The Anti-NMDA Receptor Encephalitis Foundation Newsletter

Anti-NMDA Receptor Encephalitis makes in most cases a very dramatic and frightening entrance, with symptoms coming on fast and furious. Within a matter of days …Read More…

This case suggests that anti-NMDAR encephalitis may arise after tuberculosis infection. Therefore, clinicians must be aware of this possibility, especially when cognitive and new neurological symptoms suddenly occur.

There is still a lot we don’t know about neurological conditions such as autoimmune encephalitis – but through further research and awareness-raising, we can help improve quality of life.

Autoimmune limbic encephalitis (ALE) associated with an anti-N-methyl-D-aspartate receptor (NMDAR) is a rare but occasionally fatal condition that could be accompanied by ovarian teratoma. We report a case of a 27-year-old woman with ALE combined with a mature cystic teratoma that looks like a…

Background A variety of psychiatric syndromes are associated with NMDAR autoantibodies; however, their clinical relevance when only present in the serum is unclear. We explored whether patients with CSF NMDAR autoantibodies could be distinguished from patients with serum-only NMDAR autoantibodies.

Learn what it is, who’s at risk, how it’s diagnosed, why early treatment matters, and…

AbstractBackground and Objectives Anti-NMDA receptor encephalitis (anti-NMDARE) is one of the most common causes of encephalitis. It typically presents in adolescence and young adulthood, but little is known about its potential long-term consequences across the lifespan. Adaptive behavior describes an individual’s ability to respond and adapt to environmental demands and unanticipated changes in daily routines. In this study, we evaluate the relationship between features from clinical presentation, including age, and long-term adaptive behavior in participants with anti-NMDARE.Methods Cross-sectional informant-reported data were collected between 2017 and 2019 from 41 individuals/caregivers of individuals with anti-NMDARE treated at 3 major academic hospitals. Neurologic disability was assessed by record review using the modified Rankin Scale (mRS). Functional outcomes were assessed using the validated Adaptive Behavior Assessment System, Third Edition (ABAS-3).Results The mean age at the time of study enrollment was 23.4 years (SD 17.0 years), and the mean time from symptom onset to study enrollment was 4.0 years. Seventeen participants were aged <12 years at symptom onset, 19 participants were aged 12–30 years, and 5 participants were aged >30 years. Mean ABAS-3 scores at study enrollment for all participants were in the average range (mean general adaptive composite standard score 92.5, SD 18.7). Individuals aged <12 years at symptom onset had lower mean ABAS-3 scores and were in the below average range compared with those aged 12–30 years at symptom onset, whose mean scores were in the average range (87 vs 99, p < 0.05). Similar differences were seen in 3 of the individual subscales (functional academics, health and safety, and self-care). There were no significant differences in mRS scores between age groups (p > 0.05).Discussion Although anti-NMDARE is associated with an overall favorable outcome, younger age at onset associates with worse long-term adaptive behavior despite no differences in neurologic disability. These findings suggest that the disease may have distinct consequences on the early developing brain. Future studies should evaluate behavioral recovery and quality of life after anti-NMDARE and identify additional factors associated with differential recovery.GlossaryABAS-3=Adaptive Behavior Assessment System, Third Edition; anti-NMDARE=anti-NMDA receptor encephalitis; GAC=general adaptive composite; ICU=intensive care unit; mRS=modified Rankin ScaleAnti-NMDA receptor encephalitis (anti-NMDARE) is now recognized as the most common identified cause of encephalitis in children and young adults, accounting for 40% of cases with an identified etiology and more common than any individual viral etiology.1,2 The disease manifests as subacute behavioral change or cognitive dysfunction often accompanied by reduced consciousness, speech dysfunction, seizures, movement disorder, and autonomic instability.3Recent literature has focused on advancing understanding of the long-term outcomes of individuals with anti-NMDARE. Although patients typically have dramatic and frequent improvement in motor disability,4 studies have also noted specific deficits in cognition, behavior, and psychosocial well-being, as well as substantial caregiver burden, years after initial presentation.5,-,9 Clinical features at the time of presentation that have been associated with poorer long-term outcomes include requirement for intensive care unit (ICU) admission and longer time between diagnosis and treatment initiation.4,10In this study, we aimed to evaluate long-term behavioral function in individuals with anti-NMDARE with focus on adaptive behavior,11 the ability to complete age-expected tasks in everyday environments.12 Adaptive behavior is a valuable outcome that encompasses functional outcomes in a real-world setting beyond what can be measured in performance-based testing. Furthermore, we investigated the association between features of their clinical presentations and long-term outcomes, in particular the role of age at symptom onset, based on earlier observations at a single institution of worse outcomes in those with symptom onset in childhood.13,14MethodsStudy ParticipantsChildren (aged <18 years) and adults (aged ≥18 years) treated for anti-NMDARE at the Johns Hopkins Hospital, Hospital of the University of Pennsylvania, and Children’s Hospital of Philadelphia from July 1, 2005, until June 30, 2015, were invited to participate in this study. At the Johns Hopkins Hospital, participants were identified based on chart review of all individuals with a billing diagnosis of encephalitis as part of a prior study.13 At the Hospital of the University of Pennsylvania and Children’s Hospital of Philadelphia, participants were identified through a preexisting clinical registry of all individuals with autoimmune encephalitis. At each site, chart review by a neurologist with clinical expertise in autoimmune neurology (A.Y. and E.G.-L.) confirmed that individuals invited to participate in this study met the diagnostic consensus criteria for anti-NMDARE.15 As this study aimed to assess long-term outcomes, it was also required that at least 1 year had passed from the date of diagnosis to the date of study enrollment. Eligible participants (if younger than 18 years, participants’ legal guardians) were contacted by telephone and asked to consent to participation in a structured telephone interview for this study.Standard Protocol Approvals, Registrations, and Patient ConsentsThe study was approved by the institutional review boards at each site, and verbal informed consent was obtained and documented from all participants aged 18 years or older. For participants younger than 18 years, verbal informed consent was obtained and documented from their guardian. Verbal assent was also obtained and documented for children aged 8 years or older.Clinical Data CollectionAfter consent was obtained, the following information was extracted from participants’ medical records: demographic details, symptoms and signs at initial presentation, diagnostic test results, immunotherapy administered, and clinical findings at hospital discharge and last follow-up with a neurologist.Assessment of Adaptive Behavior, Neurologic Disability, and Neuropsychiatric SymptomsThe Adaptive Behavior Assessment System, Third Edition (ABAS-3),11 was administered. The ABAS-3 is a standardized age-normalized neurobehavioral rating scale of over 200 items for individuals from early infancy to adulthood, which assesses development, behavior, and cognitive abilities. Scores on these subscales are summed and normalized to the standardization sample to generate a general adaptive composite (GAC) standard score, which comprises 3 domain standard scores (conceptual, social, and practical). The conceptual domain comprises the communication, functional academics, and self-direction subscales. The social domain comprises the leisure and social subscales. The practical domain comprises the community use, home living, health and safety, and self-care subscales. Child forms of the test include a stand-alone motor subscale, and adult forms of the test include a stand-alone work subscale. Neither the motor nor work subscales are included in the domain or composite standard scores.ABAS-3 GAC and domain standard scores are standardized to an average of 100 and SD of 15. Scores of 90–109 are classified average. Scores of 110–119 are classified above average, and 120 and above high. Scores of 80–89 are classified below average, 71–79 low, and 70 and below extremely low. For children (aged <18 years), parents or other caregivers completed the age-appropriate form for children (0–5 years or 5–21 years). For adults (aged ≥18 years), the individual themselves completed the form for adults (16–89 years).Scores for modified Rankin Scale (mRS), a motor disability scale with scores ranging from 0 for no symptoms to 6 for death,16 were assigned independently by 2 raters (A.Y. and E.G.