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

Autoimmune Encephalitis Misdiagnosis in Adults | Neurology | JAMA Neurology | JAMA Network | AntiNMDA | Scoop.it
This case series assesses the diseases misdiagnosed as autoimmune encephalitis and potential reasons for misdiagnosis.
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The Increased Interleukin-6 Levels Can Be an Early Diagnostic Marker for New-Onset Refractory Status Epilepticus - PMC

The Increased Interleukin-6 Levels Can Be an Early Diagnostic Marker for New-Onset Refractory Status Epilepticus - PMC | AntiNMDA | Scoop.it
New-onset refractory status epilepticus (NORSE) is a condition defined as the occurrence of refractory status epilepticus in patients without active epilepsy and no other acute causes of seizure. Although there is evidence that immune-mediated pathogenesis ...
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Decreased occipital lobe metabolism by FDG-PET/CT: An anti-NMDA receptor encephalitis biomarker

Decreased occipital lobe metabolism by FDG-PET/CT: An anti-NMDA receptor encephalitis biomarker | AntiNMDA | Scoop.it
Marked medial occipital lobe hypometabolism by dedicated brain FDG-PET/CT may serve as an early biomarker for discriminating anti-NMDA receptor encephalitis from other AE.Resolution of lateral and medial occipital hypometabolism may correlate with improved neurologic status in anti-NMDA receptor ...
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Clinical Reasoning: A Young Adult Man With Cognitive Changes, Gait Difficulty, and Renal Insufficiency | Neurology

