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Investigation of the Video-EEG Findings and Clinical Data in Patients Diagnosed With Epilepsy and Psychosis

Mehdikhanova, Lala, MD*; Vanli Yavuz, Ebru N., MD*,†; Çikrikçili, Uğur, MD; Baral Kulaksizoğlu, Işin, MD; Bebek, Nerses, MD, PhD*; Gürses, Candan, MD*; Gökyiğit, Ayşen, MD*; Baykan, Betül, MD*

doi: 10.1097/NRL.0000000000000195
Original Article
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Background: Studies on electrophysiological characteristics of patients with epilepsy and concomitant psychosis are limited. We aimed to investigate the clinical and video-electroencephalography (EEG) findings of patients with epilepsy-related psychosis (EP).

Materials and Methods: Fifteen patients diagnosed with EP, assessed at the video-EEG monitoring unit and were under follow-up at both epilepsy and psychiatry clinics, were included. A total of 67 nonpsychotic epilepsy patients, investigated at the video-EEG monitoring unit were randomly selected as the control group and compared statistically with the EP group.

Results: In medical history, patients with EP had experienced significantly higher level of status epilepticus (P=0.002) and perinatal cerebral injury (P=0.04), whereas drug-resistant epilepsy was detected at a lower level (P=0.015). With respect to seizure onset zone, the EP group had significantly more seizures of unknown foci, whereas the control group had mostly temporal lobe origin (P=0.0004). EEG findings showed that slow background activity was significantly common among patients with EP (P=0.009). Although only 5 of 15 patients with EP had been operated, 43 of 67 patients had undergone epilepsy surgery (P=0.04) in the control group. However, there was no significant difference between the 2 groups with respect to postoperative seizure control as per Engel classification.

Conclusions: Although our sample size could be considered small, slowed EEG background activity, and the marked frequency of initial precipitant factors such as status epilepticus, perinatal cerebral injury, and detected neuronal autoantibodies suggested that EP is associated with more extensive involvement. EP is not a contraindication for epilepsy surgery, when appropriately investigated preoperatively.

Departments of *Neurology and Clinical Neurophysiology

Psychiatry, Istanbul Faculty of Medicine, Istanbul University

Department of Neurology, Koc University School of Medicine, Istanbul, Turkey

Supported by the Turkish Scientific and Technical Research Council with a number of 214S170 and Istanbul University Research Fund (project number BAP-39729).

The authors declare no conflict of interest.

Reprints: Lala Mehdikhanova, MD, Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Capa, Fatih 34093, Istanbul, Turkey. E-mail: mehdikhanova@hotmail.com.

The incidence of psychosis (9%) is significantly higher in epileptic patients compared with the overall population (1%).1 Although this correlation has been acknowledged for a long time, the underlying mechanisms and the associated predictive factors have not been clearly determined. Studies on characteristics of video-electroencephalography (EEG) monitoring (VEM) investigation in patients with epilepsy-related psychosis (EP) are limited2,3 and they usually involve the video-EEG findings of postictal psychosis (PP) and interictal psychosis (IIP) patients with temporal lobe epilepsy (TLE) only. There is a need for studies investigating the clinical and VEM features of an unselected group including all psychosis subtypes for EP patients with frontal, temporal, and other seizures.

We aimed to investigate the clinical and VEM findings of patients with EP and compare the characteristics of these patients to those of nonpsychotic patients diagnosed with epilepsy with the hypothesis that the patients with EP showed more bilateral origin of seizures and more slowing in background activity which may indicate more diffuse involvement of related networks.

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MATERIALS AND METHODS

All epileptic patients, who were assessed at VEM unit between 2002 and 2015, were retrospectively screened. A total of 15 patients diagnosed with EP by an experienced psychiatrist were included in the study. As the control group, nonpsychotic epilepsy patients with similar types of epileptic seizures and syndromes, who were investigated at the same VEM unit with same protocols, were randomly selected. This control group included 67 patients evaluated for drug-resistant epilepsy in the VEM unit, whereas in EP group 11 of the 15 patients were evaluated for drug-resistant epilepsy and remaining 4 cases were investigated for differential diagnostic purposes.

