The Anti-NMDA Receptor Encephalitis Foundation Newsletter

Anti-NMDA receptor (NMDAR) encephalitis is characterized by mood and behavior changes,
seizures, abnormal movements, autonomic instability, and encephalopathy. It occurs
most commonly in young adults.


Children with NMDARE exhibit significant brain volume loss and failure of age-expected brain growth. Abnormal MRI findings, a clinical presentation with sensorimotor deficits, and a treatment delay > 4 weeks are associated with worse clinical outcome.


Objectives To examine the clinical characteristics of autoimmune encephalitis associated with the glutamate decarboxylase 65 (GAD 65) antibody. Materials and methods Medical records of all patients…


Monti and colleagues [1] described a patient who developed psychiatric symptoms followed
by refractory status epilepticus caused by anti N-methyl-D-aspartate receptor (NMDAr)
encephalitis. Despite the lack of lung involvement, the patient resulted positive
for SARS-CoV-2 infection.


INTRODUCTION Movement disorders developing as a direct consequence of the administration of dopamine receptor-blocking neuroleptic drugs were first reported in 1957, 5 years after their introduction into psychiatric practice. The year 1964 saw the first collective description of these movement disorders as a ‘tardive’ (from the latin tardus, meaning late) phenomenon,1 reflecting their delayed onset following medication administration, in contrast to ‘acute’ dystonic reactions, which also follow dopaminergic blockade. This term was rapidly adopted, and in the following decades, a flurry of publications were to expand the phenotypic spectrum of the disorder. Concurrently, theories aiming to explain disease pathogenesis began to emerge, and several therapeutic strategies were explored. This review provides physicians with a pragmatic, clinically based platform with which to approach tardive syndromes. In addition, we explore recent developments in our understanding of disease pathophysiology, discuss how to approach treatment of tardive syndromes and try to dispel some commonly held myths. The nosology of tardive syndromes is plagued by inconsistent use of descriptive language. The term ‘tardive dyskinesia’, when first introduced, was intended to subsume the range of diverse movements that can emerge in a delayed fashion following long-term neuroleptic administration. However, more recently, a less confusing approach which classifies tardive movements according to their clinical phenomenology has been promoted, and will be used in this review. Accordingly, we use ‘tardive syndrome’ as the umbrella term for any/all potential tardive movement disorders but reserve ‘tardive dyskinesia’ as a descriptor of a specific clinical entity, namely the characteristic oro-bucco-lingual choreiform movements (see The ‘typical’ tardive syndrome). The scale of the problem Tardive syndromes are a predictable, sometimes permanent, disabling consequence of medication administration. They occur predominantly in the psychiatric population, where they exacerbate the burden of social stigma and are linked to poorer quality of life and increased morbidity and mortality.2 3 Antipsychotic drugs are by far the most common offenders, though numerous others have also been implicated (table 1). VIEW INLINE VIEW POPUP Table 1 Examples of medications known to cause tardive syndromes4–11 Tardive syndromes affect 20%–50% of patients receiving neuroleptic drugs.12 Advancing age is the most robust risk factor, with incidence increasing from 5% per annum in those aged under 40 years to 12% or more per annum in older age groups.12–14 The risk increases cumulatively with duration of exposure and medication dose, with a cumulative incidence rate of 20%–25% after 5 years of exposure.15-17 Note however that the medication compliance rate in patients with schizophrenia is around 50%, so these figures may well be an underestimate.18 Numerous other factors may further increase the risk, including history of an affective disorder, previous organic brain damage, diabetes mellitus, female sex (oestrogen perhaps being protective premenopausally) and race.19 Indeed, disease prevalence is lower on average in Asians (roughly 20%) and higher on average in African–Americans compared with Caucasians.19–21 Disease pathophysiology The pathophysiological basis of tardive syndromes remains poorly understood, as reflected in the large number of theories purporting to explain the delayed development of these movement disorders. The earliest theory to gain popular acceptance was the so-called dopamine receptor hypersensitivity theory. This suggested that dopamine-blocking neuroleptics led to compensatory upregulation and/or hypersensitivity of postsynaptic dopamine (particularly D2) receptors.22 23 Hypersensitivity of these receptors, which are expressed on indirect pathway medium spiny neurones and are inhibitory, would have the net effect of pallidal and subthalamic nucleus disinhibition, producing abnormal hyperkinetic movements.22 This hypothesis was largely based on clinical observations, such as the greater likelihood of tardive syndromes in patients receiving potent D2 blockers and the apparent improvement in tardive dyskinesia with additional dopaminergic blockade, as well as on some animal studies.22 23 However, evidence in humans for such alterations is lacking. There is no correlation between in vivo striatal D2 receptor ligand binding assessed by positron emission tomography and the severity of tardive dyskinesia. Equally, postmortem examinations have not demonstrated significant differences in D2 receptor numbers in those with and without tardive syndromes.22 Moreover, this theory does not explain why many patients do not recover after they stop the offending medication; if the only problem were receptor upregulation/hypersensitivity, one would expect this to normalise following drug withdrawal. An alternative hypothesis is that tardive syndromes actually represent a neurodegenerative disorder of striatal interneurones