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Seizure Semiology in Antibody-Associated Autoimmune Encephalitis | Neurology Neuroimmunology & Neuroinflammation

Seizure Semiology in Antibody-Associated Autoimmune Encephalitis | Neurology Neuroimmunology & Neuroinflammation | AntiNMDA | Scoop.it
AbstractBackground and Objectives To assess seizure characteristics in antibody (ab)-associated autoimmune encephalitis (ab + AE) with the 3 most prevalent abs against N-methyl-d-aspartate receptor (NMDAR), leucine-rich glioma-inactivated protein 1 (LGI1), and glutamic acid decarboxylase (GAD).Methods Multicenter nationwide prospective cohort study of the German Network for Research in Autoimmune Encephalitis.Results Three hundred twenty patients with ab + AE were eligible for analysis: 190 NMDAR+, 89 LGI1+, and 41 GAD+. Seizures were present in 113 (60%) NMDAR+, 69 (78%) LGI1+, and 26 (65%) GAD+ patients and as leading symptoms for diagnosis in 53 (28%) NMDAR+, 47 (53%) LGI+, and 20 (49%) GAD+ patients. Bilateral tonic-clonic seizures occurred with almost equal frequency in NMDAR+ (38/51, 75%) and GAD+ (14/20, 70%) patients, while being less common in LGI1+ patients (27/59, 46%). Focal seizures occurred less frequently in NMDAR+ (67/113; 59%) than in LGI1+ (54/69, 78%) or in GAD+ patients (23/26; 88%). An aura with déjà-vu phenomenon was nearly specific in GAD+ patients (16/20, 80%). Faciobrachial dystonic seizures (FBDS) were uniquely observed in LGI1+ patients (17/59, 29%). Status epilepticus was reported in one-third of NMDAR+ patients, but only rarely in the 2 other groups. The occurrence of seizures was associated with higher disease severity only in NMDAR+ patients.Discussion Seizures are a frequent and diagnostically relevant symptom of ab + AE. Whereas NMDAR+ patients had few localizing semiological features, semiology in LGI1+ and GAD+ patients pointed toward a predominant temporal seizure onset. FBDS are pathognomonic for LGI1 + AE. Status epilepticus seems to be more frequent in NMDAR + AE.Glossaryab=antibody; AE=autoimmune encephalitis; FBDS=faciobrachial dystonic seizures; GAD=glutamic acid decarboxylase; GENERATE=German Network for Research on Autoimmune Encephalitis; ILAE=International League Against Epilepsy; LGI1=leucine-rich glioma-inactivated protein 1; mRS=modified Rankin score; NMDAR=N-methyl-d-aspartate receptor; OR=odds ratio; SE=status epilepticusSeizures are a prominent symptom in antibody (ab)-associated autoimmune encephalitis (ab + AE).1,2 Moreover, seizures can occur as the initial symptom prompting further diagnostics.3,-,5A relevant drawback in diagnosing ab + AE is still the reliance on ab test results, which will only be initiated on suspicion of the treating physician and usually results in a delay of several days or even weeks until diagnosis, thus retarding therapy onset. However, an immediate start of immunotherapy is important for a favorable outcome.6 A consensus paper has determined a more clinical diagnostic approach for AE.2 The authors suggest preliminary patient categorization along mainly clinical criteria before ab results are returned allowing early therapy initiation. Both for probable N-methyl-d-aspartate receptor AE (NMDAR + AE) and limbic encephalitis, seizures are mentioned as an important diagnostic feature, but the authors did not make further specification regarding the type of seizures or their semiology.Nevertheless, more knowledge of seizure semiology in ab + AE could improve the understanding of syndrome characteristics and may facilitate discrimination into the distinct ab + AE subgroups for treating physicians. It is tempting to assume that seizure specifications differ according to cerebral regions affected by distinct ab + AE subgroups. A keystone concerning these aspects was certainly the description of faciobrachial dystonic seizures (FBDS) in AE associated with abs against leucine-rich glioma-inactivated protein 1 (LGI1 + AE).3 FBDS serve here as a specific prodromal biomarker for LGI1 + AE with tremendous effect on therapy and outcome.7,8 Apart from FBDS and despite the abovementioned considerations of clinical relevance, descriptions of seizures in ab + AE reports usually remain imprecise even in the diagnostic consensus criteria.2 Even if semiological features might be not specific for a distinct ab + AE, a better understanding of seizure symptomatology may be important for the diagnostic recognition of AE.In this study, we aimed to reveal the characteristics of seizures of patients with ab + AE from the database of the German Network for Research on Autoimmune Encephalitis (GENERATE), a nationwide prospective registry for patients with ab + AE. Specifically, we focused on the 3 most common subtypes of AE with antibodies against NMDAR, LGI1, and glutamic acid decarboxylase (GAD). We sought for (1) the proportion of patients with seizures at first presentation and their leading role for making the diagnosis, (2) specificities in seizure semiology according to the detected ab, (3) the prevalence of pathologic EEG findings, and (4) the effect of seizure occurrence on disease severity.MethodsPatientsWe conducted a multicenter nationwide cohort study analyzing registry data of the GENERATE. The study focused on consecutively included patients diagnosed with ab + AE associated with abs against NMDAR, LGI1, or GAD between 2004 and 2016 from 40 collaborating hospitals. In GAD + AE, we applied more strict inclusion criteria concerning the laboratory diagnosis because low-titer GAD abs are currently classified as low specific for an AE.9The laboratory tests for GAD abs in serum had to meet at least 1 of the following criteria: ELISA value >1,000 IU/mL, radioimmunoprecipitation assay >2,000 U/mL, positive labeling cell-based assays (>1:10), or intrathecal ab synthesis (ab index >1.5).Data were collected at each center by local investigators gathering demographic and clinical information. To assess the severity of the disease, the local investigators provided the modified Rankin score (mRS) at disease maximum in the acute disease stage.The seizure semiology was categorized according to the current classification of the International League Against Epilepsy (ILAE).10 In the patient population with focal seizures, patient charts were analyzed to retrieve more detailed information about focal seizure semiology. Furthermore, we assessed EEG findings from the database. This study primarily focused on the early stage of AE (i.e., the first presentation at the corresponding center where the diagnosis of ab + AE was performed).Standard Protocol Approvals, Registrations, and Patient ConsentsInitial institutional review board approval was given by the ethical advisory board of the University of Luebeck, Germany, (reference number: 13–162) and consecutively by the regional ethical advisory boards of all participating centers. Written informed consent was obtained from every patient or their representative.Statistical AnalysisThe SPSS statistic computer package (version 25.0; IBM Corporation) was used for all statistical analyses. Categorical variables were presented as numbers (n/N) and percentages. Values were given as median and interquartile range.Group comparisons of categorical variables (e.g., sex of the patients) were hierarchically performed first with the Freeman-Halton test and subsequently between 2 groups with the Fisher exact test. The Kruskal-Wallis test and Bonferroni correction for multiple tests were used to compare metrical data between 3 or 2 groups, respectively. All tests were 2-tailed; p values < 0.05 were considered statistically significant.Data AvailabilityAnonymized data not published within this article will be made available on reasonable request from qualified investigators.ResultsPatient CharacteristicsWe screened 387 patients with ab + AE (205 NMDAR+, 101 LGI1+, and 81 GAD+) from the GENERATE database enrolled until 2016. Sixty-seven patients had to be excluded because of incomplete data in the documentary files. Finally, 320 patients were analyzed for this study: 190 (59%) had abs against NMDAR, 89 (28%) against LGI1, and 41 (13%) against GAD (Table 1). Corroborating previous studies, LGI1+ patients were more often males (55%) than NMDAR+ (24%) and GAD+ (12%) patients (NMDAR+/LGI1+/GAD+ p < 0.001, NMDAR+/LGI1+ p < 0.001, LGI1+/GAD+ p < 0.001). NMDAR+ patients were significantly younger (median: 34 years) at onset than LGI1+ (median: 63 years) and GAD+ patients (median: 50 years; NMDAR+/LGI1+/GAD+, NMDAR+/LGI1+, and NMDAR+/GAD+ p < 0.001 respectively). Furthermore, a paraneoplastic condition was moderately frequent in NMDAR+ patients (17%), rare in LGI1+ (3%), and absent in GAD+ patients (NMDAR+/LGI1+/GAD+ p < 0.001, NMDAR+/LGI1+ p < 0.001, and NMDAR+/GAD+ p < 0.001).View inline View popup Table 1 Demography, Seizure Frequencies, and Seizures as Leading SymptomsProportion of Patients With SeizuresOf importance, seizures were present in almost 2-thirds of patients with ab + AE (N = 208/320; 65%) at the early stage of disease. In detail, 113/190 (60%) patients with NMDAR + AE, 69/89 (78%) patients with LGI1 + AE, and 26/41 (65%) patients with GAD + AE experienced seizures. Seizures occurred less frequently in NMDAR+ than in LGI1+ patients (NMDAR+/LGI1+/GAD+ p = 0.01, NMDAR+/LGI1+ p = 0.003, Table 1). Seizures as a leading symptom to prompt further diagnostics were seen 2.9 times more often in LGI1+ and 2.4 times more often in GAD+ than in NMDAR+ patients (NMDAR+/LGI1+/GAD+ p = 0.01, NMDAR+/LGI1+ p < 0.001, and NMDAR+/GAD+ p = 0.02, Table 1).When comparing characteristics in the individual ab + AE subgroups for patients with and without seizures, we found that NMDAR+ and GAD+ patients with seizures were younger than those without (NMDAR+ p = 0.003; GAD+ p < 0.001), whereas other demographical characteristics did not differ whether seizures were present or not (for details, see Table 2).View inline View popup Table 2 Demographic Data for Patients With ab + AE With and Without SeizuresSemiology of SeizuresA detailed description of seizure semiology was available in 51 NMDAR+, 59 LGI1+, and 20 GAD+ patients, which is summarized in Table 3. Knowledge of the specific focal seizure onset was required to apply the ILAE classification guidelines.10View inline View popup Table 3 Focal Seizures and Their SemiologyFocal SeizuresWhereas focal seizures without impaired awareness were observed similarly often throughout all 3 ab + AE subgroups, focal seizures with impaired awareness were more frequently found in GAD+ patients (17/20, 85%) and in NMDAR+ patients (35/51, 69%) than in LGI1+ patients (28/59, 48%; NMDAR+/LGI1+/GAD+ p = 0.004, NMDAR+/LGI1+ p = 0.03, and LGI1+/GAD+ p = 0.004). FBDS were found solely in 17/59 (29%) of LGI1+ patients (NMDAR/LGI1/GAD p < 0.001).Motor-onset seizures were most frequently observed in NMDAR+ patients (31/51, 61%) with a broad spectrum of symptoms. Vice versa, in LGI1+ patients, motor-onset seizures were the least often observed among all 3 ab + AE subgroups with 19% of cases (NMDAR+/LGI1+/GAD+ p < 0.001, NMDAR+/LGI1+ p < 0.001, and LGI1+/GAD+ p = 0.009). Of note, FBDS were considered a unique semiology and were separately analyzed. In GAD+ patients, the phenotype of motor-onset seizures was less variable. In this study, automatisms were the key feature being present in all GAD+ patients with motor-onset seizures (NMDAR+/LGI1+/GAD+ p < 0.001, NMDAR+/GAD+ p = 0.02, and LGI1+/GAD+ p < 0.001): the likelihood of automatism was 4.1 times higher than in NMDAR+ and 10.8 times higher than in LGI1+ patients, whereas other motor signs were scarcely or never reported in GAD+ patients. A clonic motor onset was only seen in NMDAR+ patients (5/51; 10%) (NMDAR+/LGI1+/GAD+ p = 0.02, NMDAR+/LGI1+ p = 0.02, and NMDAR+/GAD+ p = 0.31). Moreover, a myoclonic motor onset was found in NMDAR+ patients in 10/51 (20%) cases, whereas it was rare in LGI1+ (3/59, 5%) and absent in GAD+ patients (NMDAR+/LGI1+/GAD+ p = 0.02, NMDAR+/LGI1+ p = 0.04, and NMDAR+/GAD+ p = 0.05).Nonmotor-onset seizures occurred more frequently in GAD+ patients (16/20, 80%) than in one of the other ab + AE subgroups (NMDAR+/LGI1+/GAD+ p ≤ 0.001, NMDAR+/GAD+ p < 0.001, and LGI1+/GAD+ p = 0.02). Whereas ictal autonomic symptoms were found in approximately half of the GAD+ (8/16; 50%) and LGI1+ (16/29, 55%) patients with nonmotor-onset seizures, they were very rare in NMDAR+ (1/51, 2%) patients (NMDAR+/LGI1+/GAD+ p < 0.001, NMDAR+/LGI1+ p < 0.001, and NMDAR+/GAD+ p < 0.001). Notably, pilomotor seizures as a particular subtype of autonomic seizures were reported only in LGI1+ (9/59, 15%) and GAD+ (1/20, 5%) patients. Ictal cognitive symptoms were seldom in LGI1+ patients (5/59, 9%) compared with GAD+ patients (7/20, 35%, p = 0.009).Phenomenology of AuraIn addition, we investigated auras as a key element of seizures that may provide information regarding the seizure onset zone. The detailed analysis of aura is summarized in Table 4. Auras were most prevalent in GAD+ patients (16/20, 