AntiNMDA
33.7K views | +1 today
Follow
 
Scooped by Nesrin Shaheen
onto AntiNMDA
Scoop.it!

Acute seizure risk in patients with encephalitis: development and validation of clinical prediction models from two independent prospective multicentre cohorts | BMJ Neurology Open

Acute seizure risk in patients with encephalitis: development and validation of clinical prediction models from two independent prospective multicentre cohorts | BMJ Neurology Open | AntiNMDA | Scoop.it
WHAT IS ALREADY KNOWN ON THIS TOPICWe searched MEDLINE for research studies published from 2000 to February 2022, in English, that examined the associations of seizures in encephalitis. Four studies focused on specific clinical settings and subgroups, however, we identified no multicentre studies, and none reported the associations with seizures in encephalitis of all aetiologies.WHAT THIS STUDY ADDSThis examination of patients with encephalitis reflecting the spectrum of aetiologies from two prospective independent multicentre studies, identified that age, Glasgow Coma Scale on admission, presence of fever and aetiology were strongly associated with seizures. Using these limited parameters in a clinical prediction model, we were able to stratify seizure risk.HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYThe findings can be used to support the development of targeted interventions, such as early specialist care involvement, for patients at highest risk of seizures and to aid the design of clinical trials of antiseizure medication prophylaxis.IntroductionEncephalitis is inflammation of the brain parenchyma, caused by infectious or immune-mediated processes, and is associated with significant morbidity and mortality despite antiviral and/or immune therapies.1 Globally, 500 000 children and adults are affected each year.2 The clinical presentation is variable, but typically includes acute or subacute onset of altered mental state alongside fever, headache, new-onset focal neurological signs and, in some, seizures.3 Seizures have particular significance as they are associated with a worse outcome and may well be amenable to prophylaxis.4 Although seizures may be a proxy marker of severe encephalitis, there are a number of mechanisms by which they could lead to further brain inflammation and damage, including hypoxia, excitotoxicity and raised intracranial pressure.5 However, the incidence of acute symptomatic seizures is highly variable (between 2% and 67%).5 Although there is some limited evidence that possible risk factors include the aetiology of encephalitis, younger age and the degree of cortical involvement, our capacity to predict who is at risk of seizures remains very poor.4 5 Consequently, there is insufficient evidence to recommend the use of antiseizure medications (ASM) as standard of care as either primary or secondary prophylaxis.4 6 Initiation and escalation of ASM is possible in most healthcare settings, and if proven to improve outcome, could be started rapidly as ASM therapy is agnostic to eventual aetiology.Therefore, if a high-risk group were established, this could be used to stratify patients for future clinical trials of primary and secondary prophylaxis with ASM or, as a minimum, to identify which patients should be managed in settings with adequate capacity to manage this severe complication.4 This study aims to establish the factors associated with seizures in encephalitis as well as develop and validate a seizure prediction model of clinical utility for patients presenting with an acute encephalitis syndrome, in accordance with the WHO approach.7 8MethodsCohort 1 (development cohort)Patients were recruited through the Aetiology Study of Encephalitis Study led by the UK Health Protection Agency (now UK Health Security Agency (UKHSA)) (Cohort 1).9 The study prospectively recruited 203 patients with encephalitis from 24 hospitals in England (2005–2008) serving 5 million people (11% of the English population). The study included any person of any age admitted to hospital with encephalitis, full case definition as previously published.3 Computerised tomography (CT), MRI and electroencephalogram (EEG) were performed when clinically indicated. Clinical and postmortem samples received enhanced diagnostic testing guided by a multidisciplinary expert panel.Cohort 2 (validation cohort)A second cohort of 233 patients with encephalitis recruited as part of the Understanding and Improving Outcome of Encephalitis in the UK (Enceph-UK) study was used exclusively as a validation cohort for model development (Cohort 2). Enceph-UK prospectively recruited patients from 31 hospitals in England, Wales and Scotland (2013–2016). Patients were eligible if they were 16 years or older and had clinically suspected encephalitis, using the same case definition as Cohort 1.Statistical analysisSeizure definitionThe three outcome measures were (1) seizure occurrence at any time before or during acute admission, referred to as ‘seizures’, (2) the occurrence of seizures during acute admission, referred to as ‘inpatient seizures’ and (3) the occurrence of status epilepticus. Witness description was used to differentiate focal from generalised seizures. Further subclassification, for example, according to International League Against Epilepsy classification, was not feasible. In Cohort 2, the presence of seizures was recorded as a binary outcome under ‘symptoms on admission (or in current illness, up to 8 weeks prior to admission, including prodrome)’, and, therefore, description of subsequent ‘inpatient’ seizures was not possible.Data extractionData from the first available cerebrospinal fluid (CSF) analysis were extracted. Cut-offs were taken from the UK Standards for Microbiology Investigations: Investigation of CSF.10 Glasgow Coma Scale (GCS) was categorised as normal (15/15), mildly impaired (13–14/15), moderately impaired (9–12/15) or severely impaired (3–8/15). Outcomes were recorded according to the Glasgow Outcome Scale (GOS) 6 months after discharge from hospital. Good recovery was defined as GOS=5 and poor outcome was defined as <5, reflecting at least moderate disability.11UnivariateAll univariate analysis was conducted on Cohort 1. Categorical variables were analysed using χ2 or Fisher’s exact test. All continuous variables that were non-parametric were analysed using Mann-Whitney U test. Potential confounding variables were considered to be age, sex, ethnicity and treatment. These confounders were re-reviewed after univariate analysis and assessed for effect modification and interaction using binary logistic regression.Model developmentClinical prediction modelling was designed to be applicable to routine clinical practice to stratify seizure risk in patients presenting with the clinical features of acute encephalitis syndrome. Binary logistic regression was used to ascertain predictor variables of seizures in Cohort 1 (SPSS V.26). Due to the limited proportion of patients with a clinically indicated EEG and the risk of data availability bias, EEG results were not considered for inclusion. Collinearity was assessed using correlation matrices and one of any two highly correlated variables omitted. The pattern of missing data was reviewed to assess whether data were missing completely at random. Data not missing ‘completely at random’ by Little’s test but deemed to be missing ‘at random’ were imputed using multiple imputation in clinical variables with >5% missing data. Candidate variables were selected by univariate selection (p<0.25) and those identified in the literature. A selection of strongest contributing predictors was made through backward selection based on likelihood ratio. The final binary logistic regression model based on pooled estimates was converted to a provisional clinical scoring system by dividing regression coefficients of each factor by the smallest regression coefficient among the variables to the nearest integer.Model development: inpatient seizuresTo aid translation to clinical practice, a second binary logistic regression model for inpatient seizure risk was developed using the same approach to represent (1) risk at time point of admission and, (2) with maximal discrimination, and was assessed using receiver operating characteristics (ROC) curve and Hosmer-Lemeshow test (Cohort 1).Model validationBoth scoring systems were internally validated using leave-one-out cross-validation performed in R (The R Foundation).12 The provisional scoring system for seizures was externally validated on Cohort 2 using ROC curves, Hosmer-Lemeshow test and calibration plot.ResultsDescription of Cohort 1The median (IQR) age was 31 (9–55) years, and 109 (54%) were men. The aetiology included 86 (43%) infectious causes, 42 (21%) immune-mediated and 75 (37%) unknown as previously detailed9 (table 1). Immune-mediated causes included 23 (11%) with acute disseminated encephalomyelitis (ADEM), 9 (4%) N-methyl-D-aspartate receptor antibodies and 7 (3%) were defined as ‘voltage-gated potassium channel’ (VGKC) antibodies. At the time of recruitment, distinction between subtypes of antibody directed at epitopes of the VGKC were not available.View inline View popup Table 1 Demographic, clinical and investigatory factors associated with seizures in Cohort 1Seizures during the acute illnessIn Cohort 1, 121 (60%) patients had a seizure during their acute illness and 103 (51%) had a seizure while an inpatient. Of patients with a known presenting report, 43/167 (26%) presented with a history of seizures, which were reported most frequently in patients with autoantibody-associated, 7/14 (50%), and Herpes simplex virus (HSV), 13/29 (45%), aetiologies. A semiotic description of the seizures was available for 73 (36%) patients, of whom 43 (59%) had generalised seizures only, 14 (19%) had focal seizures only and 16 (22%) had both. Four patients had a history of epilepsy, of whom three had a seizure.Overall, patients with seizures had a lower median (IQR) age at 25 (9–50) years than those without 39 (11–60), (p=0.051) and presented to hospital earlier, at 5 (1–12) versus 9 (4–24) days from symptom onset (p=0.012) (figure 1).