induced by oxidative stress. This theory, which is supported by animal and human neuropathological studies,24 25 holds that dopaminergic receptor blockade causes increased dopamine turnover and oxygen free radical production by monoamine oxidase.22 These free radicals are thought to be toxic to striatal interneurones, causing gliosis within the basal ganglia, thus explaining why the symptoms persist after stopping the medication. However, the significant and sustained improvement that sometimes follows deep-brain stimulation for tardive syndromes might argue against this idea. A further theory implicates damaged or dysfunctional striatal gamma-aminobutyric acid (GABA)ergic neurones in the pathogenesis of tardive dyskinesia. These neurones synapse on the soma of medium spiny neurones, providing potent feedforward inhibition, balancing activity in the direct and indirect basal ganglia pathways, and providing surround inhibition.22 23 Selective lesioning of these neurones produces dyskinesia.26 Long-term D2 agonism, in theory, could potentially damage GABAergic interneurones via glutamate-mediated excitotoxicity and increased oxidative stress from dopamine turnover.27 Finally, altered N-methyl-D-aspartate (NMDA)-mediated synaptic plasticity may provide a unifying theory. Antipsychotics are known to influence NMDA receptor-mediated synaptic plasticity. In this setting, patterns of abnormal neurotransmission, for example, secondary to D2 receptor hypersensitisation could be abnormally potentiated, perpetuating a cycle of abnormal sensorimotor integration and abnormal tardive movements.22 Of course, not everyone who is exposed to neuroleptic drugs develops a tardive syndrome, implying that other, possibly genetic factors are at play, conferring increased vulnerability to tardive syndromes. Genome-wide association studies have identified some potential candidate genes, though their relevance to clinical practice remains unclear.28 Making the diagnosis: the devil is in the detail This section describes the typical (or perhaps simply better recognised) and less typical presentations of tardive syndromes. One must be mindful however that individual components of the syndrome rarely occur in isolation, but rather generally coexist to greater or lesser degrees (though one may be dominant). A confident diagnosis often depends on identifying multiple movement phenomena that are compatible with a tardive syndrome. Thus, an important part of the evaluation involves not only identifying a movement of potentially tardive aetiology, but actively searching for the presence of other compatible abnormalities. Failing to notice clues, such as a fidgety patient (akathisia) who sighs deeply (respiratory dyskinesia) and moves his legs back and forth during the consultation (stereotypies), can rapidly lead one down the wrong diagnostic path. Although diagnostic criteria for tardive syndromes have been developed (table 2), only three questions matter in clinical practice: Is there a history of taking a dopamine receptor-blocking or other tardive syndrome-causing drug, as prescription medication, over-the-counter/traditional remedies or poisoning? What is the temporal relationship of taking this drug intake to the onset of the movement disorder? Is the clinical phenomenology compatible with a tardive syndrome (see below)? VIEW INLINE VIEW POPUP Table 2 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition of tardive syndromes The ‘typical’ tardive syndrome ‘Classic’ tardive dyskinesia involves stereotyped choreoathetoid movements predominantly involving the lips, tongue and perioral region. The movements often predominate in the lower face, with frontalis involvement being unusual. Patients often move the tongue in a writhing motion inside the mouth, are prone to frequent rapid tongue protrusion (‘flycatcher tongue’) and pushing of the tongue against the inside of the cheek, creating a bulge (‘bonbon sign’). Chewing and/or grimacing movements, lip smacking and puckering are typical. This may be accompanied by low amplitude choreiform movements of the distal limbs, the so-called ‘piano player dyskinesia’, resembling finger movements on piano keys.29 Patients are often unaware of these involuntary movements, though those involving the lips and tongue may cause problems with feeding. Tardive dyskinesia is usually accompanied by one or more of the following tardive phenomena: Tardive akathisia This is an uncomfortable sense of inner restlessness, requiring the affected individual to repeatedly move about in order to ease the unpleasant sensation. Movements can include rocking in one place when seated, marching when standing, repetitively scratching or rubbing, or just appearing generally ‘fidgety’ during the consultation. Tardive stereotypies These are patterned, purposeless, repetitive and somewhat ritualistic movements that may appear as truncal rocking, pelvic thrusting, to-and-fro leg movements, hand-wringing or crossing/uncrossing of the legs. They may outwardly resemble akathisia but are not accompanied by inner restlessness. Tardive dystonia As with most tardive syndromes, tardive dystonia adopts distinct phenomenological characteristics which are easily identified by the trained observer. The disorder frequently involves the craniocervical region, manifesting as retrocollis. Dystonia may extend to the trunk as opisthotonic posturing, while in the arms, abduction, internal rotation and wrist flexion is the classically adopted posture.29 Blepharospasm may also emerge. In contrast to other tardive syndromes, tardive dystonia is particularly common in young men aged around 40 years.24 Remission is also less likely than with tardive dyskinesia, particularly with drug exposure beyond 10 years.24 The following tardive disorders are less well defined, with only a handful of reported cases. Tardive tourettism This rare disorder manifests as multiple motor and verbal tics that emerge after exposure to dopamine receptor-blocking agents. The tics generally resemble those of primary tic