Status epilepticus and psychosis: Lessons from SEEG

Psychotic manifestations are a classic feature of non-convulsive status epilepticus (NCSE) of temporal origin. For several decades now, the various psychiatric manifestations of NCSE have been described, and in particular, the diagnostic challenges they pose. However, studies using stereotactic-EEG (SEEG) recordings are very rare. Only a few cases have been reported, but they demonstrated the anatomical substrate of certain manifestations, including hallucinations, delusions, and emotional changes. The post-ictal origin of some of the manifestations should be emphasized. More generally, SEEG has shown that seizures affecting the temporal and frontal limbic systems can lead to intense emotional experiences and behavioural disturbances.


Introduction
The occurrence of psychotic manifestations during status epilepticus was reported for the first time in the modern area in 1956 by Gastaut & Roger [1], who proposed the term "complex partial status epilepticus".They reported a patient who experienced hallucinations, psychotic behaviour, and automatisms with epileptic fugues caused by prolonged seizure activity.Later, during the X th Marseille Colloquium of 1962, various forms of convulsive and non-convulsive status epilepticus (NCSE) were formally defined, with the description of psychiatric manifestations occurring in NCSE [2].The ILAE classification of status epilepticus [3] currently list behavioral disturbances (psychoses) in epilepsy patients as "indeterminate conditions or boundary syndromes.".
Psychiatric symptoms in NCSE are particularly prevalent in temporal lobe NCSE [4].Overall, it has been reported an incidence of 6-8 % of hallucinatory, emotional, and behavioural disturbances in NCSE [4].These psychiatric manifestations may present misleading clinical pictures, which can only be resolved by EEG and sometimes intracerebral EEG [5], mainly when they represent the prominent clinical manifestations [6].According to the DSM5, psychosis is defined by the occurrence of a range of phenomena, including [7] delusions (fixed beliefs that are not amenable to change in light of conflicting evidence), hallucinations (any sensory modality), disorganized thinking and speech, negative symptoms (diminished emotional expression, avolition, alogia, anhedonia, and asociality) and disorganized or abnormal motor behaviour (including catatonia or agitation).Such manifestations (often limited to one or several of these features) can be observed in different situations in epileptic patients, defining interictal psychosis, post-ictal psychosis, and ictal psychosis [8].In status epilepticus, both ictal and post-ictal activity may account for the psychiatric manifestations.Stereo-electroencephalography (SEEG) is a presurgical technique that allows to precisely determine the regions of seizure origin ("the epileptogenic zone") thanks to the implantation of depth electrodes recording the intracerebral EEG [9].SEEG involves the video-SEEG recording of patients during several days in epilepsy monitoring units (EMUs).Such monitoring exposes patients to possible complications including status epilepticus (incidence less than 5 % of EMU patients) [10].In this context, SEEG recordings of status epilepticus have rarely been reported.However, although anecdotal, recordings of psychiatric manifestations during SE can demonstrate the cerebral anatomical origin of specific atypical symptoms [11,12] and distinguish more easily between what is related to the ictal period and the post-ictal period [13][14][15].
Most cases of NCSE have been diagnosed using non-invasive investigations.Only a few cases were reported using SEEG approaches.

SEEG of non-convulsive status epilepticus with psychiatric manifestations
NCSE during SEEG recordings were first published by Wieser in 1980 [19] in temporal lobe epilepsy (TLE) and by Williamson et al. in 1985 for extra-temporal, mainly frontal cases [33].Cases including psychiatric manifestations are, however, very rare.All the reported cases in the literature are TLE cases.In the first case [19], SEEG showed that a complex musical hallucination status was linked to discharges in the Heschl's gyrus while propagation to the medial temporal lobe was associated with behavioural manifestations, including anxiety and mutism.In a short series of 4 cases [18] (including the previous one), Wieser et al. described a patient (case 4) with awareness alteration, changes in personality, and confusion.These alterations were associated with repeated discharges in the left hippocampus, while no discharge was observed on the scalp EEG (simultaneous recording).Later, Kanemoto ( [34] described a patient developing during SEEG recordings a cluster of seizures with prominent fear involving the left amygdala and hippocampus.Moreover, a delusional Capgras syndrome was developed by the patient in the period of seizures (the delusion that one or more impostors have replaced a person close to the patient).It was, however, difficult to state if the manifestations were due to the ictal or post-ictal period or both.The distinction between ictal and post-ictal states can be indeed difficult to make.The work of Takeda et al. illustrates this well, [14] who reported on a patient who developed NCSE during intracerebral exploration.A psychotic picture emerged after a prolonged seizure cluster characterized by depersonalization syndrome, stupor, and fear.Recordings showed that this state was associated with a post-ictal aspect in most regions explored, but with persistent intermittent discharges in the amygdala.A very similar pattern was reported by So et al. [13] in a patient with post-ictal psychosis characterized by a severe delusional state developed after several seizures affecting the mesial temporal lobe.This state was also characterized by persisting intermittent discharges in the amygdala.