The detailed neurological and psychiatric examination findings, seizure semiology and long-term EEG features and surgery outcomes of all epileptic patients were obtained from patient files and archives of the VEM unit.

The present study was carried out in accordance with the research protocol after the approval of our local Noninterventional Clinical Researches Ethics Committee.

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The Definition of EP

All patients and their companions were seen by the same experienced psychiatrist (I.B.K.). Patients with psychotic symptoms had been diagnosed as“psychotic disorder secondary to medical disease” through clinical evaluation with DSM-4 diagnostic criteria. Patients with drug abuse and mental retardation were excluded. All EP patients have a long follow-up of 7.6±5.7 (1 to 15) years, and at least 3 visits in the psychiatry department.

As the definition of psychosis, the presence of phenomenological findings accompanied by positive symptoms including loosening of associations, impaired ability to evaluate the reality, disorganized speaking/behaviors, hallucinations and delusion and negative symptoms including impoverishment of thought content, social isolation, apathy, loss of affection and reduced attention/concentration were accepted.

EP was categorized as preictal or prodromal, ictal, postictal, interictal (chronic) psychosis and forced normalization depending on the seizures and relation to treatment.4,5

The following points were noted in detail:

  • During the preictal period, the present condition disappeared upon occurrence of seizures and the symptoms could last for a few hours to few days before onset of seizure.4
  • During the ictal period, the attacks for psychotic experiences were usually short-term (<1 to 3 min), stereotypical; they abruptly started and ended; and they were potentially associated with other ictal phenomena such as automatism. In some cases, such symptoms are followed by alteration of consciousness.4–6 We included only patients with documented ictal EEG changes.
  • Criteria defined by Logstail and Toone7 were used for the definition of PP:
    • Occurrence of psychosis within 1 week of seizure development.
    • Continued psychosis for >15 hours or <3 months.
    • Development of delusions and hallucinations, strange, and disorganized behaviors, formal thought disorder, or affective changes in state of consciousness.
    • Absence of conditions such as antiepileptic drug toxicity, nonconvulsive status epilepticus, alcohol or drug poisoning or withdrawal, previous psychotic disorder.
  • IIP was defined as follows8:
    • Psychosis is not temporally associated with seizure.
    • There is no evidence on antiepileptic drug toxicity, nonconvulsive status epilepticus, head trauma, alcohol or drug poisoning or withdrawal.
    • Delusions and hallucinations, strange and disorganized behaviors, formal thought disorder, or affective changes occurring in a state of consciousness.
    • Psychotic symptoms should have a duration of <1 year; if they continue for >1 year, the condition is considered chronic psychosis.
  • “Forced normalization” is a condition, where psychosis occurs following achievement of seizure control in epileptic patients, and was originally defined by Landolt.9 The following diagnostic criteria are established for the definition of “forced normalization”1,10:
    • Epilepsy confirmed by history and EEG records.
    • Newly emerging behavioral disorder.
    • 50% reduction in number of spikes on EEG.
    • Absence of seizures for a week.
    • Similarity with previous attacks.
    • Occurrence of these events upon change in antiepileptic treatment.

During the VEM investigations, 5 patients of the 7 IIP cases and the patient with forced normalization were using mostly low doses of antipsychotic drugs as shown in Table 1. The remaining 2 patients with IIP, all 3 patients with IP, 2 patients with PP, and the patients with prodromal psychosis did not use regular antipsychotics during the VEM recording, related to their psychiatric situations. Only 1 patient with PP used antipsychotics due to the high seizure frequency and long-lasting postictal severe symptoms. Seven patients (IP, PP, and preictal/prodromal) showed active psychotic findings during VEM as indicated in Table 1.

