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Abstract Background In recent years, significant advances have been made in the field of rare diseases (RDs). However, there is a large number of RDs without specific treatment and half of these treatments have public funding in Spain. The aim of the FINEERR project was to carry out a multidisciplinary strategic discussion on the challenge of funding and access to RD-targeted drugs in Spain, in order to agree on specific proposals for medium-term improvement and hence support decision-making in the Spanish National Healthcare System (SNHS). Results The FINEERR Project was organized around a CORE Advisory Committee, which provided an overview, agreed on the design and scope of the project, and selected the members within each of four working groups (WG). Overall, 40 experts discussed and reached a consensus on different relevant aspects, such as conditioning factors for initial funding and access, evaluation and access to RD-targeted therapies, funding of these therapies, and implementation of a new funding and access model. From these meetings, 50 proposals were defined and classified by their level of relevance according to the experts. A descriptive analysis of responses was performed for each proposal. Thereafter, experts completed another questionnaire where they ranked the 25 most relevant proposals according to their level of feasibility of being implemented in the SNHS. The most relevant and feasible proposals were to improve: process of referral of patients with RDs, control over monitoring mechanisms, and communication between healthcare professionals and patients. Conclusions The FINEERR project may provide a starting point for stakeholders involved in the process of funding and access to RD-targeted therapies in Spain to provide the necessary resources and implement measures to improve both the quality of life and life expectancy of patients with RDs.

We offer a primer to the modifiability of genetic neurological disease, particularly during development. One goal is to harness several unexpected observations made in the course of experimental gene modification or therapy into an explanatory conceptual context based on biological first principles. To this end, we anchor growing, disparate reports of unusual or untoward effects to a plausible framework wherein genes exhibit different degrees of modifiability and may result, when mutated or therapeutically modified, in unsuspected consequences. We propose that genetic pathogenic variant effects and modifiability depend on the number and complexity of associated protein-protein or higher-order interactions. Thus, gene malleability may range from that characteristic of the favorably modifiable primarily structural genes that subserve relatively invariant or circumscribed phenomena such as cell shape to that typical of some transcription factors, which are less functionally predictable when altered. The latter may be expressed developmentally, in compartmentalized manner, or only intermittently and yet exert vastly ramified influences sometimes circumscribed only to select species. We also argue that genetic diseases may steer the organism toward often poorly understood biological end points and co-opt multiple processes into hardly modifiable biology. Addition or modification of genes to approximate a normal state not previously experienced by the organism may lead to further aberration due to extraneous interference with the native biology of the disease state. Therefore, an understanding as perspicuous as possible of gene function, regulation, modifiability, and biological directionality down to seemingly minute but disease-relevant consequences is a prerequisite to intervention. Although we provide some groundwork steps to such an understanding, this may occasionally prove unattainable., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Epilepsy constitutes the most common paroxysmal manifestation of glucose transporter type 1 deficiency (G1D) and is generally considered medication-refractory. It can also prove therapeutic diet-resistant. We examined acetazolamide effects in G1D motivated by several longstanding and recent observations: First, the electrographic spike-waves characteristic of absence seizures often resemble those of G1D and, since the 1950s, they have occasionally been treated successfully with acetazolamide, well before G1D was segregated from absence epilepsy as a distinct syndrome. Second, synaptic