disorders, exhibiting suppressibility, build-up of tension before the tic and release of tension afterwards.30 31 Tardive tremor This was first proposed as an entity in a 1992 report of five patients with a 3–5 Hz postural and action greater than rest tremor but without parkinsonism.32 Although similar to parkinsonian tremor, tardive tremor is distinguished by its postural and kinetic (rather than rest) predominance, its coarse disabling nature, its lack of levodopa responsiveness and its occasional improvement with further dopaminergic blockade or tetrabenazine.32 33 The syndrome generally persists despite withdrawal of dopamine receptor-blocking agents. Tardive myoclonus This describes brief, upper-limb predominant postural myoclonic movements that are said to result from long-term dopaminergic blockade.34 35 However, there is only very limited literature on this entity, which should therefore be interpreted with caution.34 35 Tardive gait This is a poorly characterised and non-uniform phenomenon, with gait disturbances having been described as ‘dancing’ (multiple short steps followed by a long step) or ‘duck-like’ (broad based with short stride length and some steppage features). Other abnormalities include walking with initial floor contact with toes rather than heels, spastic qualities and abnormal arm swing.36 Some ‘atypical’ presentations Patients with tardive syndromes not infrequently exhibit other less recognised, but nonetheless characteristic features that point towards the diagnosis. Among these, the most important are respiratory phenomena, tardive Pisa syndrome and withdrawal emergent dyskinesia. Respiratory dyskinesia First described in 1964, respiratory dyskinesia involves periodic disturbances of ventilatory rate, rhythm and amplitude, sometimes with ventilatory pauses or forced inspiration against a closed glottis.37 Patients may complain of dyspnoea or dysphonia, or may be seen to huff, grunt, gasp or take short, rapid breaths.38 These phenomena often accompany other more classic tardive motor features. Tardive Pisa syndrome This phenomenon, predominantly affecting older women, describes a drug-induced persistent truncal dystonia manifesting as tonic lateral flexion, occasionally with slight rotation.39 The ‘laterally leaning patient’ is an important clue to a tardive aetiology. Withdrawal emergent dyskinesia This syndrome is considered a variant of tardive dyskinesia, which generally develops after either abruptly stopping or significantly reducing the dose of neuroleptic medications.40 It predominantly affects children and usually manifests as generalised chorea (as opposed to the facial-predominant movements observed in classic tardive dyskinesia). It is usually self-limiting and resolves after days to weeks.40 Tardive oculogyric crises Oculogyric crises were originally described as being characteristic of encephalitis lethargica, although now they are more commonly associated with medication-related acute dystonic reactions (as well as dopamine synthesis pathway defects). However, oculogyric crises can also rarely develop as a tardive phenomenon in patients chronically exposed to antipsychotic medications.41 42 Tardive oculogyric crises often accompany other tardive motor phenomena and may go unrecognised. They are sometimes associated with transient recurrences of psychiatric symptoms, including anxiety, auditory hallucinations and bizarre behaviour.41 Tardive pain syndromes A variety of tardive pain syndromes have also been described, temporally associated with neuroleptic use and often responding to standard tardive syndrome treatments. Examples include tardive oral pain, which describes an uncomfortable, often burning sensation in the mouth and lips, and painful genital syndrome, with similar affliction of the genital region.43 Tardive bruxism Bruxism, of either the grinding or mixed grinding-clenching type, may develop as a side effect of long-term neuroleptic exposure. It probably represents a forme fruste of tardive oromandibular dystonia.44 A striking feature of the syndrome is noise production, sometimes sufficiently severe to annoy roommates. The movements disappear during sleep. Assessing the severity of tardive syndromes Before prescribing dopamine receptor-blocking drugs, clinicians should strive to document the presence or absence of abnormal involuntary movements. While both physician and nurse-led standardised assessment tools (such as the abnormal involuntary movement scale and ScanMove instrument, respectively) may not always be practical in the busy clinical setting,45 46 a focused examination is nevertheless important. It was recognised over 140 years ago that psychiatric patients may exhibit stereotypies, chorea or abnormal facial grimacing as a result of their disease—failure to document this before treatment may lead to these later being misattributed to a drug effect.47 48 It has also been suggested that some older people develop spontaneous movements of the face as part of normal ageing. Whether this is true or merely represents the emergence of facial or craniocervical dystonic syndromes with age is yet to be resolved. FACTS AND FALLACIES Myth number 1: Second-generation antipsychotics, with their lower D2 binding affinity, have reduced the incidence of tardive syndromes This has been a particularly contentious issue and it is difficult to make a definite statement in either direction. What can be said with certainty is that the introduction of second-generation antipsychotics has not done away with tardive syndromes. Rather, due to rapid uptake in their prescription, including off-label use for mood disorders and sleep, ironically they may have contributed further to the problem. While some studies suggest that the incidence of tardive syndromes with second-generation antipsychotics is not vastly dissimilar from that of their first-generation counterparts,10 49 the largest literature review to date, involving 34, 555 patients treated with antipsychotics across 56 studies, found an annualised incidence rate