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Tardive syndromes | Practical Neurology

Tardive syndromes | Practical Neurology | AntiNMDA | Scoop.it
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. 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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. 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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.
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Neural Antibody Testing in Patients with Suspected Autoimmune Encephalitis | Clinical Chemistry | Oxford Academic

Neural Antibody Testing in Patients with Suspected Autoimmune Encephalitis | Clinical Chemistry | Oxford Academic | AntiNMDA | Scoop.it
AbstractBackground. Autoimmunity is an increasingly recognized cause of encephalitis with a similar prevalence to that of infectious etiologies. Over the past d
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Ten Point Guide to Mental State Examination (MSE) in Psychiatry

Ten Point Guide to Mental State Examination (MSE) in Psychiatry | AntiNMDA | Scoop.it
This 10 point guide to mental state exam (MSE) enhaces your psychiatric evaluation skills. An accurate MSE assists in the diagnosis of mental illness.
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Hallucinations Lead to Ovarian Cancer Diagnosis for Young Woman

Hallucinations Lead to Ovarian Cancer Diagnosis for Young Woman | AntiNMDA | Scoop.it
Lauren went from a psychiatric ward in a local hospital to the ICU....
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Pathophysiology of paraneoplastic and autoimmune encephalitis: genes, infections, and checkpoint inhibitors - Alberto Vogrig, Sergio Muñiz-Castrillo, Virginie Desestret, Bastien Joubert, Jérôme Hon...

Pathophysiology of paraneoplastic and autoimmune encephalitis: genes, infections, and checkpoint inhibitors - Alberto Vogrig, Sergio Muñiz-Castrillo, Virginie Desestret, Bastien Joubert, Jérôme Hon... | AntiNMDA | Scoop.it
Paraneoplastic neurological syndromes (PNSs) are rare complications of systemic cancers that can affect all parts of the central and/or peripheral nervous system. A body of experimental and clinica...
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Relationship between serum NMDA receptor antibodies and response to antipsychotic treatment in first episode psychosis

Relationship between serum NMDA receptor antibodies and response to antipsychotic treatment in first episode psychosis | AntiNMDA | Scoop.it
When psychosis develops in NMDAR antibody encephalitis it usually has an acute or
subacute onset, and antipsychotic treatment may be ineffective and associated with
adverse effects. Serum NMDAR antibodies have been reported in a minority of patients with first episode psychosis (FEP), but their...
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https://www.researchgate.net/publication/343817904_Anti-N-methyl-D-Aspartate_NMDA_Receptor_Encephalitis_A_Case_Report

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Defying the odds, U of T's Carisse Samuel to graduate after spending five months in a coma

Defying the odds, U of T's Carisse Samuel to graduate after spending five months in a coma | AntiNMDA | Scoop.it
When Carisse Samuel joins her fellow graduates at the University of Toronto’s virtual convocation this Saturday, the celebration will be both an academic and personal victory.
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Clinical features which predict neuronal surface autoantibodies in new-onset focal epilepsy: implications for immunotherapies | Journal of Neurology, Neurosurgery & Psychiatry

