The Anti-NMDA Receptor Encephalitis Foundation Newsletter

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. 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Autoimmune psychosis may be caused by well-characterized anti-neuronal autoantibodies,
such as those against the NMDA receptor. However, the presence of additional anti–central
nervous system (CNS) autoantibodies in these patients has not been systematically
assessed.

 




The autoimmune encephalitis is a rare group of neurological disorders mediated by immune mechanisms. Neuropsychiatric symptoms often occur in the early stages of the disease, so many patients seek treatment in psychiatry for the first time.

 




Article Text Article menu PDF Epilepsy Original research Epileptic phenotypes in autoimmune encephalitis: from acute symptomatic seizures to autoimmune-associated epilepsy http://orcid.org/0000-0002-4403-6342Sara Matricardi1, Sara Casciato2, Silvia Bozzetti3,4, http://orcid.org/0000-0002-7806-3103Sara Mariotto3, Andrea Stabile5, Elena Freri6, http://orcid.org/0000-0003-0808-3042Francesco Deleo5, Stefano Sartori7,8, http://orcid.org/0000-0002-6395-7614Margherita Nosadini7,8, Irene Pappalardo9, http://orcid.org/0000-0003-0334-539XStefano Meletti10,11, http://orcid.org/0000-0002-3585-5872Giada Giovannini10,11, http://orcid.org/0000-0001-5604-4529Elisabetta Zucchi10,11, http://orcid.org/0000-0003-1890-5409Carlo Di Bonaventura12, Giancarlo Di Gennaro2, Sergio Ferrari3, Luigi Zuliani13, Marco Zoccarato14, http://orcid.org/0000-0002-3652-7061Alberto Vogrig15, Simona Lattanzi16, Roberto Michelucci17, http://orcid.org/0000-0001-7384-3074Antonio Gambardella18, Edoardo Ferlazzo19,20, Lucia Fusco21, Tiziana Granata6, http://orcid.org/0000-0002-2762-4599Flavio Villani9 On behalf of the Immune Epilepsies Study Group of the Italian League Against Epilepsy Child Neurology and Psychiatry Unit, Children’s Hospital “G. Salesi”, Ospedali Riuniti Ancona, Polytechnic University of Marche, Ancona, Italy IRCCS Neuromed, Pozzilli, Italy Neurology Unit, Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Verona, Italy Department of Neurology/Stroke Unit, San Maurizio Hospital, Bolzano, Italy Epilepsy Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy Department of Paediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy Paediatric Neurology and Neurophysiology Unit, Department of Women’s and Children’s Health, University Hospital of Padova, Padova, Italy Neuroimmunology Group, Paediatric Research Institute “Città della Speranza”, Padova, Italy Division of Clinical Neurophysiology and Epilepsy Centre, IRCCS Ospedale Policlinico San Martino, Genova, Italy Dept of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy Neurology Dept, Azienda Ospedaliera-Universitaria di Modena, Modena, Italy Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy Neurology Unit, Vicenza, Italy Neurology Unit O.S.A. – Azienda Ospedale Università Padova, Padova, Italy Department of Neurosciences, Santa Maria della Misericordia University Hospital, Udine, Italy Neurological Clinic, Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy IRCCS – Istituto delle Scienze Neurologiche di Bologna, Unit of Neurology, Bologna, Italy Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy Regional Epilepsy Center, BMM Great Metropolitan Hospital, Reggio Calabria, Italy Department of Medical and Surgical Sciences, Magna Græcia University of Catanzaro, Catanzaro, Italy Department of Neuroscience, Bambino Gesù Children’s Hospital, Rome, Italy Italian League Against Epilepsy, Rome, Italy Correspondence to Dr Sara Matricardi, Child Neurology and Psychiatry Unit, Children’s Hospital “G. Salesi”, Ospedali Riuniti Ancona, Polytechnic University of Marche, Ancona 60123, Italy; sara.matricardi{at}yahoo.it; Dr Tiziana Granata; Tiziana.Granata{at}istituto-besta.it AbstractObjective To describe the clinical and paraclinical findings, treatment options and long-term outcomes in autoimmune encephalitis (AE), with a close look to epilepsy.Methods In this retrospective observational