-L.) based on documentation in medical records. In the event of a discrepancy, scores were adjudicated to consensus. Each participant was assigned a score at hospital admission, hospital discharge, and last neurology follow-up. A score at study enrollment was also determined based on the structured telephone interview. As has been done in other studies of autoimmune encephalitis, a good score was defined by mRS score 0–2 and a poor score by mRS score 3–6.4 Participants were also asked to respond yes or no to whether they were currently experiencing neuropsychiatric symptoms in multiple domains including fatigue, emotional lability, short-term memory, and concentration.Statistical AnalysesStatistical analyses were performed using STATA software version 14 (College Station, TX). The χ2 and Fisher exact tests were used to test for associations between categorical variables, and 2-sided t tests were used to evaluate differences in means for continuous variables. p Value < 0.05 was considered significant.The individual effects of participant and clinical factors on each outcome measure (ABAS-3 GAC standard score and mRS score at study enrollment) were tested with simple regression analyses, and the combined effects of multiple participant and clinical factors, adjusting for potential confounders, were tested in multiple regressions analysis. Examined participant and clinical factors included age at symptom onset, sex, percentage of White participants, seizure presence, tumor presence, requirement for ICU admission, immunotherapy administered (first-line treatment defined as steroids, plasma exchange, and/or IV immunoglobulin vs second-line treatment defined as rituximab and/or cyclophosphamide), and time interval from symptom onset to study enrollment. Given the cohort size, analyses for smaller subgroups were not performed.Age at symptom onset was initially evaluated as a continuous variable. Subsequently, based on prior literature and examination of the distribution of data within this cohort,4 age at symptom onset was subsequently categorized as the following: <12 years (presumed prepubertal), 12–30 years (presumed postpubertal age through young adulthood), and >30 years (older adulthood).Data AvailabilityThe data that support the findings of this study can be made available by the corresponding author on request.ResultsParticipant Characteristics and Clinical ProfilesA total of 41 participants with anti-NMDARE were enrolled in this study (eFigure 1, links.lww.com/NXI/A731). Thirty (73%) were female sex, and the mean age at the time of study enrollment was 23.4 years (SD 17.0 years). The mean time from symptom onset to study enrollment was 4.0 years (SD 2.4 years).Nearly all participants had an mRS score of 3–5 on admission (some dependence on others for age-expected tasks; 39/41, 95%), and 21/41 (51%) required ICU admission during their acute hospitalization. No individual had a prior history of herpes simplex virus encephalitis. All individuals received immunotherapy (24% first-line only; 76% first-line and second-line). Additional details regarding participant characteristics and clinical profiles are displayed in Table 1.View inline View popup Table 1 Participant Characteristics and Clinical ProfilesCategorization of Age at Symptom OnsetSeventeen participants were aged <12 years at symptom onset, 19 participants were aged 12–30 years, and 5 participants were aged >30 years (eTable 1, links.lww.com/NXI/A731). Comparing participants aged <12 years and those aged 12–30 years, there were no differences seen in sex, percentage of White participants, presence of seizures, presence of tumor, requirement for ICU admission, mRS score at admission, or time interval from symptom onset to study enrollment. However, there was a difference in immunotherapy administered: participants aged <12 years were more likely to receive first-line treatment only compared with those aged 12–30 years (8/17 vs 2/19, p = 0.02). Given the low representation of individuals aged >30 years, similar demographic comparisons with this age group were not performed.Adaptive Behavior, Neurologic Disability, and Neuropsychiatric Symptoms at Study EnrollmentOn the ABAS-3 completed at the time of study enrollment (Table 2), mean standard scores of the GAC for all participants in this study were in the average range (mean GAC standard score 92.5, SD 18.7). Twenty-five participants scored in average (n = 16), above average (n = 6), or high (n = 3) ranges. Fifteen participants scored in the below average (n = 6), low (n = 4), or extremely low (n = 5) ranges.View inline View popup Table 2 Adaptive Function, Neurologic Disability, and Neurobehavioral Features at Study EnrollmentThese findings were corroborated by assessment of neurologic disability, on which 35 participants (35/40, 88%) had a good outcome (mRS score of 0–2) at the time of study enrollment. This percentage was higher than at the time of initial hospital presentation (2/40, 5%; p < 0.0001), indicating that clinical improvement occurred in the time between initial presentation and study enrollment. At the time of study enrollment, 30 participants (30/39, 77%) endorsed at least one of the following persistent neuropsychiatric symptoms: fatigue (27%), emotional lability (46%), memory difficulties (41%), or concentration difficulties (39%).Factors Associated With Adaptive Behavior OutcomesIn individual comparative analyses, ABAS-3 GAC standard scores at study enrollment did not differ based on race (White vs non-White), presence of seizures, presence of tumor, requirement for ICU admission, immunotherapy administered, ABAS-3 rater (self vs parent/caregiver), or time interval from symptom onset to study enrollment (eTable 2, links.lww.com/NXI/A731). Of interest, male participants had lower scores in comparison to female participants (p < 0.01).The relationship between age at symptom onset and ABAS-3 GAC standard scores was examined (Figure 1, eFigure 2, links.lww.com/NXI/A731). However, given the low representation of individuals aged >30 years, they were excluded from these analyses. Among participants aged ≤30 years, those aged <12 years at symptom onset had lower ABAS-3 GAC standard scores and were in the below average range compared with those aged 12–30 years at symptom onset, who scored in the average range (87 vs 99, p < 0.05; Figure 2 and eTable 3, links.lww.com/NXI/A731). Similar differences were seen in 3 of the individual subscales (functional academics, health and safety, and self-care). Analysis was repeated after removing cases that were outliers across any of the domains, and this resulted in even more striking differences in scores between the age groups. Analyses coexamining the effect of age group and treatment received on outcomes were not performed because of sample size limitations.<img src=”https://nn.neurology.org/content/nnn/9/5/e200013/F1.medium.gif”; class=”highwire-fragment fragment-image” width=”440″ height=”213″ alt=”Figure 1″>Download figure Open in new tab Download powerpoint Figure 1 Age at Symptom Onset and Adaptive BehaviorNote: Adaptive Function as measured by the Adaptive Behavior Assessment System, Third Edition General Adaptive Composite standard score.<img src=”https://nn.neurology.org/content/nnn/9/5/e200013/F2.medium.gif”; alt=”Figure 2″ height=”300″ class=”highwire-fragment fragment-image” width=”440″>Download figure Open in new tab Download powerpoint Figure 2 Categorical Age at Symptom Onset and Adaptive Function (Total and Domain Scores)^Note: Adaptive Function as measured by the Adaptive Behavior Assessment System, Third Edition General Adaptive Composite and Conceptual, Social, and Practical Domain standard scores.Factors Associated With Neurologic Disability and Neuropsychiatric SymptomsAs noted in eTable 4, links.lww.com/NXI/A731, there was no association between age at symptom onset and mRS scores at study enrollment (p = 0.17), accounting for duration of follow-up, in participants aged 0–30 years. Likewise, there was no difference seen in mRS scores at study enrollment between participants aged <12 years and participants aged 12–30 years (p = 0.17). Furthermore, no associations were seen between age at symptom onset and current fatigue, short-term memory difficulties, and concentration difficulties at study enrollment. Individuals with emotional lability at study enrollment appear to have had an older age at symptom onset than those without emotional lability (p = 0.04); however, this is no longer the case when applying a correction for multiple comparisons (eTable 4, links.lww.com/NXI/A731).DiscussionThis study explores adaptive behavior outcomes after anti-NMDARE and demonstrates that although overall outcomes on this domain appear to be favorable, differences are seen by age such that younger children appear to have worse outcomes compared with adolescents and young adults. Long-term outcomes after anti-NMDARE appear to be favorable overall, as suggested by the fact that the average adaptive behavior score for participants in this study falls in the average range. Through use of a standardized age-normalized rating scale, adaptive behavior assesses an individual’s ability to function independently and meet environmental demands. It has been demonstrated by our group13,17 and others18,19 that adaptive behavior and other outcomes following anti-NMDARE may be better than those following other forms of autoimmune encephalitis and infectious encephalitis. In this study, our findings regarding adaptive behavior are corroborated by examination of neurologic disability, for which we found that the majority of participants have good