<img height="295" alt="Figure 1" class="highwire-fragment fragment-image" src="https://neurologyopen.bmj.com/content/bmjno/4/2/e000323/F1.medium.gif"; width="440">Download figure Open in new tab Download powerpoint Figure 1 Demographic, clinical and investigatory factors associated with seizures in encephalitis. CSF, cerebrospinal fluid; EEG, electroencephalogram; GCS, Glasgow Coma Scale; HSV, Herpes simplex virus.Patients with seizures were less likely to have CSF pleocytosis (OR 0.45 (95% CI 0.22 to 0.90), p=0.021) or low CSF glucose (OR 0.52 (95% CI 0.28 to 0.98), p=0.042).Seizures at any point during the acute illness were associated with a worse outcome, with 42/80 (53%) of those with seizures having a poor outcome as opposed to 44/116 (38%) without seizures (OR 1.81 (95% CI 1.01 to 3.23), p=0.044) (figure 2).<img alt="Figure 2" src="https://neurologyopen.bmj.com/content/bmjno/4/2/e000323/F2.medium.gif"; class="highwire-fragment fragment-image" width="440" height="260">Download figure Open in new tab Download powerpoint Figure 2 Glasgow Outcome Scale at 6 months stratified by presence and nature of seizures.Inpatient seizuresIn Cohort 1, inpatient seizures were present in 27/43 (67%) of patients presenting with a history of seizures, and 64/124 (52%) without a history of seizures. In patients who did not present with a history of seizures, those that would go on to develop an inpatient seizure presented with a shorter duration of symptoms at 6 (1–13) versus 9 (4–21) days (p=0.034).Reduced GCS on admission was associated with subsequent inpatient seizures. This association remained when stratifying data according to whether the patient presented with a history of seizures. In 92 patients with known GCS and without a history of seizures at presentation, those with severely impaired GCS were more likely to have at least one subsequent inpatient seizure (11/13 (85%), OR 6.57 (95% CI 1.37 to 31.5)), compared with those with moderately impaired (11/21 (52%), OR 1.07 (95% CI 0.40 to 2.93)) or mildly impaired/normal GCS (25/58 (43%), OR 0.41 (95% CI 0.17 to 0.99)) (p=0.025).Status epilepticusStatus epilepticus occurred in 19/203 (9%) of patients with median (IQR) age of 20 (6–31) years. Three had non-convulsive status epilepticus (NCSE) identified on EEG. Four patients had autoantibody-associated encephalitis, three HSV, two Mycobacterium tuberculosis, one probable influenza A, one ADEM and eight had an unknown aetiology. Patients with status epilepticus were more likely to present with a seizure, 10/19 (53%) (of whom three presented with status epilepticus), than those who did not develop status epilepticus 33/148 (22%) (p=0.004). Fever was present in all patients with status epilepticus (19/19, 100%, p=0.009).All 17 EEGs were abnormal, 16/17 (94%) were consistent with encephalitis and 15/17 (88%) had focal changes. These focal changes were significantly more frequently identified in patients with status epilepticus, 15/17 (88%), compared with those without status epilepticus, 31/92 (34%) (p<0.001).The probability of subsequent disability was significantly higher in patients with status epilepticus. In survivors with previous status epilepticus a minority, 4/15 (26%) made a good recovery, 2/15 (13%) had mild disability and most 9/15 (60%) had severe disability (figure 2). In survivors without history of status epilepticus most, 82/158 (52%), made a good recovery, 40/158 (25%) had mild disability and 36/158 (23%) severe disability (p=0.028).Description of Cohort 2Patients in Cohort 2 were older, median (IQR), 54 (34–68) years, more likely to be of white ethnicity, 210/233 (91%), and less frequently reported to have a history of seizures, 84/233 (36%), or fever, 102/233 (44%) (online supplemental table 1). Consistent with Cohort 1, autoimmune and HSV aetiology (p=0.002) and low GCS on admission (p<0.001) were associated with seizures.Supplemental material[bmjno-2022-000323supp001.pdf]Provisional modelPresenting with a seizure and GCS were co-linear, however, GCS was most strongly associated with seizures and likely also captures whether a patient has a history of seizures due to the postictal phase, so was retained in the model. The provisional model of seizures at any time included GCS on admission and probable aetiology of encephalitis (χ2=42.53, p<0.001) (online supplemental table 2). Consistent with the univariate analysis, autoantibody-associated (OR 11.99 (95% CI 2.09 to 68.86), p=0.017) and HSV encephalitis (3.58 (95% CI 1.06 to 12.12), p=0.096) were associated with seizures. Internal cross-validation demonstrated 68% sensitivity, 72% specificity, with a positive predictive value (PPV) of 62% and negative predictive value (NPV) of 77%, with overall accuracy 70%.The model demonstrated good discrimination in Cohort 1 and when externally validated in Cohort 2, area under ROC (AUROC)=0.775 (95% CI 0.701 to 0.848) and 0.744 (95% CI 0.677 to 0.811) respectively (figure 3) and Hosmer-Lemeshow test equalled p=0.737 on the original data. Further evaluation of provisional model calibration is provided in online supplemental table 3 and online supplemental figure 1. The provisional model systematically overestimated risk in Cohort 2, but seizures were less commonly reported in Cohort 2 compared with Cohort 1, 84/233 (36%) and 121/203 (60%) patients, respectively.<img alt="Figure 3" src="https://neurologyopen.bmj.com/content/bmjno/4/2/e000323/F3.medium.gif"; class="highwire-fragment fragment-image" width="440" height="436">Download figure Open in new tab Download powerpoint Figure 3 Model performance. Receiver operating characteristics (ROC) curve for seizure risk according to provisional seizure model in Cohort 1 (A), Area under ROC (AUROC)=0.775 (95% CI 0.701 to 0.848), and Cohort 2 (B), AUROC 0.744 (95% CI 0.6770.811). (C) ROC curve for inpatient seizure risk according to SEIZUre Risk in Encephalitis (SEIZURE) score in Cohort 1.Inpatient seizure risk: SEIZURE scoreA second binary logistic regression model was developed to identify predictors of inpatient seizures based on the information available on admission and then on these parameters combined with aetiology once established (Cohort 1) (table 2). The derived, points-based SEIZUre Risk in Encephalitis (SEIZURE) score stratified risk by decile and is designed to be applied by healthcare professionals when a patient of any age with suspected encephalitis is admitted to hospital with two weighted scoring systems for application prior to and following identification of the probable aetiology (figure 4). Internal cross-validation demonstrated 66% sensitivity, 72% specificity, PPV 69% and NPV 69%, with overall accuracy 69%. Patients in the highest risk category on admission had an OR 7.17 (95% CI 2.55 to 20.16) of seizures compared with those in the lowest risk categories and an OR of 15.51 (95% CI 5.60 to 42.96) once probable aetiology was established (table 3).<img alt="Figure 4" src="https://neurologyopen.bmj.com/content/bmjno/4/2/e000323/F4.medium.gif"; width="180" class="highwire-fragment fragment-image" height="440">Download figure Open in new tab Download powerpoint Figure 4 SEIZUre Risk in Encephalitis (SEIZURE) score for stratifying inpatient seizure risk by decile. ADEM, acute disseminated encephalomyelitis.View inline View popup Table 2 Development of scoring system for inpatient seizure risk in encephalitis using binary logistic regression model based on pooled estimates from imputed data in Cohort 1View inline View popup Table 3 Performance of SEIZURE score by cut-off in complete data, Cohort 1The admission SEIZURE score, including age, admission GCS and fever, showed good discrimination (AUROC=0.716 (95% CI 0.634 to 0.798)). Addition of probable aetiology, once known, slightly increased discrimination (AUROC 0.761 (95% CI 0.684 to 0.839), p<0.001) and Hosmer-Lemeshow for the complete model was p=0.285 on original data.DiscussionAcute seizures affect many patients with encephalitis and are associated with increased need for intensive care support and a worse outcome, and moreover may further contribute to brain injury through excitotoxicity, host immune responses and raised intracranial pressure.5 12–15 However, there are currently no established tools to stratify patients as to their risk of seizures and status epilepticus. Without such risk stratification, it is currently not possible to identify which patients would be best managed in centres with adequate clinical facilities, such as those with intensive therapy units and continuous EEG monitoring, and also to identify whom might benefit from primary and secondary ASM prophylaxis.Through our evaluation of two independent prospective multicentre cohort studies, we identified multiple factors associated with increased risk of seizures during the acute illness, particularly low GCS on admission, fever and an autoantibody-associated or HSV aetiology. Patients with seizures presented to hospital earlier, even in those who have not yet had their first seizure at the time of presentation. Models for seizure risk could be established which, despite requiring a small number of variables, were strongly predictive of acute seizures. Low GCS on admission was more strongly associated with inpatient seizures than whether the patient presented with a seizure history or not. The provisional score accurately