Catatonia and epilepsy: An underappreciated relationship

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Introduction
Catatonia is a neuropsychiatric disorder that has historically been viewed through multiple lenses, including that of a movement disorder, a neurodegenerative disorder, a neurodevelopmental disorder, a form of schizophrenia, and a psychomotor disorder [1][2][3][4][5][6].A relationship to epilepsy has been suggested in a number of cases in the literature, but it has received little theoretical attention.
This review approaches this relationship from several perspectives.First, we provide a brief introduction to catatonia, before outlining the established temporal relationships in which catatonia and seizures may be comorbid.We then examine the evidence for electroencephalographic (EEG) findings in catatonia.Having reviewed the myriad ways in which catatonia and epilepsy may exhibit a rather dysfunctional relationship, we outline the paradoxical potential for iatrogenic seizures to effectively treat catatonia.We then critically examine the evidence for a new lens through which to view catatonia: that catatonia may be a seizure disorder in some patients.
To conduct the review, we searched PubMed from inception to 2024 using keywords 'catatonia' and 'epilepsy', which generated 148 articles.We identified relevant themes and then conducted further secondary searches on these themes.

The conventional understanding of catatonia
Catatonia as a term was coined by the German psychiatrist Kahl Ludwig Kahlbaum [7], but historical examples that likely correspond to the same phenomenon have been described since antiquity in Graeco-Roman literature [8] and in India as early as the 1st century CE [9].Kahlbaum's aim in delineating catatonia as a distinct disorder was to emulate the successful clinico-pathological correlation that had been achieved with neurosyphilis [10].
The great psychiatric nosologist of the early 20th century Emil Kraepelin incorporated catatonia into his concept of dementia praecox, which was inherited by subsequent psychiatric classifications in the form of catatonic schizophrenia.It was in this form that the major diagnostic manualsthe International Classification of Diseases from the World Health Organization and the Diagnostic and Statistical Manual of Mental Disorders from the American Psychiatric Associationencapsulated catatonia until recently [11].
Since the 1970s, however, evidence has emerged that catatonic features are not exclusive to schizophrenia and in fact occur in a wide range of psychiatric and general medical conditions [12,13].Today, catatonia is conceived as a syndrome that may appear in a diverse selection of conditions, ranging from depression, schizophrenia and autism to autoimmune encephalitis, neurodegenerative disorders and drug-induced conditions [14][15][16][17][18].
What unites this syndrome is a collection of rather diverse clinical signs indicative of reduced, increased or abnormal psychomotor activity [19].These signs may be motor (e.g.catalepsy, echopraxia, ambitendency, stupor), verbal (e.g.mutism, verbigeration, echolalia) or behavioural (e.g.staring, negativism, withdrawal) [20].The other unifying feature is the response to treatment with benzodiazepines or electroconvulsive therapy, which is often rapid and dramatic, though not entirely ubiquitous [21].
The neurochemistry of catatonia, however, remains obscure.Neuroimaging findings have largely been diffuse and non-specific [22,23], although an intriguing result from an iomazenil single photon emission tomography (SPECT) study suggested a reduced density of GABA-A receptors in the left sensorimotor cortex [24].However, evidence implicating the role of dopamine [25], glutamate [17] and acetylcholine [26] suggests that the pathophysiological basis is unlikely to be as simple as involving a single neurotransmitter.

Temporal relationships between catatonia and seizures
In a systematic review, Oldham estimated that approximately 20 % of cases of catatonia have an underlying general medical condition, of which 9.3 % are thought to be due to epilepsy [14], suggesting that approximately 2 % of all cases of catatonia are seizure-related.As is the case with epileptic psychoses [27][28][29], catatonia may occur in three temporal relationships to seizures: ictal catatonia, postictal catatonia and interictal catatonia, as illustrated in Fig. 1.
Ictal catatonia is a manifestation of non-convulsive status epilepticus.A systematic review identified 66 such cases with a mean age of 42 years and an approximately equal sex ratio [30].The authors emphasised the importance of making this diagnosis, but they highlighted several difficulties in doing so.Specifically, only 38 % had any prior history of seizures, only 29 % exhibited subtle ictal phenomena during the catatonic episodes and most responded to benzodiazepines, which is diagnostically non-specific in catatonia [31,32].Common semiology of ictal catatonia includes mutism, stupor, staring, catalepsy, rigidity and negativism [33], all of which are frequent in catatonia samples of mixed aetiology [34,35].
Postictal catatonia has been described less frequently.Catatonia has been reported as starting on the same day as the seizure [36,37] and there are sometimes multiple episodes [37,38].EEG has been reported to be normal [37] or to show generalised background slowing [36,38].High doses of lorazepam are sometimes required [36,37] and ECT has successfully been used [38].The pathophysiology of postictal catatonia is not understood, but by analogy with epileptic psychosis, it could be due to ongoing seizure activity not visible on scalp EEG.Postictal behavioural arrest with features suggestive of catatonia has been induced in rats by electrically or chemically induced seizures [39].
Interictal catatonia can be defined as catatonia in an individual with epilepsy without any clearcut temporal relationship between catatonic signs and seizures.Table 1 provides the prevalences of catatonia and epilepsy in various conditions in which both appear at what is likely to be a higher-than-expected prevalence.It also worth noting conditions in which seizures are directly provoked during an acute illness, such as NMDA receptor encephalitis, where seizures have been reported in 76 % and catatonia in 88 % [40].In such conditions it is possible that the seizures and catatonia are caused by the underlying pathology and have no causal relationship to each other.The causal relationship in interictal catatonia without a clearcut precipitant is unknown.It is possible that there is a long-term effect of seizures on the risk of catatonia through neuronal damage, as has been speculated to occur in postictal psychosis [41].However, given that there are some individuals with the conditions in Table 1 who experience catatonia without seizures, it is perhaps more likely that catatonia and seizures result from shared neurobiological dysfunction.