inhibitory neuron failure characterizes G1D and, in other experimental models, this can be ameliorated by drugs that modify cellular chloride gradient such as acetazolamide. Third, acetazolamide potently stimulates model cell glucose transport in vitro. Seventeen antiepileptic drug or therapeutic diet-refractory individuals with G1D treated with acetazolamide were thus identified via medical record review complemented by worldwide individual survey. Acetazolamide was tolerated and decreased seizures in 76% of them, with 58% of all persons studied experiencing seizure reductions by more than one-half, including those who first manifested myoclonic-astatic epilepsy or infantile spams. Eighty-eight percent of individuals with G1D continued taking acetazolamide for over 6 months, indicating sustained tolerability and efficacy. The results provide a novel avenue for the treatment and mechanistic investigation of G1D., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Fuel influx and metabolism replenish carbon lost during normal neural activity. Ketogenic diets studied in epilepsy, dementia and other disorders do not sustain such replenishment because their ketone body derivatives contain four carbon atoms and are thus devoid of this anaplerotic or net carbon donor capacity. Yet, in these diseases carbon depletion is often inferred from cerebral fluorodeoxyglucose-positron emission tomography. Further, ketogenic diets may prove incompletely therapeutic. These deficiencies provide the motivation for complementation with anaplerotic fuel. However, there are few anaplerotic precursors consumable in clinically sufficient quantities besides those that supply glucose. Five-carbon ketones, stemming from metabolism of the food supplement triheptanoin, are anaplerotic. Triheptanoin can favorably affect Glucose transporter type 1 deficiency (G1D), a carbon-deficiency encephalopathy. However, the triheptanoin constituent heptanoate can compete with ketogenic diet-derived octanoate for metabolism in animals. It can also fuel neoglucogenesis, thus preempting ketosis. These uncertainties can be further accentuated by individual variability in ketogenesis. Therefore, human investigation is essential. Consequently, we examined the compatibility of triheptanoin at maximum tolerable dose with the ketogenic diet in 10 G1D individuals using clinical and electroencephalographic analyses, glycemia, and four- and five-carbon ketosis. 4 of 8 of subjects with pre-triheptanoin beta-hydroxybutyrate levels greater than 2 mM demonstrated a significant reduction in ketosis after triheptanoin. Changes in this and the other measures allowed us to deem the two treatments compatible in the same number of individuals, or 50% of persons in significant beta-hydroxybutyrate ketosis. These results inform the development of individualized anaplerotic modifications to the ketogenic diet.ClinicalTrials.gov registration NCT03301532, first registration: 04/10/2017., (© 2023. The Author(s).)

Augmentation of anaplerosis, or replenishment of carbon lost during intermediary metabolic transitions, is desirable in energy metabolism defects. Triheptanoin, the triglyceride of 7-carbon heptanoic acid, is anaplerotic via direct oxidation or 5-carbon ketone body generation. In this context, triheptanoin can be used to treat Glucose transporter type 1 deficiency encephalopathy (G1D). An oral triheptanoin dose of 1 g/Kg/day supplies near 35% of the total caloric intake and impacted epilepsy and cognition in G1D. This provided the motivation to establish a maximum, potentially greater dose. Using a 3 + 3 dose-finding approach useful in oncology, we studied three age groups: 4-6, 6.8-10 and 11-16 years old. This allowed us to arrive at a maximum tolerated dose of 45% of daily caloric intake for each group. Safety was ascertained via analytical blood measures. One dose-limiting toxicity, occurring in 1 of 6 subjects, was encountered in the middle age group in the context of frequently reduced gastrointestinal tolerance for all groups. Ketonemia following triheptanoin was determined in another group of G1D subjects. In them, β-ketopentanoate and β-hydroxypentanoate concentrations were robustly but variably increased. These results enable the rigorous clinical investigation of triheptanoin in G1D by providing dosing and initial tolerability, safety and ketonemic potential.ClinicalTrials.gov registration: NCT03041363, first registration 02/02/2017., (© 2023. The Author(s).)