determined seizure risk in the first cohort, but potentially overestimated seizure risk in the second cohort, perhaps reflecting under-documentation of seizures in this cohort as seizures were limited to those documented at presentation. The ‘SEIZURE score’ for inpatient seizures requires further external validation. Improved access to easy EEG-monitoring on a wider scale, or the establishment of novel biomarkers could enhance the accuracy of risk-stratification. In addition, the impact of ASM prescription as primary and secondary prophylaxis requires further evaluation.4 5There are likely to be multiple structural and biochemical mechanisms underlying seizure risk in patients with acute encephalitis syndrome. For example, HSV encephalitis has a predisposition to affect epileptogenic areas within the frontotemporal region and in autoimmune encephalitis, the antibodies associated with neuronal cell-surface antigens, that are highly expressed in this region, are themselves often directly involved in the disease process.16–18 The differential disease mechanisms observed in specific aetiologies of encephalitis may influence seizure risk, however, there was inadequate power in this analysis to establish factors associated with seizures within aetiological subgroups. Certain clinical features were less common in patients with seizures, specifically, stiff neck, photophobia, lethargy and any focal deficit on neurological examination. This may in part be explained by aetiological distinctions, as focal neurological deficits were most frequently reported in encephalitis caused by Varicella zoster virus and ADEM, which were least strongly associated with seizures; and particularly the latter which is associated with subcortical white matter lesions as opposed to cortical inflammation which drives seizures.19 Many clinical features associated with seizures in our analysis are likely to be proxies for underlying mechanisms, rather than risk factors in themselves. Nevertheless, these features can inform future mechanistic studies, particularly through in vivo models of encephalitis.20EEG abnormalities were strongly associated with clinical seizure activity and EEG also identified three cases of NCSE, which is increasingly recognised in encephalitis, particularly autoimmune aetiologies.21 22 Status epilepticus in the context of encephalitis is frequently refractory and has a poor outcome.23 24 Patients with seizures were less likely to have CSF pleocytosis or low CSF glucose. Given that lumbar puncture is contraindicated until patients are stabilised following a seizure, we hypothesise that this result could be related in part to delayed lumbar puncture, or also may reflect the increased proportion with autoimmune encephalitis in this group.19 These CSF parameters likely reflect aetiological distinctions rather than direct biomarkers of seizures. Nevertheless, these data sets did not provide sufficient granularity to determine the CSF white cell count relative to the time from/before a seizure and this requires further study. No relationship was observed between the presence of normal or abnormal CT or MRI findings and seizure risk. It may be that the imaging variables in this analysis were too crude as they were based on retrospective interpretation of clinically indicated scans performed at multiple sites. Volumetric analysis for research purposes of specific brain regions or structures would be more sensitive.6 25–27 The finding may additionally reflect the high incidence of seizures in those with autoimmune encephalitis, who often have normal or near-normal neuroimaging. A single-centre study of 94 patients in China found cortical or hippocampal abnormalities on neuroimaging independently predicted progression to super-refractory status epilepticus.28 Notably, the potential associations of seizures identified in our study; aetiology, GCS and younger age, were also reported in a single-centre study in Northern India, despite large differences in the cohort.26 The likelihood of a seizure being witnessed may confound associations, for example, younger children in community settings may be more likely to have a seizure witnessed.Our study corroborates previous work demonstrating an association between seizure activity and poor outcome in encephalitis.14 29–31 Although seizures may be a proxy marker of severe disease, there are a number of mechanisms through which seizures could cause further brain damage. Seizures cause significant systemic metabolic and biochemical disturbance including hypoxia, hypoglycaemia, metabolic acidosis as well as direct central nervous system perturbations including glutaminergic activity, raised intracranial pressure and blood–brain barrier permeabilisation, as well as low CSF glucose and high CSF lactate.32 A study of 144 patients with Japanese encephalitis presenting to hospital in Vietnam, showed that patients with recent seizures had high CSF lactate:glucose ratios and high CSF opening pressures and that patients with opening pressure >25 cm were more likely to die.14 A more recent analysis of CSF biomarkers in HSV encephalitis indicated that acute inflammation may drive subsequent synaptic autoimmunity and proposed a trial of post-acute corticosteroids.33 In addition, several inflammatory markers have been associated with a lower GCS, increased oedema and a worse outcome in encephalitis, especially the interleukin-1 family relative to their endogenous antagonists.13 It remains unknown whether seizures intervene with the underlying encephalitic process.Despite the high prevalence and prognostic importance of seizures, the most recent Cochrane review concluded that there is insufficient evidence to support or refute the routine use of antiepileptic drugs for the primary or secondary prevention of seizures in viral encephalitis.4 A recent randomised controlled trial of secondary prophylaxis for acute symptomatic seizures in children with encephalitis demonstrated that a 4-week course of ASM was comparable to 12 weeks in terms of the incidence of seizure recurrence.34 A rabbit model of HSV-1 encephalitis, untreated with aciclovir, showed that all animals that had a seizure became moribund or died, but that phenobarbital prevented seizures and significantly reduced mortality.35 Further questions remain regarding choice and duration of antiepileptic agents.6 Any intervention strategy would need to consider the high baseline risk of seizures in patients with encephalitis and the presence of subtle and subclinical seizures including NCSE.14 21 36Our findings reflect two relatively large prospectively recruited cohorts but have limitations, principally due to the retrospective nature of seizure-focused analysis. The observational nature of the study has an intrinsic risk of confounding which we have attempted to address in both the analysis and interpretation of results but there may be a residual impact. Additionally, the data were collected from 2005 to 2016 and seizures were not the primary focus of the initial data collection, potentially resulting in missing data. The diagnosis and management of encephalitis may have changed over this time period, particularly the identification of autoantibodies. These factors are balanced by the substantial sample size for a relatively uncommon condition, the granularity of the UKHSA data and the enhanced diagnostic testing performed.ConclusionThese finding indicate that patients with seizures during encephalitis present earlier, but despite this, have a worse outcome, suggesting there may be a window of opportunity for intervention that is currently not being exploited. This study provides a foundation for risk stratification of seizures in encephalitis on clinical grounds alone. Biomarkers and improved access to EEG-monitoring could enhance model accuracy and allow for the development of targeted interventions. The SEIZURE score can be used to aid the design of clinical trials of primary and secondary prophylaxis with ASM.Data availability statementData are available upon reasonable request. The de-identified data that support the findings of this study are available from the corresponding author, for any purpose for which there is ethical approval, immediately following publication and ending in September 2022. Researchers should provide a methodologically sound proposal for approval by the UK Health Security Agency, Virus Reference Department. Data are available alongside study protocol.Ethics statementsPatient consent for publicationNot applicable.Ethics approvalThe original HPA study had ethical approval granted by The North and East Devon Multicentre Research Ethics Committee (05/Q2102/22). The proposal for this follow-on study was granted approval by Public Health England (now UK Health Security Agency). The ENCEPH-UK Study was approved by the East Midlands Committee of the National Research Ethics Service (NRES) (11/EM/0442). Participants gave informed consent to participate in the study before taking part.AcknowledgmentsWe would like to thank the patients involved in this research. UK Health Protection Agency Aetiology of Encephalitis Study Group: Helen E Ambrose, Nicholas W S Davies, Jonathan P Clewley, Amanda L Walsh, Dilys Morgan, Richard Cunningham, Mark Zuckerman, Ken J Mutton, Katherine N Ward, Michael P T Lunn, Natasha S Crowcroft, Craig Ford, Emily Rothwell, William Tong, Jean-Pierre Lin, Ming Lim, Nicholas Price, Javeed Ahmed, David Cubitt, Sarah Benton, Cheryl Hemingway, David Muir, Hermione Lyall, Ed Thompson, Geoff Keir, Viki Worthington, Paul Griffiths, Susan Bennett, Rachel Kneen, Paul Klapper. ENCEPH-UK Study Group: Ruth Backman, Gus Baker, Nicholas J Beeching, Rachel Breen, Chris Cheyne, Enitan D Carrol, Nicholas W S Davies, Martin Eccles, Robbie Foy, Marta Garcia-Finana, Julia Griem, Michael Griffiths, Alison Gummery, Lara Harris, Helen Hickey, Helen Hill, Ann Jacoby, Hayley Hardwick, Ciara Kierans, Michael Kopelman, Rachel Kneen, Gill Lancaster, Michael Levin, Rebecca McDonald, Antonieta Medina-Lara, Esse Menson, Natalie Martin, Andrew Pennington, Andrew Pollard, Julie Riley, Manish Sadarangani, Anne Salter, Maria Thornton, Charles Warlow. AGM is a National Institute for Health Research (NIHR) Senior Investigator and also part funded by NIHR ARC North West Coast.References↵Venkatesan A, Michael BD, Probasco JC, et al. Acute encephalitis in immunocompetent adults. Lancet 2019;393:702–16.doi:10.1016/S0140-6736(18)32526-1pmid:http://www.ncbi.nlm.nih.gov/pubmed/30782344OpenUrlPubMed↵Society E. Encephalitis Facts & Figures, 2022. Available: https://www.encephalitis.info/facts [Accessed 25 Feb 2022].