by JP Rogers · 2019 · Cited by 53 — which can account for the full spectrum of catatonic features. Autoimmunity appears to cause catatonia less by systemic inflammation than by

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620 Vol 6 July 2019 Catatonia 2Catatonia and the immune system: a review Jonathan P Rogers, Thomas A Pollak, Graham Blackman, Anthony S David Catatonia is a psychomotor disorder featuring stupor, posturing, and echophenomena. This Series paper examines the evidence for immune dysregulation in catatonia. Activation of the innate immune system is associated with mutism, withdrawal, and psychomotor retardation, which constitute the neurovegetative features of catatonia. Evidence is sparse and con˜icting for acute-phase activation in catatonia, and whether this feature is secondary to immobility is unclear. Various viral, bacterial, and parasitic infections have been associated with catatonia, but it is primarily linked to CNS infections. The most common cause of autoimmune catatonia is N-methyl-D-aspartate receptor (NMDAR) encephalitis, which can account for the full spectrum of catatonic features. Autoimmunity appears to cause catatonia less by systemic in˜ammation than by the downstream e˚ects of speci˛c actions on extracellular antigens. The speci˛c association with NMDAR encephalitis supports a hypothesis of glutamatergic hypofunction in catatonia.IntroductionCatatonia is a psychomotor disorder characterised by diverse clinical signs, including mutism, negativism, ambitendency, stereotypy, posturing, waxy ˜exibility, and echophenomena.1 The structure and neural mechanisms of the disorder are reviewed elsewhere in this issue of The Lancet Psychiatry by Walther and colleagues. 2 Understanding the pathophysiology of this severe disorder is crucial given its high rate of medical complications, including pressure ulcers, infections, and venous thromboembolism. 3 Moreover, such under- standing might aid the comprehension of other neuro- psychiatric disorders.Although catatonia has numerous possible symptom combinations,4 compelling reasons to study it as a single entity exist. Clinical and demographic factors can dis- tinguish catatonia from other psychotic and a˚ective disorders.5 Di˚erent forms of catatonia (retarded catatonia, malignant catatonia, and neuroleptic malignant syndrome) are highly comorbid.1 In terms of treatment, response rates to benzodiazepines and electroconvulsive therapy (ECT) are high, regardless of the cause of the catatonia.6 Moreover, catatonia is not a common disorder, so pragmatically, to study it in depth, considering it as a whole is useful.Immune dysregulation is gaining interest as a patho-physiological mechanism underlying neuro psychi atric disorders as diverse as narcolepsy, some dementias, depression, and psychosisŠ with converging evidence from biochemical, neuroimaging, genetic, and post- mortem studies.7,8 Roles for both the innate immune system, which concerns the rapid, undirected response to pathogen-associated or injury-related signals, and the adaptive immune system, which functions over a longer timescale and involves the selection and maturation of antigen-speci˛c T-cell and B-cell mediated responses, have been identi˛ed.In this Series paper, we discuss the evidence for the involvement of the immune system in catatonia. This line of enquiry appears to be valuable, given the wide range of infective and in˜ammatory conditions that can cause catatonia (tables 1, 2). We address whether the immune system has a role in catatonia, using some direct and some more circumstantial evidence, and endeavour to establish speci˛c models. We consider immunity in terms of innate and adaptive systems for the purposes of clarity, while acknowledging that strictly demarcating the two is not always possible.Innate immune systemCatatonia due to infection A systematic review reported that 20% of catatonia has a general medical cause, of which CNS in˜ammation (comprising both infective and immune causes) accounts for 29%.9 Numerous infectious diseases have been reported to cause catatonia. Here, we present the results of a new systematic search of the literature (table 1; appendix ). We identi˛ed 124 cases, the majority of which were published as case reports, with the remaining reported as case series. Laboratory evidence of infection (such as isolation of the organism in the serum, or viral DNA in the cerebrospinal ˜uid [CSF]) was reported in 85 of the cases (69%). A robust temporal association between the infection and catatonia was reported in 82 of the cases (66%). A previous psychiatric disorder was recorded in 16 cases (13%) and a previous medical disorder in 26 cases (21%), although the absence of a pre-existing condition