80%; NMDAR+/LGI1+/GAD+ p < 0.001), seen 21.5 times more often than in NMDAR+ (8/51, 16%, p < 0.001) and 5.4 times more often than in LGI1+ patients (25/59, 42%, p = 0.004). Déjà vu seemed to serve as a specific aura phenomenon of GAD+ patients (7/20, 35%) compared with that of NMDAR+ (2/51, 2%) and LGI1+ patients (0/59, 0%; NMDAR+/LGI1+/GAD+ p < 0.001, NMDAR+/GAD+ p < 0.001, and LGI1+/GAD+ p < 0.001). An epigastric aura was equally common in LGI1+ (12/59, 20%) and GAD+ (6/20, 30%) patients, but rare in NMDAR+ (1/51, 2%) patients (NMDAR+/LGI1+/GAD+ p < 0.001, NMDAR+/LGI1+ p = 0.003, NMDAR+/GAD+ p = 0.002).View inline View popup Table 4 Phenomenology of AuraBilateral Tonic-Clonic SeizuresBilateral tonic-clonic seizures were detected in all ab + AE subgroups (79/130, 61%); they occurred with almost equal frequency in NMDAR+ (38/51, 75%) and in GAD+ (14/20, 70%) patients, while being less common in LGI1+ patients (27/59, 46%) (NMDAR+/LGI1+/GAD+ p = 0.006, NMDAR+/LGI1+ p = 0.003, NMDAR+/GAD+ p = 0.77, and LGI1+/GAD+ p = 0.074, Table 5).View inline View popup Table 5 Bilateral Tonic-Clonic Seizures and Status EpilepticusStatus EpilepticusBecause the information, whether status epilepticus (SE) occurred, was a mandatory entry in the database, we could analyze all patients with seizures regarding this issue. SE was reported in more than a quarter of NMDAR+ patients with seizures (30/113, 26.5%), whereas it was rare in the other 2 ab + AE subgroups with only 4/69 (6%) LGI1+ and 1/26 (4%) GAD+ patients affected (NMDAR+/LGI1+/GAD+ p < 0.001, NMDAR+/LGI1+ p < 0.001, NMDAR+/GAD+ p = 0.009). Thus, NMDAR + patients had a 5.8 and 9.0 times higher probability to experience SE in comparison with LGI1+ and GAD+, respectively (Table 5).EEGEEG data were available in most cases (NMDAR+ 164/190, 86%; LGI1+ 81/89, 91%, GAD+ 32/41, 78%) with pathologic abnormalities in most of the ab + AE patients (NMDAR+ 73%, LGI1+ 68% and GAD+ 75%, p = 0.62). Despite the fact that generalized slowing was found mainly in NMDAR + patients, all other parameters did not differ in the ab + AE subgroups: generalized slowing in NMDAR + AE patients (48%) has been reported twice as often than in LGI1+ (21%) and 3 times more often than in GAD+ (16%) patients (NMDAR+/LGI1+/GAD+ p < 0.001, NMDAR+/LGI1+ p < 0.001, NMDAR+/GAD+ p < 0.001, eTable 1, links.lww.com/NXI/A747).We additionally analyzed whether the EEG differed between patients with and without seizures within the ab + AE subgroups (eTable 2, links.lww.com/NXI/A747). In general, EEG was more often pathologic in patients with seizures in the NMDAR+ (p = 0.002) and GAD+ (p = 0.005) subgroups than in the LGI1+ subgroup with seizures in comparison with the subgroup without seizures, respectively. The analysis of epileptiform discharges and ictal patterns was of particular interest. Whereas in NMDAR + patients, both epileptiform discharges and ictal patterns were not significantly different in patients with and without clinical seizures, epileptiform discharges were observed only in GAD+ patients with clinical seizures (p = 0.029). In LGI1+ and GAD+ patients, ictal patterns were detected only in patients with clinical seizures (LGI1+ 15/63, p = 0.02, GAD+ 6/25, p = 0.3).Seizures and mRS at Disease MaximumIn general, the mRS was significantly higher in NMDAR+ patients in comparison with LGI1+ and GAD+ patients (Figure 1). In total, 60% of NMDAR+ patients revealed a mRS >4, whereas only 21% GAD+ and 20% LGI1+ patients did (NMDAR+/LGI1+/GAD+ p < 0.001, LGI1+/GAD+ p < 0.001, NMDAR+/GAD+ p < 0.001).<img width="411" src="https://nn.neurology.org/content/nnn/9/6/e200034/F1.medium.gif"; height="440" class="highwire-fragment fragment-image" alt="Figure 1">Download figure Open in new tab Download powerpoint Figure 1 Scores of the Modified Rankin Scale (mRS) at Disease Maximum in the Acute Stage(A) Shows the distribution of scores of all patients in the 3 subgroups of ab + AE. mRS was significantly higher in NMDAR+ patients in comparison with that in LGI1+ (mRS >4, OR = 11.2, p < 0.001) and GAD+ patients (mRS >4, OR = 6.2, p < 0.001). (B) Shows the scores in patients with and without seizures within the individual ab + subgroups. In the NMDAR+ subgroup, the occurrence of seizures was associated with a 2.8-fold increased risk to show a higher level of disease severity (mRS >4, OR = 2.800; p < 0.001), whereas it had no significant effect in LGI1+ and GAD+ patients. GAD = glutamic acid decarboxylase; LGI1 = leucine-rich glioma-inactivated protein 1; NMDAR = N-methyl-d-aspartate receptor.Of note, within the NMDAR+ subgroup, the occurrence of seizures was associated with a 2.8-fold increased risk to show a higher level of disease severity (mRS >4, odds ratio [OR] = 2.800; p < 0.001, Figure 1B). SE in NMDAR+ patients even leads to 5.0-fold increased probability to express an mRS >4 than in NMDAR+ patients without seizures (OR = 5.063; p = 0.001). By contrast, in LGI1+ and GAD+ patients, the occurrence of seizures had no significant effect on the level of disability at disease maximum (Figure 1B).DiscussionSeizures are a common and often leading symptom in early stages of ab + AE. In this study, we provide a large dataset of well-characterized ab + AE patients with documented seizures. In our nationwide multicentric cohort, 2-thirds of all patients with AE positive for the 3 most prevalent abs against NMDAR, LGI1, or GAD presented with seizures at the early stages of disease.In approximately half of the LGI1+ and GAD+ patients, seizures were the dominating symptom, leading to further diagnostics. NMDAR+ patients were less likely to experience seizures at the early stages compared with the other 2 ab + AE subgroups, and these were indicative for diagnosis only in approximately one-third of cases. If seizures occurred in NMDAR+, they had a significant effect on disease severity, particularly if they evolved into SE.The occurrence of seizures and their semiology differed throughout the ab + AE subgroups, revealing several characteristic features. Except for the LGI1+ subgroup, patients with seizures were younger than patients without seizures.According to the more widespread and diffuse cerebral lesion pattern in NMDAR + AE, patients presented with focal and frequent bilateral tonic-clonic seizures. Semiological features of focal seizures in the NMDAR+ subgroup were diverse regarding impaired awareness and motor or nonmotor onset. In motor-onset seizures, clonic and myoclonic features were characteristics for NMDAR+ patients. An aura was uncommon in this ab + AE subgroup compared with that in both LGI1+ and GAD+ patients. On the contrary, bilateral tonic-clonic seizures were typical in NMDAR+ patients, and SE was present in 27% of NMDAR+ cases with seizures, whereas it was a rarity in the 2 other ab + AE subgroups.In summary, our study points to diverse sites of seizure origins in NMDAR + including the frontal motor zones, which is in line with the findings of Niehusmann et al.11 Thus, our results do not support the common hypothesis that most seizures originate from the temporal lobe in NMDAR+.12 Extrapyramidal movements are very common in NMDAR+ patients, particularly orofacial dyskinesia, which might be mistaken for temporal seizure symptoms.13 In general, the differentiation between epileptic seizures and extrapyramidal movements within the NMDAR+ population is challenging. Studies with continuous video-EEG monitoring are required to further investigate and clarify these aspects. Similarly, a more frequent application of video-EEG monitoring would also help to determine more precisely the incidence of SE in NMDAR + AE. In our study, the proportion of SE was highest in NMDAR+ patients with 27%. These data should be interpreted with caution because we were not able to explicitly reanalyze the EEG data from each center. A previous study revealed that in NMDAR+ AE, abnormal EEG findings such as rhythmic delta activity, movement disorders, and impaired awareness are frequently misinterpreted as SE.14 In a recent systemic review dealing with EEG abnormalities and seizures in AE, “SE on EEG” was even found in only 0.2% of NMDAR+ patients.15 Considering the diagnostic difficulties mentioned earlier, this result should be also viewed with caution because the classification, whether SE was present or not, thus considerably depended largely on the epileptological expertise of the reporting physician.In our LGI1+ population, a significant proportion of patients experienced only focal seizures (48%). Thereby, focal seizures with and without impaired awareness occurred with a similar prevalence. The more detailed analysis revealed that nonmotor-seizure onset with autonomic features was the most typical semiology in LGI1+ patients. An aura was reported in 42% of cases, in half of them as an epigastric aura, suggesting a temporal origin. As a peculiar symptom, we observed pilomotor seizures in 15% of the LGI1+ patients, which also indicates involvement of the limbic structures. In line with these findings, previous smaller case series also reported seizures with temporal semiology with autonomic symptoms and impaired awareness as main seizure type in LGI1 + AE.16,17 Besides the temporal lobe seizures, FBDS were frequently observed in our LGI1+ cohort (28%), and their occurrence was unique in the LGI1+ subgroup. Hence, our study adds further evidence to the assumption that FBDS can be nearly considered as pathognomonic for LGI1 + AE and are not detected in other forms of AE.3,12 The frequency of FBDS in our LGI1+ cohort might be underestimated due to challenges of detecting and categorizing this seizure type properly in the beginning phase of the GENERATE database. We included patients from 2006 to 2016, and the awareness of FBDS has just started since their first description in 2011.3 Hence, FBDS might be missed in early LGI1 patients before 2011. In previous case studies and smaller patient series, the frequency of FBDS in LGI1 were 32%,18 48%,17 and 69%.16GAD+ patients presented with both focal and bilateral tonic-clonic seizures. Focal seizures occurred predominantly with impaired awareness, with motor onset or nonmotor onset. Typical features were automatisms in motor-onset seizures. Regarding aura phenomenon, déjà vu was nearly specific for GAD+ patients. The epigastric aura was the second most common aura phenomenon. Altogether, seizure semiology in GAD+ patients is characteristic for a temporal seizure origin. SE was very rare in this ab + subgroup. A comprehensive analysis of seizure semiology in GAD+ patients is lacking so far. In previous studies of GAD + AE, descriptions of seizure semiology mainly simplified to terms such as “localization-related seizures, temporal lobe seizures, or seizures with temporal semiology.”19,-,21 Hence, our study provides unique information on detailed semiological features of a large cohort of GAD+ patients. Consistent with the literature, the limbic structures appear thereby the predominant target in GAD + AE with seizures.9,20 Of note, few recent case reports discuss musicogenic reflex seizures as typical semiology in GAD + AE, which were not detected in our analysis.22,-,24 A possible explanation could be underreporting because this association was recognized after the inclusion period of this study. Nevertheless, the occurrence of musicogenic reflex seizures in GAD+ patients is in line with a predominant temporal seizure onset in this ab + AE subgroup. Besides the clinical constellation of intractable temporal lobe seizures, a second scenario with acute onset and SE has been described in GAD + AE.19,25,26 In this study, we detected only 1 patient with SE; thus, SE may rather be a rare clinical manifestation in GAD + AE.Despite the wide use of EEG in ab + AE in clinical practice, there exist only few systematic data on that subject regarding sensitivity and specificity of pathologic findings, especially in assessing the risk of seizures. The best knowledge exists for pathologic EEG findings in NMDAR + AE with diffuse and focal slowing as most relevant findings.13,27 In a recent study focusing on the predictive value of EEG recordings in NMDAR+ adult and children patients, 96% of adults and all children had abnormal findings at their first EEG recording, pointing to a high sensitivity. Furthermore, an abnormal posterior EEG rhythm at onset was considered to have a negative predictive value for clinical outcome.27 In studies with LGI1+ patients, approximately 25% of patients showed focal slowing,17 and approximately 30% of patients had epileptiform discharges.17,28 We are not aware of a larger cohort of GAD+ patients exploring systemic EEG data. There are only a few cases in heterogenic ab + AE patient cohorts reporting EEG findings, revealing mainly focal interictal discharges.29,30In our cohort, we could confirm previous findings that focal and generalized slowing are the most prevalent EEG findings. Generalized slowing was present in nearly half of the NMDAR+ patients but only in 21% of LGI1+ and 