Clinical Reasoning: A Young Adult Man With Cognitive Changes, Gait Difficulty, and Renal Insufficiency | Neurology | AntiNMDA | Scoop.it
AbstractA 22-year-old right-handed man with recently diagnosed gout and renal insufficiency presented with 3 months of progressive gait instability and cognitive changes. He initially presented to an outside institution and underwent a broad workup, but an etiology for his symptoms was not found. On subsequent presentation to our institution, his examination revealed multidomain cognitive dysfunction, spasticity, hyperreflexia, and clonus. A broad workup was again pursued and was notable for an MRI of the brain, revealing cortical atrophy advanced for his age, bland CSF, and a weakly positive serum acetylcholine receptor ganglionic neuronal antibody of unclear significance. The history of gout and inadequately explained renal insufficiency led to a workup for inborn errors of metabolism, including urine amino acid analysis, which revealed a homocysteine peak. This finding prompted further evaluation, revealing markedly elevated serum homocysteine and methylmalonic acid and low methionine. He ultimately developed superficial venous thromboses, a segmental pulmonary embolism, and clinical and electrographic seizures. He was initiated on appropriate treatment, and his symptoms markedly improved. The case serves as a reminder to include late-onset inborn errors of metabolism in the differential for young adult patients with onset of neurologic, psychiatric, renal, and thromboembolic symptoms.Section 1A 22-year-old right-handed man with recently diagnosed gout and worsening renal function presented with 3 months of gait instability and cognitive changes. Approximately 5 months before presentation, he was diagnosed with gout, confirmed by uric acid crystals on synovial fluid. He was recommended to start a vegan diet then. He also developed worsening renal function. Until 3 months before presentation, he was a high-functioning student at his university. He then started struggling in classes, stopped interacting with family, stopped going to school, and became more introverted. He became clumsier, with difficulty going upstairs and downstairs. He initially presented to an outside hospital, where an extensive workup was performed, but no clear etiology was found, and he was discharged with a diagnosis of catatonia.Three months after onset of neurologic symptoms, the patient presented to our institution with worsened condition. He had recently become violent and started having abnormal movements of his extremities. Two weeks earlier, he had stopped walking and required assistance to move. He was urinating on himself and no longer told his parents when he needed to use the bathroom. There was no significant family history. On neurologic examination, mental status examination was notable for prominent inattention, perseveration, psychomotor slowing, and inappropriate laughter. He could not follow multistep commands and had reduced spontaneous speech with increased latency. Motor examination revealed mild spasticity in the lower greater than upper extremities. Detailed motor and sensory testing were limited by his mental status, but he had at least antigravity strength in the upper and lower extremities bilaterally. His tendon reflexes were 3 + throughout with crossed adductors, and he had bilateral ankle clonus for greater than 10 beats and a positive Hoffman reflex on the left.Questions for Consideration:What are the localization and broad categories to consider in the differential diagnosis?What diagnostic studies should be ordered initially?GO TO SECTION 2Section 2The multidomain cognitive dysfunction suggests diffuse bilateral cerebral hemispheric involvement, whereas the prominent spasticity, hyperreflexia, and clonus suggest upper motor neuron involvement, specifically within the corticospinal tracts. The bilateral pyramidal tract dysfunction could be localized intracranially, anywhere from the primary motor cortex to the internal capsule on down to the brainstem. Processes that could lead to such a diffuse bihemispheric process leading to cognitive symptoms and gait difficulties broadly include the following: vascular (e.g., CNS vasculitis); infectious and inflammatory (e.g., subacute to chronic meningoencephalitides); neoplastic or paraneoplastic; autoimmune (e.g., autoimmune encephalitis, demyelinating disease); toxic and metabolic (e.g., B12 deficiency leading to subacute combined degeneration)1; and inborn errors of metabolism, considered initially due to young age and gout history,2,3 as summarized in the Table.View inline View popup Table Broad Differential Diagnosis for Diffuse, Bihemispheric Processes Leading to Cognitive Symptoms and Gait DifficultiesBasic laboratory workup revealed SARS-CoV-2 positivity with lymphopenic leukopenia. B12 was 462 pg/mL and folate >20.0 ng/mL. Uric acid was 6.8 mg/dL (2.3–7.6, normal). An MRI of the brain with and without contrast revealed cortical atrophy (Figure 1) but no other acute findings, and an MRI of the cervical spine (not shown) was unremarkable. Continuous EEG (cEEG) monitoring for 48 hours revealed generalized continuous delta slow activity with superimposed faster frequencies. CSF studies revealed normal cell count, protein, glucose, IgG synthesis rate/index, and a negative meningitis panel. Encephalopathy, autoimmune, serum, and CSF panels were ordered. Given the patient's age and recent development of gout and renal dysfunction, urine amino acid analysis was sent.