TABLE 1

TABLE 1

TABLE 1

TABLE 1

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Data Collection

The following clinical and demographic variables were collected:

  • Demographics: age, sex, presence of pathologic findings on neurological examination.
  • Epilepsy features: age of seizure onset, perinatal cerebral injury, febrile seizure, history of status epilepticus, family history of epilepsy, presence of aura (especially fear as aura was questioned), type of seizures,11 epilepsy syndrome, drug-resistant epilepsy. The diagnosis of the epileptic syndrome was established based on the type of semiology of the seizures, supported by ictal and interictal EEG findings, functional-anatomic neuroimaging studies and neuropsychological test findings.12
  • Regarding localization and lateralization data, the presence of compliant results from at least 2 diagnostic methods [eg, ictal EEG and magnetic resonance imaging (MRI) or ictal EEG and positron emission tomography (PET)] and the absence of any findings to suggest the opposite of these findings were considered. In patients with nonspecific MRI and functional imaging results, epileptogenic area determination was based solely on ictal EEG findings and seizure semiology. The term “unknown” was used to indicate that the recorded real epileptic seizures started with artefacts or with nonspecific EEG correlates, obscuring the onset zone.
  • Drug resistance was defined as the failure of adequate trials of 2 tolerated, appropriately chosen and administered antiepileptic drugs (whether as monotherapy or in combination) to achieve seizure freedom.13
  • Long-term VEM findings: interictal and ictal EEG data and seizure semiology.
  • Slow background activity was defined as an alteration of background activity and emergence of varying degrees of theta-delta slowing in the EEG recording, when awake and alert. Bilateral independent foci were diagnosed when (asynchronous) spikes/sharp waves showing phase reversal appeared independently in each hemisphere.14 Fast rhythmic activity was defined as persistent high frequency, 12 to 25 Hz repetitive rhythmic discharges.
  • Surgery outcomes of the operated patients were classified as per modified Engel classification.
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Video-EEG Investigation

Interictal, ictal and postictal EEG activities of patients undergoing noninvasive VEM were investigated with standardized forms. VEM was performed using a 32-channel digital recording system (Nihon Kohden and Medelec software). Electrodes were placed in accordance with the 10 to 20 system (Fp1, Fp2, Fz, F3, F4, F7, F8, Cz, C3, C4, Pz, P3, P4, T3, T4, T5, T6, Oz, O1, O2) and in some patients, Ch1 and Ch2 or T1 and T2 electrodes were also used. Seizures were assessed with frequency filters at 0.5 to 70 and 50 Hz notch filter at a sensitivity of 7 to 10 μV.

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MRI Technique

MRI studies were performed with a 1.5-T scanner (Magnetom Siemens Symphony, Erlangen, Germany) with thin coronal in addition to sagittal and axial planes including T1, T2, and fluid-attenuated inversion recovery (FLAIR) images to visualize mesial temporal regions optimally. We proceed with investigation of mesial temporal lobe structures with the following series: T2 W paracoronal series [repetition time (TR): 4900, echo time (TE): 104, field-of-view (FOV): 230, matrix: 256×512, flip angle: 150 degrees, slice thickness: 3 mm, recording time: 4.31 min], paracoronal FLAIR (TR: 8080, TE: 111, TI: 2500, FOV: 230, matrix: 179×256, flip angle: 150 degrees, slice thickness: 3 mm, recording time: 4.31 min) and paracoronal multiplanar reconstruction (TR: 1900, TE: 3.3, FOV: 250, matrix: 179×256, flip angle: 15 degrees, slice thickness: 3 mm, recording time: 5.42 min) series. Images taken at conditions in compliance with 1.5 T MRI epilepsy protocol were reviewed by an experienced neuroradiologist.

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Statistical Analysis

Statistical assessment was performed using SPSS 20.0 software. Psychotic and nonpsychotic patients’ groups were compared by selecting the appropriate tests for nominal or numeric values. The significance level of P-value was set at below 0.05 to represent statistically significant results.

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RESULTS

We found 15 patients diagnosed with EP; the demographic and epilepsy features of EP patients, the type of psychosis, interictal, and ictal EEG findings, MRI results and data on postoperative seizure outcome are presented in Table 1. Figure 1 showed interictal EEGs and MRI example of the patient with forced normalization and ictal EEGs of a successfully operated patient with EP (Fig. 2).