Introduction: Outcome measures traditionally used in spinal muscular atrophy (SMA) clinical trials are inadequate to assess the full range of disease severity. The aim of this study was to assess the psychometric properties of a set of existing questionnaires and new items, gathering information on the impact of SMA from the patient and caregiver perspectives., Methods: This was a multicenter, prospective, noninterventional study including patients with a confirmed diagnosis of 5q-autosomal-recessive SMA aged 8 years and above, or their parents (if aged between 2 and 8 years). The set of outcome measurements included the SMA Independence Scale (SMAIS) patient and caregiver versions, the Neuro-QoL Fatigue Computer Adaptive Test (CAT), the Neuro-QoL Pain Short Form-Pediatric Pain, the PROMIS adult Pain Interference CAT, and new items developed by Fundación Atrofia Muscular España: perceived fatigability, breathing and voice, sleep and rest, and vulnerability. Reliability, construct validity, discriminant validity, and sensitivity to change (4 months from baseline) were measured., Results: A total of 113 patients were included (59.3% 2-17 years old, 59.3% male, and 50.4% with SMA type II). Patients required moderate assistance [mean patient and caregiver SMAIS (SD) scores were 31.1 (12.8) and 7.6 (11.1), respectively]. Perceived fatigability was the most impacted domain, followed by vulnerability. Cronbach's alpha coefficient for perceived fatigability, breathing and voice, and vulnerability total scores were 0.92, 0.88, and 0.85, respectively. The exploratory factor analysis identified the main factors considered in the design, except in the sleep and rest domain. All questionnaires were able to discriminate between the Clinical Global Impression-Severity scores and SMA types. Sensitivity to change was only found for the SMAIS caregiver version and vulnerability items., Conclusions: This set of outcome measures showed adequate reliability, construct validity, and discriminant validity and may constitute a valuable option to measure symptom severity in patients with SMA., (© 2022. The Author(s).)

Introduction: There are many uncertainties about treatment selection and expectations regarding therapeutic goals and benefits in the new landscape of spinal muscular atrophy (SMA). Our aim was to assess treatment preferences and expectations of pediatric neurologists caring for patients with SMA., Methods: DECISIONS-SMA is a non-interventional, cross-sectional pilot study that assessed pediatric neurologists with expertise in SMA from across Spain. Participants were presented with 11 simulated case scenarios of common encounters of patients with SMA type 1 and 2 to assess treatment initiation, escalation, or switches. We also asked for the expected benefit with new therapies for four simulated case scenarios. Participants completed a behavioral battery to address their tolerance to uncertainty and aversion to ambiguity. The primary outcome was therapeutic inertia (TI), defined as the number of simulated scenarios with lack of treatment initiation or escalation when warranted over the total (11) presented cases., Results: A total of 35 participants completed the study. Participants' mean (SD) expectation for achieving an improvement by starting a new therapy for SMA type 1 (case 1, a 5-month-old) and SMA type 2 (case 6, a 1-year-old) were both 59.6% (± 21.8), but declined to 20.2% (± 12.2) for a case scenario of a 16-year-old treatment-naïve patient with long-standing SMA type 2 with severe disability. The mean (SD) TI score was 4.2 (1.7), and 3.29 (1.5) for treatment initiation. Of a total 385 individual responses, TI was observed in 147 (38.2%) of treatment choices. The multivariable analysis showed that lower aversion to ambiguity (p = 0.019) and lower expectation of treatment response (p = 0.007) were associated with higher TI after adjustment for participants' age and years of experience. Older age (p = 0.019), lower years of experience (p = 0.035), lower aversion to ambiguity (p = 0.015), and lower expectation of treatment benefits (p = 0.006) were associated with inertia for treatment initiation., Conclusions: Pediatric neurologists managing patients with SMA were optimistic regarding treatment improvement in cases with early diagnosis, but had lower expectations when treatment delays and advanced patient age were present. Low aversion to ambiguity, low expectation of treatment benefits, and lower clinical experience were more likely to make suboptimal decisions, resulting in lack of treatment initiation, escalation, and TI., (© 2022. The Author(s).)