<img height="440" width="438" class="highwire-fragment fragment-image" src="https://n.neurology.org/content/neurology/100/4/206/F1.medium.gif"; alt="Figure 1">Download figure Open in new tab Download powerpoint Figure 1 Representative Neuroimaging From the CaseA) Sagittal T1-weighted MRI of the brain and B) axial T2/FLAIR MRI of the brain revealing cortical atrophy; C) continuous video EEG recording sample showing lateralized periodic discharges (black arrows) seen in the right fronto-central region consistent with an area of epileptogenic potential.Question for Consideration:Which entities on the differential are less likely, given this initial workup?GO TO SECTION 3Section 3Given the bland CSF and MRI brain without enhancement or FLAIR signal changes, meningoencephalitides, CNS vasculitis, demyelinating diseases, and CNS neoplastic processes are less likely. However, paraneoplastic or autoimmune encephalitis can present without MRI abnormalities.4 Furthermore, there was a weakly positive serum acetylcholine receptor ganglionic neuronal antibody from the previous institution. While this antibody is classically reported in the setting of autoimmune autonomic ganglionopathy,5 it has rarely been associated with predominantly neuropsychiatric presentations of autoimmune encephalitis.6 The patient was empirically initiated on IVIG for this possibility while awaiting other laboratory test results. In addition, inborn errors of metabolism remained high in the differential consideration, given the oddity of gout and inadequately explained renal insufficiency. Normal serum vitamin levels did not exclude the possibility of inborn errors of metabolism because they can classically be normal in these conditions.7The serum and CSF encephalopathy panels returned negative, and the serum NeoComplete Paraneoplastic Evaluation again revealed borderline anti-α 3AChR antibody. Notably, the urine amino acid analysis revealed a peak of homocysteine.Questions for Consideration:What is the significance of the homocysteine peak on urine amino acid analysis?What further studies should be ordered?GO TO SECTION 4Section 4Elevated urine homocysteine is classically found in the homocystinurias. This finding prompted a serum homocysteine level, which was >50.0 µmol/L (0–14.9, normal range), with the quantitative serum homocysteine measured at 283.3 µmol/L (6.1–10.8). Serum homocysteine is a key biochemical marker of disruption of the remethylation pathway. When elevated homocysteine is found, serum methionine and quantitative methylmalonic acid (MMA) levels in the serum should be ordered to isolate the defect in the biochemical pathway of cobalamin metabolism.7 Serum MMA was significantly elevated to 452,000 nmol/L (87–318). Serum methionine was 9 umol/L (16–34). This pattern is the biochemical hallmark of cobalamin C (CblC) deficiency.7 Genetic testing revealed 2 heterozygous pathogenic variants in the MMACHC gene: c.328_331del (p.Asn110Aspfs*13) and c.482G>A (p.Arg161Gln).DiscussionCobalamin C deficiency is the most common inherited disorder of intracellular cobalamin metabolism.8,9 It is most often due to pathogenic variants of the MMACHC gene. Because of defective gene product, methylcobalamin and adenosylcobalamin are not produced intracellularly. Methylcobalamin and adenosylcobalamin are critical cofactors for the remethylation of homocysteine to methionine and conversion of MMA to succinic acid, respectively (Figure 2). Thus, the deficiency of methylcobalamin and adenosylcobalamin leads to elevated serum homocysteine and MMA, low methionine levels, and normal serum B12 and folate.7<img src="https://n.neurology.org/content/neurology/100/4/206/F2.medium.gif"; height="251" class="highwire-fragment fragment-image" alt="Figure 2" width="440">Download figure Open in new tab Download powerpoint Figure 2 Schematic of Intracellular Cobalamin MetabolismCobalamin (Cbl) III is bound to transcobalamin (TC) in the blood. This complex is endocytosed into the cell. On entering the lysosome, Cbl III becomes unbound from TC. Cbl III then enters the cytosol and undergoes enzymatic reduction from Cbl III to Cbl II aided by MMACHC. Cbl II then undergoes adenosylation to form adenosylcobalamin (AdoCbl) in the mitochondrion and methylation to form methylcobalamin (MeCbl) in the cytosol, respectively. AdoCbl is a cofactor for methylmalonyl-CoA-mutase (MMUT), which catalyzes the conversion of L-Methylmalonyl-CoA (MMA-CoA) to succinyl-CoA. MeCbl is a cofactor in the conversion of homocysteine to methionine, mediated by the enzyme methionine synthase (MTR).7CblC disease is typically classified into 2 forms: early onset (typically within the first year of life)10 and late onset (which includes late-onset pediatric and adult cases).11 In the past couple of decades, there have been great advancements in newborn screening for cobalamin deficiencies, but many adults were born before such screening. The late-onset form was first reported in 197012 and the adult-onset (aged 18 years or older) form in 2001.13 As of 2022, only 45 cases of adult-onset CblC disease have been reported, but this is likely a vast underrepresentation. Whereas early-onset disease has a poor prognosis even with early diagnosis, the adult-onset form generally exhibits robust response to treatment. There is a genotype-phenotype correlation with adult-onset forms tending to have compound heterozygosity of missense variants, which leads to some residual protein function,7 as seen in our patient.In the adult-onset form, neuropathy or myelopathy are the most common clinical signs, followed by ataxia or dysarthria, cognitive decline, psychiatric symptoms, lower limb weakness, and seizures. Other features include thromboembolic disease and kidney failure often due to damage from thrombotic microangiopathy (TMA).7,14 Our patient did ultimately develop acute bilateral upper extremity cephalic vein thromboses and a right lower lobe