of 2.98% with second-generation antipsychotics versus 7.7% with first-generation antipsychotics, supporting the claim that second-generation antipsychotics may indeed carry a lower risk.50 A recent large meta-analysis of 57 studies on tardive syndromes also supported this.9 Myth number 2: Prolonged exposure to a causative drug is necessary to be at risk of tardive syndromes Although, as detailed above, the cumulative risk of tardive syndromes increases year-on-year and most patients develop the disorder after at least 1–2 years of drug exposure,23 24 there are reports of its occurrence after just a single dose of neuroleptic. Prolonged drug exposure is therefore not always necessary. Myth number 3: Some neuroleptics are safe The recognition that first-generation (‘typical’) antipsychotics were associated with a number of extrapyramidal side-effects prompted the development of newer compounds, termed ‘atypical’ antipsychotics, which were supposedly defined by the absence of extrapyramidal symptoms at therapeutic doses. Numerous mechanistic differences of these newer compounds, including effects on serotonergic signaling, more rapid dissociation from the D2 receptor, limbic selectivity and in the case of aripiprazole, partial dopaminergic agonism were posited as the reason behind their more favourable side effect profiles. While it is true that not every neuroleptic has the same propensity to cause tardive syndromes, none is devoid of risk. All classes of antipsychotics can produce tardive syndromes.20 51 Nevertheless, newer ‘atypical’ agents probably carry about half the risk of producing later tardive syndromes as compared with their ‘typical’ counterparts.9 Furthermore, it is important to remember that it is not just neuroleptics that are implicated in the development of tardive syndromes (table 1). Differential diagnoses not to miss, and how to spot them Differentiating spontaneous from drug-induced movement disorders in patients with psychiatric illness can be a challenging endeavour. Nonetheless, it is imperative to give adequate thought to excluding important differential diagnoses that can present with the combination of psychiatric disease and abnormal movements,29 and particularly the following conditions: Huntington’s disease As a trinucleotide repeat expansion disorder with the cardinal manifestations of chorea, psychiatric disease and cognitive decline, Huntington’s disease is one of the most important differential diagnoses of tardive dyskinesia. Psychiatric disease (often requiring neuroleptic treatment) can precede the development of hyperkinetic movements in this condition by several years. Inexperienced observers can therefore easily misdiagnose such hyperkinetic movements as tardive. In this setting, there are some particularly helpful clinical clues52 including Hyperkinetic movements: In tardive dyskinesia, these movements tend to be stereotyped and semi-purposeful, as opposed to the random, flowing movements of chorea that typify Huntington’s disease. Topographical distribution: In tardive syndromes, the movements are predominately lower facial and axial, manifesting as retrocollis and opisthotonus. In contrast, patients with Huntington’s disease often have significant limb chorea, which is unusual in tardive syndromes. Hyperkinetic movements of the frontalis muscle are also common in Huntington’s disease but uncommon in tardive syndromes. Eye movements: Eye movement disorders are often a prominent, early feature of Huntington’s disease. They can involve disorders of saccadic initiation, broken pursuits and gaze impersistence. However, in tardive dystonia, the eye movements are generally normal. Thus, a careful oculomotor examination is an important part of the evaluation of all tardive syndromes. Motor impersistence (of grip, tongue protrusion or gaze fixation): This is a classic feature of Huntington’s disease but is very uncommon in tardive dyskinesia, and therefore a valuable clinical sign. Other features: Akathisia and opisthotonus strongly suggest tardive syndromes. Conversely, a family history suggesting dominant inheritance and caudate atrophy on MR scan of brain would suggest Huntington’s disease. Anti-NMDA receptor encephalitis Several autoimmune movement disorders can have co-existent neurobehavioural features, which are extensively reviewed elsewhere.53 Anti-NMDA receptor encephalitis in particular however, could be confused with tardive dyskinesia, due to the prominent stereotyped perioral dyskinesia that typifies the disorder. The condition presents differently depending on age: children have more ‘neurological’ (seizures, movement disorders) phenotypes, while adults tend to present with neurobehavioural syndromes, which can be mistaken for psychosis.54 Sometimes, the neuropsychiatric features require neuroleptic treatment, creating an additional pitfall in the diagnostic pathway. A ‘full house’ of symptoms, including autonomic dysfunction, generally develops within 1 month.54 Clinical suspicion should prompt testing for the causative antibody in serum and cerebrospinal fluid. Wilson’s disease This condition should always be kept in the differential diagnosis of any movement disorder, especially in patients under the age of 40 years (though late presentations are reported). Psychiatric symptoms are common in Wilson’s disease, and perioral movements are also classic. However, they tend to assume a more dystonic quality, frequently producing risus sardonicus. Dysarthria and drooling are also common in Wilson’s disease, but unusual in tardive dyskinesia. Edentulous dyskinesia This hyperkinetic movement disorder affects 15% of the edentulous population,55 manifesting as stereotyped, choreiform perioral and lip movements which bear striking resemblance to tardive oro-bucco-lingual dyskinesia. It presents in people with partial or complete edentulism, and often resolves or significantly improves with the introduction of dentures to the mouth. Its pathogenesis is thought to relate to altered sensory feedback from oral structures