Objective: Wolf-Hirschhorn syndrome is a rare disease of genetic origin caused by the deletion of the distal end of chromosome 4, including at least the region p16.3. The objectives of this work were to determine the prevalence of the disease in the Spanish population, as well as to establish the geographical distribution of the syndrome throughout the Spanish geography, elucidating the age range in which there are more patients., Methods: Patients diagnosed with the disease for nine years (2013-2021) throughout the Spanish territory were recruited for the research, thanks to agreements with the Spanish Association of Wolf-Hirschhorn Syndrome (AESWH). The clinical information of the patients was obtained from referring physicians using two standardized questionnaires completed with data from medical reports and the parent interview. The molecular characterization of the disease was made using SNP (single nucleotide polymorphism) microarrays (cytoSNP850K, Illumina, USA). The data were statistically processed using Microsoft Excel (Microsoft Corporation) and SPSS (IBM) software, using comparisons between two groups s with Student's t-test (for continuous variables) or with Chi-square tests (for categorical ones). For more than two groups, ANOVA analyses were performed (followed by Bonferroni or T3-Dunnett post hoc tests) for continuous variables and z-tests between column proportions for categorical variables., Results: In Spain (until 2021) eighty people are diagnosed with this syndrome, estimating its prevalence at 1.69x10-4 per 10,000 inhabitants and / or 1/172,904 for each live newborn. This paper remarks the existence of important differences in prevalence between the different regions in Spain. The region with the most diagnosed patients was Madrid, although the highest prevalence was observed in Asturias. Significant differences have been established in terms of sex and disease (ratio of women to men of 2:1), and the mean age at diagnosis has been established at 7.20 years., Conclusions: The prevalence of this syndrome in Spain has been estimated well below the prevalence that is handled in scientific texts (1/50,000 newborns). In addition, we have determined that this prevalence shows large geographical differences, which allows us to affirm that this syndrome could be under-diagnosed in our country. Most of the patients included in this cohort are of paediatric age. It has not been possible to corroborate that mortality in this syndrome, in our population, occurs preferably during the first two years of life, as has been claimed., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: The therapeutic landscape for spinal muscular atrophy has changed in the last few years, encompassing respiratory/motor function and life expectancy benefits. However, physicians still have the challenge of tailoring individuals' treatment to therapeutic goals, disease progression, patient/caregiver's preferences, and personal experience to achieve an optimal risk/benefit balance. This study aims to provide insight into the preferred treatment choices of pediatric neurologists managing spinal muscular atrophy in their daily practice and to recognize behavioral factors that may influence decision-making., Methods: This is a noninterventional, cross-sectional pilot study involving 50 pediatric neurologists managing spinal muscular atrophy in Spain. We designed an online platform that contains 13 simulated case scenarios of common presentations of patients with spinal muscular atrophy. The primary study outcome will be treatment preferences according to the percentages of participants who select treatment initiation when recommended, switch therapies when there is evidence of disease progression, and select treatment discontinuation when disease progression puts patients outside treatment recommendation (11 case scenarios). Secondary outcomes include therapeutic inertia prevalence (11 case scenarios), herding phenomenon prevalence (2 case scenarios), care-related regret prevalence (specific questions) and intensity (10-item Regret Intensity Scale), occupational burnout prevalence (nonproprietary single-item measure), and risk preferences (uncertainty test and risk aversion assessment)., Conclusions: The study findings will contribute to better understand relevant factors associated with therapeutic decisions of pediatric neurologists in spinal muscular atrophy, identifying treatment preferences and evaluating the role of behavioral aspects such as therapeutic inertia, herding, regret, and workplace burnout., Competing Interests: The study was funded by Roche Medical Department, Spain (SL42765). This does not alter our adherence to PLoS ONE policies on sharing data and materials. Gustavo Saposnik received unrestricted grants and personal fees from Hoffman La Roche (Canada) and Roche Farma (Spain), and reported being supported by the Heart and Stroke Foundation of Canada Scientist Award following an open peer-reviewed competition. Paola Díaz-Abós, Victoria Sánchez-Menéndez, Carmen Álvarez, Jorge Maurino, and María Brañas-Pampillón are employees of Roche Farma Spain. María Terzaghi and Ignacio Málaga declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: GRIN-related disorders (GRD), the so-called grinpathies, is a group of rare encephalopathies caused by mutations affecting GRIN genes (mostly GRIN1 , GRIN2A and GRIN2B genes), which encode for the GluN subunit of the N -methyl D-aspartate (NMDA) type ionotropic glutamate receptors. A growing number of functional studies indicate that GRIN-encoded GluN1 subunit disturbances can be dichotomically classified into gain- and loss-of-function, although intermediate complex scenarios are often present., Methods: In this study, we aimed to delineate the structural and functional alterations of GRIN1 disease-associated variants, and their correlations with clinical symptoms in a Spanish cohort of 15 paediatric encephalopathy patients harbouring these variants., Results: Patients harbouring GRIN1 disease-associated variants have been clinically deeply-phenotyped. Further, using computational and in vitro approaches, we identified different critical checkpoints affecting GluN1 biogenesis (protein stability, subunit assembly and surface trafficking) and/or NMDAR biophysical properties, and their association with GRD clinical symptoms., Conclusions: Our findings show a strong correlation between GRIN1 variants-associated structural and functional outcomes. This structural-functional stratification provides relevant insights of genotype-phenotype association, contributing to future precision medicine of GRIN1-related encephalopathies.

