency in schizophrenia and epilepsy.

BACKGROUND: The association between temporal lobe epilepsy and schizophrenia suggests that the critical abnormality may be pathology within the temporal lobes. People with schizophrenia-like psychosis of epilepsy (SLPE) provide a useful group in which to examine the importance of temporal and frontal lobe dysfunction in schizophrenia. METHOD: A verbal fluency activation paradigm and a 99mTc HMPAO SPET were used to study frontotemporal function in people with SLPE (n = 12), schizophrenia (n = 11) and epilepsy (n = 16). RESULTS: People with SLPE differed from both other groups by showing lower blood flow in the left superior temporal gyrus during performance of a verbal fluency task compared with a word repetition task (F = 5.4, P = 0.01). During the verbal fluency task people with primary schizophrenia showed a greater increase in blood flow in anterior cingulate (F = 4.5, P = 0.02) than the other two groups. There were no between-group differences in frontal brain regions. CONCLUSION: Our findings support an association between left temporal lobe abnormality and SLPE. The different patterns of activation observed in people with primary schizophrenia and SLPE suggests that different pathophysiological mechanisms may operate in these two groups. In SLPE the pathophysiology may be relatively confined to the dominant temporal lobe.

Do obstetric complications cause the earlier age at onset in male than female schizophrenics?

We compared the age at onset of 184 patients with functional psychoses with and without a history of obstetric complications (OCs) as defined by the scale of Lewis et al. (1989). OCs had no significant influence on the age at onset in those patients who had affective psychoses or were non-white. There were 73 white patients with a DSM-III-R diagnosis of schizophrenia. The mean age at onset of those 25 who had a history of at least one definite OC was 2.6 years earlier than that of the 48 patients with no history of OCs. This effect was entirely due to the male patients with histories of OCs who had, on average, a 3.5 years earlier age at onset. There were no gender differences in age at onset among schizophrenics without a history of OCs. We suggest that a subgroup of male patients with a history of OCs is responsible for the earlier age at onset in male compared to female schizophrenics.

Family history of autoimmune diseases in psychosis.

The mothers of 101 psychotic patients and 116 normal controls were interviewed using a semi-structured questionnaire designed to determine the presence or absence of autoimmune disorders in first degree relatives of the probands. Thyrotoxicosis and insulin-dependent diabetes mellitus were significantly more common in the relatives of the psychotic patients than in the control relatives; in particular thyrotoxicosis was more frequent in the mothers of patients (11%) than the mothers of controls (2.6%). None of the examined characteristics of the patients, including RDC-diagnosis, family history of psychosis, age at onset of psychosis and winter birth, was predictive of thyrotoxicosis and insulin-dependent diabetes mellitus in relatives.

Mixed-handedness in patients with functional psychosis.

BACKGROUND: An excess of non-right-handedness has been shown among patients with schizophrenia. However it is not clear whether this finding can be accounted for by an increase in left-handedness, mixed-handedness or both. It is not known whether atypical patterns of hand preferences occur in other functional psychotic illnesses. METHOD: The Annett hand preference questionnaire was administered to patients with schizophrenia (n = 120); affective psychosis (n = 55); schizoaffective psychosis (n = 41), and control subjects (n = 86). Handedness was classified into three categories: right, mixed and left-handedness. RESULTS: The hand preference patterns of patients with functional psychotic illnesses were not significantly different from controls. Patients with schizophrenia showed a non-significant excess of mixed-handedness compared with controls. Patients with schizophrenia and affective psychosis showed a non-significant decrease in left-handedness compared with controls. CONCLUSIONS: Although our results showed a trend in the hypothesised direction, we failed to demonstrate that patients with psychotic illness differed from controls on self-reported hand preference patterns.

A factor analytic study of symptoms in acute schizophrenia.

The three-syndrome model of schizophrenic phenomenology has been well established in chronic illness. We report an attempt to replicate this concept in a sample of acutely unwell schizophrenic patients. Factor analysis was performed using PSE data collected within a week of admission from 114 patients who met DSMIII(R) diagnostic criteria for schizophrenia. Four main factors accounted for 58% of the variance. The first two factors closely resembled Liddle's disorganisation and psychomotor poverty syndromes. Hallucinations and delusions loaded separately under the third and fourth factors. To examine the validity of these four syndromes, the relationships between factor scores and other clinical data were examined. The disorganisation syndrome was associated with a history of multiple past admissions and a longer lifetime duration of in-patient treatment.

Cerebral ventricle dimensions as risk factors for schizophrenia and affective psychosis: an epidemiological approach to analysis.

A case-control study was undertaken of volumetric computerized tomographic scan measures in 216 consecutive admissions for functional psychosis and 67 healthy community controls. Odds ratio analysis demonstrated significant linear trends in the association between increasing lateral and third ventricle volumes, and both RDC schizophrenia (N = 121) and schizo-affective disorder (N = 41); cases were consistently associated with larger volumes than controls. There was an association between larger third, but not lateral, ventricle size in affective psychoses (N = 54). These associations were statistically independent of intracranial volume, sex, social class and ethnicity, factors which were significantly associated with ventricular measures in the controls. There was no evidence of a threshold corresponding to the notion of normal versus enlarged ventricles. Within the schizophrenia group, there were no large or significant associations between ventricle dimensions and age at onset, duration of illness or pre-morbid social functioning. Neither obstetric complications nor a family history of schizophrenia or other psychiatric illness was associated with large ventricles in these cases.

Neural correlates of planning ability: frontal lobe activation during the Tower of London test.

Single-photon emission computerised tomography (SPECT) was used to investigate whether pre-frontal cerebral blood flow in normal adults is increased during planning activity. A subtraction technique was used in which regional cerebral blood flow (rCBF) was measured in subjects during a computerised version of the Tower of London task. Both rCBF and performance on this task were compared to a motor control condition requiring the same responses and using the same visual display. The level of rCBF was significantly increased in the left pre-frontal cortex during the Tower of London task. In addition, subjects who took more time planning their moves, and less moves to complete a problem had a significantly higher level of rCBF in the left pre-frontal cortex. Subsequent execution latencies for the task were correlated negatively with both left and right rCBF.