↵Venkatesan A, Tunkel AR, Bloch KC, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the International encephalitis Consortium. Clin Infect Dis 2013;57:1114–28.doi:10.1093/cid/cit458pmid:http://www.ncbi.nlm.nih.gov/pubmed/23861361OpenUrlCrossRefPubMed↵Pandey S, Rathore C, Michael BD, et al. Antiepileptic drugs for the primary and secondary prevention of seizures in viral encephalitis. Cochrane Database Syst Rev 2016;2016:CD010247.doi:10.1002/14651858.CD010247.pub3↵Michael BD, Solomon T. Seizures and encephalitis: clinical features, management, and potential pathophysiologic mechanisms. Epilepsia 2012;53 Suppl 4:63–71.doi:10.1111/j.1528-1167.2012.03615.xpmid:http://www.ncbi.nlm.nih.gov/pubmed/22946723OpenUrlPubMed↵Huang Q, Ma M, Wei X, et al. Characteristics of seizure and antiepileptic drug utilization in outpatients with autoimmune encephalitis. Front Neurol 2018;9:1136.doi:10.3389/fneur.2018.01136pmid:http://www.ncbi.nlm.nih.gov/pubmed/30671012OpenUrlPubMed↵. Surveillance guide for vaccine-preventable diseases in the who south-east Asia region. [New Delhi] World Health Organization, Regional Office for South-East Asia; 2017. https://apps.who.int/iris/bitstream/handle/10665/277459/Module9-JE.pdf [Accessed 20 Jul 2022].↵Kumar R. Understanding and managing acute encephalitis. F1000Res 2020;9:F1000 Faculty Rev-60:60.doi:10.12688/f1000research.20634.1pmid:http://www.ncbi.nlm.nih.gov/pubmed/32047620OpenUrlPubMed↵Granerod J, Ambrose HE, Davies NW, et al. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis 2010;10:835–44.doi:10.1016/S1473-3099(10)70222-Xpmid:http://www.ncbi.nlm.nih.gov/pubmed/20952256OpenUrlCrossRefPubMedWeb of Science↵England PH. Investigation of cerebrospinal fluid. UK standards for microbiology investigations UK, 2017. Available: https://www.gov.uk/uk-standards-for-microbiology-investigations-smi-quality-and-consistency-in-clinical-laboratories [Accessed 27Oct 2019].↵Jennett B, Bond M. Assessment of outcome after severe brain damage a practical scale. Lancet 1975;305:480–4.doi:10.1016/S0140-6736(75)92830-5OpenUrlCrossRef↵Nguyen CD, Carlin JB, Lee KJ. Model checking in multiple imputation: an overview and case study. Emerg Themes Epidemiol 2017;14:8.doi:10.1186/s12982-017-0062-6pmid:http://www.ncbi.nlm.nih.gov/pubmed/28852415OpenUrlPubMed↵Michael BD, Griffiths MJ, Granerod J, et al. The interleukin-1 balance during encephalitis is associated with clinical severity, blood-brain barrier permeability, neuroimaging changes, and disease outcome. J Infect Dis 2016;213:1651–60.doi:10.1093/infdis/jiv771pmid:http://www.ncbi.nlm.nih.gov/pubmed/26712949OpenUrlCrossRefPubMed↵Solomon T, Dung NM, Kneen R, et al. Seizures and raised intracranial pressure in Vietnamese patients with Japanese encephalitis. Brain 2002;125:1084–93.doi:10.1093/brain/awf116pmid:http://www.ncbi.nlm.nih.gov/pubmed/11960897OpenUrlCrossRefPubMedWeb of Science↵Vezzani A, Fujinami RS, White HS, et al. Infections, inflammation and epilepsy. Acta Neuropathol 2016;131:211–34.doi:10.1007/s00401-015-1481-5pmid:http://www.ncbi.nlm.nih.gov/pubmed/26423537OpenUrlCrossRefPubMed↵Misra UK, Tan CT, Kalita J. Viral encephalitis and epilepsy. Epilepsia 2008;49 Suppl 6:13–18.doi:10.1111/j.1528-1167.2008.01751.xpmid:http://www.ncbi.nlm.nih.gov/pubmed/18754956OpenUrlPubMed↵Zhang P, Yang Y, Zou J, et al. Seizures and epilepsy secondary to viral infection in the central nervous system. Acta Epileptologica 2020;2:12.doi:10.1186/s42494-020-00022-0OpenUrl↵Bien CG, Holtkamp M. "Autoimmune Epilepsy": Encephalitis With Autoantibodies for Epileptologists. Epilepsy Curr 2017;17:134–41.doi:10.5698/1535-7511.17.3.134pmid:http://www.ncbi.nlm.nih.gov/pubmed/28684941OpenUrlCrossRefPubMed↵Solomon T, Michael BD, Smith PE, et al. Management of suspected viral encephalitis in adults--Association of British Neurologists and British Infection Association National Guidelines. J Infect 2012;64:347–73.doi:10.1016/j.jinf.2011.11.014pmid:http://www.ncbi.nlm.nih.gov/pubmed/22120595OpenUrlCrossRefPubMedWeb of Science↵Michael BD, Bricio-Moreno L, Sorensen EW, et al. Astrocyte- and neuron-derived CXCL1 drives neutrophil transmigration and blood-brain barrier permeability in viral encephalitis. Cell Rep 2020;32:108150.doi:10.1016/j.celrep.2020.108150pmid:http://www.ncbi.nlm.nih.gov/pubmed/32937134OpenUrlCrossRefPubMed↵Mitchell JW, Valdoleiros SR, Jefferson S, et al. Autoimmune encephalitis as an increasingly recognised cause of non-convulsive status epilepticus: a retrospective, multicentre evaluation of patient characteristics and electroencephalography (EEG) results. Seizure 2020;80:153–6.doi:10.1016/j.seizure.2020.06.020pmid:http://www.ncbi.nlm.nih.gov/pubmed/32574837OpenUrlCrossRefPubMed↵Towne AR, Waterhouse EJ, Boggs JG, et al. Prevalence of nonconvulsive status epilepticus in comatose patients. Neurology 2000;54:340–5.doi:10.1212/WNL.54.2.340pmid:http://www.ncbi.nlm.nih.gov/pubmed/10668693OpenUrlCrossRefPubMed↵Vooturi S, Jayalakshmi S, Sahu S, et al. Prognosis and predictors of outcome of refractory generalized convulsive status epilepticus in adults treated in neurointensive care unit. Clin Neurol Neurosurg 2014;126:7–10.doi:10.1016/j.clineuro.2014.07.038pmid:http://www.ncbi.nlm.nih.gov/pubmed/25194304OpenUrlPubMed↵Barzegar M, Mahdavi M, Galegolab Behbehani A, et al. Refractory convulsive status epilepticus in children: etiology, associated risk factors and outcome. Iran J Child Neurol 2015;9:24–31.pmid:http://www.ncbi.nlm.nih.gov/pubmed/26664438OpenUrlPubMed↵Wang ZI, Krishnan B, Shattuck DW, et al. Automated MRI volumetric analysis in patients with Rasmussen syndrome. AJNR Am J Neuroradiol 2016;37:2348–55.doi:10.3174/ajnr.A4914pmid:http://www.ncbi.nlm.nih.gov/pubmed/27609620OpenUrlAbstract/FREE Full Text↵Misra UK, Kalita J. Seizures in encephalitis: predictors and outcome. Seizure 2009;18:583–7.doi:10.1016/j.seizure.2009.06.003pmid:http://www.ncbi.nlm.nih.gov/pubmed/19581112OpenUrlCrossRefPubMedWeb of Science↵Khoury MN, Alsop DC, Agnihotri SP, et al. Hyperintense cortical signal on magnetic resonance imaging reflects focal leukocortical encephalitis and seizure risk in progressive multifocal leukoencephalopathy. Ann Neurol 2014;75:659–69.doi:10.1002/ana.24144pmid:http://www.ncbi.nlm.nih.gov/pubmed/24752885OpenUrlCrossRefPubMed↵Yuan F, Yang F, Jia R, et al. Multimodal predictions of super-refractory status epilepticus and outcome in status epilepticus due to acute encephalitis. Front Neurol 2018;9:832.doi:10.3389/fneur.2018.00832pmid:http://www.ncbi.nlm.nih.gov/pubmed/30349506OpenUrlPubMed↵Hansen MA, Samannodi MS, Castelblanco RL, et al. Clinical epidemiology, risk factors, and outcomes of encephalitis in older adults. Clin Infect Dis 2020;70:2377–85.doi:10.1093/cid/ciz635pmid:http://www.ncbi.nlm.nih.gov/pubmed/31294449OpenUrlPubMed↵Herrmann EK, Hahn K, Kratzer C, et al. Status epilepticus as a risk factor for postencephalitic parenchyma loss evaluated by ventricle brain ratio measurement on MR imaging. AJNR Am J Neuroradiol 2006;27:1245–51.pmid:http://www.ncbi.nlm.nih.gov/pubmed/16775274OpenUrlPubMed↵Rao S, Elkon B, Flett KB, et al. Long-term outcomes and risk factors associated with acute encephalitis in children. J Pediatric Infect Dis Soc 2017;6:20–7.doi:10.1093/jpids/piv075pmid:http://www.ncbi.nlm.nih.gov/pubmed/26553786OpenUrlPubMed↵Löscher W, Köhling R, Functional KR. Functional, metabolic, and synaptic changes after seizures as potential targets for antiepileptic therapy. Epilepsy Behav 2010;19:105–13.doi:10.1016/j.yebeh.2010.06.035pmid:http://www.ncbi.nlm.nih.gov/pubmed/20705520OpenUrlCrossRefPubMedWeb of Science↵Westman G, Aurelius E, Ahlm C, et al. Cerebrospinal fluid biomarkers of brain injury, inflammation and synaptic autoimmunity predict long-term neurocognitive outcome in herpes simplex encephalitis. Clin Microbiol Infect 2021;27:1131–6.doi:10.1016/j.cmi.2020.09.031pmid:http://www.ncbi.nlm.nih.gov/pubmed/32979577OpenUrlPubMed↵Dhawan SR, Sahu JK, Singhi P, et al. Comparison of 4 weeks versus 12 weeks antiseizure medication for acute symptomatic seizures in children with acute encephalitis syndrome: an open-label, randomized controlled trial. Seizure 2021;92:182–8.doi:10.1016/j.seizure.2021.09.005pmid:http://www.ncbi.nlm.nih.gov/pubmed/34543779OpenUrlPubMed↵Schlitt M, Bucher AP, Stroop WG, et al. Neurovirulence in an experimental focal herpes encephalitis: relationship to observed seizures. Brain Res 1988;440:293–8.doi:10.1016/0006-8993(88)90998-5pmid:http://www.ncbi.nlm.nih.gov/pubmed/2833994OpenUrlPubMed↵Sellner J, Trinka E. Seizures and epilepsy in herpes simplex virus encephalitis: current concepts and future directions of pathogenesis and management. J Neurol 2012;259:2019–30.doi:10.1007/s00415-012-6494-6pmid:http://www.ncbi.nlm.nih.gov/pubmed/22527234OpenUrlCrossRefPubMed
No comment yet.
AntiNMDA
Your new post is loading...
Scooped by Nesrin Shaheen
Scoop.it!