16% of GAD+ patients, once again reflecting the more diffuse distribution in NMDAR + AE. Of interest, NMDAR+ patients had both epileptiform discharges and ictal patterns irrespective of clinical seizure occurrence, whereas ictal patterns in LGI1+ and GAD+ patients were only detected in patients with clinical seizures. However, we found no significant relevance of EEG to predict the risk of having seizures in the early stage of disease.Our study has several limitations. First, we included only patients from the GENERATE database, which is a free alliance of hospitals with different medical care standards throughout Germany. Thus, the study may bear a relevant risk for a selection bias. Indeed, such a selection bias can be assumed in many if not almost all other reports on the topic of ab + AE. To our knowledge, only the group of Titulaer from Rotterdam, the Netherlands, reported country-wide epidemiologic data of ab + AE because they serve as the only national reference ab laboratory in Netherlands.18 All other reports share the problem of data retrieved from specialized reference laboratory databases or from single specialized centers. With the GENERATE cohort, we aim to overcome the limitations of small monocentric studies or studies of some specialized centers. The nationwide approach widens the spectrum of patients reported not only from specialized tertiary but also from other medical care standard centers involved in the treatment of AE patients (generate-net.de). A further argument against relevant selection bias in our population is the matching demographical distribution with previous reports of the distinct ab + AE subgroups. NMDAR+ patients are mainly females of middle or younger age with a tumor rate of approximately 20%.13,18 LGI1+ patients are predominantly older males with rare tumor association,3,17 and finally, GAD+ patients are mainly middle-aged women without tumor association.9,19,31 Second, the data quality in a multicentric registry study has to be critically questioned. Indeed, there could be a relevant information gap because we were not able to reevaluate in person all data included in the database. Instead, we asked the collaborating centers to provide anonymized full and detailed descriptions of seizure semiologies and EEG recordings. We therefore cannot exclude some missing details according to the level of epileptological expertise in the different sites. Third, our aim was to assess seizure characteristics in the early stage of ab-associated AE. The distinction between acute symptomatic seizures due to an active encephalitis and autoimmune-associated epilepsy as a chronic disease, as conceptualized by Geis et al.,1 was behind the scope of our study and will be addressed in future investigations. After a subset of patients with coexisting NMDAR and myelin oligodendrocyte glycoprotein abs was first reported in 2014,32 this topic has gained increasing interest. However, the clinical relevance of these coexisting antibodies remains controversial at present.33 Because these findings were largely unknown during patient recruitment in this study, we cannot report any further results regarding this.Seizures are a frequent and important clinical symptom in the early stages of ab + AE with abs against NMDAR, LGI1, and GAD with relevant effect on diagnosis and disease severity. Patients with NMDAR + AE had only few characteristic semiological features according to the more diffuse cerebral affection, but developing seizures is associated with a more severe disease course. By contrast, semiology in LGI1+ and GAD+ patients clearly pointed to a more focal and temporal seizure onset. FBDS are pathognomonic for LGI1+AE. SE seems to be more frequent for NMDAR + AE.Study FundingThe authors report no targeted funding.DisclosureT. Kaaden, M. Madlener, and K. Angstwurm report no disclosures relevant to the manuscript; C.G. Bien receives research support from the Deutsche Forschungsgemeinschaft (German Research Council, Bonn, Germany) and Gerd-Altenhof-Stiftung (Deutsches Stiftungs-Zentrum, Essen, Germany); Y. Bogarin, K. Doppler, A. Finke, S. T. Gerner, G. Reimann, M. Häusler, R. Handreka, K. Hellwig, and M. Kaufmann report no disclosures relevant to the manuscript; C. Kellinghaus received speakers honoraria from Eisai, UCB Pharma, GW Pharma, Marinus, Angelini Pharma, Zogenix; he served in advisory boards for UCB Pharma, Eisai, GW Pharma; P. Koertvelyessy, A. Kraft, J. Lewerenz, T. Menge, and A. Paliantonis report no disclosures relevant to the manuscript; F. von Podewils reports industry-funded travel with the support of Desitin Arzneimittel GmbH (Hamburg, Germany), Bial (Mörfelden-Walldorf, Germany), Eisai Pharma (Frankfurt, Germany), Arvelle Therapeutics/Angelinipharma (München, Germany), GW Pharmaceuticals companies (München, Germany), and UCB Pharma (Monheim, Germany), honoraria obtained for speaking engagements from Desitin Arzneimittel GmbH (Hamburg, Germany), Zogenix (München, Germany), Bial (Mörfelden-Walldorf, Germany), Arvelle Therapeutics/Angelinipharma (München, Germany), GW Pharmaceuticals companies (München, Germany), and UCB Pharma (Monheim, Germany), and as part of a speaker's bureau for Bial (Mörfelden-Walldorf, Germany), Eisai Pharma (Frankfurt, Germany), Arvelle Therapeutics/Angelinipharma (München, Germany), GW Pharmaceuticals companies (München, Germany), and UCB Pharma (Monheim, Germany); H. Prüss, S. Rauer, M. Ringelstein, K. Rostásy, I. Schirotzek, J. Schwabe, P. Sokolowski, and M. Suesse report no disclosures relevant to the manuscript; K.-W. Sühs obtained honoraria for speaking engagements and consultancy from Merck, Biogen, and Bristol-Myers Squibb; R. Surges has received fees as speaker or consultant from Angelini, Arvelle, Bial, Desitin, Eisai, LivaNova, Novartis, UCB Pharma, and UnEEG; S. C. Tauber, F. Thaler, F. Then Bergh, C. Urbanek, K.-P. Wandinger, B. Wildemann, S. Mues, U. Zettl, F. Leypoldt, N. Melzer, and C. Geis report no disclosures relevant to the manuscript; M. P. Malter obtained honoraria for speaking engagements and consultancy from UCB (Monheim, Germany) and EISAI (Frankfurt, Germany); A: Kunze reports no disclosures relevant to the manuscript. Go to Neurology.org/NN for full disclosure.AcknowledgmentThe authors are indebted to all members of the GENERATE e.V. (generate-net.de) and all patients and their relatives for supporting this study. Particularly The authors would like to thank Dr. Thomas Lehmann (Institute of Medical Statistics and Computer Science, University Hospital Jena, Germany) for support with the statistical analysis.Appendix Authors<img width="599" class="highwire-fragment fragment-image" alt="Table" src="https://nn.neurology.org/content/nnn/9/6/e200034/T6.medium.gif"; height="4706">Footnotes↵* These authors contributed equally as first authors.↵† These authors contributed equally as senior authors.Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.The Article Processing Charge was funded by University Hospital Jena.Submitted and externally peer reviewed. The handling editor was Josep O. Dalmau, MD, PhD, FAAN.Received February 2, 2022.Accepted in final form August 8, 2022.Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.References1.↵Geis C, Planaguma J, Carreno M, Graus F, Dalmau J. Autoimmune seizures and epilepsy. J Clin Invest. 2019;129(3):926-940.OpenUrlCrossRefPubMed2.↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.OpenUrlCrossRefPubMed3.↵Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol. 2011;69(5):892-900.OpenUrlCrossRefPubMed4.↵Liimatainen S, Peltola M, Sabater L, et al. Clinical significance of glutamic acid decarboxylase antibodies in patients with epilepsy. Epilepsia. 2010;51(5):760-767.OpenUrlCrossRefPubMed5.↵Viaccoz A, Desestret V, Ducray F, et al. Clinical specificities of adult male patients with NMDA receptor antibodies encephalitis. Neurology. 2014;82(7):556-563.OpenUrlCrossRefPubMed6.↵Dalmau J, Geis C, Graus F. Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system. Physiol Rev. 2017;97(2):839-887.OpenUrlCrossRefPubMed7.↵Irani SR, Stagg CJ, Schott JM, et al. Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype. Brain. 2013;136(pt 10):3151-3162.OpenUrlCrossRefPubMed8.↵Thompson J, Bi M, Murchison AG, et al., Faciobrachial Dystonic Seizures Study Group. The importance of early immunotherapy in patients with faciobrachial dystonic seizures. Brain. 2018;141(2):348-356.OpenUrlCrossRefPubMed9.↵Malter MP, Helmstaedter C, Urbach H, Vincent A, Bien CG. Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann Neurol. 2010;67(4):470-478.OpenUrlCrossRefPubMed10.↵Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the international League against epilepsy: position paper of the ILAE commission for classification and terminology. Epilepsia. 2017;58(4):522-530.OpenUrlCrossRefPubMed11.↵Niehusmann P, Dalmau J, Rudlowski C, et al. Diagnostic value of N-methyl-D-aspartate receptor antibodies in women with new-onset epilepsy. Arch Neurol. 2009;66(4):458-464.OpenUrlCrossRefPubMed12.↵Vogrig A, Joubert B, Andre-Obadia N, Gigli GL, Rheims S, Honnorat J. Seizure specificities in patients with antibody-mediated autoimmune encephalitis. Epilepsia. 2019;60(8):1508-1525.OpenUrlCrossRefPubMed13.↵Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):1091-1098.OpenUrlCrossRefPubMed14.↵Jeannin-Mayer S, Andre-Obadia N, Rosenberg S, et al. EEG analysis in anti-NMDA receptor encephalitis: description of typical patterns. Clin Neurophysiol. 2019;130(2):289-296.OpenUrl15.↵Yeshokumar AK, Coughlin A, Fastman J, et al. Seizures in autoimmune encephalitis-A systematic review and quantitative synthesis. Epilepsia. 2021;62(2):397-407.OpenUrlCrossRefPubMed16.↵Navarro V, Kas A, Apartis E, et al., collaborators. Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis. Brain. 2016;139(pt 4):1079-1093.OpenUrlCrossRefPubMed17.↵van Sonderen A, Thijs RD, Coenders EC, et al. Anti-LGI1 encephalitis: clinical syndrome and long-term follow-up. Neurology. 2016;87(14):1449-1456.OpenUrlCrossRefPubMed18.↵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(19):e2185-e2196.OpenUrlCrossRefPubMed19.↵Daif A, Lukas RV, Issa NP, et al. Antiglutamic acid decarboxylase 65 (GAD65) antibody-associated epilepsy. Epilepsy Behav. 2018;80:331-336.OpenUrl20.↵Falip M, Rodriguez-Bel L, Castaner S, et al. Hippocampus and insula are targets in epileptic patients with glutamic acid decarboxylase antibodies. Front Neurol. 2018;9:1143.OpenUrl21.↵Peltola J, Kulmala P, Isojarvi J, et al. Autoantibodies to glutamic acid decarboxylase in patients with therapy-resistant epilepsy. Neurology. 2000;55(1):46-50.OpenUrlCrossRefPubMed22.↵Falip M, Rodriguez-Bel L, Castaner S, et al. Musicogenic reflex seizures in epilepsy with glutamic acid decarbocylase antibodies. Acta Neurol Scand. 2018;137(2):272-276.OpenUrl23.↵Jesus-Ribeiro J, Bozorgi A, Alkhaldi M, Shaqfeh M, Fernandez-Baca Vaca G, Katirji B. Autoimmune musicogenic epilepsy associated with anti-glutamic acid decarboxylase antibodies and Stiff-person syndrome. Clin Case Rep. 2020;8(1):61-64.OpenUrl24.↵Smith KM, Zalewski NL, Budhram A, et al. Musicogenic epilepsy: expanding the spectrum of glutamic acid decarboxylase 65 neurological autoimmunity. Epilepsia. 2021;62(5):e76-e81.OpenUrl25.↵Khawaja AM, Vines BL, Miller DW, Szaflarski JP, Amara AW. Refractory status epilepticus and glutamic acid decarboxylase antibodies in adults: presentation, treatment and outcomes. Epileptic Disord. 2016;18(1):34-43.OpenUrl26.↵Kanter IC, Huttner HB, Staykov D, et al. Cyclophosphamide for anti-GAD antibody-positive refractory status epilepticus. Epilepsia. 2008;49(5):914-920.OpenUrlCrossRefPubMed27.↵Sonderen AV, Arends S, Tavy DLJ, et al. Predictive value of electroencephalography in anti-NMDA receptor encephalitis. J Neurol Neurosurg Psychiatry. 2018;89(10):1101-1106.OpenUrlAbstract/FREE Full Text28.↵Gadoth A, Pittock SJ, Dubey D, et al. Expanded phenotypes and outcomes among 256 LGI1/CASPR2-IgG-positive patients. Ann Neurol. 2017;82(1):79-92.OpenUrlCrossRefPubMed29.↵Baysal-Kirac L, Tuzun E, Altindag E, et al. Are there any specific EEG findings in autoimmune epilepsies? Clin EEG Neurosci. 2016;47(3):224-234.OpenUrlCrossRefPubMed30.↵Quek AML, Britton JW, McKeon A, et al. Autoimmune epilepsy: clinical characteristics and response to immunotherapy. Arch Neurol. 2012;69(5):582-593.OpenUrlCrossRefPubMed31.↵Bien CG, Bien CI, Dogan Onugoren M, et al. Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome. J Neurol. 2020;267(7):2101-2114.OpenUrl32.↵Titulaer MJ, Höftberger R, Iizuka T, et al. Overlapping demyelinating syndromes and anti–N-methyl-D-aspartate receptor encephalitis. Ann Neurol. 2014;75(3):411-428.OpenUrlCrossRefPubMed33.↵Ding J, Li X, Tian Z. Clinical features of coexisting anti-NMDAR and MOG antibody-associated encephalitis: a systematic review and meta-analysis. Front Neurol. 2021;12:711376.OpenUrl
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Josep Dalmau receives the “Scientific Breakthrough 2023” Award from the American Brain Foundation