outcome (mRS score 0–2), akin to what has been found in other studies in this disease.4 Furthermore, less than 50% of participants reported ongoing difficulties with fatigue, emotional lability, memory difficulties, and concentration difficulties.Despite overall favorable adaptive behavior outcomes, we demonstrate that children with anti-NMDARE had worse scores compared with those who experienced anti-NMDARE onset in adolescence or young adulthood. Of note, younger age at onset did not lead to a higher risk of neurologic disability as assessed using the mRS. This finding emphasizes the importance of evaluating aspects of daily performance beyond traditional measures of motoric and fine motor functioning. Although children’s outcomes were worse than those of adults, they did not, on average, fall into the ranges of low or extremely low. However, modest impairments in adaptive functioning can still affect quality of life at home, at school, and in the community.20 Our findings of worse adaptive behavior outcomes in younger children are supported by previous literature examining the effects of age at symptom onset on long-term neurologic disability, as measured by mRS scores. An early and pivotal study of treatment and prognostic factors for long-term outcomes demonstrated in analyses restricted to adolescents and children a relationship of improved odds of good outcome (defined as mRS score of 0–2) after 24 months of follow-up with increasing age.4 In a more recent meta-analysis of individual patient data of 1,550 cases, infants younger than 2 years (along with adults aged 65 years and older) were likewise observed to have a more than 3 times increased odds of poor outcome, defined as mRS score of 3–6 after a median follow-up of 12.0 months (range 0.5–268.0 months).21 Conversely, in a separate literature review and meta-analysis of 80 previously reported cases of children with anti-NMDARE, no association was found between age at onset and rates of incomplete recovery, defined as mRS score of 2–6, after a median follow-up of 12 months (range 1.3–54 months).22 Future research is required to determine whether pediatric-onset anti-NMDARE portends a higher likelihood of need for school and social supports. It will also be of value to quantify the effect of anti-NMDARE on family functioning, not just the acute effect experienced during the acute illness, but the longer-term effect.Early-onset anti-NMDARE might have a greater effect in the context of the developing brain. It has been demonstrated that clinical recovery results from downregulation of B-cell production of anti-NMDAR antibodies, leading to restoration of NMDARs and subsequent reversal of impairment in NMDAR function.23 However, it is not clear that such restoration of NMDARs would lead to restoration of all activity of NMDAR-related networks in a developing brain. Furthermore, profound encephalopathy can occur for months in anti-NMDARE during periods of critical neural development in children. It is possible that the prolonged loss of environmental enrichment, such as missed school and socialization, during the acute periods of anti-NMDARE may in itself lead to impairment in neural networks underlying learning and development that would otherwise be normally developing. Such phenomena have been reported in studies of pediatric traumatic brain injury.24,25 Even subtle alterations of these developmental trajectories may lead to reductions in daily function and quality of life, which can have critical consequences in social and educational settings.Another potential explanation may be a difference in clinical factors by age that may play a role in outcomes. Prior studies have demonstrated that requirement for ICU admission and longer time between diagnosis and treatment initiation4,10 are associated with poorer long-term neurologic disability outcomes in anti-NMDARE. Although no differences were seen in this study in rates of ICU admission, delays in treatment initiation were not able to be evaluated, as it was difficult to accurately ascertain this information in many patients who had been transferred from outside hospitals. Furthermore, fewer children did receive second-line treatment (defined as rituximab and/or cyclophosphamide) compared with adults in this study. This may reflect physician discomfort with the use of these medications in children, despite several studies indicating safety and efficacy in the pediatric population, as they are not approved by the United States Food and Drug Administration for pediatric use.26 Correspondingly, prior studies have demonstrated a decreased risk of relapse in individuals receiving second-line treatment as well as improved neurologic disability outcomes in those who received second-line treatment after failing first-line treatment.10A final possibility is a difference in sociologic factors between children and adults. Although an adult’s independence in activities of daily living is typically self-motivated, a child’s independence occurs within the context of a family. Given the often severe and protracted course of anti-NMDARE, it is possible that parents remain guarded about the freedom and independence they afford to a child who is recovering from severe illness. Such imposed limitations would be reflected in many of the questions on the ABAS-3 (e.g., “makes simple meals that require no cooking” or “attends fun activities at another’s home”). This may contribute to the observed lower scores in children in comparison to adolescents and young adults (notably, in the domains of health and safety, and self-care). Although this phenomenon may affect adaptive behavior in this patient population, it, nonetheless, may still represent an important psychosocial consequence of this disease and an important dynamic to consider when counseling families. Relatedly, because both children and adults were included in this study, respondents to the ABAS-3 included both participants themselves and their primary caregivers. Our analyses did not identify differences in ABAS-3 scores between those who responded themselves and those for which a caregiver responded. However, as seen in studies of other conditions,27,28 it is possible that individuals with anti-NMDARE themselves may answer differently than the parents/caregivers responding on their behalf.Adaptive behavior outcomes of older adults with anti-NMDARE were partially examined in this study. Five participants in this cohort were over the age of 30 years and, in fact, all 5 were over the age of 50 years. Given the small number of participants in this age group, they were excluded from subgroup analyses examining the role of age on outcomes. Although not specifically analyzed in this study, qualitatively, 2 participants scored in the above average range and 3 participants in the below average range on the ABAS-3. Of interest, the 2 participants who scored well both had a tumor discovered; however, there were no other apparent differences between the 2 groups in the clinical variables collected. Other comorbidities, including reasons for neurodegeneration, were not evaluated. Future studies should look at a larger cohort of older participants with anti-NMDARE with appropriate healthy controls and extraction of comprehensive medical information to determine if and how outcomes in this age group differ from those of children, adolescents, and young adults.This study across 3 subspecialty centers demonstrates that anti-NMDARE is associated with an overall favorable outcome, although younger age at onset associates with worse long-term adaptive behavior. Limitations include the retrospective identification of patients, which may have introduced the possibility of selection bias (e.g., the inclusion of a large children’s hospital as one of the 3 cohorts led to a relative abundance of children and adolescents in this study.) An additional limitation was the cross-sectional assessment of participants, which led to variabilities in factors such as time from symptom onset to study enrollment. Future work through prospective and larger studies will evaluate behavioral recovery and quality of life after anti-NMDARE and identify additional factors associated with differential recovery. This will enable the examination of the role of factors that could not be examined in this study due to inconsistent data availability such as time from symptom onset to immunotherapy initiation and MRI brain findings. Although this study included a sizeable cohort because of its multisite nature, larger studies are needed to examine other variables such as potential differences between the outcomes of very young children and older adults compared with those of adolescents and young adults. Ultimately, improved understanding of outcomes may have implications for clinical management and the design of interventional (both pharmacologic and nonpharmacologic) studies in this patient population.Study FundingThe authors report no targeted funding.DisclosureA.K. Yeshokumar is a full-time employee at Bristol Myers Squibb but was not at the time that this work was completed. E. Gordon-Lipkin, A. Arenivas, and M. Rosenfeld report no disclosures relevant to the manuscript. K.R. Patterson is a full-time employee at Horizon but was not at the time that this work was completed. R.A. Blum, B. Banwell, and Arun Venkatesan report no disclosures relevant to the manuscript. E. Lancaster has consulted for Merck and receives patent money from Novartis. J. Panzer is deceased: disclosures are not included for this author. J. Probasco reports no disclosures relevant to the manuscript; he serves as Editor-in-Chief for NEJM Journal Watch Neurology. Go to Neurology.org/NN for full disclosures.AcknowledgmentDr. Panzer is deceased.Appendix Authors<img alt=”Table” width=”600″ src=”https://nn.neurology.org/content/nnn/9/5/e200013/T3.medium.gif”; height=”1553″ class=”highwire-fragment fragment-image”>FootnotesGo to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.The Article Processing Charge was funded by the authors.Submitted and externally peer reviewed. The handling editor was Josep O. Dalmau, MD, PhD, FAAN.Received November 9, 2021.Accepted in final form May 17, 2022.