was often not stated. Only 66 of the cases (53%) recorded the presence of at least two features from the Bush -Francis C atatonia Screening Instrument (BFCSI); the remainder had insu˝cient description or only one feature.10 In some cases, the catatonia resolved with antimicrobial therapy, 11 but in others, it required treatment with benzodiazepines12 or ECT. 13How infection might result in catatonia is unclear from the literature. Possibilities include a direct neurotoxic e˚ect, a psychological reaction to the infection, or mediation by an acute-phase response. Out of the 47 cases where a speci˛c virus was implicated, 45 of these involved known neurotropic viruses, suggesting a direct neuro toxic Lancet Psychiatry 2019; 6: 620Œ30Published Online June 10, 2019 S2215-0366(19)30190-7See Comment page 554This is the second in a Series of two papers on catatonia Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King™s College London, London, UK (Dr J P Rogers MBBChir, Dr T A Pollak PhD, Dr G Blackman MBBS) ; South London and Maudsley National Health Service Foundation Trust, Bethlem Royal Hospital, UK (Dr J P Rogers, Dr T A Pollak, Dr G Blackman) ; and Institute of Mental Health, University College London, London, UK (Prof A S David FRCPsych) Correspondence to: Dr Jonathan P Rogers, Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King™s College London, London, SE5 8AF, UK. See Online for appendix

PAGE – 2 ============ Vol 6 July 2019 621e˚ect. Some bacterial agents, such as Borrelia burgdorferi and Treponema pallidum are also known to infect the CNS.The immunological response might also be important, given that in some neurological disorders, such as meningoencephalitis, damage is caused primarily by an immune reaction.14 In several cases, an explicit immune response was suggested by the authors to explain the catatonia, such as in paediatric autoimmune neuropsy- chiatric disorders associated with streptococcal infection (PANDAS),15 or in N-methyl-D-aspartate receptor (NMDAR) encephalitis purportedly triggered by yellow fever vaccination,16 herpes simplex virus infection,17 or Epstein-Barr virus infection.18 In cases of pyrexia of unknown origin in which an infective cause was often assumed, a yet uncharacterised disorder might have been responsible.19,20Depression and in˜ammationAlthough cases of overt catatonia in the context of infections are dramatic, the more common neuro- psychiatric presentation of infection is a broader pheno- type of illness behaviour that resembles depression. This presentation includes reductions in motor activity, oral intake, and social interaction,8 all of which are seen in catatonia. Psychomotor activity is also slowed in mild experimentally induced infection.21 This might be due to impaired spatial memory performance and aberrant activity in parts of the brain involved in interoception. Hence, the brain™s response to in˜ammation, if severe, could result in a complex movement disorder such as catatonia.22,23In response to an acute stressor, immune cell tra˝cking occurs, with the movement of leukocytes to, and within, a target organ.24 However, in chronic stress, increased monocyte production and microglial activation result in neuroin˜ammation and are associated with depressive behaviour. 8 Depression is often associated with raised levels of pro-in˜ammatory cytokines, granulocytes, and monocytes.8 Regarding subtypes of depression, atypical depression (characterised by mood reactivity, hyperphagia, hypersomnia, and leaden paralysis)25 is most associated with raised in˜ammatory markers. 26 Conversely, psycho- motor retardation is more commonly seen in melancholic depression, which is less associated with a peripheral pro-in˜ammatory state.26 Seasonal a˚ective disorder has also been associated with a pro-in˜ammatory state, but there has been little research to date on the motor phenotype of this disorder. 27Neuroleptic malignant syndrome and in˜ammationNeuroleptic malignant syndrome is a neurological emergency precipitated by antipsychotic use and charac- terised by muscular rigidity, autonomic dysfunction, and altered consciousness. Patients treated with anti psychotics who have pre-existing catatonia are at an increased risk of developing neuroleptic malignant syndrome compared with those who do not have catatonia (3·6% vs Cases (n)Suspected organisms (cases, n) Bacterial meningitis or encephalitis5Borrelia burgdorferi (4), unspeci˜ed (1) Viral meningitis or encephalitis26Adenovirus (1), cytomegalovirus (1), coronavirus (1), EpsteinŒBarr virus (1), human herpesvirus 6 (1), herpes simplex virus (8), Japanese encephalitis virus (1), measles virus (2), tick-borne encephalitis virus (1), varicella-zoster virus (1), unspeci˜ed (9)Cerebral malaria2Plasmodium