The accolade recognises the commitment of this Clínic Barcelona-IDIBAPS researcher to deepening our understanding of autoimmune neurological diseases such...
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IDIBAPS creates three multidisciplinary research programs to encourage collaboration among its groups

They are the Translational cancer research program, the Synaptic autoimmunity in neurology, psychiatry and cognitive neuroscience program and the Lymphoid...
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ExTINGUISH: A Beacon of Hope for NMDAR Encephalitis

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MR Imaging Findings in a Large Population of Autoimmune Encephalitis | American Journal of Neuroradiology

MR Imaging Findings in a Large Population of Autoimmune Encephalitis | American Journal of Neuroradiology | AntiNMDA | Scoop.it
Research ArticleAdult Brain MR Imaging Findings in a Large Population of Autoimmune Encephalitis S. Gillon, M. Chan, J. Chen, E.L. Guterman, X. Wu, C.M. Glastonbury and Y. Li American Journal of Neuroradiology July 2023, 44 (7) 799-806; DOI: https://doi.org/10.3174/ajnr.A7907 ArticleFigures & DataInfo & MetricsReferences PDF This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased. AbstractBACKGROUND AND PURPOSE: Autoimmune encephalitis is a rare condition in which autoantibodies attack neuronal tissue, causing neuropsychiatric disturbances. This study sought to evaluate MR imaging findings associated with subtypes and categories of autoimmune encephalitis.MATERIALS AND METHODS: Cases of autoimmune encephalitis with specific autoantibodies were identified from the medical record (2009–2019). Cases were excluded if no MR imaging of the brain was available, antibodies were associated with demyelinating disease, or >1 concurrent antibody was present. Demographics, CSF profile, antibody subtype and group (group 1 intracellular antigen or group 2 extracellular antigen), and MR imaging features at symptom onset were reviewed. Imaging and clinical features were compared across antibody groups using χ2 and Wilcoxon rank-sum tests.RESULTS: Eighty-five cases of autoimmune encephalitis constituting 16 distinct antibodies were reviewed. The most common antibodies were anti-N-methyl-D-aspartate (n = 41), anti-glutamic acid decarboxylase (n = 7), and anti-voltage-gated potassium channel (n = 6). Eighteen of 85 (21%) were group 1; and 67/85 (79%) were group 2. The median time between MR imaging and antibody diagnosis was 14 days (interquartile range, 4–26 days). MR imaging had normal findings in 33/85 (39%), and 20/33 (61%) patients with normal MRIs had anti-N-methyl-D-aspartate receptor antibodies. Signal abnormality was most common in the limbic system (28/85, 33%); 1/68 (1.5%) had susceptibility artifacts. Brainstem and cerebellar involvement were more common in group 1, while leptomeningeal enhancement was more common in group 2.CONCLUSIONS: Sixty-one percent of patients with autoimmune encephalitis had abnormal brain MR imaging findings at symptom onset, most commonly involving the limbic system. Susceptibility artifact is rare and makes autoimmune encephalitis less likely as a diagnosis. Brainstem and cerebellar involvement were more common in group 1, while leptomeningeal enhancement was more common in group 2.ABBREVIATIONS:AIEautoimmune encephalitisanti-Gq1banti-ganglioside Q1banti-LGI1anti-leucine-rich glioma inactivated 1CASPR2contactin-associated protein-like 2GABAgamma-aminobutyric acidGADglutamic acid decarboxylaseGFAPglial fibrillary acidic proteinNMDAN-methyl-D-aspartatePD-1programmed cell death protein 1VGCCvoltage gated calcium channelVGKCvoltage-gated potassium channel© 2023 by American Journal of NeuroradiologyView Full Text Log in using your username and password Username * Password * Forgot your user name or password? PreviousNext Back to top In this issue American Journal of Neuroradiology Vol. 44, Issue 7 1 Jul 2023 Table of ContentsIndex by authorComplete Issue (PDF) Print Download PDF Email Article Citation Tools Share Tweet WidgetFacebook LikeGoogle Plus One Purchase Related ArticlesNo related articles found.PubMedGoogle Scholar Cited By...No citing articles found.CrossrefGoogle Scholar More in this TOC Section Cost-Effectiveness Analysis of 68Ga-DOTATATE PET/MRI in Radiotherapy Planning in Patients with Intermediate-Risk Meningioma Choroid Plexus Calcification Correlates with Cortical Microglial Activation in Humans: A Multimodal PET, CT, MRI Study Show more ADULT BRAIN Similar Articles
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Elevated blood and cerebrospinal fluid biomarkers of microglial activation and blood‒brain barrier disruption in anti-NMDA receptor encephalitis | Journal of Neuroinflammation | Full Text