EEG findings in catatonia
EEG and cortical movement potentials in catatonia have been studied by a variety of methods [49,50].In a systematic review of 355 studies, Hosseini et al identified EEG reports from 707 patients with catatonia [51].This study suggested that focal abnormalities, epileptiform discharges, evidence of status epilepticus and features of limbic encephalitiswhile rare in catatoniawere seen almost always in catatonia due to general medical conditions such as autoimmune encephalitis rather than in catatonia in primary psychiatric conditions.Generalised background slowing was not useful in differential diagnosis and occurred in 23 % of the primary psychiatric cases.
If the EEG is sometimes abnormal in catatonia, it is important to establish whether this is a trait or a state.That is, do EEG abnormalities represent an enduring latent vulnerability to catatonia, or are they transient phenomena that are closely linked to the clinical presentation?In catatonia secondary to an epileptic seizure, it is to be expected that EEG changes represent a state and are closely linked to the clinical presentation, but even in this scenario the evidence is not straightforward.In a series of three cases of catatonia in the context of status epilepticus, catatonic stupor persisted after electroencephalographic resolution of the seizure, subsequently resolving with either a further benzodiazepine dose or electroconvulsive therapy (ECT) [52].In a classic study by Gjessing and colleagues, three individuals with periodic catatonia showed an increase in the alpha frequency during phases of stupor [53].Several studies have examined cases where generalised slowing was observed during the catatonia.In one study, there were 6 Fig. 1.Illustrative temporal relationships between catatonic episodes and seizures.patients who had an EEG during and after catatonia, all of whom showed some improvement, mostly in generalised slowing, but there was not complete normalisation in all patients [32].Other small reports have also described generalised slowing during catatonia (or transition to it) with normal traces before or afterwards [54,55].Perhaps most convincingly, in one case report, investigators administered intravenous diazepam during a catatonic state with continuous EEG monitoring, observing marked diminishing of high-amplitude slow activity as the diazepam took effect [56].However, a recent series including cases of catatonia with comorbid delirium and generalised periodic discharges who had an EEG after treatment found that the EEG of only one had normalised after clinical improvement of the catatonia [57].Overall, the evidence on the persistence of EEG abnormalities in catatonia is inconclusive and may depend on the presence of comorbid conditions.Beyond clinical EEG, some quantitative EEG techniques have also been employed in this field.In a study of 10 patients with catatonia, who were compared to psychiatric and healthy controls, participants were asked to extend their right index finger when they wanted to.EEG monitoring found that late Bereitschaftspotentials were delayed in the catatonic group compared to both control groups [49].