© 2022 American Academy of NeurologyReferences1.↵Gable MS, Gavali S, Radner A. Anti-NMDA receptor encephalitis: report of ten cases and comparison with viral encephalitis. Eur J Clin Microbiol Infect Dis. 2009;28:1421-1429.OpenUrlCrossRefPubMed2.↵Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA. The frequency of autoimmune N-methyl-d-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California encephalitis project. Clin Infect Dis. 2012;54:899-904.OpenUrlCrossRefPubMed3.↵Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7:1091-1098.OpenUrlCrossRefPubMed4.↵Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12:157-165.OpenUrlCrossRefPubMed5.↵Finke C, Kopp UA, Scheel M, et al. Functional and structural brain changes in anti-N-methyl-D-aspartate receptor encephalitis. Ann Neurol. 2013;74:284-296.OpenUrlCrossRefPubMed6.↵de Bruijn MAAM, Aarsen FK, van Oosterhout MP, et al. Long-term neuropsychological outcome following pediatric anti-NMDAR encephalitis. Neurology. 2018;90:e1997–e2005.OpenUrlAbstract/FREE Full Text7.↵Blum RA, Tomlinson AR, Jette N, Kwon CS, Easton A, Yeshokumar AK. Assessment of long-term psychosocial outcomes in anti-NMDA receptor encephalitis. Epilepsy Behav. 2020;108:107088.OpenUrl8.↵Tomlinson AR, Blum RA, Jette N, Kwon CS, Easton A, Yeshokumar AK. Assessment of care transitions and caregiver burden in anti-NMDA receptor encephalitis. Epilepsy Behav. 2020;108:107066.OpenUrl9.↵Heine J, Kopp UA, Klag J, Ploner CJ, Prüss H, Finke C. Long-term cognitive outcome in anti-NMDA receptor encephalitis. Ann Neurol. 2021;90:949–961.OpenUrl10.↵Balu R, McCracken L, Lancaster E, Graus F, Dalmau J, Titulaer MJ. A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis. Neurology. 2019;92:e244–e252.OpenUrlAbstract/FREE Full Text11.↵Harrison P, Oakland T. Adaptive Behavior Assessment System (ABAS-3). 3rd ed. Pearson Education Inc; 2015.12.↵Balboni G, Incognito O, Belacchi C, Bonichini S, Cubelli R. Vineland-II adaptive behavior profile of children with attention-deficit/hyperactivity disorder or specific learning disorders. Res Dev Disabil. 2017;61:55-65.OpenUrl13.↵Yeshokumar AK, Gordon-Lipkin E, Arenivas A, et al. Neurobehavioral outcomes in autoimmune encephalitis. J Neuroimmunol. 2017;312:8-14.OpenUrl14.↵Gordon-Lipkin E, Yeshokumar AK, Saylor D, Arenivas A, Probasco JC. Comparative outcomes in children and adults with anti- N-Methyl-D-Aspartate (anti-NMDA) receptor encephalitis. J Child Neurol. 2017;32:930-935.OpenUrl15.↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15:391-404.OpenUrlCrossRefPubMed16.↵Banks JL, Marotta CA. Outcomes validity and reliability of the modified Rankin scale: implications for stroke clinical trials: a literature review and synthesis. Stroke. 2007;38:1091-1096.OpenUrlAbstract/FREE Full Text17.↵Diaz-Arias LA, Yeshokumar AK, Glassberg B, et al. Fatigue in survivors of autoimmune encephalitis. Neurol Neuroimmunol Neuroinflamm. 2021;8:e1064.OpenUrlAbstract/FREE Full Text18.↵Ilyas-Feldmann M, Prüß H, Holtkamp M. Long-term seizure outcome and antiseizure medication use in autoimmune encephalitis. Seizure. 2021;86:138-143.OpenUrlPubMed19.↵Zhang Y, Huang HJ, Chen WB, Liu G, Liu F, Su YY. Clinical efficacy of plasma exchange in patients with autoimmune encephalitis. Ann Clin Transl Neurol. 2021;8:763-773.OpenUrl20.↵Meert K, Slomine BS, Silverstein FS, et al. Therapeutic Hypothermia after Paediatric Cardiac Arrest (THAPCA) Trial Investigatorss. One-year cognitive and neurologic outcomes in survivors of paediatric extracorporeal cardiopulmonary resuscitation. Resuscitation. 2019;139:299-307.OpenUrl21.↵Nosadini M, Eyre M, Molteni E, et al. Use and safety of immunotherapeutic management of N-Methyl-d-Aspartate receptor antibody encephalitis: a meta-analysis. JAMA Neurol. 2021;78:1333-1344.OpenUrl22.↵Byrne S, Walsh C, Hacohen Y, et al. Earlier treatment of NMDAR antibody encephalitis in children results in a better outcome. Neurol Neuroimmunol Neuroinflamm. 2015;2:e130.OpenUrlAbstract/FREE Full Text23.↵Hughes EG, Peng X, Gleichman AJ, et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci. 2010;30:5866-5875.OpenUrlAbstract/FREE Full Text24.↵Donders J, DeWit C. Parental ratings of daily behavior and child cognitive test performance after pediatric mild traumatic brain injury. Child Neuropsychol. 2017;23:554-570.OpenUrl25.↵Kriel RL, Krach LE, Sheehan M. Pediatric closed head injury: outcome following prolonged unconsciousness. Arch Phys Med Rehabil. 1988;69:678-681.OpenUrlPubMed26.↵Dale RC, Brilot F, Duffy LV, et al. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology. 2014;83:142-150.OpenUrlAbstract/FREE Full Text27.↵Ferreira MC, Garcia NR, Prudente COM, Ribeiro MFM. Quality of life of adolescents with cerebral palsy: agreement between self-report and caregiver’s report. Rev Lat Am Enfermagem. 2020;28:e3300.OpenUrl28.↵Colombatti R, Casale M, Russo G. Disease burden and quality of life of in children with sickle cell disease in Italy: time to be considered a priority. Ital J Pediatr. 2021;47:163.OpenUrl

WHAT IS ALREADY KNOWN ON THIS TOPICThere is increasing recognition of a broad spectrum of autoimmune encephalitis (AE) with acute symptomatic epileptic seizures and autoimmune-associated epilepsy, among the most challenging issues in terms of diagnosis and management.Long-term data are of paramount importance for identifying predisposing factors and biomarkers that may predict the development of chronic epilepsy.WHAT THIS STUDY ADDSAutoimmune-associated epilepsy was the long-term sequela in 43.73% of this cohort of AE patients. Independent predictors of developing epilepsy were difficult to treat seizures at the onset with numerous prescribed antiseizure medications, persisting interictal epileptiform discharges at follow-up and poor response to immunotherapy during the acute phase.HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE AND/OR POLICYThe severity of seizures at onset is the major risk factor for the development of chronic epilepsy in AE. This added information may be a driver for understanding the pathophysiological mechanisms of acute seizure through the identification of specific seizure biomarkers. Clinicians will be supported in their treatment decisions.IntroductionThe role of neuroinflammation is recognised in triggering or sustaining epileptic activity. A growing number of antineuronal autoantibodies have been identified in various neurological syndromes with seizures.1 Identifying these antibodies in patients with seizures of so far unknown aetiology has provided new insights into the relationship between autoimmunity, seizure triggering and epilepsy.2 3 On these bases, the latest 2017 International League Against Epilepsy (ILAE) classification of the epilepsies defined ‘epilepsy of immune aetiology’, referring to those epilepsies resulting ‘directly from an immune disorder in which seizures are a core symptom’.4 The ILAE Autoimmunity and Inflammation Taskforce challenged this concept and defined two main diagnostic entities: ‘acute symptomatic seizures secondary to autoimmune encephalitis’ (AE) and ‘autoimmune-associated epilepsy’, the latter of which requires the presence of an enduring predisposition to seizures.5 Whether ‘immune epilepsy’ is always the ‘poor’ outcome of an acute encephalitic condition and the related brain damage or may represent an enduring predisposition to seizures from its onset is still debated. Collecting more data on different epileptic phenotypes and long-term data is paramount to answering this question.Despite the increasing evidence in this field, these conditions are still under-recognised without standardised diagnostic and management guidelines.This study aims to assess clinical features, seizure semiology, paraclinical findings and treatment options of a large retrospective multicentric cohort of patients with seizures secondary to AE. We analysed long-term data to identify predisposing factors and biomarkers that may predict the development of chronic epilepsy.MethodsStudy design and settingWe performed a retrospective observational cohort study over ten years (from 2010 to 2020). A nationwide study was carried out in 34 Italian epilepsy centres of the Italian League Against Epilepsy.The primary endpoint was the characterisation of the epileptic phenotypes. Secondary endpoints addressed treatment options and outcomes to identify potential factors predicting the development of chronic epilepsy.We selected patients who experienced epileptic seizures at the onset or during the acute phase of AE. The diagnosis of AE was defined according to consensus criteria in adults6 and paediatric patients7 including: (1) definite antibody-positive AE and (2) probable antibody-negative AE (table 1).View inline View popup Table 1 Inclusion criteria for