Introduction Neuronal surface-directed antibodies (NSAbs) are considered pathogenic in patients with autoimmune encephalitis (AE). AE commonly presents with prominent seizures and neuropsychiatric features and shows a preferential response to immunotherapies versus anti-seizure medications (ASMs).1–4 This has prompted the introduction of ‘epilepsy of immune aetiology’ within the International League Against Epilepsy (ILAE) 2017 classification.5 The same NSAbs, as well as high levels of antibodies to intraneuronal glutamic acid decarboxylase-65 (GAD65), are also described in the serum of people with more isolated forms of epilepsy, without core features of encephalitis.6–8 In this context, their clinical, aetiological and therapeutic relevance is unclear, but of major potential importance to all neurologists who manage new-onset epilepsy. In our large, prospective, real-world study of new-onset focal epilepsy, we predicted that formes frustes of AE would help identify clinical features suggesting the presence of NSAbs and asked whether detection of these NSAbs should alter patient management. Materials and methods Between 9 December 2011 and 4 November 2015, consecutive adult patients (≥18 years) with a diagnosis of new-onset focal epilepsy and their first seizure within the previous 12 months were prospectively recruited from the routine practice of two epileptologists at the Oxford University Hospitals NHS Foundation Trust. Written informed consent and sera were obtained (Ethical approvals: Oxfordshire RECA 07/Q160X/28 and REC16/YH/0013). Clinical data gathered at onset (online supplemental table 1) included detailed phenotype and investigation results, Quality of Life in Epilepsy-31, Hospital Anxiety and Depression Score, Addenbrooke’s Cognitive Examination (ACE) and modified Rankin Score (mRS); as well as information to inform the Antibody Prevalence in Epilepsy and Encephalopathy (APE2) score (online supplemental table 2)9 10 and diagnostic criteria for possible or definite AE.11 Subsequently, 1-year and 3-year mRS were ascertained from patients with NSAbs. Supplemental material For NSAbs, sera were tested against autoantigen-expressing live HEK293 cells (live cell-based assay; online supplemental table 3), and for reactivity with the surface of live cultured hippocampal neurons, using sensitive protocols.12 13 Autoantibodies to GAD65 were determined using a commercial radioimmunoprecipitation assay. Statistical analysis was conducted in R (V.3.6.1). Dimensionality reduction was performed using Multiple Factor Analysis in ‘FactoMineR’ with up to 10% missing data imputed using missForest. Stepwise Bayesian general linear modelling analysis was undertaken using ‘arm’. Wilson 95% CIs with continuity correction were calculated using ‘DescTools’. Results NSAb findings Of 241 recruited patients, 22 were excluded (online supplemental table 4). Of the remaining 219, median age was 49 years (range 16–91) and 109 (49.8%) were female. In 23/219 (10.5%) patients, serum NSAbs were detected across candidate and novel autoantigens (table 1) including roughly equal frequencies against leucine-rich glioma inactivated-1 (LGI1), contactin-associated protein-like 2 (CASPR2), plus the N-methyl-d-aspartate receptor (NMDAR) and γ-aminobutyric acid A/B receptors (GABAAR and GABABR). An additional five patients had antibodies to the surface of live neurons, without an established autoantigen. Autoantibodies to contactin-2, the glycine receptor and the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) were each found in one patient. No dipeptidyl-peptidase-like protein 6 (DPPX) or high-titre GAD65 antibodies were detected. Overall, from the 23 people with NSAbs, 9 had a clinical diagnosis of AE (7/9 fulfilling published criteria).11 By contrast, none of the 196 without NSAbs had a clinical diagnosis of AE (p<0.0001; Fisher’s exact test). VIEW INLINE VIEW POPUP Table 1 Clinical and laboratory features of patients with epilepsy and positive neuronal surface autoantibodies Factors associated with the presence of NSAbs and AE Dimensionality reduction with multiple factor analysis showed that patients were highly heterogeneous and the modest clustering of those with NSAbs was largely driven by a clinical diagnosis of AE (figure 1A,B). Univariate analysis identified 11 clinical parameters that differed significantly between patients with and without NSAbs: age (p=0.04), ictal piloerection (p=0.02), lesional MRI (p=0.04), self-reported mood disturbance (p=0.007), ACE attention domain (p=0.01), ACE total score (p=0.04), QOLIE-31 score (p=0.02), self-reported neuropsychiatric features (p=0.03), epilepsy risk factors (p=0.05), inflammatory cerebrospinal fluid (CSF; p=0.004) and limbic system lesions on MRI (p=0.0002). A multivariate stepwise regression model allocated weighted scores to six of these: age ≥54 years=+1, self-reported mood disturbance=+1, limbic system lesions on MRI=+2, ictal piloerection=+2.5, ACE attention score ≥16=−1.5 and epilepsy risk factors=−1.5 (figure 1C). The probability of NSAb positivity increased with higher scores (Spearman’s ρ=0.99, p<0.0001; figure 1C) and receiver operating characteristic (ROC) analysis confirmed these features strongly predicted NSAb status (area under the curve (AUC)=0.83; total score ≥0; sensitivity=66.7%, specificity=84.9%; figure 1D). By contrast, the APE2 score performed less well in predicting NSAb status (sensitivity 43.5%, specificity 79.1%, AUC=0.68) and more accurately predicted criteria-defined AE, particularly if associated with NSAbs (sensitivity 85.7%, specificity 78.8%, AUC=0.94; figure 1E). Figure 1 Clinical phenotypes associated with NSAb status in new-onset focal epilepsy. The first two dimensions are shown, highlighting: (A) NSAb-positive (red) or NSAb-negative (grey) status and (B) NSAb-positive (pale red) or NSAb-negative (grey) without encephalitis (dots), or NSAb-positive (dark red) with clinically diagnosed autoimmune encephalitis (triangles). (C) The proportion of patients by total model score. Error bars show 95% CIs. The inset shows the weighting and SE of each factor within the regression model. (D) Receiver operator characteristic (ROC) curve of the total model score for predicting NSAb status across all patients. (E) ROC curve of the APE2 score for predicting NSAb status across all patients (black), patients not meeting the criteria for autoimmune encephalitis (blue), patients meeting the criteria for autoimmune encephalitis (red) and predicting NSAb-positive criteria-confirmed autoimmune encephalitis across all patients. (F) Scatter plot of modified Rankin score in NSAb-positive patients by immunotherapy status over time (Mann-Whitney U test p values<0.05). AE, autoimmune encephalitis; APE2, Antibody Prevalence in Epilepsy and Encephalopathy; epilepsy RF, epilepsy risk factors; MRI limbic Δ, changes within the limbic system on MRI. Comparisons of those with and without AE From 23 patients with NSAbs (table 1), a comparison of those with (n=9) and without (n=14) a clinical diagnosis of AE revealed several differences in the AE cohort: more ASMs (median of 3 vs 1; p=0.0073), more frequent immunotherapies (7/9 vs 0/14, p=0.0001), higher APE2 scores (median of 6 vs 2; p<0.0001), more frequent MRI limbic inflammation (6/9 vs 0/14; p=0.0008) and a trend towards greater positivity of serum IgGs targeting the surface of live neurons (7/9 vs 5/14, p=0.09). Compared with the seven patients administered immunotherapy, those with NSAbs who were not administered immunotherapy showed lower disability after 1 and 3 years (both p<0.05), and 11/16 (68.8%) were asymptomatic at 3-year follow-up (mRS=0 ; figure 1F). Hence, despite no immunotherapy, patients with NSAbs, but without AE, generally showed good outcomes. Discussion In this prospective study of 219 consecutive adults with new-onset focal epilepsy, NSAb