as a result of malocclusion. Meige syndrome This primary dystonic disorder mostly affects women in their 50s and 60s, being characterised by the combination of blepharospasm and oromandibular dystonia. Differentiation from tardive conditions on purely clinical grounds can be particularly difficult; hence, a history of exposure to dopamine receptor-blocking agents is critical to explore thoroughly in the history. TREATMENT The management of tardive syndromes should incorporate three key aspects. First, prevention is always better than cure. As such, medications with documented potential for inducing tardive syndromes should be used at the lowest possible dose for the shortest period of time possible. This may of course not always be possible. Second comes the question of medication withdrawal. In actual fact, the evidence that withdrawing the offending drug significantly alters the natural history of tardive syndromes is not as strong as one might think.56 Nevertheless, this is an intuitive move in clinical medicine—remove the thing that is causing the problem. Most movement disorder physicians would therefore advocate stopping the offending dopamine receptor-blocking agent, or at least changing it to a drug with less potential for tardive phenomena, if possible. The alternative drug of choice in this setting is often clozapine, both due to its proven efficacy in the treatment of and its lower risk of inducing tardive syndromes.57–59 Close consultation with psychiatric services is necessary before embarking on such a course of action. It is also important to realise that tardive symptoms may initially worsen following neuroleptic drug withdrawal and that equally the symptoms may be suppressed by switching to a more potent dopamine receptor-blocking agent.60 Finally comes the question of symptomatic treatments for tardive syndromes. Numerous agents have been trialled in this regard, with varying evidence for their effectiveness. As mentioned earlier, tardive syndromes are often a complex medley of different movement disorders, and approaches that may work for one movement may worsen another. It is therefore important to adopt a tailored approach, focused on addressing the issue that primarily bothers the patient; generally, this will be either tardive dyskinesia or tardive dystonia. Concerning tardive dyskinesia, the mainstay of medical treatment resides around the administration of vesicular monoamine transporter-2 (VMAT-2) inhibitors (tetrabenazine, deutetrabenazine, valbenazine—the latter two being the only Food and Drug Administration-approved drugs for the treatment of tardive dystonia), which act through presynaptic dopamine depletion. The main side effects of these medications are the development of reversible parkinsonism, as well as dose-dependent mood changes, particularly in the elderly; the side effect profiles of deutetrabenazine and valbenazine appear significantly more favourable.61 Other compounds worth mentioning include amantadine, which has shown antidyskinetic properties in multiple controlled and uncontrolled studies, and is supported by American Academy of Neurology guidelines for short-term treatment of tardive dyskinesia. Propranolol has surprisingly good data to support its use, though this is likely due to its effect of increasing neuroleptic drug concentrations.47 Clonazepam also appears effective, though in the randomised controlled trial setting it appeared to lose its efficacy after 5–8 months and thus can only be tentatively recommended for short-term use. Several antioxidants have also been trialled but data on their efficacy are largely inconclusive.60 Other options such as additional dopaminergic blockade, for example, with haloperidol, have proven efficacy in reducing tardive dyskinesia, at least in the short term. However, this comes at the cost of an increase in akinetic rigid syndromes. Furthermore, there are insufficient data on the long-term effects of such approaches, and given that these agents have great propensity to cause tardive syndromes, additional potent dopaminergic blockade is not recommended as a treatment for these conditions.60 Botulinum toxin is an effective option for tardive dystonia.23 Trihexyphenidyl can also improve dystonic syndromes, though occasionally at the cost of worsening dyskinesia. Functional neurosurgery is gaining increasing recognition as a treatment for both tardive dyskinesia and dystonia. Indeed, pallidal deep-brain stimulation can be greatly beneficial, and early referral to a centre with experience in this procedure should be encouraged in refractory or debilitating cases.62 Physicians may be reluctant to recommend this procedure due to the risk of worsening underlying psychiatric comorbidity, though in practice, this is seldom an issue, especially with pallidal targets.62 Pallidotomy can also be considered in poor surgical candidates. Tardive akathisia can be equally bothersome, but there is little evidence regarding its optimal treatment. Clonidine, moclobemide and benzodiazepines as well as electroconvulsive therapy have been used in some instances, with varying degrees of success.63–66 Tardive pain syndromes often respond to VMAT-2 inhibitors, though other options such as electroconvulsive therapy have been used.43 Withdrawal emergent dyskinesia often settles spontaneously over a few weeks without treatment. Severe symptoms can however be managed by reintroduction of the offending drug, followed by a slower taper. PATIENT OUTCOMES In an ideal world, patients developing tardive syndromes would have their causative neuroleptic treatment stopped. Then, and only then, could the true reversibility of the syndrome be assessed. However, the nature of psychiatric disease means that ongoing treatment is often needed, making it difficult to assess the outcomes of tardive syndromes. Predictors of poor outcome appear similar to those of developing tardive syndromes in the first place and include advanced age, longer duration of antipsychotic treatment and greater cumulative dose.67 