definite antibody-positive and probable antibody-negative autoimmune encephalitis (AE) according with consensus criteria6 7Patients affected by epilepsy with other identified aetiologies (structural, genetic, infectious or metabolic causes) were excluded.Study setup and data collectionAll medical charts were reviewed. Demographic data and clinical information were collected, and for each patient, we recorded: current age, gender, family and personal history for neurological and autoimmune diseases, tumour diagnosis in the last 3 years, and previous prodromal symptoms. We also analysed the age at onset, seizure type and frequency, the occurrence of episodes of status epilepticus (SE), and frequency and quality of other associated symptoms at onset and during the follow-up. Paraclinical findings, including cerebrospinal fluid (CSF) analysis, electroencephalography (EEG) and neuroimaging characteristics at diagnosis and follow-up, were reviewed. Timing of treatment and regimens with antiseizure medications (ASMs) and immunotherapies were evaluated.We applied the Antibody Prevalence in Epilepsy and Encephalopathy (APE2) predictive model for identifying patients in whom antineuronal antibody profiles may be negative, estimating the likelihood of an autoimmune aetiology.8–10 The APE2 score of the entire cohort was assigned blindly by two authors (SM and TG) to further reduce selection bias. The Response to Immunotherapy in Epilepsy and Encephalopathy [RITE2] scores were assessed among patients who received immunotherapy.All paired serum and CSF samples were analysed for antineuronal antibodies either with commercial kits (Euroimmun, Germany), or with in-house assays. In detail, commercial fixed cell-based assays (CBAs) were used for the detection of antibodies to leucine-rich glioma-inactivated protein1 (LGI1), N-methyl-D-aspartate receptor (NMDAR), contactin-associated protein 2 (Caspr2), gamma-aminobutyric acid type B receptor (GABABR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR1/2) and commercial fixed tissue-based assays (TBAs) and immunoblots for antibodies to intracellular neuronal antigens (Hu, Yo, Ri, Ma1/2, glutamic acid decarboxylase 65 (GAD65), amphiphysin, etc), whereas, in a few specialised laboratories, live CBAs and TBAs were used for antibodies to neuronal cell-surface antigens, including gamma-aminobutyric acid type A receptor (GABAAR) and glycine receptor (GlyR).11Neurological functioning was assessed during the acute phase and at the last available follow-up with the modified Rankin Scale (mRS) for children and adults.12Response to treatment with ASMs and immunotherapy was defined as seizure freedom, significant seizure reduction (>50%), or unchanged seizure frequency. In particular, seizure freedom was defined as no clinical evidence of seizures, neither observed nor reported; at follow-up, seizures have to be absent for at least 6 months. Otherwise, drug-resistant seizures were defined as failure to achieve seizure freedom, despite treatment with two tolerated, adequately dosed ASMs.The overall clinical improvement was defined as the resolution of associated symptoms or persisting impairment in neurological functioning.Relapses of AE were defined clinically as recurrence or clear worsening of encephalitis symptoms after 3 months of complete remission or plateauing from prior symptoms, associated to worsening of ancillary testing findings. The clinical and paraclinical findings of relapses were reviewed to assess signs and symptoms at the time of relapse and to evaluate whether these included seizures.Chronic epilepsy was diagnosed when seizures persisted beyond the timeframe that can be considered the active phase of the AE or the presence of an enduring predisposition to seizures at the long-term follow-up (eg, previous breakthrough seizures when weaning ASMs or interictal epileptiform discharges, IEDs).13 14 For each enrolled patient, the diagnosis of chronic epilepsy and the time definition of the acute phase of AE were determined by consensus according to a combination of clinical evidence of active encephalitis and laboratory findings.StatisticsDescriptive statistics were expressed as proportions and percentages for categorical variables and medians and ranges for continuous variables.Univariate analyses for categorical variables were performed applying χ2 and Fisher’s exact test, while the assessment of normal distribution of independent variables was performed by independent t-test, and non-normal data were analysed using Mann-Whitney U test.A multivariate regression model was used to compare variables significant by univariate analyses to identify independent predictors of outcome.A p≤0.05 was considered statistically significant.Data were analysed using STATA/IC V.15.ResultsDemographicsDuring the 10-year study period, 306 cases were identified based on selection criteria. Forty-three patients were subsequently excluded due to missing data. Overall, we enrolled 263 patients with a current median age of 55 years (IQR 28–70; range 4–86), 138 (52.47%) were female. The median age at onset was 48 years (IQR 20–65; range 2–82). At disease onset, 60 patients (22.81%) were in paediatric age (<18 years old: median age at onset 9 years; IQR 5.5–14; range 1–17).The median follow-up duration for the entire cohort was 30 months (IQR 20–50; range 12–120).Antibody evaluationAntineuronal antibodies were identified in 167 patients (63.50%), of which 133 (79.65%) had antibodies targeting neuronal cell-surface antigens: LGI1 (n=64), NMDAR (n=48), Caspr2 (n=14), GABAAR (n=3), GABABR (n=3), GlyR (n=1). Antibody against intracellular antigens were detected in 34 patients (20.35%) including anti-GAD65 (n=18), and other onconeural antibodies (n=4 anti-Hu, n=6 anti-Ma2, n=2 anti-Yo, n=1 anti-amphiphysin, n=3 anti-cerebellum).Among the remaining cases, no antineuronal antibodies were identified (n=96, 36.50%), but these patients met the inclusion criteria for probable antibody-negative AE, and other causes of epilepsy were ruled out.The median APE2 score of the whole cohort was 6 (IQR 5–8; range 3–15), and the percentages of the APE2 score cut-off >4 did not significantly differ between antibody-positive and antibody-negative patients (95.21% vs 89.58%), while their respective medians differed significantly (p=0.0002). Online supplemental table S1 summarises the comparison of clinical and paraclinical data between antibody-positive and antibody-negative patients.Supplemental material[jnnp-2022-329195supp001.pdf]Clinical featuresAccording to the ILAE 2017 operational classification of seizure types,13 we recorded during the acute phase: generalised (n=15, 5.70%), focal motor (n=114, 43.35%), focal non-motor (n=107, 40.68%), focal to bilateral (n=72, 27.38%) and faciobrachial dystonic seizures (FBDS) (n=34, 12.93%). No significant differences were detected in the seizure type at onset between antibody-positive and antibody-negative patients (in online supplemental table S1), except for FBDS, which are strictly related to LGI1 encephalitis (p<0.001). Overall, multiple seizure types were detected in 43 patients (16.35%), with a significant prevalence in antibody-positive patients (p=0.01); but this difference was no longer detectable when applying a multivariate model.Seizure semiology showed a significant prevalence of bitemporal seizures in antibody-positive patients (p=0.02), and extratemporal ones in antibody-negative patients (p=0.007). However, these differences did not maintain statistical significance at the multivariate analysis. Figure 1 summarises seizure types (figure 1A) and semiology (figure 1B) of the entire cohort according to antibody findings.<img src=”https://jnnp.bmj.com/content/jnnp/early/2022/07/25/jnnp-2022-329195/F1.medium.gif”; height=”440″ alt=”Figure 1″ width=”316″ class=”highwire-fragment fragment-image”>Download figure Open in new tab Download powerpoint Figure 1 Seizure types (A) and semeiology (B) according to the antibody findings. NMDAR, N-methyl-D-aspartate receptor; LGI1, leucine-rich glioma inactivated-1; Caspr2, Contactin-associated protein-2 receptor; GABAA, gamma-aminobutyric acid type A; GABAB, gamma-aminobutyric acid type B; Gly, glycine receptor; GAD65, glutamic acid decarboxylase 65; FBDS, facio-brachial dystonic seizures; T Unilat, temporal unilateral; BiTemp, temporal bilateral; Extra-T, extra-temporal.Most patients presented a stormy seizure onset, with daily (n=176, 66.92%) or weekly (n=39, 14.83%) frequency.During the acute phase, 143 patients (87.73%) presented drug-resistant seizures to most common ASMs, without any significant prevalence between antibody-positive and antibody-negative patients.Overall, 107 patients (40.68%) had at least one episode of SE at disease onset, which was refractory in most (n=79, 73.83%). A higher prevalence of SE was found in antibody-negative patients (p<0.001), and this significant difference was confirmed by the multivariate regression analysis (OR 0.23, 95% CI 0.12 to 0.45; p<0.001).The acute phase of the disease was also marked by a constellation of symptoms of brain dysfunction (n=245, 93%). In most antibody-positive patients, the clinical presentation was correlated with full-blown encephalitis, and multiple symptoms were prominent in this group (p<0.001) (online supplemental table S1).The assessment of the neurological status revealed a significant difference in the mRS scores between antibody-positive and antibody-negative patients (p<0.02), not confirmed