status was best predicted by a combination of clinical parameters which closely resemble features observed in AE. Almost half of our patients with NSAbs were diagnosed with AE, and ~30% fulfilled stringent criteria for AE.11 Of those with NSAbs and more isolated forms of epilepsy, without individual features of AE, almost all were treated with ASMs alone and typically remained asymptomatic at long-term follow-up. Overall, these findings suggest that detection of NSAbs in patients with new-onset seizures, but without features of AE, should not alter current clinical management. Our observations should help guide the frequent clinical dilemma of which patients with new-onset seizures to test for autoantibodies and subsequently treat with immunotherapy. Taken together, our data suggest the clinical phenotype is paramount in guiding the relevance of autoantibody results, and provide data to address an outstanding question from a recent ILAE consensus statement.7 This ILAE statement also highlighted controversy over the term ‘autoimmune epilepsy’.7 In routine clinical practice, this nomenclature acts as a valuable signpost and aide memoire when seeing patients with seizures.2 14 However, ‘epilepsy’ carries several social stigmata and is defined by an enduring tendency to seizures. In AE, this lifelong risk is refuted by a recent study,4 despite several forms of AE commonly leading to hippocampal atrophy.2–4 7 10 The alternative concept of acute symptomatic seizures may more accurately capture the nature of seizures in patients with AE. Data-driven modifications to nomenclature will benefit from longer-term follow-up studies. Ictal piloerection, low mood and attention and MRI limbic system changes are recognised features of late-onset AE, particularly in association with LGI1 antibodies.2 4 14 15 The absence of movement disorders or more diffuse cognitive impairment as predictive factors in our model suggests the overall syndrome may reflect a formes frustes of AE. This contrasts with APE2 score parameters,9 which appear to largely reflect more florid features seen in classical AE. Our observational study has several limitations. These include limited CSF autoantibody measurements, which reflected UK practice particularly at the start of the study period. Yet,w ithout this valuable parameter, a diagnosis of NMDAR-antibody encephalitis is still possible.11 Yet, two of our four patients with serum NMDAR antibodies did not have features consistent with encephalitis, likely suggesting detection of clinically unrelated serum antibodies in these cases. In addition, our series in total only identified nine AE cases, although this may be considered substantial given the largely outpatient-based recruitment. This, and the high (~10%) seroprevalence rate, may reflect a referral bias given Oxford’s interest in AE, but is well aligned with other available estimates.6 9 10 Our serological data identified some samples with NSAbs proven by live cell-based assays, but without concomitant cell surface neuronal reactivities. This was especially evident in the cohort without a clinical diagnosis of AE, and perhaps these antibodies reflect low-affinity or low-titre autoantibodies which are not disease relevant. Their specificity, however, remains reassuring given their typical selectivity for just one of eight surface-expressed autoantigens. In the future, our prediction model will benefit from validation in independent, larger studies which may compare the risk of enduring seizures in the NSAb-positive versus NSAb-negative populations, with and without AE, something which we did not survey at follow-up. Hence, we cannot comment on long-term seizure status in the 5/16 patients (31%) who had NSAbs, no diagnosis of AE and 3-year mRS >0. In these patients, it remains possible that immunotherapy would have led to a greater benefit. However, in our view, this finding is more likely to be consistent with the predicted ~30% of all people with epilepsy who are known to become ASM resistant: this provides a testable hypothesis for a future randomised controlled trial. Overall, our observations support the concept that, in patients who present with new-onset focal seizures, clinical features which are consistent with a ‘mild encephalitis’ helps identify those with NSAbs which should alter patient management. This clinico-serological syndrome appeared characteristic and its recognition will improve detection and treatment of these patients. These findings should discourage widespread screening strategies to identify patients with autoantibodies among unselected seizure cohorts. References ↵Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol 2011;69:892–900.doi:10.1002/ana.22307 ↵Thompson J, Bi M, Murchison AG, et al. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain 2018;141:348–56.doi:10.1093/brain/awx323OpenUrlCrossRef ↵Geis C, Planagumà J, Carreño M, et al. Autoimmune seizures and epilepsy. J Clin Invest 2019;129:926–40.doi:10.1172/JCI125178OpenUrlPubMed ↵de Bruijn MAAM, van Sonderen A, van Coevorden-Hameete MH, et al. Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis. Neurology 2019;92:e2185–96.doi:10.1212/WNL.0000000000007475pmid:30979857OpenUrlPubMed ↵Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017;58:512–21.doi:10.1111/epi.13709pmid:http://www.ncbi.nlm.nih.gov/pubmed/28276062OpenUrlPubMed ↵Brenner T, Sills GJ, Hart Y, et al. Prevalence of neurologic autoantibodies in cohorts of patients with new and established epilepsy. Epilepsia 2013;54:1028–35.doi:10.1111/epi.12127pmid:http://www.ncbi.nlm.nih.gov/pubmed/23464826OpenUrlCrossRefPubMed ↵Steriade C, Britton J, Dale RC, et al. Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions. Epilepsia 2020;61:1341–51.doi:10.1111/epi.16571pmid:http://www.ncbi.nlm.nih.gov/pubmed/32544279OpenUrlPubMed ↵von Podewils F, Suesse M, Geithner J, et al. Prevalence and outcome of late-onset seizures due to autoimmune etiology: a prospective observational population-based cohort study. Epilepsia 2017;58:1542–50.doi:10.1111/epi.13834pmid:http://www.ncbi.nlm.nih.gov/pubmed/28681401OpenUrlPubMed ↵Dubey D, Alqallaf A, Hays R, et al. Neurological autoantibody prevalence in epilepsy of unknown etiology. JAMA Neurol 2017;74:397–402.doi:10.1001/jamaneurol.2016.5429pmid:http://www.ncbi.nlm.nih.gov/pubmed/28166327OpenUrlPubMed ↵Dubey D, Kothapalli N, McKeon A, et al. Predictors of neural-specific autoantibodies and immunotherapy response in patients with cognitive dysfunction. J Neuroimmunol 2018;323:62–72.doi:10.1016/j.jneuroim.2018.07.009pmid:http://www.ncbi.nlm.nih.gov/pubmed/30196836OpenUrlPubMed ↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.doi:10.1016/S1474-4422(15)00401-9pmid:http://www.ncbi.nlm.nih.gov/pubmed/26906964OpenUrlCrossRefPubMed ↵Makuch M, Wilson R, Al-Diwani A, et al. N-Methyl-D-aspartate receptor antibody production from germinal center reactions: therapeutic implications. Ann Neurol 2018;83:553–61.doi:10.1002/ana.25173pmid:http://www.ncbi.nlm.nih.gov/pubmed/29406578OpenUrlPubMed ↵Ramberger M, Berretta A, Tan JMM, et al. Distinctive binding properties of human monoclonal LGI1 autoantibodies determine pathogenic mechanisms. Brain 2020;143:1731–45.doi:10.1093/brain/awaa104pmid:http://www.ncbi.nlm.nih.gov/pubmed/32437528OpenUrlPubMed ↵Quek AML, Britton JW, McKeon A, et al. Autoimmune epilepsy: clinical characteristics and response to immunotherapy. Arch Neurol 2012;69:582–93.doi:10.1001/archneurol.2011.2985pmid:http://www.ncbi.nlm.nih.gov/pubmed/22451162OpenUrlCrossRefPubMed ↵Rocamora R, Becerra JL, Fossas P, et al. Pilomotor seizures: an autonomic semiology of limbic encephalitis? Seizure 2014;23:670–3.doi:10.1016/j.seizure.2014.04.013pmid:http://www.ncbi.nlm.nih.gov/pubmed/24890932OpenUrlCrossRefPubMed
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Sleep disorders in autoimmune encephalitis