Autoimmune Encephalitis Misdiagnosis in Adults | Neurology | JAMA Neurology | JAMA Network

Autoimmune Encephalitis Misdiagnosis in Adults | Neurology | JAMA Neurology | JAMA Network | AntiNMDA | Scoop.it
This case series assesses the diseases misdiagnosed as autoimmune encephalitis and potential reasons for misdiagnosis.
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

The Increased Interleukin-6 Levels Can Be an Early Diagnostic Marker for New-Onset Refractory Status Epilepticus - PMC

The Increased Interleukin-6 Levels Can Be an Early Diagnostic Marker for New-Onset Refractory Status Epilepticus - PMC | AntiNMDA | Scoop.it
New-onset refractory status epilepticus (NORSE) is a condition defined as the occurrence of refractory status epilepticus in patients without active epilepsy and no other acute causes of seizure. Although there is evidence that immune-mediated pathogenesis ...
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

Decreased occipital lobe metabolism by FDG-PET/CT: An anti-NMDA receptor encephalitis biomarker

Decreased occipital lobe metabolism by FDG-PET/CT: An anti-NMDA receptor encephalitis biomarker | AntiNMDA | Scoop.it
Marked medial occipital lobe hypometabolism by dedicated brain FDG-PET/CT may serve as an early biomarker for discriminating anti-NMDA receptor encephalitis from other AE.Resolution of lateral and medial occipital hypometabolism may correlate with improved neurologic status in anti-NMDA receptor ...
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

Clinical Reasoning: A Young Adult Man With Cognitive Changes, Gait Difficulty, and Renal Insufficiency | Neurology