by the multivariate analysis (online supplemental table S1).Paraclinical findingsAll the enrolled patients underwent CSF analysis, which revealed alteration consistent with inflammation in 144 patients (54.7%), without any significant difference between antibody-positive and antibody-negative patients. At seizure onset and during the acute phase of the disease, the most prominent interictal EEG findings were diffuse (n=51, 19.39%) or focal slowing (n=190, 72.24%). Focal or multifocal IEDs were observed with a prevalence of bitemporal involvement mainly in antibody-positive patients (p=0.002) and extratemporal prevalence in antibody-negative ones (p=0.02) (online supplemental table S1). However, these differences did not maintain statistical significance at the multivariate analysis.Brain MRI findings during the acute phase were unrevealing in a subset of patients (n=71, 27%), while T2/FLAIR hyperintensities consistent with inflammation were detected in most (n=192, 73%). There were no significant differences in the presence or prevalent localisation of neuroimaging abnormalities in the antibody-positive and antibody-negative groups.Treatment responseOverall, 233 patients (88.60%) received immunotherapy combined with ASMs. Patients were treated after a median delay from onset of 3 months (IQR 1–7; range 0.5–84), and most (n=143, 61.37%) received an early treatment (within 3 months). All patients received first-line treatment, while second-line treatment was administered in 28 patients (12%), most often with antibody-positive findings (p=0.02) (online supplemental table S1). Only five antibody-negative patients received second-line treatments. Figure 2 summarises first-line and second-line treatments according to antibody findings and responses.<img src=”https://jnnp.bmj.com/content/jnnp/early/2022/07/25/jnnp-2022-329195/F2.medium.gif”; width=”353″ class=”highwire-fragment fragment-image” alt=”Figure 2″ height=”440″>Download figure Open in new tab Download powerpoint Figure 2 Immunotherapy in responders (A) and non-responders (B) according to the antibody findings. MPN, methylprednisolone; PDN, prednisone; IVIg, intravenous immunoglobulins; PLEX, plasma exchange; RTX, rituximab; CYC, cyclophosphamide; AB+, antibody positive; AB-, antibody negative.In patients receiving immunotherapy, the median RITE2 score was 10 (IQR 8–12; range 3–16), with significant differences between antibody-positive and antibody-negative patients in their respective medians (p=0.005) and the percentages of the RITE2 score cut-off >7 (p=0.03).Among the 233 patients who received immunotherapy, 144 (61.80%) were considered responders. Online supplemental table S2 summarises the comparison between responder and non-responder patients of all disease-related factors.Neither seizure type, semiology, frequency, paraclinical findings at disease onset, nor first-line or second-line treatment regimens predicted the likelihood of response. More severely compromised patients at the onset, with difficult to treat seizures resulted to have a less favourable outcome (p<0.001), and the prevalence of drug-resistant seizures at onset in non-responders was confirmed at multivariate analysis (OR 0.39, 95% CI 0.20 to 0.76; p=0.006). Otherwise, independent predictors of a favourable response to immunotherapy were the detection of antineuronal surface antibodies (OR 2.38; 95% CI 1.15 to 4.92; p=0.01) and early initiation of immunotherapy (OR 12.08, 95% CI 5.50 to 26.50; p<0.001).All patients but 7 (97.33%) were treated with one or more ASMs, with a median number of 2 (IQR 2–3; range 1–12). At the onset, the overall prevalence of drug-resistant seizures was 54.37% (n=143), and the most commonly ASMs prescribed are reported in online supplemental figure S1.Thirty patients (11.40%) received ASMs only. The clinical presentation was less severe in these patients, and 12 patients were initially responders. Seven of them resulted positive for specific autoantibodies: 1 NMDAR, 1 GABAB, 2 LGI1 and three onconeuronal antibodies, but four had disease relapse after the initial favourable response, hence immunotherapy has been prescribed. These patients initially presented with ‘forms frustes’ of AE, and the disease course was more protracted with transitory improvement and seizure control with ASMs only. In the four patients with disease relapse, the diagnosis of AE was delayed and made afterward at that time, while in the remaining, the antibody search was performed during an oncological work-up.OutcomesEncephalitis relapses with seizures were reported in 22 patients (8.37%) during the observational period, without a significant difference in antibody-positive and antibody-negative patients. Thirteen patients (59%) regained seizure freedom after a second trial of immunotherapy.At the end of follow-up, enduring seizures after the acute phase of the disease were detected in 115 patients (43.73%), with a higher prevalence in antibody-negative patients (35.33% vs 58.33%; p<0.001). Figure 3 summarises the proportion of patients developing chronic epilepsy at the end of the follow-up according to antibody findings.<img height=”273″ class=”highwire-fragment fragment-image” src=”https://jnnp.bmj.com/content/jnnp/early/2022/07/25/jnnp-2022-329195/F3.medium.gif”; width=”440″ alt=”Figure 3″>Download figure Open in new tab Download powerpoint Figure 3 Proportion of patients developing chronic epilepsy at the end of the follow-up according to antibody findings. NMDAR, N-methyl-D-aspartate receptor; LGI1, leucine-rich glioma inactivated-1; Caspr2, contactin-associated protein-2 receptor; GABAA, gamma-aminobutyric acid type A; GABAB, gamma-aminobutyric acid type B; Gly, glycine receptor; GAD65, glutamic acid decarboxylase 65.Analysing the subgroup of antibody-negative patients only, an enduring predisposition to seizures was present in those with more difficult to treat seizures (67.86% vs 30%; p<0.001), a higher number of ASMs prescribed during the acute phase (p<0.001), longer delay to immunotherapy initiation (p=0.008), and delayed immunotherapy after 3 months from disease onset (50% vs 85.71%; p=0.001).Ninety-four patients (81.73%) also had associated symptoms, including cognitive deficits and psychiatric disorders.No differences in mRS scores were found between antibody-positive and antibody-negative patients, while higher scores were detected in patients with poor response to immunotherapy (p=0.006) (online supplemental table S2).One hundred and two patients (38.78%) had persisting IEDs at follow-up, without a significant prevalence in antibody-positive and antibody-negative patients, while they were prevalent in patients with poor response to immunotherapy during the acute phase (20.83% vs 69.66%; p<0.0001) (online supplemental materials).Fifty-five patients (20.91%) developed brain atrophy with a prevalent temporal involvement (unilateral: 5.32%, and bilateral: 9.13%). These neuroimaging findings were not significantly associated with an enduring predisposition to seizures (table 2), as well as to antibody detection, and response to immunotherapy during the acute phase (details in online supplemental materials).View inline View popup Table 2 Comparison between patients developing chronic epilepsy and those who were seizure free at last follow-upDisease-related factors associated with persisting seizures were: younger age at disease onset (p=0.03), the detection of antibodies to intracellular antigens (18.26% vs 8.78%; p=0.01), at least one episode of SE during the acute phase of the disease (49.57% vs 33.78%; p=0.007), drug-resistant seizures at onset (67.83% vs 43.92%; p<0.001), the median number of ASMs prescribed during the acute phase (p<0.001), longer delay to immunotherapy initiation (p<0.001), initiation of immunotherapy after 3 months from disease onset (41.00% vs 76.69%; p<0.001), poor response to immunotherapy during the acute phase (74% vs 11.28%; p=0.001), and persisting IEDs at follow-up (65.22% vs 18.24%; p<0.0001). Table 2 summarises the comparison between patients developing epilepsy and those who became seizure-free (see also online supplemental table S3). When performing the multivariate regression analysis, independent predictors for the development of chronic epilepsy were drug-resistant seizures at onset (OR 0.32, 95% CI 0.11 to 0.95; p=0.04), with a higher number of ASMs prescribed (OR 2.30, 95% CI 1.55 to 3.43; p<0.001), persisting IEDs at follow-up (OR 4.23, 95% CI 1.78 to 10.06; p<0.001) and poor response to immunotherapy during the acute phase (OR 0.04, 95% CI 0.02 to 0.11; p<0.001).Other sequelae such as cognitive deficits and psychiatric symptoms were detected in further 87 patients (33.07%) who did not have enduring seizures after the recovery from the acute phase. No independent predictors were detected to be significantly associated with this poor outcome.DiscussionThe increasing recognition of a broad spectrum of AE with epileptic seizures has raised interest among researchers, opening a new field with challenging issues in diagnosis and management of acute symptomatic seizures secondary to AE and in the recognition of a more chronic condition characterised by an enduring predisposition to seizures, as autoimmune-associated epilepsy. In this regard, chronic epilepsy was diagnosed when seizures continue beyond a timeframe that can be considered the active phase of the disease. The time definition of the acute phase of AE is still lacking in literature due to the wide spectrum in