Catatonia as a seizure disorder
We have established already that catatoniain rare instanceshas been shown to be the result of a seizure.Is it possible that catatonia is in fact more often intrinsically a seizure disorder?At a first glance, given that most scalp EEGs of patients with catatonia do not show obvious seizure activity, this might seem rather implausible, but epileptic activity on intracranial EEG has sometimes been shown in the absence of a scalp EEG correlate [58].
If it is possible then that a condition may feature seizures without a clear scalp EEG correlate, is it probable in catatonia?There are several arguments that may support this proposition.Firstly, there are many examples of epileptic activity demonstrated by intracranial EEG from deep-brain regions without any scalp EEG abnormalities, and which are associated with behavioural change and psychiatric features [27].Secondly, the semiology of catatonia can be indistinguishable from some presentations of non-convulsive status epilepticus, as some cases of ictal catatonia have demonstrated.It is not only the motor features of catatonia which are shared with non-convulsive status epilepticus, but also affective features such as extreme anxiety or fear [34,59,60].Thirdly, both catatonia and seizures can respond rapidly to benzodiazepinescatatonia is, in fact, highly unusual among psychiatric disorders in often responding dramatically within a few minutes to intravenous lorazepam [61].Similarly, catatonia can be precipitated by the withdrawal of antiseizure medications, such as benzodiazepines [62,63] and gabapentin [64,65].Finally, there are a wide range of conditions in which seizures and catatonia both occur, at least raising the possibility that the pathophysiology may be similar.There are also reports of individuals with catatonia with seizures that were not readily apparent.In one case, an individual with a diagnosis of catatonic schizophrenia deteriorated, exhibiting worsening psychosis, impaired memory and stereotyped movements.While this patient had a normal routine surface EEG, continuous electroencephalographic monitoring revealed seizures lasting up to two hours, which responded to treatment with antiseizure medications [66].A further case series of three patients with an apparently psychiatric catatonia, on which clinical seizure activity then became superimposed, has also been reported [52].In another study, 29 patients with catatonia were followed up to ascertain how many developed seizures during the catatonic episode, finding 4 patients (13.8 %) with an electroclinical seizure diagnosis [67].
There is also some overlap in the neurobiology of catatonia and epilepsy, although there remain substantial gaps in the understanding of both.Structural imaging studies in catatonia have found alterations in white matter tracts connecting regions including the prefrontal cortex, primary motor cortex, supplementary motor area and basal ganglia [68][69][70][71][72]. Functional MRI has identified alterations across a wide range of brain networks in catatonia [73], while a range of theories consider abnormalities in GABA, glutamate and dopamine to be implicated [72].Glutamatergic and GABA-ergic dysfunction are also thought to be central to the pathophysiology of epilepsy, indicating an imbalance between excitatory and inhibitory systems [74].While epilepsy can be highly focal, generalised-onset seizures are thought to be sustained by the thalamo-cortical networks that are hypothesised to be relevant to catatonia [75,76].
What about the counterarguments?Importantly, clozapine, which is probably effective in chronic catatonia in schizophrenia [77], is the most proconvulsant antipsychotic [78,79].Moreover, there are cases of catatonia where a psychogenic formulation seems overwhelmingly compelling: take for instance the case of a man whose catatonic episodes always occur during conflict with his parents [80], the school girl who is assaulted by a family member then chased by a wild dog whereupon she adopts a foetal position for days on end [81], or the man who develops catatonia after inadvertently amputating his hand with a malfunctioning chop saw [82].It is hard to speculate a convincing epileptic origin for these cases.

Induced seizures as a treatment for catatonia
Hitherto our discussion has focussed on the potential for seizures and abnormal electrical activity to cause catatonia.However, paradoxically, one of the most effective treatments for catatonia relies on the induction of seizures.László Meduna is credited as first person to use seizures to treat psychiatric disorders in the early 1930s.Using camphor or cardiazol for seizure induction, out of the first 15 patients with schizophrenia treated by Meduna, 13 had catatonia and 5 of these improved in an era when there was no other effective treatment [83].
Chemically induced seizures were soon supplanted by electrically induced seizures in electroconvulsive therapy (ECT).The first patient treated with ECT by its inventors, Bini and Cerletti, also had catatonia [84] and since then there have been numerous observational studies supporting the use of ECT in catatonia [85,86].Perhaps the most convincing evidence comes from a small randomised controlled trial, in which 18 inpatients with catatonia who had failed to respond to a 5-day course of lorazepam were randomised either to ECT plus an oral placebo or to sham ECT plus the oral antipsychotic medication risperidone [87].After 3 weeks, the mean Bush-Francis Catatonia Rating Scale fell by 7 points in the risperidone group and by 12 points (down to less than 1 point) in the ECT group.ECT is a recommended treatment for catatonia in various clinical guidelines [21,[88][89][90][91].
Given that electrical seizure induction is such an effective treatment for catatonia, it may seem counterintuitive to suggest that catatonia may sometimes be due to seizures.However, rather paradoxically, ECT has also been found to be an effective treatment in refractory status epilepticus with 11 of 19 patients in the literature responding at least partially [92].

Conclusion
Catatonia and epilepsy are epidemiologically linked, featuring in several of the same disorders.A seizure can present with a catatonic phenotype or may be followed by a catatonic episode.Paradoxically, however, pharmacologically or electrically induced seizures are effective treatments for catatonia.Surface EEG in catatonia is sometimes abnormal, and it is possible that some cases of catatonia have occult electrical seizure activity.This is not an adequate explanation for all cases of catatonia, but it is possible that underlying seizure activity accounts for more cases than those for which it is currently given credit.drafted the manuscript, which was edited for important intellectual content by SS and JL.

Table 1
Prevalences of epilepsy and catatonia in selected conditions, illustrating high comorbidity.
a Meta-analytic estimate based on studies using various definitions of prevalence.bRange based on findings of a narrative review using various definitions of prevalence.c Meta-analytic estimate based mainly on studies using point-prevalence.