Clinical Reasoning: A Young Adult Man With Cognitive Changes, Gait Difficulty, and Renal Insufficiency | Neurology | AntiNMDA | Scoop.it
AbstractA 22-year-old right-handed man with recently diagnosed gout and renal insufficiency presented with 3 months of progressive gait instability and cognitive changes. He initially presented to an outside institution and underwent a broad workup, but an etiology for his symptoms was not found. On subsequent presentation to our institution, his examination revealed multidomain cognitive dysfunction, spasticity, hyperreflexia, and clonus. A broad workup was again pursued and was notable for an MRI of the brain, revealing cortical atrophy advanced for his age, bland CSF, and a weakly positive serum acetylcholine receptor ganglionic neuronal antibody of unclear significance. The history of gout and inadequately explained renal insufficiency led to a workup for inborn errors of metabolism, including urine amino acid analysis, which revealed a homocysteine peak. This finding prompted further evaluation, revealing markedly elevated serum homocysteine and methylmalonic acid and low methionine. He ultimately developed superficial venous thromboses, a segmental pulmonary embolism, and clinical and electrographic seizures. He was initiated on appropriate treatment, and his symptoms markedly improved. The case serves as a reminder to include late-onset inborn errors of metabolism in the differential for young adult patients with onset of neurologic, psychiatric, renal, and thromboembolic symptoms.Section 1A 22-year-old right-handed man with recently diagnosed gout and worsening renal function presented with 3 months of gait instability and cognitive changes. Approximately 5 months before presentation, he was diagnosed with gout, confirmed by uric acid crystals on synovial fluid. He was recommended to start a vegan diet then. He also developed worsening renal function. Until 3 months before presentation, he was a high-functioning student at his university. He then started struggling in classes, stopped interacting with family, stopped going to school, and became more introverted. He became clumsier, with difficulty going upstairs and downstairs. He initially presented to an outside hospital, where an extensive workup was performed, but no clear etiology was found, and he was discharged with a diagnosis of catatonia.Three months after onset of neurologic symptoms, the patient presented to our institution with worsened condition. He had recently become violent and started having abnormal movements of his extremities. Two weeks earlier, he had stopped walking and required assistance to move. He was urinating on himself and no longer told his parents when he needed to use the bathroom. There was no significant family history. On neurologic examination, mental status examination was notable for prominent inattention, perseveration, psychomotor slowing, and inappropriate laughter. He could not follow multistep commands and had reduced spontaneous speech with increased latency. Motor examination revealed mild spasticity in the lower greater than upper extremities. Detailed motor and sensory testing were limited by his mental status, but he had at least antigravity strength in the upper and lower extremities bilaterally. His tendon reflexes were 3 + throughout with crossed adductors, and he had bilateral ankle clonus for greater than 10 beats and a positive Hoffman reflex on the left.Questions for Consideration:What are the localization and broad categories to consider in the differential diagnosis?What diagnostic studies should be ordered initially?GO TO SECTION 2Section 2The multidomain cognitive dysfunction suggests diffuse bilateral cerebral hemispheric involvement, whereas the prominent spasticity, hyperreflexia, and clonus suggest upper motor neuron involvement, specifically within the corticospinal tracts. The bilateral pyramidal tract dysfunction could be localized intracranially, anywhere from the primary motor cortex to the internal capsule on down to the brainstem. Processes that could lead to such a diffuse bihemispheric process leading to cognitive symptoms and gait difficulties broadly include the following: vascular (e.g., CNS vasculitis); infectious and inflammatory (e.g., subacute to chronic meningoencephalitides); neoplastic or paraneoplastic; autoimmune (e.g., autoimmune encephalitis, demyelinating disease); toxic and metabolic (e.g., B12 deficiency leading to subacute combined degeneration)1; and inborn errors of metabolism, considered initially due to young age and gout history,2,3 as summarized in the Table.View inline View popup Table Broad Differential Diagnosis for Diffuse, Bihemispheric Processes Leading to Cognitive Symptoms and Gait DifficultiesBasic laboratory workup revealed SARS-CoV-2 positivity with lymphopenic leukopenia. B12 was 462 pg/mL and folate >20.0 ng/mL. Uric acid was 6.8 mg/dL (2.3–7.6, normal). An MRI of the brain with and without contrast revealed cortical atrophy (Figure 1) but no other acute findings, and an MRI of the cervical spine (not shown) was unremarkable. Continuous EEG (cEEG) monitoring for 48 hours revealed generalized continuous delta slow activity with superimposed faster frequencies. CSF studies revealed normal cell count, protein, glucose, IgG synthesis rate/index, and a negative meningitis panel. Encephalopathy, autoimmune, serum, and CSF panels were ordered. Given the patient's age and recent development of gout and renal dysfunction, urine amino acid analysis was sent.<img height="440" width="438" class="highwire-fragment fragment-image" src="https://n.neurology.org/content/neurology/100/4/206/F1.medium.gif"; alt="Figure 1">Download figure Open in new tab Download powerpoint Figure 1 Representative Neuroimaging From the CaseA) Sagittal T1-weighted MRI of the brain and B) axial T2/FLAIR MRI of the brain revealing cortical atrophy; C) continuous video EEG recording sample showing lateralized periodic discharges (black arrows) seen in the right fronto-central region consistent with an area of epileptogenic potential.Question for Consideration:Which entities on the differential are less likely, given this initial workup?GO TO SECTION 3Section 3Given the bland CSF and MRI brain without enhancement or FLAIR signal changes, meningoencephalitides, CNS vasculitis, demyelinating diseases, and CNS neoplastic processes are less likely. However, paraneoplastic or autoimmune encephalitis can present without MRI abnormalities.4 Furthermore, there was a weakly positive serum acetylcholine receptor ganglionic neuronal antibody from the previous institution. While this antibody is classically reported in the setting of autoimmune autonomic ganglionopathy,5 it has rarely been associated with predominantly neuropsychiatric presentations of autoimmune encephalitis.6 The patient was empirically initiated on IVIG for this possibility while awaiting other laboratory test results. In addition, inborn errors of metabolism remained high in the differential consideration, given the oddity of gout and inadequately explained renal insufficiency. Normal serum vitamin levels did not exclude the possibility of inborn errors of metabolism because they can classically be normal in these conditions.7The serum and CSF encephalopathy panels returned negative, and the serum NeoComplete Paraneoplastic Evaluation again revealed borderline anti-α 3AChR antibody. Notably, the urine amino acid analysis revealed a peak of homocysteine.Questions for Consideration:What is the significance of the homocysteine peak on urine amino acid analysis?What further studies should be ordered?GO TO SECTION 4Section 4Elevated urine homocysteine is classically found in the homocystinurias. This finding prompted a serum homocysteine level, which was >50.0 µmol/L (0–14.9, normal range), with the quantitative serum homocysteine measured at 283.3 µmol/L (6.1–10.8). Serum homocysteine is a key biochemical marker of disruption of the remethylation pathway. When elevated homocysteine is found, serum methionine and quantitative methylmalonic acid (MMA) levels in the serum should be ordered to isolate the defect in the biochemical pathway of cobalamin metabolism.7 Serum MMA was significantly elevated to 452,000 nmol/L (87–318). Serum methionine was 9 umol/L (16–34). This pattern is the biochemical hallmark of cobalamin C (CblC) deficiency.7 Genetic testing revealed 2 heterozygous pathogenic variants in the MMACHC gene: c.328_331del (p.Asn110Aspfs*13) and c.482G>A (p.Arg161Gln).DiscussionCobalamin C deficiency