Sleep disorders in autoimmune encephalitis | AntiNMDA | Scoop.it
Sleep disorders in people with autoimmune encephalitis have received little attention,
probably overshadowed by the presence of other neurological and psychiatric symptoms
in this group of conditions.
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Cerebrospinal fluid CD20 positive B-cell expansion in a case of anti-NMDAR encephalitis - ScienceDirect

Cerebrospinal fluid CD20 positive B-cell expansion in a case of anti-NMDAR encephalitis - ScienceDirect | AntiNMDA | Scoop.it
Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a potentially fatal autoimmune encephalitis with a strong B-cell response. We measured the …
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Clinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis

Clinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis | AntiNMDA | Scoop.it
Serum neuronal autoantibodies, such as those to the NMDA receptor (NMDAR), are detectable in a subgroup of patients with psychotic disorders. It is not known if they are present before the onset of psychosis or whether they are associated with particular clinical features or outcomes. In a case–control study, sera from 254 subjects at clinical high risk (CHR) for psychosis and 116 healthy volunteers were tested for antibodies against multiple neuronal antigens implicated in CNS autoimmune disorders, using fixed and live cell-based assays (CBAs). Within the CHR group, the relationship between NMDAR antibodies and symptoms, cognitive function and clinical outcomes over 24 month follow-up was examined. CHR subjects were not more frequently seropositive for neuronal autoantibodies than controls (8.3% vs. 5.2%; OR = 1.50; 95% CI: 0.58–3.90). The NMDAR was the most common target antigen and NMDAR IgGs were more sensitively detected with live versus fixed CBAs (p < 0.001). Preliminary phenotypic analyses revealed that within the CHR sample, the NMDAR antibody seropositive subjects had higher levels of current depression, performed worse on the Rey Auditory Verbal Learning Task (p < 0.05), and had a markedly lower IQ (p < 0.01). NMDAR IgGs were not more frequent in subjects who later became psychotic than those who did not. NMDAR antibody serostatus and titre was associated with poorer levels of functioning at follow-up (p < 0.05) and the presence of a neuronal autoantibody was associated with larger amygdala volumes (p < 0.05). Altogether, these findings demonstrate that NMDAR autoantibodies are detectable in a subgroup of CHR subjects at equal rates to controls. In the CHR group, they are associated with affective psychopathology, impairments in verbal memory, and overall cognitive function: these findings are qualitatively and individually similar to core features of autoimmune encephalitis and/or animal models of NMDAR antibody-mediated CNS disease. Overall the current work supports further evaluation of NMDAR autoantibodies as a possible prognostic biomarker and aetiological factor in a subset of people already meeting CHR criteria.
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What the acute physician needs to know about Anti-NMDA receptor encephalitis: two case presentations. - The University of Liverpool Repository

What the acute physician needs to know about Anti-NMDA receptor encephalitis: two case presentations. - The University of Liverpool Repository | AntiNMDA | Scoop.it
These case reports look at two patients with anti-N-methyl-D-aspartate receptor (NMDAr) encephalitis presenting to the same acute medical unit within a month of each other. The following covers the characteristic signs, symptoms and timeline associated with this condition and discusses whether we...
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Clinical features which predict neuronal surface autoantibodies in new-onset focal epilepsy: implications for immunotherapies | Journal of Neurology, Neurosurgery & Psychiatry