Elevated blood and cerebrospinal fluid biomarkers of microglial activation and blood‒brain barrier disruption in anti-NMDA receptor encephalitis | Journal of Neuroinflammation | Full Text | AntiNMDA | Scoop.it
Background Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disease characterized by complex neuropsychiatric syndrome and cerebrospinal fluid (CSF) NMDAR antibodies. Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to be associated with inflammation of the...
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Anti-N-methyl-d-aspartate receptor encephalitis and positive human herpesvirus-7 deoxyribonucleic acid in cerebrospinal fluid: a case report | Journal of Medical Case Reports | Full Text

Anti-N-methyl-d-aspartate receptor encephalitis and positive human herpesvirus-7 deoxyribonucleic acid in cerebrospinal fluid: a case report | Journal of Medical Case Reports | Full Text | AntiNMDA | Scoop.it
Background Anti-N-methyl-d-aspartate receptor encephalitis is a neuroautoimmune syndrome typically presenting with seizures, psychiatric symptoms, and autonomic dysfunction. Human herpesvirus-7 is often found with human herpesvirus-6 and infects leukocytes such as T-cells, monocytes–macrophages,...
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We have a winner! - The Anti-NMDA Receptor Encephalitis Foundation Prize, 2023

We have a winner! - The Anti-NMDA Receptor Encephalitis Foundation Prize, 2023 | AntiNMDA | Scoop.it
It’s that time of year again, when the Foundation is delighted to offer its annual Anti-NMDA Receptor Encephalitis Foundation Prize to a promising neurology trainee ...Read More...
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Antibodies Associated With Autoimmune Encephalitis in Patients With Presumed Neurodegenerative Dementia | Neurology Neuroimmunology & Neuroinflammation