falciparum (1), unspeci˜ed (1) CNS infection unspeci˜ed 3Unspeci˜ed (3) Respiratory tract infection 10In˚uenza (1), Group A Streptococcus (2), Mycoplasma (1), Klebsiella (1), EpsteinŒBarr virus (1), unspeci˜ed (4) HIV-related 22HIV (20), HIV and John Cunningham virus (2) Syphilis3Treponema pallidum (2)Systemic bacterial infection31 Coxiella burnetti (1), Salmonella typhi (29), unspeci˜ed (2) Systemic viral infection4Cytomegalovirus (2), EpsteinŒBarr virus (1), ˚avivirus (1) Prion-related disorders7Prion protein (7)Other11Flavivirus vaccination (1), Tropheryma whipplei (1), Escherichia coli (1), Mycobacterium tuberculosis (1), Taenia solium (1), Chlamydia trachomatis (1), Trypanosoma cruzi (1), unspeci˜ed (4) Total 124·· Table ˜: Systematic review of infective causes of catatonia Cases (n)Autoimmune thyroid disorders 13Hyperthyroid state3Hypothyroid state4Euthyroid state with thyroid antibodies 4Thyroid state not stated2Autoimmune encephalitis 259GABA-AR encephalitis 2NMDAR encephalitis 249Progressive encephalomyelitis with rigidity and myoclonus 1Voltage-gated potassium channel complex encephalitis4Unspeci˜ed3Demyelinating disorders 13Acute disseminated encephalomyelitis 2Multiple sclerosis10Neuromyelitis optica 1Pernicious anaemia 4Systemic lupus erythematosus and related53Antiphospholipid syndrome2Systemic lupus erythematosus51Other4Addison™s disease 1Crohn™s disease 1MOG antibody-associated diseases 1PANDAS 1Total 346GABA=˛-aminobutyric-acid. NMDAR=N-methyl-D-aspartate receptor. MOG=myelin oligodendrocyte protein. PANDAS=paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Table ˚: Systematic review of autoimmune causes of catatonia

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622 Vol 6 July 2019 0·07Œ1·8%).28 Given that no clinical features exist that can reliably distinguish neuroleptic malignant syndrome from malignant catatonia,29 some authors consider neuroleptic malignant syndrome to be a speci˛c form of antipsychotic-induced malignant catatonia.30 Residual cata tonia frequently remains af ter the resolution of the full syndrome of neuroleptic malignant syndrome.31Some suggest that in˜ammation is important to the pathophysiology of neuroleptic malignant syndrome, with acute-phase responses such as leukocytosis, thrombo – cytosis, and low serum iron frequently reported.32,33 Low serum iron has emerged as a promising biomarker. 32,33 It has been hypothesised that in neuroleptic malignant syndrome, pro-in˜ammatory cytokines might reduce the levels of the neuroprotective kynurenic acid, impairing the activity of dopaminergic neurons in the midbrain, causing exquisite sensitivity to a further antipsychotic-induced reduction in dopamin ergic signalling.34 However, an in˜am matory pro˛le in the blood might be the consequence of rhabdomyolysis, rather than the primary pathology.Serotonin syndrome, a rare adverse e˚ect of anti- depressant medication, has also been described as a form of drug-induced catatonia, 1 but to the authors™ knowledge no research has been published linking it to the immune system.35Direct evidence for the acute-phase response The acute-phase response is a core part of the innate immune system. The response is initiated by the activation of monocytes and macrophages by a stimulus, such as muscle breakdown, infection, physical injury, or psychological stress. In response to these stimuli, cells release pro-in˜ammatory cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-˙), which in turn act on receptors throughout the body to promote fever, anorexia, muscle catabolism, and activation of the hypothalamic-pituitary-adrenal axis. Importantly, these cytokines also alter protein synthesis in the liver, causing increased production of acute -phase proteins such as C-reactive protein (CRP), procalcitonin, ferritin, and ˛brinogen. 36,37 Some features of malignant catatonia bear notable similarities to the acute -phase response, including fever, motor hypoactivity, and autonomic disturbance. Here, we include a summary of the evidence for the presence of systemic in˜ammation, as measured by acute-phase reactants and related proteins (table 3). Creatine kinase (CK) is not an acute -phase marker, but as it is a marker of muscle breakdown, the enzyme is sometimes raised as a downstream consequence of the acute-phase response. The evidence for CK elevation in catatonia is equivocal and could be argued to be the result of muscular rigidity and excessive StudyParticipants with catatonia ControlsResults White blood cell countHaouzir et al (2009) 3825 patients with acute catatonia50 patients without catatonia with similar diagnoses to patients with catatonia No di˝erence in white blood cell count White blood cell countRao et al (2011) 3977 patients