is the most common inherited disorder of intracellular cobalamin metabolism.8,9 It is most often due to pathogenic variants of the MMACHC gene. Because of defective gene product, methylcobalamin and adenosylcobalamin are not produced intracellularly. Methylcobalamin and adenosylcobalamin are critical cofactors for the remethylation of homocysteine to methionine and conversion of MMA to succinic acid, respectively (Figure 2). Thus, the deficiency of methylcobalamin and adenosylcobalamin leads to elevated serum homocysteine and MMA, low methionine levels, and normal serum B12 and folate.7<img src="https://n.neurology.org/content/neurology/100/4/206/F2.medium.gif"; height="251" class="highwire-fragment fragment-image" alt="Figure 2" width="440">Download figure Open in new tab Download powerpoint Figure 2 Schematic of Intracellular Cobalamin MetabolismCobalamin (Cbl) III is bound to transcobalamin (TC) in the blood. This complex is endocytosed into the cell. On entering the lysosome, Cbl III becomes unbound from TC. Cbl III then enters the cytosol and undergoes enzymatic reduction from Cbl III to Cbl II aided by MMACHC. Cbl II then undergoes adenosylation to form adenosylcobalamin (AdoCbl) in the mitochondrion and methylation to form methylcobalamin (MeCbl) in the cytosol, respectively. AdoCbl is a cofactor for methylmalonyl-CoA-mutase (MMUT), which catalyzes the conversion of L-Methylmalonyl-CoA (MMA-CoA) to succinyl-CoA. MeCbl is a cofactor in the conversion of homocysteine to methionine, mediated by the enzyme methionine synthase (MTR).7CblC disease is typically classified into 2 forms: early onset (typically within the first year of life)10 and late onset (which includes late-onset pediatric and adult cases).11 In the past couple of decades, there have been great advancements in newborn screening for cobalamin deficiencies, but many adults were born before such screening. The late-onset form was first reported in 197012 and the adult-onset (aged 18 years or older) form in 2001.13 As of 2022, only 45 cases of adult-onset CblC disease have been reported, but this is likely a vast underrepresentation. Whereas early-onset disease has a poor prognosis even with early diagnosis, the adult-onset form generally exhibits robust response to treatment. There is a genotype-phenotype correlation with adult-onset forms tending to have compound heterozygosity of missense variants, which leads to some residual protein function,7 as seen in our patient.In the adult-onset form, neuropathy or myelopathy are the most common clinical signs, followed by ataxia or dysarthria, cognitive decline, psychiatric symptoms, lower limb weakness, and seizures. Other features include thromboembolic disease and kidney failure often due to damage from thrombotic microangiopathy (TMA).7,14 Our patient did ultimately develop acute bilateral upper extremity cephalic vein thromboses and a right lower lobe segmental pulmonary embolism, for which he was initiated on therapeutic anticoagulation. He also had elevated creatinine (peak at 3.6–3.8 mg/dL), but the exact etiology of his renal disease was unclear, and he did not have the other accompanying signs of TMA (no hypertension, hematuria, or proteinuria). Kidney biopsy was deferred, given it was unlikely to change management and had elevated risks on therapeutic anticoagulation. In addition, his course was complicated by clinical seizures with left gaze deviation and generalized convulsions. He was reconnected to cEEG, which revealed right fronto-central lateralized periodic epileptiform discharges and seizures without definitive clinical correlation and was initiated on antiseizure medications. Finally, while gout is more commonly associated with inborn errors of metabolism dealing with purine metabolism, it has been reported in cases of methylmalonic acidemia and may be related to decreased renal clearance of uric acid.3The treatment for CblC disease is intramuscular or subcutaneous hydroxycobalamin, combined with oral betaine and folic acid.7 Of importance, oral cobalamin replacement approaches are ineffective because the patients require supplementation with the active form, which is not absorbed through the oral route; betaine facilitates the conversion of homocysteine to methionine; and folic acid can potentially augment remethylation.9 Our patient was initiated on this regimen soon after the biochemical markers confirmed the diagnosis. He improved significantly while still inpatient and was discharged to an inpatient acute rehabilitation facility. By approximately a month after discharge, he could hold an in-depth follow-up conversation over the phone, felt his cognition had significantly improved, and was able to stand and walk for 7–8 meters at a time. This case serves as a reminder to trust the neurologic examination, even if neuroimaging and other workup are unrevealing. In addition, in complicated cases, red herrings may arise,15 such as the AChR ganglionic antibody, not considered the pathogenic antibody in this case. Finally, the case reminds one to include the inborn errors of metabolism in the differential for young adult patients with onset of neurologic and psychiatric presentations, particularly when accompanied by other systemic findings.Study FundingThe authors report no targeted funding.DisclosureThe authors report no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.Appendix Authors<img class="highwire-fragment fragment-image" src="https://n.neurology.org/content/neurology/100/4/206/T2.medium.gif"; width="658" height="1273" alt="Table">Footnotes↵* These authors contributed equally to this work as senior authors.Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.Submitted and externally peer reviewed. The handling editor was Whitley Aamodt, MD, MPH.Received April 27, 2022.Accepted in final form September 16, 2022.© 2022 American Academy of NeurologyReferences1.↵Qudsiya Z, De Jesus O. Subacute combined degeneration of the spinal cord. In: StatPearls. StatPearls Publishing; 2021:1.2.↵Doucet BP, Jegatheesan D, Burke J. Late diagnosis of Lesch-Nyhan disease variant. BMJ Case Rep. 2013;2013:1-2. doi:10.1136/bcr-2013-201997OpenUrlCrossRef3.↵Charuvanij S, Pattaragarn A, Wisuthsarewong W, Vatanavicharn N. Juvenile gout in methylmalonic acidemia. Pediatr Int. 2016;58(6):501-503.OpenUrl4.↵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(2):157-165.OpenUrlCrossRefPubMed5.↵Vernino S. Autoimmune autonomic disorders. Continuum. 2020;26(1):44-57.OpenUrl6.↵McKeon A, Lennon VA, Lachance DH, Fealey RD, Pittock SJ. Ganglionic acetylcholine receptor autoantibody. Arch Neurol. 2009;66(6):735-741. doi:10.1001/archneurol.2009.78OpenUrlCrossRefPubMed7.↵Kalantari S, Brezzi B, Bracciamà V, et al. Adult-onset CblC deficiency: a challenging diagnosis involving different adult clinical specialists. Orphanet J Rare Dis. 2022;17(1):33.OpenUrl8.↵Mudd SH, Levy HL, Abeles RH. A derangement in B12 metabolism leading to homocystinemia, cystathioninemia and methylmalonic aciduria. Biochem Biophys Res Commun. 1969;35(1):121-126.OpenUrlCrossRefPubMed9.↵Adam MP, Ardinger HH, Pagon RA, et al.Sloan JL, Carrillo N, Adams D, Venditti CP. Disorders of intracellular cobalamin metabolism. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. University of Washington; 2008.10.↵Wang SJ, Yan CZ, Wen B, Zhao YY. Clinical feature and outcome of late-onset cobalamin C disease patients with neuropsychiatric presentations: a Chinese case series. Neuropsychiatr Dis Treat. 2019;15:549-555.OpenUrlCrossRefPubMed11.↵Huemer M, Scholl-Bürgi S, Hadaya K, et al. Three new cases of late-onset cblC defect and review of the literature illustrating when to consider inborn errors of metabolism beyond infancy. Orphanet J Rare Dis. 2014;9:161.OpenUrlCrossRefPubMed12.↵Goodman SI, Moe PG, Hammond KB, Mudd SH, Uhlendorf BW. Homocystinuria with methylmalonic aciduria: two cases in a sibship. Biochem Med. 1970;4(5):500-515.OpenUrlCrossRefPubMed13.↵Bodamer OA, Rosenblatt DS, Appel SH, Beaudet AL. Adult-onset combined methylmalonic aciduria and homocystinuria (cblC). Neurology. 2001;56(8):1113.OpenUrlFREE Full Text14.↵Lemoine M, François A, Grangé S, et al. Cobalamin C deficiency induces a typical histopathological pattern of renal arteriolar and glomerular thrombotic microangiopathy. Kidney Int Rep. 2018;3(5):1153-1162.OpenUrl15.↵Ebright MJ, Li SH, Reynolds E, et al. Unintended consequences of Mayo paraneoplastic evaluations. Neurology. 2018;91(22):e2057-e2066.OpenUrlAbstract/FREE Full Text
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