segmental pulmonary embolism, for which he was initiated on therapeutic anticoagulation. He also had elevated creatinine (peak at 3.6–3.8 mg/dL), but the exact etiology of his renal disease was unclear, and he did not have the other accompanying signs of TMA (no hypertension, hematuria, or proteinuria). Kidney biopsy was deferred, given it was unlikely to change management and had elevated risks on therapeutic anticoagulation. In addition, his course was complicated by clinical seizures with left gaze deviation and generalized convulsions. He was reconnected to cEEG, which revealed right fronto-central lateralized periodic epileptiform discharges and seizures without definitive clinical correlation and was initiated on antiseizure medications. Finally, while gout is more commonly associated with inborn errors of metabolism dealing with purine metabolism, it has been reported in cases of methylmalonic acidemia and may be related to decreased renal clearance of uric acid.3The treatment for CblC disease is intramuscular or subcutaneous hydroxycobalamin, combined with oral betaine and folic acid.7 Of importance, oral cobalamin replacement approaches are ineffective because the patients require supplementation with the active form, which is not absorbed through the oral route; betaine facilitates the conversion of homocysteine to methionine; and folic acid can potentially augment remethylation.9 Our patient was initiated on this regimen soon after the biochemical markers confirmed the diagnosis. He improved significantly while still inpatient and was discharged to an inpatient acute rehabilitation facility. By approximately a month after discharge, he could hold an in-depth follow-up conversation over the phone, felt his cognition had significantly improved, and was able to stand and walk for 7–8 meters at a time. This case serves as a reminder to trust the neurologic examination, even if neuroimaging and other workup are unrevealing. In addition, in complicated cases, red herrings may arise,15 such as the AChR ganglionic antibody, not considered the pathogenic antibody in this case. Finally, the case reminds one to include the inborn errors of metabolism in the differential for young adult patients with onset of neurologic and psychiatric presentations, particularly when accompanied by other systemic findings.Study FundingThe authors report no targeted funding.DisclosureThe authors report no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.Appendix Authors<img class="highwire-fragment fragment-image" src="https://n.neurology.org/content/neurology/100/4/206/T2.medium.gif"; width="658" height="1273" alt="Table">Footnotes↵* These authors contributed equally to this work as senior authors.Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.Submitted and externally peer reviewed. The handling editor was Whitley Aamodt, MD, MPH.Received April 27, 2022.Accepted in final form September 16, 2022.© 2022 American Academy of NeurologyReferences1.↵Qudsiya Z, De Jesus O. Subacute combined degeneration of the spinal cord. In: StatPearls. StatPearls Publishing; 2021:1.2.↵Doucet BP, Jegatheesan D, Burke J. Late diagnosis of Lesch-Nyhan disease variant. BMJ Case Rep. 2013;2013:1-2. doi:10.1136/bcr-2013-201997OpenUrlCrossRef3.↵Charuvanij S, Pattaragarn A, Wisuthsarewong W, Vatanavicharn N. Juvenile gout in methylmalonic acidemia. Pediatr Int. 2016;58(6):501-503.OpenUrl4.↵Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12(2):157-165.OpenUrlCrossRefPubMed5.↵Vernino S. Autoimmune autonomic disorders. Continuum. 2020;26(1):44-57.OpenUrl6.↵McKeon A, Lennon VA, Lachance DH, Fealey RD, Pittock SJ. Ganglionic acetylcholine receptor autoantibody. Arch Neurol. 2009;66(6):735-741. doi:10.1001/archneurol.2009.78OpenUrlCrossRefPubMed7.↵Kalantari S, Brezzi B, Bracciamà V, et al. Adult-onset CblC deficiency: a challenging diagnosis involving different adult clinical specialists. Orphanet J Rare Dis. 2022;17(1):33.OpenUrl8.↵Mudd SH, Levy HL, Abeles RH. A derangement in B12 metabolism leading to homocystinemia, cystathioninemia and methylmalonic aciduria. Biochem Biophys Res Commun. 1969;35(1):121-126.OpenUrlCrossRefPubMed9.↵Adam MP, Ardinger HH, Pagon RA, et al.Sloan JL, Carrillo N, Adams D, Venditti CP. Disorders of intracellular cobalamin metabolism. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. University of Washington; 2008.10.↵Wang SJ, Yan CZ, Wen B, Zhao YY. Clinical feature and outcome of late-onset cobalamin C disease patients with neuropsychiatric presentations: a Chinese case series. Neuropsychiatr Dis Treat. 2019;15:549-555.OpenUrlCrossRefPubMed11.↵Huemer M, Scholl-Bürgi S, Hadaya K, et al. Three new cases of late-onset cblC defect and review of the literature illustrating when to consider inborn errors of metabolism beyond infancy. Orphanet J Rare Dis. 2014;9:161.OpenUrlCrossRefPubMed12.↵Goodman SI, Moe PG, Hammond KB, Mudd SH, Uhlendorf BW. Homocystinuria with methylmalonic aciduria: two cases in a sibship. Biochem Med. 1970;4(5):500-515.OpenUrlCrossRefPubMed13.↵Bodamer OA, Rosenblatt DS, Appel SH, Beaudet AL. Adult-onset combined methylmalonic aciduria and homocystinuria (cblC). Neurology. 2001;56(8):1113.OpenUrlFREE Full Text14.↵Lemoine M, François A, Grangé S, et al. Cobalamin C deficiency induces a typical histopathological pattern of renal arteriolar and glomerular thrombotic microangiopathy. Kidney Int Rep. 2018;3(5):1153-1162.OpenUrl15.↵Ebright MJ, Li SH, Reynolds E, et al. Unintended consequences of Mayo paraneoplastic evaluations. Neurology. 2018;91(22):e2057-e2066.OpenUrlAbstract/FREE Full Text
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Study Warns About Frequent Autoimmune Encephalitis Misdiagnosis, Even in Specialized Centers