Anatomo-clinical correlations in SEEG recordings: A key to understanding the psychiatric manifestations?
Generally speaking, during SEEG, one of the essential elements is to relate abnormal electrical discharges affecting certain regions to the occurrence of clinical symptoms, which has been termed anatomoelectro-clinical correlations [35].
Results of spontaneous seizure recordings and direct electric stimulation have revealed a wide range of subjective symptoms that may account for many symptoms observed during seizures and, especially, NCSE.Stimulation of the mesial temporal limbic system has provoked emotional and autonomic symptoms [36][37][38].An extensive range of experiential phenomena has been studied.Dysmnesic symptoms (déjà vu, recollection of memories) have been demonstrated to originate from the mesial temporal region [ 39 40].Ecstatic experiences that may lead to mystical interpretation in some cases have been reported in temporal lobe seizures, but are probably more related to the involvement of the antero-superior insula [41].
Electrical brain stimulation can induce a range of subjective phenomena involving body ownership, self-location, first-person perspective, body image, and depersonalization.A recent review [42]provides more details on the regions involved.Alterations of one or several components of the bodily-self have been related to several brain regions: the middle cingulum, inferior parietal lobule, supplementary motor area, posterior insula, hippocampal complex/amygdala, and precuneus.
However, the anatomo-electro-clinical correlations are difficult to study when it comes to complex behavioural manifestations.Most human behaviours are linked to the functional activities of networks of neural structures, not simply the activity of a single structure.Focal epileptic seizures considerably disrupt the functional connectivity of numerous brain systems, often outside the epileptogenic zone itself [43].Thus, the disturbance of awareness usually observed in NCSE is linked to hypersynchrony in some brain regions (fronto-parietal workspace), a mechanism common to all focal seizures [44].
Certain types of seizures that cause significant behavioural disturbances, such as defensive aggression and intense emotional experiences like fear, have been studied and are relevant to this article.These seizures have been linked to discharges that affect the temporal and frontal limbic systems [45].Specifically, it has been suggested that the frontal lobe loses inhibitory control over the temporal regions.This could be due to the desynchronization between the amygdala and prefrontal regions that have been observed during these episodes [46].A case of acute ictal severe aggression occurring during a SEEG recording has been reported [47].The seizures started in the two anteromesial regions of the temporal lobe.The aggressive phase (strangulation attempt) occurred at the end of the seizure, while the frontal lobe regions disclosed an altered post-ictal activity, and the mesial temporal areas continued to seize.This again suggested a loss of the normal "brake" and inhibitory function of the frontal lobe toward aggressive behaviours.
To conclude this brief overview of the phenomena recorded in SEEG, it is interesting to note that prolonged cognitive phenomena can be purely post-ictal.This was recently demonstrated in a patient who developed a prolonged amnesic syndrome after a brief left temporal mesial seizure.Only signal analysis (quantification of entropy, i.e., signal complexity) revealed that it took several hours for activity in the medial temporal structures to return to normal [15].This case again illustrates the possibility of prolonged clinical phenomena of post-ictal origin.

Conclusions
SEEG-recorded NCSE has revealed the intracerebral origin of psychiatric/psychotic manifestations, mainly affecting the limbic temporal regions.The emergence of these symptoms is probably linked to profound changes in the brain network controlling human behaviour.The exact mechanisms are unknown, and the reported cases are very sparse.One of the limitations of the SEEG studies is the partial sampling of the networks concerned.Future studies are required to better understand the functional anatomy of these symptoms.

Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Table 1
Psychiatric symptoms in non-convulsive status epilepticus.