Once established, the severity of tardive syndromes often fluctuates over time, though in a significant proportion, the tardive syndrome fails to resolve.56 68 Key points Tardive syndromes can comprise many characteristic movement disorders; each needs to be carefully sought in suspected cases Clozapine is the drug of choice for patients with tardive syndromes who require ongoing neuroleptic treatment Vesicular monoamine transporter-2 (VMAT-2) inhibitors, such as tetrabenazine, deutetrabenazine and valbenazine, are the best medical treatment options for tardive dyskinesia Pallidal deep-brain stimulation is an effective treatment option in refractory or debilitating tardive syndromes REFERENCES ↵Faurbye A, Rasch P-J, Petersen PB, et al. Neurological symptoms in pharmacotherapy of psychoses. Acta Psychiatr Scand 1964;40:10–27. doi: 10.1111/j.1600-0447.1964.tb05731.x ↵Browne S, Roe M, Lane A, et al. Quality of life in schizophrenia: relationship to sociodemographic factors, symptomatology and tardive dyskinesia. Acta Psychiatr Scand 1996;94:118–24. doi: 10.1111/j.1600-0447.1996.tb09835.x ↵Ballesteros J, González-Pinto A, Bulbena A. Tardive dyskinesia associated with higher mortality in psychiatric patients: results of a meta-analysis of seven independent studies. J Clin Psychopharmacol 2000;20:188–94. doi: 10.1097/00004714-200004000-00011 ↵Lerner V, Miodownik C. Motor symptoms of schizophrenia: is tardive dyskinesia a symptom or side effect? A modern treatment. Curr Psychiatry Rep 2011;13:295–304. doi: 10.1007/s11920-011-0202-6OpenUrlPubMed ↵Dressler D. Tardive dystonic syndrome induced by the calcium-channel blocker amlodipine. J Neural Transm 2014;121:367–9. doi: 10.1007/s00702-013-1108-8OpenUrl ↵Caroff SN, Hurford I, Lybrand J, et al. Movement disorders induced by antipsychotic drugs: implications of the CATIE schizophrenia trial. Neurol Clin 2011;29:127–48. doi: 10.1016/j.ncl.2010.10.002OpenUrlCrossRefPubMed ↵Woods SW, Morgenstern H, Saksa JR, et al. Incidence of tardive dyskinesia with atypical versus conventional antipsychotic medications. J Clin Psychiatry 2010;71:463–74. doi: 10.4088/JCP.07m03890yel ↵Leucht S, Kissling W, Davis JM. Second-generation antipsychotics for schizophrenia: can we resolve the conflict? Psychol Med 2009;39:1591. doi: 10.1017/S0033291709005455 ↵Carbon M, Kane JM, Leucht S, et al. Tardive dyskinesia risk with first‐ and second‐generation antipsychotics in comparative randomized controlled trials: a meta‐analysis. World Psychiatry 2018;17:330–40. doi: 10.1002/wps.20579OpenUrl ↵Miller DD, Caroff SN, Davis SM, et al. Extrapyramidal side-effects of antipsychotics in a randomised trial. Br J Psychiatry 2008;193:279–88. doi: 10.1192/bjp.bp.108.050088 ↵Solmi M, Murru A, Pacchiarotti I, et al. Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review. Ther Clin Risk Manag 2017;13:757–77. doi: 10.2147/TCRM.S117321OpenUrl ↵D’Abreu A, Akbar U, Friedman JH. Tardive dyskinesia: epidemiology. J Neurol Sci 2018;389:17–20. doi: 10.1016/j.jns.2018.02.007OpenUrl ↵Jeste DV, Wyatt RJ. Changing epidemiology of tardive dyskinesia: an overview. Am J Psychiatry 1981;138:297–309. doi: 10.1176/ajp.138.3.297 ↵Tarsy D, Baldessarini RJ. Epidemiology of tardive dyskinesia: is risk declining with modern antipsychotics? Mov Disord 2006;21:589–98. doi: 10.1002/mds.20823 ↵Morgenstern H. Identifying risk factors for tardive dyskinesia among long-term outpatients maintained with neuroleptic medications. Arch Gen Psychiatry 1993;50:723. doi: 10.1001/archpsyc.1993.01820210057007 Kane JM, Woerner M, Weinhold P, et al. Incidence of tardive dyskinesia: five-year data from a prospective study. Psychopharmacol Bull 1984;20:387–9. ↵Yassa R, Jeste DV. Gender differences in tardive dyskinesia: a critical review of the literature. Schizophr Bull 1992;18:701–15. doi: 10.1093/schbul/18.4.701 ↵Corrigan PW, Liberman RP, Engel JD. From noncompliance to collaboration in the treatment of schizophrenia. Psychiatr Serv 1990;41:1203–11. doi: 10.1176/ps.41.11.1203OpenUrlCrossRefPubMed ↵Wonodi I, Adami HM, Cassady SL, et al. Ethnicity and the course of tardive dyskinesia in outpatients presenting to the motor disorders clinic at the maryland psychiatric research center. J Clin Psychopharmacol 2004;24:592–8. doi: 10.1097/ ↵Kim J, MacMaster E, Schwartz T. Tardive dyskinesia in patients treated with atypical antipsychotics: case series and brief review of etiologic and treatment considerations. Drugs Context 2014;3:1–9. doi: 10.7573/dic.212259OpenUrl ↵Go CL, Rosales RL, Caraos RJ, et al. The current prevalence and factors associated with tardive dyskinesia among Filipino schizophrenic patients. Parkinsonism Relat Disord 2009;15:655–9. doi: 10.1016/j.parkreldis.2009.02.015OpenUrlCrossRefPubMed ↵Teo JT, Edwards MJ, Bhatia K. Tardive dyskinesia is caused by maladaptive synaptic plasticity: a hypothesis. Mov Disord 2012;27:1205–15. doi: 10.1002/mds.25107OpenUrlCrossRefPubMed ↵Waln O, Jankovic J. An update on tardive dyskinesia: from phenomenology to treatment. Tremor Other Hyperkinet Mov (N Y) 2013;3. doi: 10.7916/D88P5Z71 ↵Kiriakakis V. The natural history of tardive dystonia. A long-term follow-up study of 107 cases. Brain 1998;121:2053–66. doi: 10.1093/brain/121.11.2053 ↵Nielsen EB, Lyon M. Evidence for cell loss in corpus striatum after long-term treatment with a neuroleptic drug (flupenthixol) in rats. Psychopharmacology (Berl) 1978;59:85–9. doi: 10.1007/BF00428036OpenUrlCrossRefPubMed ↵Gittis AH, Leventhal DK, Fensterheim BA, et al. selective inhibition of striatal fast-spiking interneurons causes dyskinesias. J Neurosci 2011;31:15727–31. doi: 10.1523/JNEUROSCI.3875-11.2011 ↵De Keyser J. Excitotoxic mechanisms may be involved in the pathophysiology of tardive dyskinesia. Clin Neuropharmacol 1991;14:562–6. doi: 10.1097/00002826-199112000-00009 ↵Lee H-J, Kang S-G. Genetics of tardive dyskinesia. Int Rev Neurobiol 2011;231–64. doi: 10.1016/B978-0-12-381328-2.00010-9 ↵Bhidayasiri R, Boonyawairoj S. Spectrum of tardive syndromes: clinical recognition and management. Postgrad Med J 