with catatoniaNone Responders to lorazepam had a statistically signi˜cantly lower monocyte count than non-responders; no di˝erence in other cell counts hsCRPAkanji et al (2009)4012 patients with schizophrenia with prominent catatonic features87 patients with schizophrenia without catatoniahsCRP concentration statistically signi˜cantly higher in patients with catatonia IronHaouzir et al (2009)3825 patients with acute catatonia50 patients without catatonia with similar diagnoses to patients with catatonia Iron concentration did not di˝er between patients with and without catatonia IronLee (1998)4139 patients with catatonia in psychiatric intensive care unitsNone17 patients had iron concentration below reference rangeIronPeralta et al (1999) 4240 patients with catatonia and psychosis 40 patients with psychosis without catatoniaIron concentration statistically signi˜cantly lower in patients without catatonia IronCarroll and Goforth (1995) 4312 episodes of catatonia in 11 psychiatric inpatients None3 patients had iron concentration below reference rangeIronLakshmana et al (2009)4440 catatonic patientsAge-matched and sex-matched psychiatric patientsNo di˝erence in iron concentration between patients with and without catatonia CKNortho˝ et al (1996)4532 hospital inpatients with catatonia32 dyskinetic psychiatric patients without catatonia, 32 non-dyskinetic psychiatric patients without catatonia, 32 healthy controlsCK concentration statistically signi˜cantly higher in individuals with catatonia than in healthy controls and non-dyskinetic patients without catatonia; no di˝erence between patients with catatonia and dyskinetic patients without catatonia CKHaouzir et al (2009)3825 patients with acute catatonia50 patients without catatonia with similar diagnoses to patients with catatonia No di˝erence in CK concentration CKMeltzer (1968)46Two patients with catatonia14 patients with non-catatonic psychosesNo di˝erence in CK concentration D-dimerHaouzir et al (2009)3825 patients with acute catatonia50 patients without catatonia with similar diagnoses to patients with catatonia D-dimer concentration statistically signi˜cantly higher in patients with catatonia hsCRP=high-sensitivity C-reactive protein. CK=creatine kinase. Table ˛: Systematic review of in˜ammatory markers in catatonia

PAGE – 4 ============ Vol 6 July 2019 623immobilisation rather than indicating a primary muscular pathology. In one study, a raised CK predicted a good response to treatment with lorazepam.45One study found the acute-phase marker, and ˛brin degradation product, D-dimer to be raised in all 25 catatonic patients tested, with a mean value 3 times higher than in non-catatonic psychiatric patients.38 This ˛nding is consistent with the increased risk of venous thromboembolism in catatonia, but has not yet been replicated.High -sensitivity CRP concentration was measured in one study and found to be raised in catatonic patients, but the absolute concentration of CRP was not very elevated (1·23 mg/dL).40Low serum iron was originally hypothesised to be present in catatonia given the similarities to neuroleptic malignant syndrome. Low serum iron is an established feature of the acute-phase response and arises because of the upregulated production of ferritin and hepcidin by the liver. 47 Two uncontrolled studies have shown that between 25% and 44% of catatonic episodes were accompanied by serum iron concentrations below the reference range.41,43 When catatonic patients have been compared with psychiatric controls however, the results have been ambiguous.38,42,44 The authors of one of the negative studies that used unmedicated patients speculated that iron might have been reduced in other reports because of the e˚ect of antipsychotic medi- cations.44 In several studies, low serum iron in catatonia has been associated with the subsequent development of neuroleptic malignant syndrome.41,43,48 This association might exist because iron is a cofactor for dopamine synthesis,49 so a combination of low iron impairing dopamine production and antipsychotic medications blocking dopamine receptors could result in the patho- logical hypodopaminergic signalling charac teristic of neuroleptic malignant syndrome.Glial dysfunction Abnormalities of cerebral white matter, which is composed of glial cells, have been associated with schizophrenia, depression, and autism.50 2,3-cyclic nucleotide 3-phosphodiesterase (CNP) is a myelin protein that is speci˛c to oligodendrocytes.50 In a mouse model, hetero-zygotes for a CNP loss-of-function genotype showed axonal degeneration and low-grade in˜ammation, along with a depressive and catatonic phenotype.51 Furthermore, this behaviour was alleviated by ablation of microglia, suggesting that