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

Patient and control groups have similar features with respect to age and sex and there was a female dominance in both groups. Demographics, epilepsy history, seizure semiology, interictal, and ictal EEG findings and surgery outcomes were compared between the patient and control groups (Table 2). There was no significant difference between these 2 groups with respect to age of seizure onset, sex, age of seizure onset, history of febrile seizure, presence of pathologic findings detected by neurological examination, presence, and types of aura. Comparing the focal seizures with loss of consciousness, no marked difference was detected between the 2 groups while secondary generalized convulsion occurred more frequently in psychotic patients; however, the difference was not statistically significant (P=0.063).

TABLE 2

TABLE 2

In the medical history, psychotic patients had a significantly higher level of status epilepticus (P=0.002) and perinatal cerebral injury (P=0.042) while history of drug-resistant epilepsy was detected at a lower level (P=0.015).

After excluding all patients with known neuronal autoantibodies from EP and control groups, remaining 10 EP patients had still significantly more status epilepticus in the history (P=0.019 with Fishers exact test) and their EEG background activity tended to be slower (P=0.058). Also the rate of seizures with unknown origin is still higher in EP patients (P=0.0002), whereas the control group had more patients with TLE.

In terms of seizure semiology, the EP group was detected to have more seizures of unknown origin(P<0.0001), whereas the control group had significantly more characteristics indicating TLE (P<0.001). Although oroalimentary automatisms were more commonly observed in the control group (P=0.001), there was no marked difference between the 2 groups with respect to manual and pedal automatisms. Contralateral dystonia (P=0.003) and postictal nose wiping (P=0.002) was significantly more commonly observed in the nonpsychotic patients.

Investigation of the EEG results revealed that slow background activity was significantly common in the psychotic patients (P=0.009). Moreover bilateral interictal frontotemporal epileptogenic foci were observed more commonly among psychotic patients; however the difference was not statistically significant (P=0.07). Comparison of the study groups in terms of frontal intermittent rhythmic delta activity and fast rhythmic activity, revealed no significant difference. There was also no significant difference in lateralization and localization of the ictal onset between the 2 groups.

In the group of EP, there were 11 patients (73.3%) with drug-resistant course, whereas remaining patients has well-controlled epilepsy by using antiepileptic drugs. The retrospective survey showed that 5 of 15 patients with EP (33.3%) and 43 of 67 control patients (64.2%) had been operated (P=0.04). On the basis of the Engel classification, there was no significant difference between the 2 groups with respect to postoperative seizure control.

In terms of psychiatric symptoms, we observed that 4 of the 5 operated patients remained in good conditions for a period of at least 1 year after epilepsy surgery, but then these patients deteriorated even though their seizures were still controlled. The fifth patient without any change of psychosis had died during sleep with a possible sudden unexplained death in epilepsy.

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DISCUSSION

Our results in a small group showed that slowing of the EEG background activity was more common in patients with EP in comparison to the control group. In addition, the group of psychotic patients had a significantly higher level of status epilepticus and perinatal cerebral injury in their past history. Thus, our findings may indicate a diffuse involvement of brain functioning that may relate to initial precipitating injuries, underlying both epilepsy and psychosis. Contrary to what we expected, EP patients were detected to exhibit less resistance to antiepileptic drugs compared with the control patients, mainly because of the high drug-resistance rate of the control group, randomly recruited from archive of the VEM unit. In this EP group, TLE was less common while seizures with unknown originwere more commonly observed.

In our study, we observed that psychosis was not correlated with age of seizure onset in EP patients. Except one study,15 previous studies performed in PP patients had also shown the absence of correlation between psychosis and age of seizure onset.2,16 There was no significant difference between the 2 groups; PP patients were detected to have similar findings with the literature.15,16 In PP and IIP patients, the history of status epilepticus was shown to be common.8 There are also studies reporting that status epilepticus and perinatal cerebral injury was not correlated to PP.15,16 In contrast, the absence of difference for the family history of epilepsy in the psychosis group may suggest that a marked genetic effect is not significantly involved in pathogenesis, as suggested by our results.

In contrast to previous studies, we detected no correlation between the presence of fear as aura (ictal fear) and EP.15,17 The lack of a correlation between PP and focal and generalized seizures was previously shown.15,16 Other studies reported a higher incidence of secondary generalized seizures among PP.2,8 In our study, secondarily generalized convulsion was more commonly observed in psychotic patients; however, the difference did not reach statistically significance level (P=0.063). This finding may be related to the fact that similar to status epilepticus and perinatal cerebral injury in the history, secondarily generalized convulsion may associate with more extensive cerebral involvement in related networks.