Introduction Neuronal surface-directed antibodies (NSAbs) are considered pathogenic in patients with autoimmune encephalitis (AE). AE commonly presents with prominent seizures and neuropsychiatric features and shows a preferential response to immunotherapies versus anti-seizure medications (ASMs).1–4 This has prompted the introduction of ‘epilepsy of immune aetiology’ within the International League Against Epilepsy (ILAE) 2017 classification.5 The same NSAbs, as well as high levels of antibodies to intraneuronal glutamic acid decarboxylase-65 (GAD65), are also described in the serum of people with more isolated forms of epilepsy, without core features of encephalitis.6–8 In this context, their clinical, aetiological and therapeutic relevance is unclear, but of major potential importance to all neurologists who manage new-onset epilepsy. In our large, prospective, real-world study of new-onset focal epilepsy, we predicted that formes frustes of AE would help identify clinical features suggesting the presence of NSAbs and asked whether detection of these NSAbs should alter patient management. Materials and methods Between 9 December 2011 and 4 November 2015, consecutive adult patients (≥18 years) with a diagnosis of new-onset focal epilepsy and their first seizure within the previous 12 months were prospectively recruited from the routine practice of two epileptologists at the Oxford University Hospitals NHS Foundation Trust. Written informed consent and sera were obtained (Ethical approvals: Oxfordshire RECA 07/Q160X/28 and REC16/YH/0013). Clinical data gathered at onset (online supplemental table 1) included detailed phenotype and investigation results, Quality of Life in Epilepsy-31, Hospital Anxiety and Depression Score, Addenbrooke’s Cognitive Examination (ACE) and modified Rankin Score (mRS); as well as information to inform the Antibody Prevalence in Epilepsy and Encephalopathy (APE2) score (online supplemental table 2)9 10 and diagnostic criteria for possible or definite AE.11 Subsequently, 1-year and 3-year mRS were ascertained from patients with NSAbs. Supplemental material For NSAbs, sera were tested against autoantigen-expressing live HEK293 cells (live cell-based assay; online supplemental table 3), and for reactivity with the surface of live cultured hippocampal neurons, using sensitive protocols.12 13 Autoantibodies to GAD65 were determined using a commercial radioimmunoprecipitation assay. Statistical analysis was conducted in R (V.3.6.1). Dimensionality reduction was performed using Multiple Factor Analysis in ‘FactoMineR’ with up to 10% missing data imputed using missForest. Stepwise Bayesian general linear modelling analysis was undertaken using ‘arm’. Wilson 95% CIs with continuity correction were calculated using ‘DescTools’. Results NSAb findings Of 241 recruited patients, 22 were excluded (online supplemental table 4). Of the remaining 219, median age was 49 years (range 16–91) and 109 (49.8%) were female. In 23/219 (10.5%) patients, serum NSAbs were detected across candidate and novel autoantigens (table 1) including roughly equal frequencies against leucine-rich glioma inactivated-1 (LGI1), contactin-associated protein-like 2 (CASPR2), plus the N-methyl-d-aspartate receptor (NMDAR) and γ-aminobutyric acid A/B receptors (GABAAR and GABABR). An additional five patients had antibodies to the surface of live neurons, without an established autoantigen. Autoantibodies to contactin-2, the glycine receptor and the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) were each found in one patient. No dipeptidyl-peptidase-like protein 6 (DPPX) or high-titre GAD65 antibodies were detected. Overall, from the 23 people with NSAbs, 9 had a clinical diagnosis of AE (7/9 fulfilling published criteria).11 By contrast, none of the 196 without NSAbs had a clinical diagnosis of AE (p<0.0001; Fisher’s exact test). VIEW INLINE VIEW POPUP Table 1 Clinical and laboratory features of patients with epilepsy and positive neuronal surface autoantibodies Factors associated with the presence of NSAbs and AE Dimensionality reduction with multiple factor analysis showed that patients were highly heterogeneous and the modest clustering of those with NSAbs was largely driven by a clinical diagnosis of AE (figure 1A,B). Univariate analysis identified 11 clinical parameters that differed significantly between patients with and without NSAbs: age (p=0.04), ictal piloerection (p=0.02), lesional MRI (p=0.04), self-reported mood disturbance (p=0.007), ACE attention domain (p=0.01), ACE total score (p=0.04), QOLIE-31 score (p=0.02), self-reported neuropsychiatric features (p=0.03), epilepsy risk factors (p=0.05), inflammatory cerebrospinal fluid (CSF; p=0.004) and limbic system lesions on MRI (p=0.0002). A multivariate stepwise regression model allocated weighted scores to six of these: age ≥54 years=+1, self-reported mood disturbance=+1, limbic system lesions on MRI=+2, ictal piloerection=+2.5, ACE attention score ≥16=−1.5 and epilepsy risk factors=−1.5 (figure 1C). The probability of NSAb positivity increased with higher scores (Spearman’s ρ=0.99, p<0.0001; figure 1C) and receiver operating characteristic (ROC) analysis confirmed these features strongly predicted NSAb status (area under the curve (AUC)=0.83; total score ≥0; sensitivity=66.7%, specificity=84.9%; figure 1D). By contrast, the APE2 score performed less well in predicting NSAb status (sensitivity 43.5%, specificity 79.1%, AUC=0.68) and more accurately predicted criteria-defined AE, particularly if associated with NSAbs (sensitivity 85.7%, specificity 78.8%, AUC=0.94; figure 1E). Figure 1 Clinical phenotypes associated with NSAb status in new-onset focal epilepsy. The first two dimensions are shown, highlighting: (A) NSAb-positive (red) or NSAb-negative (grey) status and (B) NSAb-positive (pale red) or NSAb-negative (grey) without encephalitis (dots), or NSAb-positive (dark red) with clinically diagnosed autoimmune encephalitis (triangles). (C) The proportion of patients by total model score. Error bars show 95% CIs. The inset shows the weighting and SE of each factor within the regression model. (D) Receiver operator characteristic (ROC) curve of the total model score for predicting NSAb status across all patients. (E) ROC curve of the APE2 score for predicting NSAb status across all patients (black), patients not meeting the criteria for autoimmune encephalitis (blue), patients meeting the criteria for autoimmune encephalitis (red) and predicting NSAb-positive criteria-confirmed autoimmune encephalitis across all patients. (F) Scatter plot of modified Rankin score in NSAb-positive patients by immunotherapy status over time (Mann-Whitney U test p values<0.05). AE, autoimmune encephalitis; APE2, Antibody Prevalence in Epilepsy and Encephalopathy; epilepsy RF, epilepsy risk factors; MRI limbic Δ, changes within the limbic system on MRI. Comparisons of those with and without AE From 23 patients with NSAbs (table 1), a comparison of those with (n=9) and without (n=14) a clinical diagnosis of AE revealed several differences in the AE cohort: more ASMs (median of 3 vs 1; p=0.0073), more frequent immunotherapies (7/9 vs 0/14, p=0.0001), higher APE2 scores (median of 6 vs 2; p<0.0001), more frequent MRI limbic inflammation (6/9 vs 0/14; p=0.0008) and a trend towards greater positivity of serum IgGs targeting the surface of live neurons (7/9 vs 5/14, p=0.09). Compared with the seven patients administered immunotherapy, those with NSAbs who were not administered immunotherapy showed lower disability after 1 and 3 years (both p<0.05), and 11/16 (68.8%) were asymptomatic at 3-year follow-up (mRS=0 ; figure 1F). Hence, despite no immunotherapy, patients with NSAbs, but without AE, generally showed good outcomes. Discussion In this prospective study of 219 consecutive adults with new-onset focal epilepsy, NSAb