2011;87:132–41. doi: 10.1136/pgmj.2010.103234 ↵Bharucha KJ, Sethi KD. Tardive tourettism after exposure to neuroleptic therapy. Mov Disord 1995;10:791–3. doi: 10.1002/mds.870100613 ↵Fountoulakis KN, Samara M, Siapera M, et al. Tardive tourette-like syndrome. Int Clin Psychopharmacol 2011;26:237–42. doi: 10.1097/YIC.0b013e32834aa924OpenUrlPubMed ↵Stacy M, Jankovic J. Tardive tremor. Mov Disord 1992;7:53–7. doi: 10.1002/mds.870070110 ↵Kertesz DP, Swartz MV, Tadger S, et al. Tetrabenazine for tardive tremor in elderly adults. Clin Neuropharmacol 2015;38:23–5. doi: 10.1097/WNF.0000000000000061OpenUrl ↵Little JT, Jankovic J. Tardive myoclonus. Mov Disord 1987;2:307–11. doi: 10.1002/mds.870020408OpenUrlCrossRefPubMed ↵Tominaga H, Fukuzako H, Izumi K, et al. Tardive myoclonus. Lancet 1987;329:322. doi: 10.1016/S0140-6736(87)92042-3 ↵S-H K, Jankovic J. Tardive gait. Clin Neurol Neurosurg 2008;110:198–201. doi: 10.1016/j.clineuro.2007.09.013OpenUrlPubMed ↵Hunter R, Earl CJ, Thornicroft S. Toxicity of psychotropic drugs. Proc R Soc Med 1964;57:758–62. doi: 10.1177/003591576405700835 ↵Rich MW, Radwany SM. Respiratory dyskinesia. Chest 1994;105:1826–32. doi: 10.1378/chest.105.6.1826OpenUrlCrossRefPubMed ↵Suzuki T, Matsuzaka H. Drug-induced Pisa syndrome (pleurothotonus). CNS Drugs 2002;16:165–74. doi: 10.2165/00023210-200216030-00003OpenUrlCrossRefPubMed ↵Mejia NI, Jankovic J. Tardive dyskinesia and withdrawal emergent syndrome in children. Expert Rev Neurother 2010;10:893–901. doi: 10.1586/ern.10.58 ↵Sachdev P. Tardive and chronically recurrent oculogyric crises. Mov Disord 1993;8:93–7. doi: 10.1002/mds.870080117OpenUrlCrossRefPubMed ↵FitzGerald PM, Jankovic J. Tardive oculogyric crises. Neurology 1989;39:1434–1434. doi: 10.1212/WNL.39.11.1434OpenUrl ↵Ford B, Greene P, Fahn S. Oral and genital tardive pain syndromes. Neurology 1994;44:2115–2115. doi: 10.1212/WNL.44.11.2115OpenUrl ↵Micheli F, Pardal MF, Gatto M, et al. Bruxism secondary to chronic antidopaminergic drug exposure. Clin Neuropharmacol 1993;16:315–23. doi: 10.1097/00002826-199308000-00003OpenUrlPubMed ↵Lane RD, Glazer WM, Hansen TE, et al. Assessment of tardive dyskinesia using the abnormal involuntary movement scale. J Nerv Ment Dis 1985;173:353–7. doi: 10.1097/00005053-198506000-00005 ↵Balint B, Killaspy H, Marston L, et al. Development and clinimetric assessment of a nurse-administered screening tool for movement disorders in psychosis. BJPsych Open 2018;4:404–10. doi: 10.1192/bjo.2018.55OpenUrl ↵Lerner PP, Miodownik C, Lerner V. Tardive dyskinesia (syndrome): current concept and modern approaches to its management. Psychiatry Clin Neurosci 2015;69:321–34. doi: 10.1111/pcn.12270OpenUrlCrossRefPubMed ↵Fenton WS. Prevalence of spontaneous dyskinesia in schizophrenia. J Clin Psychiatry 2000;61:10–14.OpenUrl ↵Peluso MJ, Lewis SW, Barnes TRE, et al. Extrapyramidal motor side-effects of first- and second-generation antipsychotic drugs. Br J Psychiatry 2012;200:387–92. doi: 10.1192/bjp.bp.111.101485 ↵Correll CU, Schenk EM. Tardive dyskinesia and new antipsychotics. Curr Opin Psychiatry 2008;21:151–6. doi: 10.1097/YCO.0b013e3282f53132 ↵Ertugrul A, Demir B. Clozapine-induced tardive dyskinesia: a case report. Prog Neuro-Psychopharmacology Biol Psychiatry 2005;29:633–5. doi: 10.1016/j.pnpbp.2005.01.014OpenUrl ↵Kumar H, Jog M. Missing Huntington’s disease for tardive dyskinesia: a preventable error. Can J Neurol Sci/J Can Des Sci Neurol 2011;38:762–4. doi: 10.1017/S0317167100012294OpenUrl ↵Balint B, Vincent A, Meinck H-M, et al. Movement disorders with neuronal antibodies: syndromic approach, genetic parallels and pathophysiology. Brain 2018;141:13–36. doi: 10.1093/brain/awx189OpenUrlCrossRefPubMed ↵Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013;12:157–65. doi: 10.1016/S1474-4422(12)70310-1 ↵Koller WC. Edentulous orodyskinesia. Ann Neurol 1983;13:97–9. doi: 10.1002/ana.410130121 ↵Gardos G, Casey DE, Cole JO, et al. Ten-year outcome of tardive dyskinesia. Am J Psychiatry 1994;151:836–41. doi: 10.1176/ajp.151.6.836 ↵Kane JM, Woerner MG, Pollack S, et al. Does clozapine cause tardive dyskinesia? J Clin Psychiatry 1993;54:327–30. ↵Pardis P, Remington G, Panda R, et al. Clozapine and tardive dyskinesia in patients with schizophrenia: a systematic review. J Psychopharmacol 2019;33:1187–98. doi: 10.1177/0269881119862535OpenUrl ↵Mentzel TQ, van der Snoek R, Lieverse R, et al. Clozapine monotherapy as a treatment for antipsychotic-induced tardive dyskinesia. J Clin Psychiatry 2018;79. doi: 10.4088/JCP.17r11852 ↵Bhidayasiri R, Fahn S, Weiner WJ, et al. Evidence-based guideline: treatment of tardive syndromes. Neurology 2013;81:463–9. doi: 10.1212/WNL.0b013e31829d86b6OpenUrl ↵Touma KTB, Scarff JR. Valbenazine and deutetrabenazine for tardive dyskinesia. Innov Clin Neurosci 2018;15:13–16.OpenUrl ↵Macerollo A, Deuschl G. Deep brain stimulation for tardive syndromes: systematic review and meta-analysis. J Neurol Sci 2018;389:55–60. doi: 10.1016/j.jns.2018.02.013OpenUrl ↵Peng L-Y, Lee Y, Lin P-Y. Electroconvulsive therapy for a patient with persistent tardive dyskinesia. J Ect 2013;29:e52–4. doi: 10.1097/YCT.0b013e31829e0aeaOpenUrl ↵Amann B, Erfurth A, Grunze H. Treatment of tardive akathisia with clonidine: a case report. Int J Neuropsychopharmacol 1999;2:S1461145799001376. doi: 10.1017/S1461145799001376 ↵Emmanuel T. Remission of treatment-resistant depression with tardive akathisia with electroconvulsive therapy. BMJ Case Rep 2019;12:e229714. doi: 10.1136/bcr-2019-229714 ↵Ebert D, Demling J. Successful treatment of tardive akathisia with moclobemide, a reversible and selective monoamine-oxidase-a inhibitor. Pharmacopsychiatry 1991;24:229–31. doi: 10.1055/s-2007-1014473OpenUrlPubMed ↵Cavallaro R, Regazzetti MG, Mundo E, et al. Tardive dyskinesia outcomes: clinical and pharmacologic correlates of remission and persistence. Neuropsychopharmacology 1993;8:233–9. doi: 10.1038/npp.1993.26 ↵Kane JM, Woerner M, Borenstein M, et al. Integrating incidence and prevalence of tardive dyskinesia. Psychopharmacol Bull 1986;22:254–8.