It is worth to emphasize that “ictal psychosis” is a highly controversial issue on many points including diagnostic spectrum, symptoms, and their time limits. Our 3 patients diagnosed with ictal psychosis have psychotic features starting at the same time with ictal EEG activity in VEM recording lasting about 0.5 to 1.5 minutes with an abrupt start and end. The patients described stereotypical hallucinations after the seizures when asked for it after regaining consciousness. In contrast, prolonged ictal psychotic states are rare and may occur as a nonconvulsive status epilepticus.6 DSM-4 criteria do not give a “time limit” for “psychotic disorder secondary to medical disease” which includes EP. Therefore we think that our patients could be considered as ictal psychosis, given that they satisfy these criteria. Interestingly, however, 2 of these patients developed IIP during the follow-up (one of them after a successful epilepsy surgery).

It was intriguing to note that, the EP group had a significantly high level of seizures of unknown origin while the control group had a significantly frequent level of TLE. This higher incidence of drug-resistant seizures originating from the temporal lobe, in our control group, may be attributed to the fact that patients with mesial temporal sclerosis represent the majority among patients, who were admitted to VEM unit for preoperative evaluation. Similarly, due to the same reason, oroalimentary automatisms, contralateral dystonia, and postictal nose wiping was significantly more common in the control group. The reason for this possible bias is that we randomly recruited the control group from the archives of the VEM unit, but selected all patients with EP who had undergone VEM investigation and in 4 of them this investigation was carried out only for differential diagnosis. These findings may also indicate that the patients with EP are more heterogenous than previously recognized with respect to ictal semiology. The high incidence of slowed background activity as well as of clinical initial precipitant factors such as status epilepticus ad perinatal cerebral injury also supported that psychosis may result from more extensive functional network disorder involving both hemispheres in these cases in contrast to a localized/lateralized involvement in temporal lobes.

It was also previously shown that psychosis and status epilepticus are related to autoimmune epilepsy and bilateral hippocampal sclerosis.18,19 As the encephalitic processes either overt or silent, related with these various known or unknown autoantibodies, often associated with cognitive and psychiatric symptoms in addition to seizures, it was reasonable to think that autoimmunity could be responsible for the etiology of EP in some patients. In contrast, the comparative analyses showed similar results after excluding the patients with detected autoantibodies.

From the view of the presence of psychosis that used to be considered as an obstacle for epilepsy surgery, only one third of patients with EP had been operated (Table 1). Although there was no significant difference between the 2 groups in postoperative seizure control as per Engel classification, these good postoperative results obtained in our small group of 5 psychotic patients are remarkable. We observed, however, that epilepsy surgery did not show any long-lasting benefits for psychotic symptoms in our small group of 4 patients. It is worth to emphasize that one of the operated patients with EP had deceased during sleep with a possible sudden unexplained death in epilepsy. Our experience in this small group may show that psychosis is not an absolute contraindication for surgery in EP patients with drug-resistant seizures.

The number of relevant studies is small and they usually involve the video-EEG findings of PP and IIP patients with TLE only.2,3 We, for the first time, investigated the clinical and video-EEG features of an unselected group with available long-term video-EEG studies including all psychosis subtypes for EP patients with frontal, temporal, and other seizures. Still, our study has certain limitations. As the study has a retrospective design, not all the EP patients could undergo VEM assessment, thus the sample size is limited. In addition, although EP patients were categorized into subtypes, no comparison could be made between these subgroups due to the small number of patients in each group and potential different clinical or electrophysiological characteristics could not be investigated.

In conclusion, our analysis of a small number of patients with heterogenous characteristics showed that patients with epilepsy and psychosis had more extensive interictal impairment of cerebral activity as reflected by the slowing of the EEG background and had certain initial precipitating factors. The good news is that some of them were responding well to antiepileptic drugs and a minority could also benefit from epilepsy surgery if a focus could be demonstrated.

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Keywords:

epilepsy; psychosis; video-EEG findings; mesial temporal sclerosis

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