microglia-mediated neuroin˜ammation was underlying the phenotype. When this polymorphism was examined in individuals with schizophrenia, a striking association existed with catatonic-depressive behaviour, a ˛nding that was replicated in an independent cohort.52 Mutations of mouse genes encoding two other myelin proteins (myelin basic protein [MBP] and myelin proteolipid protein [PLP]) also result in a catatonic phenotype.52 How glial dysfunctionŠbecause of relevant polymorphisms or other factorsŠmight contribute to the psychomotor features of catatonia clearly represents an important focus of future research.Implications of treatment The mainstay of current treatment for catatonia is benzodiazepines and ECT, neither of which is classically understood as an immunomodulatory therapy. Benzo- diazepines are positive allosteric modulators at the ˆ-aminobutyric-acid (GABA)-A receptor. Although research into the function of GABA in the immune system is at an early stage, evidence suggests that GABAergic signalling has a role in suppression of immune responses.53 Lymphocytes express GABA -A receptors, and activation of these receptors reduces production of pro-in˜ammatory cytokines.53 However, one study speci˛cally on catatonia found higher monocyte counts predicted benzodiazepine non-response.39 Data distinguishing di˚erent benzodiazepines are sparse, but some benzodiazepines, such as diazepam and lorazepam (both recognised treatments for catatonia) but not clonazepam, also bind to translocator protein (TSPO), a mitochondrial protein associated with phagocyte activity, immune cell migration, and cytokine function.54,55 In rats, diazepam reduces TSPO in the brain and decreases the number of CNS in˜ammatory cells, giving it a protective function against experimental autoimmune encephalo- myelitis.55 Reports on other GABA -A receptor modulators are scarce, but epidemiological studies exist that indicate that zolpidem use is associated with higher rates of infections (including of pyelonephritis, which would be unlikely to be related to respiratory depression), suggesting the drug might also have an immuno suppressant role.56,57Regarding ECT, a single session appears to activate the immune system, increasing concentrations of the cytokines IL-1ˇ, IL-6, IL-10, and TNF-˙. However , a course of several sessions appears to down-regulate immune system activity, at least in animal studies. 58Minocycline is an antimicrobial drug that also has anti -in˜ammatory properties.59 The drug has been shown to prevent stress -induced microglial changes in rodents 8 and has been proposed as an adjunctive treatment for schizophrenia.60 Some evidence suggests that minocycline might reduce negative symptoms in schizophrenia,61 some of which (such as poverty of speech, a˚ective blunting, and avolition) overlap with catatonia. However, a 2018 double -blinded, randomised study which speci˛cally aimed to examine the e˚ect of this drug on negative symptoms did not ˛nd any bene˛t.62 No studies of which we are aware have investigated minocycline speci˛cally for catatonia, but reports exist of two patients with schizophrenia and prominent catatonic features who responded well to minocycline in the absence of infection.63,64The evidence for innate immunityWe have argued that psychological stress and infection both cause a release of pro -in˜ammatory cytokines,

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624 Vol 6 July 2019 which result in a state of motor hypoactivity. In a normal psychomotor response, this event might be adaptive, allowing conservation of energy for eliminating a pathogen or avoiding a stressor, and resolving when the stressor ends. However, in depression, a prolonged pro -in˜ammatory state might be maladaptive and cause further dysfunction. Immobilisation itself can also result in activation of the innate immune system.65Studies speci˛cally in catatonia have been sparse and con˜icting. An argument could be made that catatonia is an exaggerated version of in˜ammatory depression, in which extreme psychomotor retardation culminates in stupor and mutismŠneurovegetative features of catatonia hypothesised to be due to disordered top-down cortico-subcortical signalling.66 However, this hypothesis would not explain the perseverative -compulsive behaviours exhibited in catatonia (posturing, stereotypy, mannerism, echophenomena, and perseveration), which have been proposed to arise due to disrupted corticocortical signalling. The infective causes of catatonia are largely pathogens that infect the CNS (table 1), which suggests that the causality is mediated by neurotoxic mechanisms, rather than by a systemic in˜ammatory responseŠ although a maladaptive immune response to the pathogen might contribute.Autoimmunity