Study Warns About Frequent Autoimmune Encephalitis Misdiagnosis, Even in Specialized Centers

Study Warns About Frequent Autoimmune Encephalitis Misdiagnosis, Even in Specialized Centers | AntiNMDA | Scoop.it
A new study warns of frequent autoimmune encephalitis misdiagnosis in the U.S. medical system, which could put patients at risk of inappropriate treatment and death.
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

Children | Free Full-Text | Long-Term Outcome of Pediatric Patients with Anti-NMDA Receptor Encephalitis in a Single Center

Children | Free Full-Text | Long-Term Outcome of Pediatric Patients with Anti-NMDA Receptor Encephalitis in a Single Center | AntiNMDA | Scoop.it
Background: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is the most common autoimmune encephalitis in children. There is a high probability of recovery if treated promptly. We aimed to analyze the clinical features and long-term outcomes of pediatric patients with anti-NMDA receptor...
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

Can you help improve treatment for autoimmune encephalitis?

No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

Vaccination-associated acute disseminated encephalomyelitis

Vaccination-associated acute disseminated encephalomyelitis | AntiNMDA | Scoop.it
While the basic definition of vaccination-associated acute disseminated encephalomyelitis (ADEM) is relatively clear and easily understandable, it is often difficult to diagnose ADEM based on clinical findings alone.
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

Antibodies | Free Full-Text | Philosophical Approach to Neural Autoantibodies in Psychiatric Disease—Multi-Systemic Dynamic Continuum from Protective to Harmful Autoimmunity in Neuronal Systems

Antibodies | Free Full-Text | Philosophical Approach to Neural Autoantibodies in Psychiatric Disease—Multi-Systemic Dynamic Continuum from Protective to Harmful Autoimmunity in Neuronal Systems | AntiNMDA | Scoop.it
(1) Background: philosophical views are important to enable a general and multi-systemic view of the potential understanding of autoimmunity in psychiatric disease that is not solely reflected by an immunological viewpoint.
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

What is Autoimmune Encephalitis?

What is Autoimmune Encephalitis? | AntiNMDA | Scoop.it
Autoimmune encephalitis (AE) is a type of brain inflammation where the body’s immune system attacks healthy cells and tissues in the brain or spinal cord. It is a rare, complex disease that can cause rapid changes in both physical and mental health.
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

Cerebrospinal fluid pentraxin 3 and CD40 ligand in anti-N-menthyl-d-aspartate receptor encephalitis

Cerebrospinal fluid pentraxin 3 and CD40 ligand in anti-N-menthyl-d-aspartate receptor encephalitis | AntiNMDA | Scoop.it
Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder of the central nervous system whose pathogenesis involves interleukin (IL)-6 and IL-17A.We examined the correlations between CSF concentrations of the acute-phase protein pentraxin 3 (PTX3), the chronic inflammatory...
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

Postpartum Psychosis or Something Else?

Postpartum Psychosis or Something Else? | AntiNMDA | Scoop.it
A case of postpartum psychosis with malignant catatonia highlights the role of immunology in the development and treatment of postpartum psychosis.
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

Neuroinflammatory syndromes in children

Neuroinflammatory syndromes in children | AntiNMDA | Scoop.it
Neuroimmunological disease data are constantly evolving. New recommendations exist for multiple common neuroimmunological disorders with behavioural, emotional, cognitive and neurological sequelae.Anti-NMDA receptor encephalitis now has well-recognized patterns of symptom semiology, diagnostic and...
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

Diagnostic Value of 18F-FDG PET/CT Versus MRI in the Setting of Antibody-Specific Autoimmune Encephalitis

Diagnostic Value of 18F-FDG PET/CT Versus MRI in the Setting of Antibody-Specific Autoimmune Encephalitis | AntiNMDA | Scoop.it
Diagnosis of autoimmune encephalitis presents some challenges in the clinical setting because of varied clinical presentations and delay in obtaining antibody panel results.We examined the role of neuroimaging in the setting of autoimmune encephalitides, comparing the utility of <sup>18</sup>F-FDG...
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

The Many Faces of Catatonia, An Under-Recognized Clinical Syndrome

The Many Faces of Catatonia, An Under-Recognized Clinical Syndrome | AntiNMDA | Scoop.it
Catatonia: learn more about how to best diagnose early.
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

Why We Still Use “Organic Causes”: Results From a Survey of Psychiatrists and Residents

The diagnostic category of “organic disorders” was officially removed from the psychiatric nosology in DSM-IV, published in 1994. Despite this change, physicians continue to use the term “organic causes” to refer to medical and neurological causes of psychiatric symptoms, and it remains part of...
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

Anti-NMDA receptor encephalitis and brain atrophy in children and adults: A quantitative study

Anti-NMDA receptor encephalitis and brain atrophy in children and adults: A quantitative study | AntiNMDA | Scoop.it
To determine whether brain atrophy was present in patients with anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDARE) using qualitative and quantitative analyses of brain magnetic resonance imaging (MRI) and to explore clinical differences in patients with anti-NMDARE with or without brain...
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

Eoin Flanagan, M.B., B.Ch., explains autoimmune encephalitis misdiagnosis in JAMA Neurology

Eoin Flanagan, M.B., B.Ch., explains autoimmune encephalitis misdiagnosis in JAMA Neurology | AntiNMDA | Scoop.it
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

Characterization of cardiac bradyarrhythmia associated with LGI1-IgG autoimmune encephalitis

LGI1-IgG AE can be rarely associated with bradyarrhythmias. Although the disease course is mostly favorable, some cases may require pacemaker placement to avoid devastating outcomes.
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

Event Announcement: Saturday, 21 January 2023, Paris, France

Event Announcement: Saturday, 21 January 2023, Paris, France | AntiNMDA | Scoop.it
Dear Subscriber, We are pleased to share with you details of an event that is being hosted by the newly established ENMDAR, a French anti-NMDA receptor encephalitis organisation. The event is free of charge and open to all. It will be in French.
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

Autoimmune Encephalitis in Critical Care: Optimizing Immunosuppression

Autoimmune Encephalitis in Critical Care: Optimizing Immunosuppression | AntiNMDA | Scoop.it
Autoimmune diseases affecting the nervous systems are a common cause of admission to the intensive care unit (ICU).Although there exist several well-described clinical syndromes, patients more commonly present with progressive neurologic dysfunction and laboratory and radiographic evidence of centr...
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

Diagnosis and Management of Autoimmune Encephalitis (Podcast) –

Diagnosis and Management of Autoimmune Encephalitis (Podcast) – | AntiNMDA | Scoop.it
The rarity and many mimics of autoimmune encephalitis make its diagnosis no easy task. An AE expert shares practical insights on how to promptly identify the condition to enable early treatment.
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

Serum cystatin C and anti-N-methyl-D-aspartate receptor encephalitis

Serum cystatin C and anti-N-methyl-D-aspartate receptor encephalitis | AntiNMDA | Scoop.it
Our results show that the serum levels of CysC are associated with anti-NMDAR encephalitis and its clinical parameters and that the changes in CysC levels correlate with therapeutic effect.Therefore, our findings provide new insights into the association between serum CysC and anti-NMDAR encephalit...
No comment yet.
Scooped by Nesrin Shaheen
Scoop.it!

Molecular mimicry of NMDA receptors may contribute to neuropsychiatric symptoms in severe COVID-19 cases

Molecular mimicry of NMDA receptors may contribute to neuropsychiatric symptoms in severe COVID-19 cases | AntiNMDA | Scoop.it
Approximately 30% of individuals with severe SARS-CoV-2 infections also develop neurological and psychiatric complaints. In rare cases, the occurrence of autoimmune encephalitis has been reported after SARS-CoV-2 infection.
No comment yet.