cohort study, we enrolled patients with new-onset seizures in the context of AE. We compared clinical and paraclinical findings in patients with and without evidence of antibodies.Results Overall, 263 patients (138 females; median age 55 years, range 4–86) were followed up for a median time of 30 months (range 12–120). Antineuronal antibodies were detected in 63.50%.Antibody-positive patients had multiple seizure types (p=0.01) and prevalent involvement of temporal regions (p=0.02). A higher prevalence of episodes of SE was found in the antibody-negative group (p<0.001).Immunotherapy was prescribed in 88.60%, and effective in 61.80%. Independent predictors of favourable outcome of the AE were early immunotherapy (p<0.001) and the detection of antineuronal surface antibodies (p=0.01).Autoimmune-associated epilepsy was the long-term sequela in 43.73%, associated with cognitive and psychiatric disturbances in 81.73%. Independent predictors of developing epilepsy were difficult to treat seizures at onset (p=0.04), a high number of antiseizure medications (p<0.001), persisting interictal epileptiform discharges at follow-up (p<0.001) and poor response to immunotherapy during the acute phase (p<0.001).Conclusions The recognition of seizures secondary to AE represents a rare chance for aetiology-driven seizures management. Early recognition and treatment at the pathogenic level may reduce the risk of long-term irreversible sequelae. However, the severity of seizures at onset is the major risk factor for the development of chronic epilepsy.This study provides class IV evidence for management recommendations.Data availability statementData are available on reasonable request. http://dx.doi.org/10.1136/jnnp-2022-329195 Statistics from Altmetric.com Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. Data availability statementData are available on reasonable request.View Full Text FootnotesTwitter @SaraMatricardi, @stefano.meletti@unimore.it, @@_mzoccarato, @flaviovillaniCollaborators Collaborators: Immune Epilepsies Study Group of the Italian League Against Epilepsy (LICE) Collaborators: Umberto Aguglia, Vincenzo Belcastro, Luana Benedetti, Simone Beretta, Stefania Maria Bova, Claudia Cagnetti, Susanna Casellato, Lorenzo Celli, Elisabetta Cesaroni, Eduard Cesnick, Giangennaro Coppola, Edvige Correnti, Giuseppe Didato, Giuseppe D’Orsi, Elena Fallica, Alessandra Ferrari, Alessandro Ferretti, Carlo Andrea Galimberti, Annateresa Giallonardo, Loretta Giuliano, Angela La Neve, Claudio Liguori, Carla Marini, Federico Massa, Massimo Mastrangelo, Laura Mumoli, Carlotta Mutti, Francesca Felicia Operto, Elena Pasini, Chiara Pastori, Daniela Passarelli, Giada Pauletto, Chiara Pizzanelli, Francesca Ragona, Patrizia Riguzzi, Romana Rizzi, Marta Elena Santarone, Delia Simula, Vito Sofia, Maria Tappatà, Elena Tartara, Francesca Vanadia, Alberto Verrotti, Laura Tassi, Lucia Zinno.Contributors SM is responsible for the overall content as the guarantor. SM, TG, EF, SL, FD and FV conceptualised and designed the study. SM, SC, FD, EF, SL, AS, SS, MN, CDB, GDG, IP, SM, GG, EZ, SB, SM, SF, LZ, MZ, AV, RM, AG, EF, LF, and FV selected and enrolled patients, critically reviewing all medical charts and records. SM, TG, FD, SM, SB, SL and FV were involved with the dataset and analysis. SM, TG and FV drafted the manuscript. All collaborators of the Immune Epilepsies Study Group of the Italian League Against Epilepsy (LICE) are responsible for each case data collection and diagnostic process. All authors and collaborators edited the manuscript.Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.Competing interests None declared.Provenance and peer review Not commissioned; externally peer reviewed.Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. Read the full text or download the PDF: Subscribe Log in

 




Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently-discovered autoimmune disorder in which antibodies target NMDAR in the brain. The number of reported cases of anti-NMDAR encephalitis has increased rapidly.