Autoimmune neurological disorders resembling catatoniaA plethora of autoimmune neurological diseases exist, many of which, such as multiple sclerosis, neuromyotonia, and Sydenham™s chorea, feature prominent movement disorders. We have chosen the examples of sti˚ person syndrome and narcolepsy to show some particular points of similarity to catatonia.Sti˚ person syndrome is a rare neurological disorder characterised by gradually progressive increased muscle tone with the preservation of muscle power, sensation, and cognitive function. Most patients have autoantibodies against the enzyme glutamic acid decarboxylase (GAD2).67 GAD2 is an enzyme that converts glutamate to GABA, although the pathogenicity of GAD2 auto- antibodies in sti˚ person syndrome is not fully established. Given that the disorder bears several similarities to catatonia, one author has suggested testing for GAD2 autoantibodies to distinguish between the two disorders.28 The syndromes share immobility, an emotionless facial expression, and marked anxiety. Moreover, hypertonic episodes in sti˚ person syndrome can have psychological triggers.67 As with catatonia, the mainstay of treatment for sti˚ person syndrome is benzodiazepines; however, immuno therapy in the form of intravenous immuno globulin, cortico steroids and the anti-B-cell monoclonal antibody rituximab are increasingly used. A sti˚ person syndrome variant, progressive encephalomyelitis with rigidity and myoclonus, responds dramatically to immuno- suppression.67,68Narcolepsy type 1 is a sleep disorder that arises due to depletion of the orexin-producing neurons in the hypothalamus. Evidence that this event is immune -mediated comes from linkage to HLA-DQB1*06:02 and outbreaks coinciding with epidemics of, and vaccination to, the H1N1 in˜uenza virus, suggesting a possible role for molecular mimicry. 69 A small study published in 2012 suggested that some patients with narcolepsy have autoantibodies to the NMDAR, without the seizures or autonomic disturbance characteristic of NMDAR auto- immune encephalitis.70 Narcolepsy type 1 also features cataplexy, a sudden loss of motor tone usually triggered by positive emotions. Cataplexy usually lasts for up to 2 min, but occasionally status cataplecticus lasting for hours to days can occur. 71 This occurrence has been hypothesised to be due to either a prolonged emotional response to the original stimulus, or an emotional response to the cataplexy per se. Here, we show a comparison between cataplexy and catatonia (table 4).Autoimmune disorders causing catatonia We did a systematic literature search for autoimmune disorders causing catatonia (table 2; appendix). Most are presented in case reports and case series, with some larger case series for NMDAR encephalitis (table 5). 224 of the 346 cases (65%) recorded at least two features from the BFCSI.10 18 patients (5%) had previously had a psychiatric disorder and 33 (10%) had previously had a medical disorder, although an absence of a pre -existing condition was often not stated. In some cases, the autoimmune disorder appeared to be the proximal cause of the catatonia. In other cases, the autoimmune disorder was a more distal cause, as in one patient with autoimmune polyendocrine syndrome who developed autoimmune destruction of the adrenal gland (Addison™s disease), resulting in hyponatraemia and subsequent CatatoniaCataplexyTrigger Strong negative emotionsStrong positive emotionsTone Increased with posturing, but preservation of respiratory musclesAtonic with preservation of respiratory musclesAwareness Retained Retained Main associated psychiatric disorders Depression, psychosisDepression, social anxietyPharmacological treatmentGABA-A receptor agonistsAntidepressants, sodium oxybate (a GABA-B receptor agonist)DurationDays to weeks Up to 2 min (longer in status cataplecticus)GABA=˛-aminobutyric-acid. Table ˝: Comparison of catatonia and cataplexy in the context of narcolepsy

PAGE – 6 ============ Vol 6 July 2019 625extrapontine myelinosis, the latter precipitating catatonia.78In addition, 22q11.2 deletion syndrome, which features thymic aplasia and a resultant absence of peripheral T cells,79 has also been linked to catatonia.80 Whether this association is due to immunode˛ciency, the high rates of various autoimmune disorders present in the syndrome, or to another cause remains unclear. The most noteworthy result from our systematic review is that 72% (249/346) of all cases of autoimmune catatonia reported were due to NMDAR encephalitis, despite the disorder only being described in 2007 (table 2).81 Before discussing this ˛nding of autoimmunity directed against the CNS in depth, we will illustrate the complexity of autoimmune catatonia with three examples