Study Warns About Frequent Autoimmune Encephalitis Misdiagnosis, Even in Specialized Centers | AntiNMDA | Scoop.it
A new study warns of frequent autoimmune encephalitis misdiagnosis in the U.S. medical system, which could put patients at risk of inappropriate treatment and death.
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Children | Free Full-Text | Long-Term Outcome of Pediatric Patients with Anti-NMDA Receptor Encephalitis in a Single Center

Children | Free Full-Text | Long-Term Outcome of Pediatric Patients with Anti-NMDA Receptor Encephalitis in a Single Center | AntiNMDA | Scoop.it
Background: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is the most common autoimmune encephalitis in children. There is a high probability of recovery if treated promptly. We aimed to analyze the clinical features and long-term outcomes of pediatric patients with anti-NMDA receptor...
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Can you help improve treatment for autoimmune encephalitis?

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Vaccination-associated acute disseminated encephalomyelitis

Vaccination-associated acute disseminated encephalomyelitis | AntiNMDA | Scoop.it
While the basic definition of vaccination-associated acute disseminated encephalomyelitis (ADEM) is relatively clear and easily understandable, it is often difficult to diagnose ADEM based on clinical findings alone.
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Antibodies | Free Full-Text | Philosophical Approach to Neural Autoantibodies in Psychiatric Disease—Multi-Systemic Dynamic Continuum from Protective to Harmful Autoimmunity in Neuronal Systems

Antibodies | Free Full-Text | Philosophical Approach to Neural Autoantibodies in Psychiatric Disease—Multi-Systemic Dynamic Continuum from Protective to Harmful Autoimmunity in Neuronal Systems | AntiNMDA | Scoop.it
(1) Background: philosophical views are important to enable a general and multi-systemic view of the potential understanding of autoimmunity in psychiatric disease that is not solely reflected by an immunological viewpoint.
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What is Autoimmune Encephalitis?

What is Autoimmune Encephalitis? | AntiNMDA | Scoop.it
Autoimmune encephalitis (AE) is a type of brain inflammation where the body’s immune system attacks healthy cells and tissues in the brain or spinal cord. It is a rare, complex disease that can cause rapid changes in both physical and mental health.
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Cerebrospinal fluid pentraxin 3 and CD40 ligand in anti-N-menthyl-d-aspartate receptor encephalitis

Cerebrospinal fluid pentraxin 3 and CD40 ligand in anti-N-menthyl-d-aspartate receptor encephalitis | AntiNMDA | Scoop.it
Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder of the central nervous system whose pathogenesis involves interleukin (IL)-6 and IL-17A.We examined the correlations between CSF concentrations of the acute-phase protein pentraxin 3 (PTX3), the chronic inflammatory...
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Postpartum Psychosis or Something Else?