Cancer-related cognitive impairment is an important complication in cancer patients,
yet the underlying mechanisms remain unknown. Over the last decade, the field of paraneoplastic neurological syndromes has been dramatically changed by the discovery of new neuronal autoantibodies, some of them…


Description An Indian woman in her 40s without any medical or psychiatric history presented with a seizure. She had become uncharacteristically quiet before suddenly cackling and banging her hands and feet repeatedly. She developed facial and upper limb dystonic posturing including the extension of one arm. The acute onset, short duration, loss of responsiveness and unilateral dystonic posturing were compatible with a frontal lobe seizure. Several episodes occurred during transfer to the hospital, each lasting 3–30 min. CT head imaging was unremarkable (figure 1). Figure 1 CT head reported as normal. She was discharged and seen in ambulatory care 3 days later. Her lymphocytosis, neutrophilia (described as ‘reactive’) and elevated creatine kinase (10 006 IU/L) were attributed to recent motor seizure activity, despite the broad differential. An electroencephalogram, brain MRI and neurology appointment were arranged, in accordance with the Trust’s ‘first fit’ pathway, which mandates follow-up within 2 weeks, similar to the established National Institute for Health and Care Excellence guidelines.1 Five days later, she was brought back to hospital: she had become increasingly withdrawn, expressing a delusion that ‘someone’ was controlling her. She had stopped recognising her children. On examination, she stared unblinkingly and demonstrated echolalia, echopraxia and stereotyped, repetitive, slow rotation of both wrists. However, she had intervals of apparent lucidity when she was able to answer simple questions. Physical examination was limited by behavioural disturbance, but no other abnormal neurological signs were noted. This syndrome of frontal lobe seizures, acute psychiatric disturbance, unusual mixed hyperkinetic movement disorder and encephalopathy with normal CT brain imaging was suggestive of N-methyl D-aspartate (NMDA) receptor encephalitis. In particular, her movements did not fit more common disorders such as tremor, chorea, myoclonus, dystonia or tics and had a bizarre appearance that experts have found difficult to classify.2 However, an MRI brain revealed a 18×16×17 mm ring-enhancing intra-axial lesion at the frontal pole with extensive surrounding vasogenic oedema and mass effect (figure 2). Given the neutrophilia and lymphocytosis, an infective lesion (particularly a tuberculoma due to her ethnicity) was then considered the foremost differential. Figure 2 MRI head showing a frontal lobe ring-enhancing lesion (left), with extensive surrounding oedema (right). She was transferred to a tertiary neuroscience centre, where investigations interrogating an infectious process were negative, including lumbar puncture, QuantiFERON, cysticercal, HIV and fungal serology. A chest–abdomen–pelvis CT was normal. A brain biopsy revealed a grade IV glioblastoma. She has been treated with levetiracetam, radiotherapy and temozolomide. Her psychiatric and motor symptoms have resolved since treatment and she has been seizure-free for 6 months. We attribute her previous symptoms to ictal activity. Glioblastoma multiforme accounts for >60% of all adult brain tumours.3 Although presentation can vary depending on the location of the lesion, this case is unusual in that the initial presentation was a phenocopy of NMDA encephalitis and fits clinical criteria for diagnosis.4 However, recognised differentials of NMDA receptor encephalitis are varied, including infective, psychiatric, metabolic, neoplastic, paraneoplastic, cerebrovascular and other inflammatory disorders.4 The orbitofrontal location of this lesion explained all the clinical features. The refutation of the top two clinical differentials (NMDA encephalitis and tuberculoma) highlights the importance of having a wide differential diagnosis with unusual neurological presentations. Learning points Simplified pathways for common presentations like ‘first fits’ can streamline services, but without careful history-taking, complex presentations such as this may be inappropriately funnelled into a standardised pathway. A psychiatric presentation with movement disorder and seizure activity may represent a frontal space-occupying lesion, not necessarily NMDA receptor encephalitis.


To describe the immunotherapy and pharmacological treatments administered to pediatric
patients with NMDARE during inpatient rehabilitation as well as to examine clinical
and demographic variables associated with early functional outcomes.


The Encephalitis Conference 2020 features 15 oral presentations and 24 posters covering all aspects of encephalitis from infectious to autoimmune, Covid-19 and neurology and an exciting book reading and interview with Brian Deer.