status was best predicted by a combination of clinical parameters which closely resemble features observed in AE. Almost half of our patients with NSAbs were diagnosed with AE, and ~30% fulfilled stringent criteria for AE.11 Of those with NSAbs and more isolated forms of epilepsy, without individual features of AE, almost all were treated with ASMs alone and typically remained asymptomatic at long-term follow-up. Overall, these findings suggest that detection of NSAbs in patients with new-onset seizures, but without features of AE, should not alter current clinical management. Our observations should help guide the frequent clinical dilemma of which patients with new-onset seizures to test for autoantibodies and subsequently treat with immunotherapy. Taken together, our data suggest the clinical phenotype is paramount in guiding the relevance of autoantibody results, and provide data to address an outstanding question from a recent ILAE consensus statement.7 This ILAE statement also highlighted controversy over the term ‘autoimmune epilepsy’.7 In routine clinical practice, this nomenclature acts as a valuable signpost and aide memoire when seeing patients with seizures.2 14 However, ‘epilepsy’ carries several social stigmata and is defined by an enduring tendency to seizures. In AE, this lifelong risk is refuted by a recent study,4 despite several forms of AE commonly leading to hippocampal atrophy.2–4 7 10 The alternative concept of acute symptomatic seizures may more accurately capture the nature of seizures in patients with AE. Data-driven modifications to nomenclature will benefit from longer-term follow-up studies. Ictal piloerection, low mood and attention and MRI limbic system changes are recognised features of late-onset AE, particularly in association with LGI1 antibodies.2 4 14 15 The absence of movement disorders or more diffuse cognitive impairment as predictive factors in our model suggests the overall syndrome may reflect a formes frustes of AE. This contrasts with APE2 score parameters,9 which appear to largely reflect more florid features seen in classical AE. Our observational study has several limitations. These include limited CSF autoantibody measurements, which reflected UK practice particularly at the start of the study period. Yet,w ithout this valuable parameter, a diagnosis of NMDAR-antibody encephalitis is still possible.11 Yet, two of our four patients with serum NMDAR antibodies did not have features consistent with encephalitis, likely suggesting detection of clinically unrelated serum antibodies in these cases. In addition, our series in total only identified nine AE cases, although this may be considered substantial given the largely outpatient-based recruitment. This, and the high (~10%) seroprevalence rate, may reflect a referral bias given Oxford’s interest in AE, but is well aligned with other available estimates.6 9 10 Our serological data identified some samples with NSAbs proven by live cell-based assays, but without concomitant cell surface neuronal reactivities. This was especially evident in the cohort without a clinical diagnosis of AE, and perhaps these antibodies reflect low-affinity or low-titre autoantibodies which are not disease relevant. Their specificity, however, remains reassuring given their typical selectivity for just one of eight surface-expressed autoantigens. In the future, our prediction model will benefit from validation in independent, larger studies which may compare the risk of enduring seizures in the NSAb-positive versus NSAb-negative populations, with and without AE, something which we did not survey at follow-up. Hence, we cannot comment on long-term seizure status in the 5/16 patients (31%) who had NSAbs, no diagnosis of AE and 3-year mRS >0. In these patients, it remains possible that immunotherapy would have led to a greater benefit. However, in our view, this finding is more likely to be consistent with the predicted ~30% of all people with epilepsy who are known to become ASM resistant: this provides a testable hypothesis for a future randomised controlled trial. Overall, our observations support the concept that, in patients who present with new-onset focal seizures, clinical features which are consistent with a ‘mild encephalitis’ helps identify those with NSAbs which should alter patient management. This clinico-serological syndrome appeared characteristic and its recognition will improve detection and treatment of these patients. These findings should discourage widespread screening strategies to identify patients with autoantibodies among unselected seizure cohorts. References ↵Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol 2011;69:892–900.doi:10.1002/ana.22307 ↵Thompson J, Bi M, Murchison AG, et al. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain 2018;141:348–56.doi:10.1093/brain/awx323OpenUrlCrossRef ↵Geis C, Planagumà J, Carreño M, et al. Autoimmune seizures and epilepsy. J Clin Invest 2019;129:926–40.doi:10.1172/JCI125178OpenUrlPubMed ↵de Bruijn MAAM, van Sonderen A, van Coevorden-Hameete MH, et al. Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis. Neurology 2019;92:e2185–96.doi:10.1212/WNL.0000000000007475pmid:30979857OpenUrlPubMed ↵Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017;58:512–21.doi:10.1111/epi.13709pmid:http://www.ncbi.nlm.nih.gov/pubmed/28276062OpenUrlPubMed ↵Brenner T, Sills GJ, Hart Y, et al. Prevalence of neurologic autoantibodies in cohorts of patients with new and established epilepsy. Epilepsia 2013;54:1028–35.doi:10.1111/epi.12127pmid:http://www.ncbi.nlm.nih.gov/pubmed/23464826OpenUrlCrossRefPubMed ↵Steriade C, Britton J, Dale RC, et al. Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions. Epilepsia 2020;61:1341–51.doi:10.1111/epi.16571pmid:http://www.ncbi.nlm.nih.gov/pubmed/32544279OpenUrlPubMed ↵von Podewils F, Suesse M, Geithner J, et al. Prevalence and outcome of late-onset seizures due to autoimmune etiology: a prospective observational population-based cohort study. Epilepsia 2017;58:1542–50.doi:10.1111/epi.13834pmid:http://www.ncbi.nlm.nih.gov/pubmed/28681401OpenUrlPubMed ↵Dubey D, Alqallaf A, Hays R, et al. Neurological autoantibody prevalence in epilepsy of unknown etiology. JAMA Neurol 2017;74:397–402.doi:10.1001/jamaneurol.2016.5429pmid:http://www.ncbi.nlm.nih.gov/pubmed/28166327OpenUrlPubMed ↵Dubey D, Kothapalli N, McKeon A, et al. Predictors of neural-specific autoantibodies and immunotherapy response in patients with cognitive dysfunction. J Neuroimmunol 2018;323:62–72.doi:10.1016/j.jneuroim.2018.07.009pmid:http://www.ncbi.nlm.nih.gov/pubmed/30196836OpenUrlPubMed ↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.doi:10.1016/S1474-4422(15)00401-9pmid:http://www.ncbi.nlm.nih.gov/pubmed/26906964OpenUrlCrossRefPubMed ↵Makuch M, Wilson R, Al-Diwani A, et al. N-Methyl-D-aspartate receptor antibody production from germinal center reactions: therapeutic implications. Ann Neurol 2018;83:553–61.doi:10.1002/ana.25173pmid:http://www.ncbi.nlm.nih.gov/pubmed/29406578OpenUrlPubMed ↵Ramberger M, Berretta A, Tan JMM, et al. Distinctive binding properties of human monoclonal LGI1 autoantibodies determine pathogenic mechanisms. Brain 2020;143:1731–45.doi:10.1093/brain/awaa104pmid:http://www.ncbi.nlm.nih.gov/pubmed/32437528OpenUrlPubMed ↵Quek AML, Britton JW, McKeon A, et al. Autoimmune epilepsy: clinical characteristics and response to immunotherapy. Arch Neurol 2012;69:582–93.doi:10.1001/archneurol.2011.2985pmid:http://www.ncbi.nlm.nih.gov/pubmed/22451162OpenUrlCrossRefPubMed ↵Rocamora R, Becerra JL, Fossas P, et al. Pilomotor seizures: an autonomic semiology of limbic encephalitis? Seizure 2014;23:670–3.doi:10.1016/j.seizure.2014.04.013pmid:http://www.ncbi.nlm.nih.gov/pubmed/24890932OpenUrlCrossRefPubMed
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Specialists and Care Centers for Autoimmune Encephalitis