 




Article Text Article menu PDF Neuro-inflammation Original research MOG antibody-associated encephalitis in adult: clinical phenotypes and outcomes Woo-Jin Lee1,2, http://orcid.org/0000-0002-3588-274XYoung Nam Kwon1, Boram Kim1, Jangsup Moon1, Kyung-Il Park3, http://orcid.org/0000-0001-5863-0302Kon Chu1, Jung-Joon Sung1, Sang Kun Lee1, Sung-Min Kim1, http://orcid.org/0000-0003-4767-7564Soon-Tae Lee1Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South KoreaDepartment of Neurology, Seoul National University Bundang Hospital, Seoul, South KoreaDepartment of Neurology, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, South KoreaCorrespondence to Dr Soon-Tae Lee, Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea; staelee{at}snu.ac.kr; Professor Sung-Min Kim; sueh916{at}gmail.com AbstractBackground We investigated the clinical characteristics and outcomes of myelin oligodendrocyte glycoprotein (MOG) antibody-associated autoimmune encephalitis (MOGAE) in adult patients.Methods From an institutional cohort, we analysed adult patients with MOGAE followed-up for more than 1 year. Disease severity was assessed using the modified Rankin scale (mRS) and Clinical Assessment Scale in Autoimmune Encephalitis scores. Immunotherapy profiles, outcomes and disease relapses were evaluated along with serial brain MRI data.Results A total of 40 patients were enrolled and categorised into cortical encephalitis (18 patients), limbic encephalitis (LE, 5 patients) and acute disseminated encephalomyelitis (ADEM, 17 patients). 80.0% of patients achieved good clinical outcomes (mRS 0‒2) and 40.0% relapsed. The LE subtype was associated with an older onset age (p=0.004) and poor clinical outcomes (p=0.014) than the other subtypes but with a low rate of relapse (0.0%). 21/25 (84.0%) relapse attacks were associated with an absence or short (≤6 months) immunotherapy maintenance. On MRI, the development of either diffuse cerebral or medial temporal atrophy within the first 6 month was correlated with poor outcomes. MOG-antibody (MOG-Ab) was copresent with anti-N-methyl-D-aspartate receptor (NMDAR)-antibody in 13 patients, in whom atypical clinical presentation (cortical encephalitis or ADEM, p<0.001) and disease relapse (46.2% vs 0.0%, p<0.001) were more frequent compared with conventional NMDAR encephalitis without MOG-Ab.Conclusions Outcomes are different according to the three phenotypes in MOGAE. Short immunotherapy maintenance is associated with relapse, and brain atrophy was associated with poor outcomes. Patients with dual antibodies of NMDAR and MOG have a high relapse rate.Data availability statementData are available on reasonable request. The datasets generated during and/or analysed during the current study are available from the corresponding author on request. http://dx.doi.org/10.1136/jnnp-2022-330074 Statistics from Altmetric.com Request Permissions If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways. Data availability statementData are available on reasonable request. The datasets generated during and/or analysed during the current study are available from the corresponding author on request.View Full Text FootnotesContributors W-JL acquired study data, performed data analysis and interpretation, and drafted the manuscript. YNK and BK. contributed in the acquisition and management of the laboratory data. JM and K-IP significantly participated in the data acquisition and analysis. KC, J-JS and SKL contributed in the design of the study, patient management and data acquisition. S-MK contributed in the initial conceptualisation and design of the study, patient management, revised the manuscript and supervised the entire procedures in this study. S-TL contributed in the initial conceptualisation and design of the study, patient management, acquired study data, performed data interpretation, drafted the manuscript, managed the entire study cohort, and is responsible for the overall content as the guarantor.Funding This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Science, ICT and Future Planning, Republic of Korea (2019R1A2C1009003) and by the Korea Health Industry Development Institute, Ministry of Health and Welfare, Republic of Korea (HI21C0539). W-JL and S-TL were supported by Lee Sueng Moon research fund of Seoul National University Hospital (3020170130).Competing interests S.-TL reports advisory roles for Roche/Genentech, UCB, Biofire Diagnostics, GC Pharma, and Advanced Neural Technologies.S-MK has lectured, consulted, and received honoraria from Bayer Schering Pharma, Genzyme, Merck Serono, and UCB; received a grant from the National Research Foundation of Korea and the Korea Health Industry Development Institute Research; is an Associate Editor of the Journal of Clinical Neurology. SMK and Seoul National University Hospital has transferred the technology of flow cytometric autoantibody assay to EONE Laboratory, Korea.Provenance and peer review Not commissioned; externally peer reviewed.Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. Read the full text or download the PDF: Subscribe Log in

 




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