Antibodies Associated With Autoimmune Encephalitis in Patients With Presumed Neurodegenerative Dementia | Neurology Neuroimmunology & Neuroinflammation | AntiNMDA | Scoop.it
AbstractBackground & Objectives Autoimmune encephalitis (AIE) may present with prominent cognitive disturbances without overt inflammatory changes in MRI and CSF. Identification of these neurodegenerative dementia diagnosis mimics is important because patients generally respond to immunotherapy. The objective of this study was to determine the frequency of neuronal antibodies in patients with presumed neurodegenerative dementia and describe the clinical characteristics of the patients with neuronal antibodies.Methods In this retrospective cohort study, 920 patients were included with neurodegenerative dementia diagnosis from established cohorts at 2 large Dutch academic memory clinics. In total, 1,398 samples were tested (both CSF and serum in 478 patients) using immunohistochemistry (IHC), cell-based assays (CBA), and live hippocampal cell cultures (LN). To ascertain specificity and prevent false positive results, samples had to test positive by at least 2 different research techniques. Clinical data were retrieved from patient files.Results Neuronal antibodies were detected in 7 patients (0.8%), including anti-IgLON5 (n = 3), anti-LGI1 (n = 2), anti-DPPX, and anti-NMDAR. Clinical symptoms atypical for neurodegenerative diseases were identified in all 7 and included subacute deterioration (n = 3), myoclonus (n = 2), a history of autoimmune disease (n = 2), a fluctuating disease course (n = 1), and epileptic seizures (n = 1). In this cohort, no patients with antibodies fulfilled the criteria for rapidly progressive dementia (RPD), yet a subacute deterioration was reported in 3 patients later in the disease course. Brain MRI of none of the patients demonstrated abnormalities suggestive for AIE. CSF pleocytosis was found in 1 patient, considered as an atypical sign for neurodegenerative diseases. Compared with patients without neuronal antibodies (4 per antibody-positive patient), atypical clinical signs for neurodegenerative diseases were seen more frequently among the patients with antibodies (100% vs 21%, p = 0.0003), especially a subacute deterioration or fluctuating course (57% vs 7%, p = 0.009).Discussion A small, but clinically relevant proportion of patients suspected to have neurodegenerative dementias have neuronal antibodies indicative of AIE and might benefit from immunotherapy. In patients with atypical signs for neurodegenerative diseases, clinicians should consider neuronal antibody testing. Physicians should keep in mind the clinical phenotype and confirmation of positive test results to avoid false positive results and administration of potential harmful therapy for the wrong indication.GlossaryAD=Alzheimer dementia; AIE=autoimmune encephalitis; CBA=cell-based assays; DLB=dementia with Lewy bodies; IHC=immunohistochemistry; LN=live hippocampal cell cultures; PPA=primary progressive aphasia; PSP=progressive supranuclear palsy; RPD=rapidly progressive dementia; VGCC=voltage-gated calcium channelCognitive dysfunction can be the presenting and most prominent symptom in patients with autoimmune encephalitis (AIE).1,2 In contrast to neurodegenerative diseases, patients with antibody-mediated encephalitis might benefit from immunotherapy and improve considerably.3,4 The presence of neuronal antibodies has been reported predominantly in rapidly progressive dementia (RPD).5,6 However, AIE can present less fulminantly and is therefore potentially missed, resulting in diagnosis and treatment delay or even misdiagnosis.7,8 We hypothesized that a small—but not insignificant—part of dementia syndromes is indeed caused by antibody-mediated encephalitis and underdiagnosed, withholding these patients' available treatments. The wish to diagnose every single patient with autoimmune encephalitis is in opposition with the risk for false positive tests.9 Therefore, we strictly adhere to confirmation of positive test results with 2 different test techniques. In this study, we describe the frequency of neuronal antibodies in a cohort of patients diagnosed with various dementia syndromes in a memory clinic. In addition, we present clues to improve clinical recognition of AIE in dementia syndromes.MethodsPatients and Laboratory StudiesIn this retrospective multicenter study, we tested for the presence of neuronal antibodies in serum and CSF samples from patients diagnosed with neurodegenerative dementia diagnosis, included earlier prospectively in established cohorts at 2 large Dutch academic memory clinics (Erasmus University Medical Center, Amsterdam University Medical Centers, location VUmc)10 between 1998 and 2016 (84% last 10 years). All patients fulfilled the core clinical criteria for dementia, as defined by the National Institutes of Aging-Alzheimer Association workgroups.11 Patients were classified into 4 subgroups (based on diagnostic criteria): Alzheimer dementia (AD), frontotemporal dementia (FTD; both behavioral variant and primary progressive aphasia [PPA]), dementia with Lewy bodies (DLB), and other dementia syndromes.11,-,14 Rapidly progressive dementia was defined as dementia within 12 months or death within 2 years after the appearance of the first cognitive symptoms.15 Patients with vascular dementia were not included. Clinic information was retrieved from the prospectively collected data. A subacute deterioration was defined as a marked progression of symptoms in 3 months and a fluctuating course as a disease course fluctuating over a longer period (e.g., weeks to months; different from the fluctuations within a day as seen in some patients with DLB). Dementia markers were scored according to the reference values (per year and per center; included in Table 1).View inline View popup Table 1 Patient Characteristics of Auto-antibody Positive PatientsAll samples, stored in both cohorts' biobanks, were screened for immunoreactivity with immunohistochemistry (IHC), as previously described.16 Preferably, paired serum and CSF were tested for optimal sensitivity and specificity. Samples that were showing a positive or questionable staining pattern were tested more extensively using validated commercial cell-based assays (CBA) and in-house CBA (eTable 1, links.lww.com/NXI/A869). In addition, these samples were tested with live hippocampal cell cultures (LN).16,17 To ascertain specificity, only samples that could be confirmed by CBA or LN were scored as positive because there is a higher risk for false-positive test results in this population with a low a priori chance to have encephalitis.9,18 If IHC was suggestive for antibodies against intracellular (paraneoplastic) targets, this was explored by a different IHC technique.19 Anti-thyroid peroxidase (TPO), voltage-gated calcium channel (VGCC), or low titer glutamic acid decarboxylase antibodies were not tested for because these are generally nonspecific at these ages and are not associated with dementia syndromes.Antibody-positive patients were described exploratory and compared with a randomly selected antibody-negative group (ratio 1:4) matched for memory clinic, dementia subtype, sex, and age (±5 years). For these comparisons, medical records were additionally assessed for both the antibody-positive and antibody-negative patients. All antibody-positive patients were reviewed by a panel consisting of neurologists specialized in neurodegenerative (F.J., H.S., J.S.) or autoimmune diseases (J.V., P.S.S., M.T.), and a consensus classification of AIE vs AIE with a neurodegenerative dementia comorbidity was reached.Statistical AnalysisWe used IBM SPSS 25.0 (SPSS Inc) and Prism 8.4.3 (GraphPad) for statistical analysis. Baseline characteristics were analyzed using the Fisher exact test, the Fisher-Freeman-Halton test, or the Kruskal-Wallis test, when appropriate. For group comparisons, encompassing categorical data, we used the Pearson χ2 test or the Fisher-Freeman-Halton test, when appropriate. Continuous data were analyzed using the Mann-Whitney U test. All p-values were two-sided and considered statistically significant when below 0.05. We applied no correction for multiple testing, and therefore, p values between 0.05 and 0.005 should be interpreted carefully.Standard Protocol Approvals, Registrations, and Patient ConsentsThe study was approved by The Institutional Review Boards of Erasmus University Medical Center Rotterdam and Amsterdam University Medical Center, location VUmc. Written informed consent was obtained from all patients.Data AvailabilityAny data not published within this article are available at the Erasmus MC University Medical Center. Patient-related data will be shared on reasonable request from any qualified investigator, maintaining anonymization of the individual patients.ResultsIn total, 1,398 samples from 920 patients were tested (Figure; in 478, both CSF and serum [52%]). Three-hundred fifty-eight patients were classified as AD (39%), 283 FTD (31%), and 161 DLB (17%). The fourth subgroup with other dementia syndromes consisted of 118 patients (13%), including progressive supranuclear palsy (n = 48, 5%) and corticobasal syndrome (n = 29, 3%). The median age at disease onset was 62 years (range 16–90 years). Male patients were overrepresented (n = 542, 59%), and 60 patients (7%) fulfilled the criteria for rapidly progressive dementia (RPD; eTable 2, links.lww.com/NXI/A869).<img class="highwire-fragment fragment-image" alt="Figure" width="440" height="305" src="https://nn.neurology.org/content/nnn/10/5/e200137/F1.medium.gif">Download figure Open in new tab Download powerpoint Figure Flowchart of Patient Inclusion With Antibody ResultsIn total, 920 patients (1,398 samples) with a presumed neurodegenerative dementia syndrome were tested for the presence of neuronal antibodies in serum and CSF. Neuronal antibodies were detected in 7 patients (0.8%, 95% CI 0.2–1.3); five among the 358 Alzheimer disease patients. Subclassification of the ‘other’ group is provided in supplementary table eTable 2 (links.lww.com/NXI/A869). AD = Alzheimer disease; DLB = diffuse Lewy body dementia; DPPX = dipeptidyl aminopeptidase-like protein 6; FTD = frontotemporal dementia; IgLON5 = Ig-like domain-containing protein family member 5; LGI1 = leucin-rich glioma inactivated protein 1; NMDAR = N-methyl-d-aspartate receptor; S = serum.Neuronal antibodies were detected in 7 patients (0.8%; 5 in the AD group: 1.4%; Figure), including anti-IgLON5 (n = 3), anti-LGI1 (n = 2), anti-DPPX (n = 1), and anti-NMDAR antibodies (n = 1; Table 1). Among these 7, 4 patients were diagnosed retrospectively with an exclusive diagnosis of AIE, while 3 patients were classified to have AIE (anti-IgLON5 [n = 2] and anti-NMDAR antibodies [n = 1]) with a neurodegenerative dementia comorbidity. No patients with antibodies fulfilled the criteria for RPD, yet a subacute deterioration later in the disease was reported in 3 patients. Atypical clinical signs for neurodegenerative diseases were present in 7 of 7 antibody-positive patients (100% vs 21% in antibody-negative patients, p = 0.0003; Table 2). These included a subacute deterioration (n = 3), myoclonus (n = 2), a fluctuating disease course over months (n = 1), a history of autoimmune disease (n = 2), and epileptic seizures (n = 1; Table 1). Brain MRI of none of the patients demonstrated abnormalities suggestive for active AIE, in particular no hippocampal swelling nor increased T2-signal intensity. CSF pleocytosis was found in 1 patient. CSF biomarkers (t-tau, p-tau, and Aβ42) were tested in 5 of 7 patients, and t-tau and p-tau were increased in 4, while a low Aβ42 was seen in 2. Of note, only 1 patient had the combination of reduced Aβ42 and increased p-tau/t-tau, and was diagnosed with a comorbid AD. No patient received immunotherapy. Two patients still alive (1 anti-LG1, 1 anti-DPPX positive) were contacted but refused to visit our clinic to try very delayed immunotherapy trials. It is of interest that the patient with anti-DPPX antibodies showed spontaneous improvement of cognitive disturbances, atypical for a pure neurodegenerative disease.View inline View popup Table 2 Comparisons Between Patients With Neuronal Auto-antibodies and Antibody-Negative PatientsCompared with the patients without neuronal antibodies, subacute cognitive deterioration or fluctuating course was present more frequently (4/7 [57%] vs 2/28 [7%], p = 0.009). Although movement disorders (myoclonus) and autoimmune disorders were present in 2 of 7 patients each, this did not reach significance (Table 2).DiscussionIn this large, multicenter, cohort study consisting of patients with a presumed neurodegenerative dementia diagnosis, we show that a small, but clinically relevant proportion (0.8%) have neuronal antibodies. In this particular group, 4 of 7 antibody-positive patients presented with an atypical clinical course (subacute deterioration or fluctuating disease course), which is considered as a clinical clue (‘red flag’) for an antibody-mediated etiology of dementia.4 It is important that a fluctuating disease course was observed over a longer period (e.g., weeks or months) in AIE and should not be confused with shorter fluctuations of cognition or alertness (over the day) in DLB. Other known red flags, which we observed in these 7 patients, were myoclonus, epilepsy, pleocytosis, or a history of autoimmune disorders, as described earlier.1,4,-,6 Compared with antibody-negative patients, no significant difference was found related to these symptoms alone, probably due to the low number of positive patients and related low power. However, atypical clinical signs for neurodegenerative diseases together were seen significantly more frequently in the antibody-positive group. Within this cohort mostly devoid of patients with RPD, none of the antibody-positive patients fulfilled the criteria for RPD, nor ancillary testing showed specific signs for AIE in most patients. This implicates that AIE can resemble more protracted, progressive neurodegenerative dementia syndromes, as we reported earlier.1Three antibody-positive patients had IgLON5 antibodies, which is a very rare and known to have heterogeneous (chronic) clinical manifestations, including pronounced sleep problems, cognitive dysfunction, and movement disorders.20,21 Misdiagnosis with progressive supranuclear palsy (PSP) is reported, mainly associated with the preceding movement disorders. In addition, half of the patients have cognitive impairment of whom 20% fulfilled clinical criteria for dementia.21 It is of interest that IgLON5 disease shares features with neurodegeneration because autopsy studies showed tau deposits.22 However, there is a strong HLA association,20 and studies show that antibodies directly bind to surface IgLON5 on neurons and directly alter neuronal function and structure,23 suggesting a primary inflammatory disease.In previous research, a notably higher frequency (14%) of neuronal antibodies in patients with dementia was reported by Giannocaro et