Specialists and Care Centers for Autoimmune Encephalitis | AntiNMDA | Scoop.it
The Northwestern Medicine Autoimmune Encephalitis and Paraneoplastic Disorders clinic takes a multidiscplinary approach to the diagnosis and care of patients affected by these disorders.
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Neurologic Emergencies at the Extremes of Age

Neurologic Emergencies at the Extremes of Age | AntiNMDA | Scoop.it
The diagnosis and management of neurologic conditions are more complex at the extremes
of age than in the average adult. In the pediatric population, neurologic emergencies
are somewhat rare and some may require emergent consultation.
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(PDF) Anti-N-methyl-D-Aspartate (NMDA) Receptor Encephalitis: A Case Report

(PDF) Anti-N-methyl-D-Aspartate (NMDA) Receptor Encephalitis: A Case Report | AntiNMDA | Scoop.it
PDF | We report case of a 42 years old female who came with a constellation of behavioral symptoms, delirium, body stiffness, and fever for one week....| Find, read and cite all the research you need on ResearchGate...
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RACGP - Old doc, new disease: Anti-NMDA receptor encephalitis

RACGP - Old doc, new disease: Anti-NMDA receptor encephalitis | AntiNMDA | Scoop.it
Dr Casey Parker reflects on an intriguing presentation that made him ask: What else do I not know?
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Cost-Effectiveness of Routine Screening for Autoimmune Encephalitis in Patients With First-Episode Psychosis in the United States |J Clin Psychiatry

Autoimmune encephalitis (AE) is a highly treatable neurologic condition that can cause psychosis. This study estimated the cost-effectiveness of routine screening for AE compared with clinically targeted screening in first-episode psychosis patients.
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Unremitting diarrhoea in a girl diagnosed anti-N-methyl-D-aspartate-receptor encephalitis: A case report | Read by QxMD