of peripheral autoimmunity. Two cases of catatonia in pernicious anaemia have been reported, both of whom responded to vitamin B12 supplementation.82,83 Dietary vitamin B12 de˛ciency might also cause catatonia.84,85In thyroid disease, catatonia has been reported in patients with thyroid autoantibodies with hyper- thyroid,86Œ88 hypothyroid,90,91 and euthyroid91,92 states. However, catatonia has also occurred in hypothyroidism due to thyroidectomy; 93 whether thyroid status or the presence of the autoantibodies is the causally relevant factor therefore remains unclear. In systematic lupus erythematosus, 51 cases of catatonia have been reported, generally with high titres of antinuclear antibody and anti-double-stranded DNA; however, making further comparisons is di˝cult because testing panels have varied across studies (appendix).One group reported 84 cases of paediatric catatonia of which they suspected 7 had an autoimmune origin, including two patients with evidence of in˜ammation who were responsive to immunosuppression but who could not be diagnosed with any known disorder. 94Autoimmune disorders directed at CNS targets causing catatoniaPANDAS and the broader concept of paediatric acute-onset neuropsychiatric syndrome (PANS) are characterised by an abrupt onset of obsessive behaviours or motor tics.27 This behaviour might be due to molecular mimicry, whereby antigens on the infective agent bear a similarity to and provoke a host immune response to self-CNS antigens.95 Antistreptococcal antibodies are often positive, 96 although results of immunotherapy have been equivocal.97 One case has been reported of a boy who developed catatonic symptoms in addition to obsessionality following infection with group A Streptococcus; he responded well to lorazepam and plasmapheresis.98Autoimmune encephalopathies, as examples of auto- immune disorders directed at CNS targets, merit special consideration. T-cell mediated disorders, such as acute demyelinating encephalomyelitis can occasionally present with catatonia.99 However, catatonia is more commonly a feature of autoimmune encephalitides associated with antineuronal antibodies. These antibodies can cause internalisation of the antigen, inhibiting its function.14That catatonia has been reported in two patients with GABA-A receptor antibodies is unsurprising, given the centrality of benzodiazepines in treatment for catatonia.100,101 Catatonia might be more common than these case reports would suggest, as careful psychiatric phenotyping has not been done among this population.102 In one of the patients reported with catatonia, GABA-A receptor antibodies were present in the serum on the original presentation, but not in the context of relapse, highlighting that testing serum only on a single occasion might increase the risk of missing a clinically signi˛cant syndrome.100NMDAR encephalitis is increasingly considered as an organic cause of psychosis, although controversy exists as to whether this idea is only relevant in the context of the classical encephalitis or also in isolated psychiatric presentations.7,103 The association NMDAR encephalitis with catatonia seems to be even stronger than the association with psychosis. 72 Where catatonia is reported, it is often malignant catatonia and tends to co -occur with psychosis104 and mania. 105 NMDAR encephalitis is strongly linked to neuroleptic malignant syndrome, with one study suggesting as many as 21 out of 36 (58%) patients with NMDAR antibody encephalitis who were administered antipsychotics developed suspected neuro leptic malignant syndrome.106 Of the total 222 cases of NMDAR encephalitis documented across seven studies where rates of catatonia were reported, 141 (64%) cases of catatonia were identi˛ed (table 5). The range of catatonic features reported is wide and includes echolalia, grimacing, posturing, and alternating hypermotor and hypomotor activity. 72A few studies have examined comparative rates of NMDAR autoantibody positivity among di˚erent diagnostic groups. Of 459 patients with psychiatric disorders, two had IgG antibodies against the NMDAR subunit NR1a in serum and CSF; both had catatonia and Participants (N) Cases of catatonia (n [%])Dalmau et al (2008)7210088 (88%)Tsutsui et al (2012) 7032 (67%)DeSena et al (2014)73*85 (63%)Kruse et al (2015)74129 (75%)Duan et al (2016)752819 (68%)Granata et al (2018)76*188 (44%)Herken and Prüss (2017) 77ƒ53 10 (19%)Total 222141 (64%)NMDAR=N-methyl-D-aspartate receptor. *All paediatric cases. ƒRelied on retrospective analysis of charts, so probably underestimated prevalence of catatonia.Table ˙: Prevalence of catatonia (as identi˚ed by authors) in case series of NMDAR encephalitis

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