al.24 The discrepancy with our test results is probably explained by differences in patient selection and antibody testing methodology. First, 30% of the patients in the cohort described by Giannocaro et al. demonstrated CSF inflammatory abnormalities, indicating a relatively high pretest probability of antibody-positivity compared with our study.24 A lack of CSF pleocytosis probably better represents the population of memory clinics. Second, the previous study exclusively tested serum by cell-based assay without confirmatory tests nor testing antibodies in CSF.24 We only considered antibody test results positive when confirmed by additional techniques to avoid suboptimal specificity and false-positive test results.9Previous studies, including our own, suggested RPD as a relevant red flag for AIE,1,4,9,25 but we cannot determine this from our study based on the design of our study. We included patients at tertiary memory clinics without overt signs or symptoms suggestive for encephalitis. Therefore, the amount of patients with RPD included was very limited (7%), comparable with other large dementia cohort studies, as was the amount of patients with abnormal ancillary testing suggestive for AIE because this would have prompted a different approach than referral to a tertiary memory clinic. These patients with RPD and ancillary testing suggestive of AIE were not included in our study. Inclusion of those patients would have likely increased our rate of positivity.The strength of our study is the large number of paired samples (serum and CSF combined) from a cohort with various presumed neurodegenerative diseases without AIE suspicion, representative for academic memory clinics. A limitation is the lack of neuropathologic data to support our findings and make diagnoses of neurodegeneration or inflammation definite. To confirm if the symptoms are related to the presence of antibodies, we tried to overcome this concern in different ways. First, the presence of antibodies in serum and CSF was confirmed by different techniques (cell-based assay, tissue immunohistochemistry, and cultured live neurons), indicating optimal test specificity. Second, afterward patients were thoroughly reviewed by a panel of neurologists specialized in neurodegenerative or autoimmune disease to detect atypical signs and symptoms related to AIE. This is a very large cohort of patients with dementia examined for the presence of neuronal antibodies. Nevertheless, an important limitation of this study is the small number of antibody-positive patients, underpowering the probability to identify significant differences between antibody-positive and antibody-negative patients. The low number of patients with RPD has probably added to this small number, and a prospective study including patients with RPD is recommended. Nevertheless, several probable red flags could be identified. Diagnosing AIE in patients with dementia is highly relevant because these patients might respond to immunotherapy. Therefore, clinicians should test for neuronal antibody in patients demonstrating red flags suggestive for an autoimmune etiology, if possible early in disease course. When profound temporal lobe atrophy already has developed, little effect is to be expected. Red flags identified in this study are subacute deterioration or fluctuating course. Other red flags described previously, we also see reflected in our study, are autoimmune disorders, myoclonus, seizures, and pleocytosis,1,4,-,6 Preferably, both serum and CSF should be tested and confirmed by additional techniques. Always consider the possibility of a false positive test result, especially when only using a single technique (like the commercial cell-based assay). If the clinical phenotype is atypical, confirmation in a research laboratory should be mandatory. The use of antibody panels is discouraged, especially including the paraneoplastic blots, because these are associated with higher risks of lack of clinical relevance.26 This caution is even more warranted for tests not associated with neurodegenerative syndromes, but with a history of nonspecificity, including VGKC (in the absence of LGI1 or CASPR2), VGCC, anti-TPO, and low-titer anti-GAD65.27,-,30 Further research should focus on improving clinical recognition of AIE in patients with dementia determining the effect of immunotherapy in this specific patient category and assessing the frequency of AIE in RPD.In conclusion, we have shown that a clinically relevant, albeit small proportion of patients with a suspected neurodegenerative disease and nonrapidly progressive course have neuronal antibodies indicative of AIE.Study FundingM.J. Titulaer was supported by an Erasmus MC fellowship and has received funding from the Netherlands Organization for Scientific Research (NWO, Veni incentive), ZonMw (Memorabel program), the Dutch Epilepsy Foundation (NEF 14-19 & 19-08), Dioraphte (2001 0403), and E-RARE JTC 2018 (UltraAIE, 90030376505). F. Leypoldt has received funding from the German Ministry of Education and Research (01GM1908A) and the Era-Net funding program (LE3064/2-1).DisclosureA.E.M. Bastiaansen reports no disclosures. R.W. van Steenhoven reports no disclosures. Research programs of Wiesje van der Flier have been funded by ZonMW, now, EUFP7, EU-JPND, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health∼Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, and Combinostics. W.M. van der Flier holds the Pasman chair. W.M. van der Flier is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). All funding is paid to her institution. WF has performed contract research for Biogen MA Inc and Boehringer Ingelheim. All funding is paid to her institution. W.M. van der Flier has been an invited speaker at Boehringer Ingelheim, Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), and Springer Healthcare. All funding is paid to her institution. W.M. van der Flier is consultant to Oxford Health Policy Forum CIC, Roche, and Biogen MA Inc. All funding is paid to her institution. W.M. van der Flier participated in advisory boards of Biogen MA Inc and Roche. All funding is paid to her institution. W.M. van der Flier is a member of the steering committee of PAVE and Think Brain Health. W.M. van der Flier was an associate editor of Alzheimer, Research & Therapy in 2020/2021. W.M. van der Flier is an associate editor at Brain. Research of C. Teunissen was supported by the European Commission (Marie Curie International Training Network, Grant Agreement No. 860197 (MIRIADE)), Innovative Medicines Initiatives 3TR (Horizon 2020, Grant No. 831434), EPND (IMI 2 Joint Undertaking (JU) under Grant Agreement No. 101034344) and JPND (bPRIDE), National MS Society (Progressive MS alliance) and Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands, and Alzheimer Association. C. Teunissen is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP-allowance, #LSHM20106). ABOARD also receives funding from Edwin Bouw Fonds and Gieskes-Strijbisfonds. C. Teunissen has a collaboration contract with ADx Neurosciences, Quanterix, and Eli Lilly, performed contract research or received grants from AC-Immune, Axon Neurosciences, Bioconnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Grifols, Novo Nordisk, PeopleBio, Roche, Toyama, and Vivoryon. She serves on editorial boards of Medidact Neurologie/Springer, Alzheimer Research and Therapy, and Neurology: Neuroimmunology & Neuroinflammation and is an editor of a Neuromethods book Springer. She had speaker contracts for Roche, Grifols, and Novo Nordisk. E. de Graaff holds a patent for the detection of anti-DNER antibodies. M.M.P. Nagtzaam reports no disclosures. M. Paunovic reports no disclosures. S. Franken reports no disclosures. M.W.J. Schreurs reports no disclosures. F. Leypoldt has received speakers honoraria from Grifols, Roche, Novartis, Alexion, and Biogen and serves on an advisory board for Roche and Biogen. He works for an academic institution (University Hospital Schleswig-Holstein) which offers commercial autoantibody testing. P.A.E. Sillevis Smitt holds a patent for the detection of anti-DNER and received research support from Euroimmun. J.M. de Vries reports no disclosures. H. Seelaar reports no disclosures. J.C. van Swieten reports no disclosures. F.J. de Jong reports no disclosures. Y.A.L. Pijnenburg Research of Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The chair of Wiesje van der Flier is supported by the Pasman stichting. M.J. Titulaer has filed a patent, on behalf of the Erasmus MC, for methods for typing neurologic disorders and cancer, and devices for use therein, and has received research funds for serving on a scientific advisory board of Horizon Therapeutics, for consultation at Guidepoint Global LLC, for consultation at UCB, for teaching colleagues by Novartis. MT has received an unrestricted research grant from Euroimmun AG and from CSL Behring. Go to Neurology.org/NN for full disclosure.AcknowledgmentThe authors thank all patients for their participation. The authors also thank Esther Hulsenboom and Ashraf Jozefzoon-Aghai for their technical assistance. M.W.J. Schreurs, F. Leypoldt, P.A.E. Sillevis Smitt, J.M. de Vries, and M.J. Titulaer of this publication are members of the European Reference Network for Rare Immunodeficiency, Autoinflammatory, and Autoimmune Diseases—Project ID No. 739543 (ERN-RITA; HCP Erasmus MC and University Hospital Schleswig-Holstein). H. Seelaar, J.C. van Swieten, and F.J. de Jong of this publication are members of the European Reference Network for Rare Neurological Diseases—Project ID 73910. Research of the VUmc Alzheimer center is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center VUmc is supported by Alzheimer Nederland and Stichting VUmc Fonds. The clinical database structure was developed with funding from Stichting Dioraphte.Appendix Authors<img class="highwire-fragment fragment-image" alt="Table" src="https://nn.neurology.org/content/nnn/10/5/e200137/T3.medium.gif"; width="599" height="2531">FootnotesGo to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.The Article Processing Charge was funded the authors.Submitted and externally peer reviewed. The handling editor was Editor Josep O. Dalmau, MD, PhD, FAAN.Received December 8, 2022.Accepted in final form May 8, 2023.Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.References1.↵Bastiaansen AEM, van Steenhoven RW, de Bruijn M, et al. Autoimmune encephalitis resembling dementia syndromes. Neurol Neuroimmunol Neuroinflamm. 2021;8(5):e1039.OpenUrlAbstract/FREE Full Text2.↵Lancaster E, Lai M, Peng X, et al. Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol. 2010;9(1):67-76.OpenUrlCrossRefPubMed3.↵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.OpenUrlCrossRefPubMed4.↵Flanagan EP, McKeon A, Lennon VA, et al. Autoimmune dementia: clinical course and predictors of immunotherapy response. Mayo Clin Proc. 2010;85(10):881-897.OpenUrlCrossRefPubMed5.↵Geschwind MD, Tan KM, Lennon VA, et al. Voltage-gated potassium channel autoimmunity mimicking creutzfeldt-jakob disease. Arch Neurol. 2008;65(10):1341-1346.OpenUrlCrossRefPubMed6.↵Grau-Rivera O, Sanchez-Valle R, Saiz A, et al. Determination of neuronal antibodies in suspected and definite Creutzfeldt-Jakob disease. JAMA Neurol. 2014;71(1):74-78.OpenUrl7.↵Titulaer MJ, McCracken L, Gabilondo I, et al. Late-onset anti-NMDA receptor encephalitis. Neurology. 2013;81(12):1058-1063.OpenUrlAbstract/FREE Full Text8.↵Gaig C, Graus F, Compta Y, et al. Clinical manifestations of the anti-IgLON5 disease. Neurology. 2017;88(18):1736-1743.OpenUrlAbstract/FREE Full Text9.↵Bastiaansen AEM, de Bruijn M, Schuller SL, et al. Anti-NMDAR encephalitis in The Netherlands, focusing on late-onset patients and antibody test accuracy. Neurol Neuroimmunol Neuroinflamm. 2022;9(2):e1127.OpenUrl10.↵van der Flier WM, Scheltens P. Amsterdam dementia cohort: performing research to optimize care. J Alzheimers Dis. 2018;62(3):1091-1111.OpenUrl11.↵McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):263-269.OpenUrlCrossRefPubMed12.↵Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134(Pt 9):2456-2477.OpenUrlCrossRefPubMed13.↵Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011;76(11):1006-1014.OpenUrlAbstract/FREE Full Text14.↵McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology. 2017;89(1):88-100.OpenUrlAbstract/FREE Full Text15.↵Geschwind MD. Rapidly progressive dementia. Continuum (Minneap Minn). 2016;22(2 Dementia):510-537.OpenUrl16.↵Ances BM, Vitaliani R, Taylor RA, et al. Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain. 2005;128(Pt 8):1764-1777.OpenUrlCrossRefPubMed17.↵Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol. 2014;13(2):167-177.OpenUrlCrossRefPubMed18.↵Martinez-Martinez P, Titulaer MJ. Autoimmune psychosis. Lancet Psychiatry. 2020;7(2):122-123.OpenUrl19.↵van Coevorden-Hameete MH, Titulaer MJ, Schreurs MW, et al. Detection and characterization of autoantibodies to neuronal cell-surface antigens in the central nervous system. Front Mol Neurosci. 2016;9:37.OpenUrl20.↵Sabater L, Gaig C, Gelpi E, et al. A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study. Lancet Neurol. 2014;13(6):575-586.OpenUrlCrossRefPubMed21.↵Gaig C, Compta Y, Heidbreder A, et al. Frequency and characterization of movement disorders in anti-IgLON5 disease. Neurology. 2021;97(14):e1367–e1381.OpenUrlAbstract/FREE Full Text22.↵Gelpi E, Hoftberger R, Graus F, et al. Neuropathological criteria of anti-IgLON5-related tauopathy. Acta Neuropathol. 2016;132(4):531-543.OpenUrlCrossRefPubMed23.↵Landa J, Gaig C, Plaguma J, et al. Effects of IgLON5 antibodies on neuronal cytoskeleton: a link between autoimmunity and neurodegeneration. Ann Neurol. 2020;88(5):1023-1027.OpenUrlCrossRefPubMed24.↵Giannoccaro MP, Gastaldi M, Rizzo G, et al. Antibodies to neuronal surface antigens in patients with a clinical diagnosis of neurodegenerative disorder. Brain Behav Immun. 2021;96:106-112.OpenUrl25.↵Hermann P, Zerr I. Rapidly progressive dementias - aetiologies, diagnosis and management. Nat Rev Neurol. 2022;18(6):363-376.OpenUrl26.↵Dechelotte B, Muniz-Castrillo S, Joubert B, et al. Diagnostic yield of commercial immunodots to diagnose paraneoplastic neurologic syndromes. Neurol Neuroimmunol Neuroinflamm. 2020;7(3):e701.OpenUrlAbstract/FREE Full Text27.↵van Sonderen A, Schreurs MW, de Bruijn MA, et al. The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. Neurology. 2016;86(18):1692-1699.OpenUrlCrossRefPubMed28.↵Muñoz Lopetegi A, Boukhrissi S, Bastiaansen A, et al. Neurological syndromes related to anti-GAD65: clinical and serological response to treatment. Neurol Neuroimmunol Neuroinflamm. 2020;7(3):e696.OpenUrlAbstract/FREE Full Text29.↵Mattozzi S, Sabater L, Escudero D, et al. Hashimoto encephalopathy in the 21st century. Neurology. 2020;94(2):e217-e224.OpenUrlAbstract/FREE Full Text30.↵Flanagan EP, Geschwind MD, Lopez-Chiriboga AS, et al. Autoimmune encephalitis misdiagnosis in adults. JAMA Neurol. 2023;80(1):30-39.OpenUrl
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Research study - can you help?