Unremitting diarrhoea in a girl diagnosed anti-N-methyl-D-aspartate-receptor encephalitis: A case report | Read by QxMD | AntiNMDA | Scoop.it
Create a free QxMD account to take advantage of the features offered by Read like saving your papers and creating collections. Get Started Unremitting diarrhoea in a girl diagnosed anti-N-methyl-D-aspartate-receptor encephalitis: A case report Norrapat Onpoaree, Montida Veeravigrom, Anapat Sanpavat, Narissara Suratannon, Palittiya Sintusek World Journal of Clinical Cases 2020 October 26, 8 (20): 4866-4875 BACKGROUND: Asymptomatic cytomegalovirus (CMV) infection is common in children; in contrast, in children with a weakened immune system, invasive CMV can occur. This is the first case report of a severe manifestation of CMV esophago-enterocolitis in a girl diagnosed with anti-N-methyl-D-aspartate-receptor (anti-NMDAR) encephalitis who received only a moderate dose of corticosteroid therapy. CASE SUMMARY: A 12-year-old-Thai girl presented with acute behavioural change and headache for 6 d. Electroencephalogram and positivity for NMDAR autoantibodies were compatible with anti-NMDAR encephalitis. Hence, she received pulse methylprednisolone 10 mg/kg per day for 4 d and continued with prednisolone 1.2 mg/kg per day. On day 42 of corticosteroid therapy, she developed unremitting vomiting and diarrhoea. Endoscopy showed multiple ulcers and erythaematous mucosa along the gastrointestinal tract. Tissue CMV viral load and viral-infected cells confirmed CMV esophago-enterocolitis. Therefore, the patient received ganciclovir 5 mg/kg per dose every 12 h for 3 wk and then 5 mg/kg per dose once daily for 3 wk. Unremitting diarrhoea slowly improved from stool output 1-4 L per day to 1-2 L per day after 3 wk of treatment. Pulse methylprednisolone 20 mg/kg for 5 d was initiated and continued with prednisolone 1 mg/kg per day. After this repeated pulse methylprednisolone treatment, surprisingly, diarrhoea subsided. Immunologic work-up was performed to rule out underlying immune deficiency with unremarkable results. CONCLUSION: Unremitting diarrhoea from CMV esophago-enterocolitis subsided with antiviral and methylprednisolone therapy, implying the immune and NMDAR dysregulation in anti-NMDAR encephalitis. Full Text Links We have located links that may give you full text access. Additional links Discussion You are not logged in. Sign Up or Log In to join the discussion. Trending Papers Colchicine in Patients with Chronic Coronary Disease. Stefan M Nidorf, Aernoud T L Fiolet, Arend Mosterd, John W Eikelboom, Astrid Schut, Tjerk S J Opstal, Salem H K The, Xiao-Fang Xu, Mark A Ireland, Timo Lenderink, Donald Latchem, Pieter Hoogslag, Anastazia Jerzewski, Peter Nierop, Alan Whelan, Randall Hendriks, Henk Swart, Jeroen Schaap, Aaf F M Kuijper, Maarten W J van Hessen, Pradyot Saklani, Isabel Tan, Angus G Thompson, Allison Morton, Chris Judkins, Willem A Bax, Maurits Dirksen, Marco M W Alings, Graeme J Hankey, Charley A Budgeon, Jan G P Tijssen, Jan H Cornel, Peter L Thompson New England Journal of Medicine 2020 August 31 Extracorporeal life support for adults with acute respiratory distress syndrome. Alain Combes, Matthieu Schmidt, Carol L Hodgson, Eddy Fan, Niall D Ferguson, John F Fraser, Samir Jaber, Antonio Pesenti, Marco Ranieri, Kathryn Rowan, Kiran Shekar, Arthur S Slutsky, Daniel Brodie Intensive Care Medicine 2020 November 2 Clinical strategies for implementing lung and diaphragm-protective ventilation: avoiding insufficient and excessive effort. Ewan C Goligher, Annemijn H Jonkman, Jose Dianti, Katerina Vaporidi, Jeremy R Beitler, Bhakti K Patel, Takeshi Yoshida, Samir Jaber, Martin Dres, Tommaso Mauri, Giacomo Bellani, Alexandre Demoule, Laurent Brochard, Leo Heunks Intensive Care Medicine 2020 November 2 Emergency Department Management of COVID-19: An Evidence-Based Approach. Nicholas M McManus, Ryan Offman, Jason D Oetman Western Journal of Emergency Medicine 2020 September 25 Glucocorticoids: surprising new findings on their mechanisms of actions. Frank Buttgereit Annals of the Rheumatic Diseases 2020 November 8 Prone position in ARDS patients: why, when, how and for whom. Claude Guérin, Richard K Albert, Jeremy Beitler, Luciano Gattinoni, Samir Jaber, John J Marini, Laveena Munshi, Laurent Papazian, Antonio Pesenti, Antoine Vieillard-Baron, Jordi Mancebo Intensive Care Medicine 2020 November 10 Severe organising pneumonia following COVID-19. István Vadász, Faeq Husain-Syed, Peter Dorfmüller, Fritz C Roller, Khodr Tello, Matthias Hecker, Rory E Morty, Stefan Gattenlöhner, Hans-Dieter Walmrath, Friedrich Grimminger, Susanne Herold, Werner Seeger Thorax 2020 November 11 Analgesia and sedation in patients with ARDS. Gerald Chanques, Jean-Michel Constantin, John W Devlin, E Wesley Ely, Gilles L Fraser, Céline Gélinas, Timothy D Girard, Claude Guérin, Matthieu Jabaudon, Samir Jaber, Sangeeta Mehta, Thomas Langer, Michael J Murray, Pratik Pandharipande, Bhakti Patel, Jean-François Payen, Kathleen Puntillo, Bram Rochwerg, Yahya Shehabi, Thomas Strøm, Hanne Tanghus Olsen, John P Kress Intensive Care Medicine 2020 November 10
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Possible coexistence of MOG-IgG-associated disease and anti-Caspr2 antibody-associated autoimmune encephalitis: a first case report

Possible coexistence of MOG-IgG-associated disease and anti-Caspr2 antibody-associated autoimmune encephalitis: a first case report | AntiNMDA | Scoop.it
Myelin oligodendrocyte glycoprotein antibody-associated disease has been proposed as a separate inflammatory demyelinating disease of the central nervous system (CNS) since the discovery of pathogenic antibodies against myelin oligodendrocyte glycoprotein ...
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The Anti-NMDA Receptor Encephalitis Foundation Newsletter

The Anti-NMDA Receptor Encephalitis Foundation Newsletter | AntiNMDA | Scoop.it
On your Marks, Get Set, Register for the WORLD ENCEPHALITIS DAY CONFERENCE 2021 From...
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Autoimmune encephalitis: When your body attacks your brain, and people think you’re going mad

Autoimmune encephalitis: When your body attacks your brain, and people think you’re going mad | AntiNMDA | Scoop.it
Four PhD candidates from Monash University, who are already Doctors of the medical kind, are conducting research on a rare and debilitating neurological illness affecting the Australian population. It’s described as feeling like your brain is on fire.
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Characteristics of internalization of NMDA-type GluRs with antibodies to GluN1 and GluN2B - ScienceDirect

Characteristics of internalization of NMDA-type GluRs with antibodies to GluN1 and GluN2B - ScienceDirect | AntiNMDA | Scoop.it
To characterize internalization of NMDA-type glutamate receptors (GluRs) by antibodies to NMDA-type GluRs, we produced rabbit antibodies to N-terminal…
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