Postpartum Psychosis or Something Else? | AntiNMDA | Scoop.it
A case of postpartum psychosis with malignant catatonia highlights the role of immunology in the development and treatment of postpartum psychosis.
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Neuroinflammatory syndromes in children

Neuroinflammatory syndromes in children | AntiNMDA | Scoop.it
Neuroimmunological disease data are constantly evolving. New recommendations exist for multiple common neuroimmunological disorders with behavioural, emotional, cognitive and neurological sequelae.Anti-NMDA receptor encephalitis now has well-recognized patterns of symptom semiology, diagnostic and...
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Diagnostic Value of 18F-FDG PET/CT Versus MRI in the Setting of Antibody-Specific Autoimmune Encephalitis

Diagnostic Value of 18F-FDG PET/CT Versus MRI in the Setting of Antibody-Specific Autoimmune Encephalitis | AntiNMDA | Scoop.it
Diagnosis of autoimmune encephalitis presents some challenges in the clinical setting because of varied clinical presentations and delay in obtaining antibody panel results.We examined the role of neuroimaging in the setting of autoimmune encephalitides, comparing the utility of <sup>18</sup>F-FDG...
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The Many Faces of Catatonia, An Under-Recognized Clinical Syndrome

The Many Faces of Catatonia, An Under-Recognized Clinical Syndrome | AntiNMDA | Scoop.it
Catatonia: learn more about how to best diagnose early.
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Why We Still Use “Organic Causes”: Results From a Survey of Psychiatrists and Residents

The diagnostic category of “organic disorders” was officially removed from the psychiatric nosology in DSM-IV, published in 1994. Despite this change, physicians continue to use the term “organic causes” to refer to medical and neurological causes of psychiatric symptoms, and it remains part of...
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Anti-NMDA receptor encephalitis and brain atrophy in children and adults: A quantitative study

Anti-NMDA receptor encephalitis and brain atrophy in children and adults: A quantitative study | AntiNMDA | Scoop.it
To determine whether brain atrophy was present in patients with anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDARE) using qualitative and quantitative analyses of brain magnetic resonance imaging (MRI) and to explore clinical differences in patients with anti-NMDARE with or without brain...
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Eoin Flanagan, M.B., B.Ch., explains autoimmune encephalitis misdiagnosis in JAMA Neurology

Eoin Flanagan, M.B., B.Ch., explains autoimmune encephalitis misdiagnosis in JAMA Neurology | AntiNMDA | Scoop.it
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Characterization of cardiac bradyarrhythmia associated with LGI1-IgG autoimmune encephalitis

LGI1-IgG AE can be rarely associated with bradyarrhythmias. Although the disease course is mostly favorable, some cases may require pacemaker placement to avoid devastating outcomes.
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Event Announcement: Saturday, 21 January 2023, Paris, France

Event Announcement: Saturday, 21 January 2023, Paris, France | AntiNMDA | Scoop.it
Dear Subscriber, We are pleased to share with you details of an event that is being hosted by the newly established ENMDAR, a French anti-NMDA receptor encephalitis organisation. The event is free of charge and open to all. It will be in French.
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Autoimmune Encephalitis in Critical Care: Optimizing Immunosuppression

Autoimmune Encephalitis in Critical Care: Optimizing Immunosuppression | AntiNMDA | Scoop.it
Autoimmune diseases affecting the nervous systems are a common cause of admission to the intensive care unit (ICU).Although there exist several well-described clinical syndromes, patients more commonly present with progressive neurologic dysfunction and laboratory and radiographic evidence of centr...
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Diagnosis and Management of Autoimmune Encephalitis (Podcast) –

Diagnosis and Management of Autoimmune Encephalitis (Podcast) – | AntiNMDA | Scoop.it
The rarity and many mimics of autoimmune encephalitis make its diagnosis no easy task. An AE expert shares practical insights on how to promptly identify the condition to enable early treatment.
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Serum cystatin C and anti-N-methyl-D-aspartate receptor encephalitis

Serum cystatin C and anti-N-methyl-D-aspartate receptor encephalitis | AntiNMDA | Scoop.it
Our results show that the serum levels of CysC are associated with anti-NMDAR encephalitis and its clinical parameters and that the changes in CysC levels correlate with therapeutic effect.Therefore, our findings provide new insights into the association between serum CysC and anti-NMDAR encephalit...
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Molecular mimicry of NMDA receptors may contribute to neuropsychiatric symptoms in severe COVID-19 cases

Molecular mimicry of NMDA receptors may contribute to neuropsychiatric symptoms in severe COVID-19 cases | AntiNMDA | Scoop.it
Approximately 30% of individuals with severe SARS-CoV-2 infections also develop neurological and psychiatric complaints. In rare cases, the occurrence of autoimmune encephalitis has been reported after SARS-CoV-2 infection.
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