clinical presentation, which may vary depending on the associated antibody and timing of immunotherapy. In this regard, for each patient, the determination of the active disease may stem from a combination of clinical evidence and paraclinical findings.5 Although antineuronal antibodies may be responsible for a small proportion of acute seizures, identifying such cases is paramount because many patients may benefit from disease-modifying immunotherapy.Epileptic seizures in AE may present in patients at any age. These patients most often present with new-onset seizures drug-resistant to common ASMs, along with subacute progressive cognitive decline and psychiatric dysfunctions.3 15–17Although there is substantial overlap among different AE in terms of clinical presentation and paraclinical findings, some clinical features and different biomarkers may suggest a specific antigen, response to treatment and long-term prognosis for seizures and cognitive/psychiatric disturbances.2 18Our multicentre study, based on a large series with long-term data, allows a significant comparison of clinical features, response to ASMs and immunotherapy, and evolution to chronic epilepsy in different groups of patients.We found a predominant involvement of the limbic regions in patients harbouring antineuronal antibodies and an extra-temporal prevalence in antibody-negative patients, probably due to a high proportion of limbic encephalitis, mostly LGI1 antibody-related, in our cohort. In this regard, the temporal lobe involvement in seizure activity does not represent an independent predictor of antibody detection. Epileptic seizures occur as one of the key symptoms in a broad clinical spectrum of brain dysfunction. No specific seizure semiology was related to antibody positivity, except for FBDS.Our study underscores the importance of clinical features that increase suspicion for an autoimmune aetiology, such as stormy onset, SE in a previous healthy subject, multiple seizure types and a high prevalence of drug-resistance. The higher prevalence of episodes of SE in antibody-negative patients, which also usually leads to a less favourable prognosis, could reflect the underlying pathogenetic mechanisms related to inflammation per se.19 20 However, antibody-negative findings should prompt further investigations since the prevalent rate of SE in the antibody-negative subgroup could reflect an antibody-related mechanism so far undiscovered.Our study emphasises the importance of early diagnosis and prompt immunotherapy, with disease-modifying treatments, the only way to limit the extent of the brain damage and neurological disability.8 15 21Although increasing expert opinions and recommendations are available, there are no current guidelines for choosing a specific medication, length of treatment or timing for switching to second-line treatment.22 23 The initiation of immunotherapy remains a challenging concern for clinicians in cases of drug-resistant seizures due to AE, particularly for those cases in which the antibody search is negative.8 15 21 In this subgroup, the prescription of second-line treatments is still scanty due to limited evidence-based medicine data in these cases and legislative limitations.Early immunotherapy has been proven to be a pivotal independent predictor of response and outcome in our cohort. Another independent predictor of response to immunotherapy and a favourable outcome is the detection of antineuronal surface antibodies, as already pointed out in the literature.15 24Previous reports have demonstrated that the response to immunotherapy may vary depending on the type of antibody that reflects the different forms of central nervous system inflammation.3 15 25Epileptic seizures occurring in AE are typically refractory to conventional ASMs in most patients. However, ASMs could effectively control seizures in selected cases.26 Some studies have suggested the potential effects on humoral immune responses of some ASMs.27 28A long-lasting prescription of ASMs does not appear to be necessary for most patients, and discontinuation should be considered after a period of clinical stability.29Some authors have argued against the definition of ‘autoimmune epilepsy’,3 5 18 30 referring to epilepsy with an autoimmune origin during the acute phase of the encephalitis,4 13 reserving it to those patients who develop an enduring predisposition to seizures after the encephalitis has been resolved.In our series, 43.73% of patients had chronic epilepsy at long-term follow-up, varying according to antibody type (figure 3), associated with other neuropsychological and psychiatric sequelae in 81.73% of them. Younger age at disease onset, the detection of intracellular antibodies, and delay in immunotherapy may be risk factors for persisting seizures after the acute phase. Moreover, a more severely compromised neurological status at the onset, with drug-resistant seizures, episodes of refractory SE and multiple comorbidities, may predict this worst outcome. In this regard, difficult to treat seizures at onset, with a high number of ASMs prescribed, persisting IEDs at follow-up, and a poor response to immunotherapy during the acute phase, are independent predictive factors of seizure outcome.Geis et al suggested that persisting seizures for more than 1 year in patients with AE should lead to the diagnosis of chronic epilepsy.3 On the other hand, Rada et al showed that it can take up to 7 years before continuously recurrent seizures secondary to an AE subside.31 Recent studies have evaluated seizure outcomes in patients with AE associated with antibodies to the neuronal cell surface and intracellular antigens,14 30–34 in which the definition of seizure outcome was variable. We adopted the definition of ‘autoimmune-associated epilepsy’5 to refer to those patients with seizures that persist after the resolution of the acute phase of the AE, according to a combination of clinical and paraclinical findings. In previous studies, the reported risk factors for epilepsy included younger age at disease onset and female gender,14 immunotherapy delay, and the presence of IEDs on EEG.33 According to Smith et al,14 in our series, the delay in the initiation of immunotherapy was not an independent predictor for the development of epilepsy. In this regard, patients with autoimmune-associated epilepsy tend to have a poor response to immunotherapy, while early immunotherapy has been shown to be effective for acute symptomatic seizures secondary to AE, particularly in cases with antibodies to cell-surface antigens.Chronic epilepsy may result from an ongoing inflammatory process that persists after the acute phase, or as sequelae due to irreversible changes altering the neuronal networks and persisting after the inflammatory process resolves, or a combination of both.5 The exact mechanism has not been elucidated, but the intrinsic severity of the disease may be a possible explanation.Unexpectedly, the presence of brain atrophy at follow-up was not an independent predictor for epilepsy, according to some previous observations.14 33 Indeed, not all patients developing chronic epilepsy have MRI or histopathological evidence of brain atrophy, and structural changes may be microscopic and not always detectable on neuroimaging.5The detection of predictive factors of seizure outcome may be beneficial to develop alternative interventions to prevent the development of autoimmune-associated epilepsy and determine the best comprehensive management of seizures during the acute phase and at the long-term.The limitations of our study are related to its retrospective design. Some patients with seizures due to AE could have been missed, and the number of cases is likely to be underestimated, mostly of those who do not have full-blown encephalitis. Furthermore, the heterogeneity of clinical syndrome and assessment makes comparison and correlation difficult. Patients were not treated per protocol and received different immunotherapy regimens and a variety of ASMs schedules, thus making the comparison more challenging.Early diagnosis and timely treatment of seizures of autoimmune aetiology are paramount and significantly associated with a better overall clinical outcome.9 15–17 21Future prospective studies are warranted to determine the ideal immunomodulatory treatment regimen for patients based on clinical presentation and antibody-specificity.Clinicians should maintain a high level of suspicion in the evaluation of patients with new-onset seizures since AE could be associated with other symptoms of brain dysfunction and, in such cases, could remain under-recognised. Antibody-negative patients and cases in whom seizures may be associated with only subtle signs of encephalitis represent important but challenging clinical groups.This study provides class IV evidence for management recommendations.Although AE is still considered a rare cause of epilepsy, the real impact of this aetiology is still to be clarified, considering the high prevalence of autoantibodies in epileptic populations.8 The appropriate management and early treatment with disease-modifying treatments may reduce the risk of irreversible long-term sequelae, including epilepsy.Data availability statementData are available on reasonable request.Ethics statementsPatient consent for publicationNot applicable.Ethics approvalThis study has been approved by the Regional Ethics Committee of Liguria, Italy at the ID 12278. Participants gave informed consent to participate in the study before taking part.AcknowledgmentsWe gratefully thank the Italian League Against Epilepsy (LICE) for supporting the work of the Immune Epilepsies Study Group. We also thank Diego Franciotta, MD, for fruitful discussion.References↵Toledano M, Pittock SJ. Autoimmune epilepsy. Semin Neurol 2015;35:245–58.doi:10.1055/s-0035-1552625pmid:http://www.ncbi.nlm.nih.gov/pubmed/26060904OpenUrlCrossRefPubMed↵Bien CG, Holtkamp M. “Autoimmune Epilepsy”: Encephalitis with autoantibodies for Epileptologists. Epilepsy Curr 2017;17:134–41.doi:10.5698/1535-7511.17.3.134pmid:http://www.ncbi.nlm.nih.gov/pubmed/28684941OpenUrlCrossRefPubMed↵Geis C, Planagumà J, Carreño M, et al. Autoimmune seizures and epilepsy. J Clin Invest 2019;129:926–40.doi:10.1172/JCI125178pmid:http://www.ncbi.nlm.nih.gov/pubmed/30714986OpenUrlCrossRefPubMed↵Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for classification and terminology. Epilepsia 2017;58:512–21.doi:10.1111/epi.13709pmid:http://www.ncbi.nlm.nih.gov/pubmed/28276062OpenUrlCrossRefPubMed↵Steriade C, Britton J, Dale RC, et al. Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: conceptual definitions. Epilepsia 2020;61:1341–51.doi:10.1111/epi.16571pmid:http://www.ncbi.nlm.nih.gov/pubmed/32544279OpenUrlCrossRefPubMed↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.doi:10.1016/S1474-4422(15)00401-9pmid:http://www.ncbi.nlm.nih.gov/pubmed/26906964OpenUrlCrossRefPubMed↵Cellucci T, Van Mater H, Graus F, et al. Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient. Neurol Neuroimmunol Neuroinflamm 2020;7:e663.doi:10.1212/NXI.0000000000000663pmid:http://www.ncbi.nlm.nih.gov/pubmed/31953309OpenUrlAbstract/FREE Full Text↵Dubey D, Alqallaf A, Hays R, et al. Neurological autoantibody prevalence in epilepsy of unknown etiology. JAMA Neurol 2017;74:397–402.doi:10.1001/jamaneurol.2016.5429pmid:http://www.ncbi.nlm.nih.gov/pubmed/28166327OpenUrlCrossRefPubMed↵Dubey D, Singh J, Britton JW, et al. Predictive models in the diagnosis and treatment of autoimmune epilepsy. Epilepsia 2017;58:1181–9.doi:10.1111/epi.13797pmid:http://www.ncbi.nlm.nih.gov/pubmed/28555833OpenUrlCrossRefPubMed↵Dubey D, Pittock SJ, McKeon A. Antibody prevalence in epilepsy and encephalopathy score: increased specificity and applicability. Epilepsia 2019;60:367–9.doi:10.1111/epi.14649pmid:http://www.ncbi.nlm.nih.gov/pubmed/30727035OpenUrlCrossRefPubMed↵Graus F, Vogrig A, Muñiz-Castrillo S, et al. Updated diagnostic criteria for paraneoplastic neurologic syndromes. Neurol Neuroimmunol Neuroinflamm 2021;8:e1014.doi:10.1212/NXI.0000000000001014pmid:http://www.ncbi.nlm.nih.gov/pubmed/34006622OpenUrlAbstract/FREE Full Text↵Bigi S, Fischer U, Wehrli E, et al. Acute ischemic stroke in children versus young adults. Ann Neurol 2011;70:245–54.doi:10.1002/ana.22427pmid:http://www.ncbi.nlm.nih.gov/pubmed/21823153OpenUrlCrossRefPubMed↵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;58:522–30.doi:10.1111/epi.13670pmid:http://www.ncbi.nlm.nih.gov/pubmed/28276060OpenUrlCrossRefPubMed↵Smith KM, Dubey D, Liebo GB, et al. Clinical course and features of seizures associated with LGI1-antibody encephalitis. Neurology 2021;97:e1141–9.doi:10.1212/WNL.0000000000012465pmid:http://www.ncbi.nlm.nih.gov/pubmed/34233939OpenUrlCrossRefPubMed↵Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013;12:157–65.doi:10.1016/S1474-4422(12)70310-1pmid:http://www.ncbi.nlm.nih.gov/pubmed/23290630OpenUrlCrossRefPubMedWeb of Science↵Thompson J, Bi M, Murchison AG, et al. The importance of early immunotherapy in patients with Faciobrachial dystonic seizures. Brain 2018;141:348–56.doi:10.1093/brain/awx323pmid:http://www.ncbi.nlm.nih.gov/pubmed/29272336OpenUrlCrossRefPubMed↵Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol 2018;83:166–77.doi:10.1002/ana.25131pmid:http://www.ncbi.nlm.nih.gov/pubmed/29293273OpenUrlCrossRefPubMed↵Spatola M, Dalmau J. Seizures and risk of epilepsy in autoimmune and other inflammatory encephalitis. Curr Opin Neurol 2017;30:345–53.doi:10.1097/WCO.0000000000000449pmid:http://www.ncbi.nlm.nih.gov/pubmed/28234800OpenUrlCrossRefPubMed↵Gaspard N, Hirsch LJ, Sculier C, et al. New-Onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (fires): state of the art and perspectives. Epilepsia 2018;59:745–52.doi:10.1111/epi.14022pmid:http://www.ncbi.nlm.nih.gov/pubmed/29476535OpenUrlCrossRefPubMed↵Lattanzi S, Leitinger M, Rocchi C, et al. Unraveling the enigma of new-onset refractory status epilepticus: a systematic review of aetiologies. Eur J Neurol 2022;29:626–47.doi:10.1111/ene.15149pmid:http://www.ncbi.nlm.nih.gov/pubmed/34661330OpenUrlCrossRefPubMed↵Toledano M, Britton JW, McKeon A, et al. Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy. Neurology 2014;82:1578–86.doi:10.1212/WNL.0000000000000383pmid:http://www.ncbi.nlm.nih.gov/pubmed/24706013OpenUrlCrossRefPubMed↵Abboud H, Probasco JC, Irani S, et al. Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management. J Neurol Neurosurg Psychiatry 2021;92:757–68.doi:10.1136/jnnp-2020-325300pmid:http://www.ncbi.nlm.nih.gov/pubmed/33649022OpenUrlAbstract/FREE Full Text↵Abboud H, Probasco J, Irani SR, et al. Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management. J Neurol Neurosurg Psychiatry 2021;92:897–907.doi:10.1136/jnnp-2020-325302pmid:http://www.ncbi.nlm.nih.gov/pubmed/33649021OpenUrlAbstract/FREE Full Text↵Bozzetti S, Rossini F, Ferrari S, et al. Epileptic seizures of suspected autoimmune origin: a multicentre retrospective study. J Neurol Neurosurg Psychiatry 2020;91:1145–53.doi:10.1136/jnnp-2020-323841pmid:http://www.ncbi.nlm.nih.gov/pubmed/32859745OpenUrlAbstract/FREE Full Text↵Dalmau J, Graus F. Antibody-Mediated encephalitis. N Engl J Med 2018;378:840–51.doi:10.1056/NEJMra1708712pmid:http://www.ncbi.nlm.nih.gov/pubmed/29490181OpenUrlCrossRefPubMed↵Feyissa AM, López Chiriboga AS, Britton JW. Antiepileptic drug therapy in patients with autoimmune epilepsy. Neurol Neuroimmunol Neuroinflamm 2017;4:e353.doi:10.1212/NXI.0000000000000353pmid:http://www.ncbi.nlm.nih.gov/pubmed/28680914OpenUrlAbstract/FREE Full Text↵Beghi E, Shorvon S. Antiepileptic drugs and the immune system. Epilepsia 2011;52 Suppl 3:40–4.doi:10.1111/j.1528-1167.2011.03035.xpmid:http://www.ncbi.nlm.nih.gov/pubmed/21542845OpenUrlPubMed↵Gómez CD, Buijs RM, Sitges M. The anti-seizure drugs vinpocetine and carbamazepine, but not valproic acid, reduce inflammatory IL-1β and TNF-α expression in rat hippocampus. J Neurochem 2014;130:770–9.doi:10.1111/jnc.12784pmid:http://www.ncbi.nlm.nih.gov/pubmed/24903676OpenUrlCrossRefPubMed↵Britton JW, Dalmau J. Recognizing autoimmune encephalitis as a cause of seizures: treating cause and not effect. Neurology 2019;92:877–8.doi:10.1212/WNL.0000000000007444pmid:http://www.ncbi.nlm.nih.gov/pubmed/30979858OpenUrlCrossRefPubMed↵de Bruijn MAAM, van Sonderen A, van Coevorden-Hameete MH, et al. Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABA B R encephalitis. Neurology 2019;92:e2185–96.doi:10.1212/WNL.0000000000007475pmid:http://www.ncbi.nlm.nih.gov/pubmed/30979857OpenUrlCrossRefPubMed↵Rada A, Birnbacher R, Gobbi C, et al. Seizures associated with antibodies against cell surface antigens are acute symptomatic and not indicative of epilepsy: insights from long-term data. J Neurol 2021;268:1059–69.doi:10.1007/s00415-020-10250-6pmid:http://www.ncbi.nlm.nih.gov/pubmed/33025119OpenUrlCrossRefPubMed↵Zhang W, Wang X, Shao N, et al. Seizure characteristics, treatment, and outcome in autoimmune synaptic encephalitis: a long-term study. Epilepsy Behav 2019;94:198–203.doi:10.1016/j.yebeh.2018.10.038pmid:http://www.ncbi.nlm.nih.gov/pubmed/30974347OpenUrlCrossRefPubMed↵Shen C-H, Fang G-L, Yang F, et al. Seizures and risk of epilepsy in anti-NMDAR, anti-LGI1, and anti-GABA B R encephalitis. Ann Clin Transl Neurol 2020;7:1392–9.doi:10.1002/acn3.51137pmid:http://www.ncbi.nlm.nih.gov/pubmed/32710704OpenUrlCrossRefPubMed↵Yao L, Yue W, Xunyi W, et al. Clinical features and long-term outcomes of seizures associated with autoimmune encephalitis: a follow-up study in East China. J Clin Neurosci 2019;68:73–9.doi:10.1016/j.jocn.2019.07.049pmid:http://www.ncbi.nlm.nih.gov/pubmed/31331752OpenUrlCrossRefPubMed

Some patients with first-episode psychosis had antibodies against NMDAR that might
be relevant to their illness, but did not differ from patients without NMDAR antibodies
in clinical characteristics. Our study suggests that the only way to detect patients with these potentially pathogenic…

Crouch End screenwriter Abi Morgan launched her memoir at a fundraiser for the neurological hospital where husband Jacob was treated for 15 months…

Using UT Southwestern’s Cryo-Electron Microscopy Facility, researchers for the first time have captured images of an autoantibody bound to a nerve cell surface receptor, revealing the physical mechanism behind a neurological autoimmune disease.

Of the patients with drug-resistant epilepsy in the cohort, 54% had status epilepticus during their acute admission, and 2 of 3 patients with NORSE ended up developing drug-resistant epilepsy at 12 months.

In its early stages, anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is often characterized by prominent psychiatric manifestations that can lead to delays in diagnosis and treatment. The authors aimed to address this problem by providing a detailed description of the psychiatric phenotype…

Co-expression of anti-NMDAR and anti-GAD65 antibodies.A case of autoimmune encephalitis in a post-COVID-19 patient…