Research study - can you help? | AntiNMDA | Scoop.it
Researchers at Kings College London are looking for young people to travel to London and help with an encephalitis study...
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Sociocultural Influences in Autoimmune Encephalitis Without Neurologic Symptoms

Sociocultural Influences in Autoimmune Encephalitis Without Neurologic Symptoms | AntiNMDA | Scoop.it
This complex case highlights barriers to identifying autoimmune encephalitis when no neurologic symptoms are present, which are normally central to disease detection.
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Anti N-Methyl-D-Aspartate receptor antibody associated Acute Demyelinating Encephalomyelitis in a patient with COVID-19: a case report | Journal of Medical Case Reports | Full Text

Anti N-Methyl-D-Aspartate receptor antibody associated Acute Demyelinating Encephalomyelitis in a patient with COVID-19: a case report | Journal of Medical Case Reports | Full Text | AntiNMDA | Scoop.it
Background Anti N-Methyl-D-Aspartate (NMDA) receptor antibody associated ADEM is a diagnosis that was first described relatively recently in 2007 by Dalmau et al. The recent COVID-19 pandemic has resulted in multiple neurological complications being reported.
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Autoimmune Encephalitis Consensus Criteria | Neurology Clinical Practice

Autoimmune Encephalitis Consensus Criteria | Neurology Clinical Practice | AntiNMDA | Scoop.it
June 2023; 13 (3) Editorial Autoimmune Encephalitis Consensus CriteriaLessons Learned From Real-World Practice View ORCID ProfileJeffrey M. Gelfand, Chu-Yueh Guo First published April 25, 2023, DOI: https://doi.org/10.1212/CPJ.0000000000200155 Full PDF Citation Permissions Make Comment See Comments Downloads133 Share Article Info & Disclosures This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased. Autoimmune encephalitis (AE) encompasses a spectrum of neurologic disorders caused by brain inflammation, a subset of which is associated with autoantibodies to neuronal cell-surface antigens such as anti-N-methyl-d-aspartate (NMDA) receptor AE or anti-leucine-rich glioma-inactivated 1 (LGI1) AE.1 Up to half of patients with AE, however, do not have abnormal neuronal or glial autoantibodies identified and are classified as having “seronegative” AE.2 Clinical antibody testing can take several days to result, a time in which clinicians caring for patients with suspected AE may wish to initiate empiric immunosuppressive therapy. Antibody testing is also not readily accessible in some health care settings and, even when technically available, may require time-consuming advocacy with local clinical laboratories to justify relatively costly send-out testing. To add further complexity, some patients with immunoreactive (e.g., laboratory true-positive) antibodies do not have clinical AE, and over-reliance and misapplication of antibody testing were identified as important contributors to AE misdiagnosis in a 2023 multicenter analysis.3FootnotesFunding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.See page e200151© 2023 American Academy of NeurologyView Full Text AAN Members We have changed the login procedure to improve access between AAN.com and the Neurology journals. If you are experiencing issues, please log out of AAN.com and clear history and cookies. (For instructions by browser, please click the instruction pages below). After clearing, choose preferred Journal and select login for AAN Members. You will be redirected to a login page where you can log in with your AAN ID number and password. When you are returned to the Journal, your name should appear at the top right of the page. Google Safari Microsoft Edge Firefox Click here to login AAN Non-Member Subscribers Click here to login Purchase access For assistance, please contact: AAN Members (800) 879-1960 or (612) 928-6000 (International) Non-AAN Member subscribers (800) 638-3030 or (301) 223-2300 option 3, select 1 (international) Sign Up Information on how to subscribe to Neurology and Neurology: Clinical Practice can be found here Purchase Individual access to articles is available through the Add to Cart option on the article page. Access for 1 day (from the computer you are currently using) is US$ 39.00. Pay-per-view content is for the use of the payee only, and content may not be further distributed by print or electronic means. The payee may view, download, and/or print the article for his/her personal, scholarly, research, and educational use. Distributing copies (electronic or otherwise) of the article is not allowed. You May Also be Interested in Back to top Safety and Efficacy of Tenecteplase and Alteplase in Patients With Tandem Lesion Stroke: A Post Hoc Analysis of the EXTEND-IA TNK Trials Dr. Nicole Sur and Dr. Mausaminben Hathidara ► Watch Related Articles Autoimmune Encephalitis Criteria in Clinical Practice Topics Discussed All Clinical Neurology Autoimmune diseases Encephalitis Alert Me Alert me when eletters are published
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Predictive Value of Serum Neurofilament Light Chain Levels in Anti-NMDA Receptor Encephalitis

Predictive Value of Serum Neurofilament Light Chain Levels in Anti-NMDA Receptor Encephalitis | AntiNMDA | Scoop.it
Increased serum NfL levels reflect neuroaxonal damage in anti-NMDAR encephalitis. No relationship was identified with disease severity, whereas the association with outcome was confounded by age.The implied role of sampling timing on NfL levels also limits the applicability of NfL as a prognostic...
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Frontiers | The MOG antibody associated encephalitis preceded by COVID-19 infection; a case study and systematic review of the literature

Frontiers | The MOG antibody associated encephalitis preceded by COVID-19 infection; a case study and systematic review of the literature | AntiNMDA | Scoop.it
BackgroundNew neurological complications of COVID-19 infection have been reported in recent research. Among them, the spectrum of anti-MOG positive diseases, defined as anti-MOG antibody associated disease (MOGAD), is distinguished, which can manifest as optic neuritis, myelitis, or various forms...
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Enceph-IG Study - Institute of Infection, Veterinary and Ecological Sciences - University of Liverpool

Enceph-IG Study - Institute of Infection, Veterinary and Ecological Sciences - University of Liverpool | AntiNMDA | Scoop.it
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A Rare Presentation of Steroid-responsive Encephalopathy Associated with Autoimmune Thyroiditis with Neuropsychiatric Symptoms: A Case Report

A Rare Presentation of Steroid-responsive Encephalopathy Associated with Autoimmune Thyroiditis with Neuropsychiatric Symptoms: A Case Report | AntiNMDA | Scoop.it
A 42-year-old woman presented in the emergency department with acute onset whole-body myoclonic jerks for 1 day.On enquiry, the patient’s parents advised...
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Pioneering Research in Autoimmune Neurology: Vanda Lennon, M.D., Ph.D.

Pioneering Research in Autoimmune Neurology: Vanda Lennon, M.D., Ph.D. | AntiNMDA | Scoop.it
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New center to spotlight neurological autoimmune disorders

New center to spotlight neurological autoimmune disorders | AntiNMDA | Scoop.it
How do neurological disorders arise that are caused, triggered, or influenced by antibodies? What better possibilities are there for diagnosis – and above all for treatment? These are the questions addressed by the new Clinical Research Unit “BecauseY” headed by Charité – Universitätsmedizin Berlin.
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Progressive alliance advances science through patient-powered research

Progressive alliance advances science through patient-powered research | AntiNMDA | Scoop.it
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ENCEPH-IG Trial: The Challenges Of Running A Rare Disease Trial - Centre for Trials Research

ENCEPH-IG Trial: The Challenges Of Running A Rare Disease Trial - Centre for Trials Research | AntiNMDA | Scoop.it
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30 neurological disorders every doctor should know about –

30 neurological disorders every doctor should know about – | AntiNMDA | Scoop.it
Neurology is a jungle of disorders and syndromes. This creates a challenge for doctors and medical students... What to prioritise for learning and practice? *** To solve this conundrum... We combed the extensive database of Neurochecklists...
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A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis

A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis | AntiNMDA | Scoop.it
The NEOS score accurately predicts 1-year functional status in patients with anti-NMDAR encephalitis. This score could help estimate the clinical course following diagnosis and may aid in identifying patients who could benefit from novel therapies.
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Canadian Blood Services needs thousands more donors to roll up their sleeves | CBC News

Canadian Blood Services needs thousands more donors to roll up their sleeves | CBC News | AntiNMDA | Scoop.it
Canadian Blood Services is looking to fill 150,000 appointments for people willing to donate their blood or plasma to tackle a shortage.
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A catatonic woman awakened after 20 years. Her story may change psychiatry – My Health CRM

A catatonic woman awakened after 20 years. Her story may change psychiatry – My Health CRM | AntiNMDA | Scoop.it
New research suggests that a subset of patients with psychiatric conditions such as schizophrenia may actually have autoimmune disease that attacks the brain...
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Case Report: Paroxysmal weakness of unilateral limb as an initial symptom in anti-LGI1 encephalitis: a report of five cases

Case Report: Paroxysmal weakness of unilateral limb as an initial symptom in anti-LGI1 encephalitis: a report of five cases | AntiNMDA | Scoop.it
Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis is the second most common kind of autoimmune encephalitis following anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis.Anti-LGI1 encephalitis is characterized by cognitive impairment or rapid progressive dementia, psychiatric disorders...
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Medical Moment: The signs of ‘brain-on-fire’ disease

Medical Moment: The signs of ‘brain-on-fire’ disease | AntiNMDA | Scoop.it
(WNDU) - Imagine being totally fine one day, then the next, you’re having hallucinations, seizures, memory loss, and even trouble talking.It’s called “brain-on-fire” disease or anti-NMDA receptor encephalitis. It’s a rare neurological disorder that can cause inflammation in the brain.It occurs when the body’s immune system mistakenly attacks the NMDA receptors in the brain, which are responsible for regulating communication between nerve cells. Brain-on-fire disease is often misdiagnosed as other neurological disorders or psychiatric illnesses because its symptoms are similar to those of many other conditions.However, a blood or cerebrospinal fluid test can help diagnose the disease by detecting the presence of antibodies that attack the NMDA receptors in the brain. The disease is rare as it affects one in 1.5 million people a year.Katie Miller would be one of those people.Hunting, mountain biking, horseback riding - you name it, Katie Miler would do it... until she couldn’t.“I just didn’t feel like myself, like normal,” Katie recalled.“Katie said, ‘Mom, I feel like my brain snapped,’” said Colleen Miller, Katie’s mother.Local doctors admitted Katie into a psychiatric ward, but what was happening to Katie wasn’t mental; it was physical.“What happens is you’re perfectly normal one day, and suddenly overnight, this person can become paranoid, can start having visual hallucinations, auditory hallucinations,” explained Stacy Clardy, MD, PhD, an autoimmune neurologist at the University of Utah.Anti-NMDA receptor encephalitis is misdiagnosed as a psychiatric disorder in up to 40% of patients.“So, for many of the females, especially after puberty, they can develop what’s called an ovarian dermoid cyst or an ovarian teratoma,” Dr. Clardy said.These cysts often have hair and teeth in them. The immune system sees it as foreign and attacks it, but...“In these cysts, there is a component of tissue that really is brain tissue,” Dr. Clardy continued.Within four days, Katie was catatonic and needed a ventilator to breathe. There is no single approved treatment. That’s why a five-year, nationwide clinical trial is testing whether a drug called Inebilizumab will stop the assault on the brain. It has the potential to improve outcomes for patients who are not responding to other treatments and may also lead to fewer long-term neurological effects.Katie had her cyst removed; she can’t remember three months of her life. But now, with various medications, Katie is on her way to recovery.Up to 50% of patients can suffer long-term consequences, especially cognitive and mood symptoms.Copyright 2023 WNDU. All rights reserved.
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