Background: Investigations of myelin oligodendrocyte glycoprotein (MOG) antibodies are usually focused on demyelinating syndromes, but the entire spectrum of MOG antibody-associated syndromes in children is unknown. In this study, we aimed to determine the frequency and distribution of paediatric demyelinating and encephalitic syndromes with MOG antibodies, their response to treatment, and the phenotypes associated with poor prognosis., Methods: In this prospective observational study, children with demyelinating syndromes and with encephalitis other than acute disseminated encephalomyelitis (ADEM) recruited from 40 secondary and tertiary centres in Spain were investigated for MOG antibodies. All MOG antibody-positive cases were included in our study, which assessed syndromes, treatment and response to treatment (ie, number of relapses), outcomes (measured with the modified Rankin scale [mRS]), and phenotypes associated with poor prognosis. We used Fisher's exact and Wilcoxon rank sum tests to analyse clinical features, and survival Cox regression to analyse time to antibody negativity., Findings: Between June 1, 2013, and Dec 31, 2018, 239 children with demyelinating syndromes (cohort A) and 296 with encephalitis other than ADEM (cohort B) were recruited. 116 patients had MOG antibodies, including 94 (39%) from cohort A and 22 (7%) from cohort B; 57 (49%) were female, with a median age of 6·2 years (IQR 3·7-10·0). Presenting syndromes in these 116 patients included ADEM (46 [68%]), encephalitis other than ADEM (22 [19%]), optic neuritis (20 [17%]), myelitis (13 [11%]), neuromyelitis optica spectrum disorders (six [5%]), and other disorders (nine [8%]). Among the patients with autoimmune encephalitis in cohort B (n=64), MOG antibodies were more common than all neuronal antibodies combined (22 [34%] vs 21 [33%]). After a median follow-up of 42 months (IQR 22-67), 33 (28%) of the 116 patients had relapses, including 17 (17%) of 100 diagnosed at first episode. Steroids, intravenous immunoglobulin, or plasma exchange were used in 100 (86%) patients at diagnosis, and 32 (97%) of 33 at relapses. Rituximab was mainly used at relapses (11 [33%]). 99 (85%) of 116 patients had substantial recovery (mRS <2) and 17 (15%) moderate to severe deficits (mRS >2; one died). Phenotypes of poor prognosis included ADEM-like relapses progressing to leukodystrophy-like features, and extensive cortical encephalitis evolving to atrophy. Time to antibody negativity was longer in patients with relapses (HR 0·18, 95% CI 0·05-0·59)., Interpretation: The spectrum of paediatric MOG antibody-associated syndromes is wider than previously reported and includes demyelinating syndromes and encephalitis. Recognition of these disorders has important clinical and prognostic implications., Funding: Mutua Madrileña Foundation; ISCIII-Subdirección General de Evaluación y Fomento de la Investigación Sanitaria; Fondo Europeo de Desarrollo Regional; Pediatrics Spanish Society; Departament de Salut, Generalitat de Catalunya; Marato TV3 Foundation; Red Española de Esclerosis Múltiple; La Caixa Foundation; and Fundació CELLEX., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Panayiotopoulos syndrome (PS) is a common form of epilepsy in childhood that is classified as one of the benign idiopathic focal epilepsies. There is no consensus on the indication of neuroimaging in the presence of an electroclinical picture consistent with this disorder. Two cases are presented that began with an electroclinical pattern compatible with PS and in which alterations in the occipital structure were finally detected., Case Reports: Two girls aged 5 and 6 years who began with episodes consistent with PS. In both cases neuroimaging showed structural lesions (cortical dysplasia and pleomorphic xanthoastrocytoma), and hence the final diagnosis was occipital symptomatic focal epilepsy, with the ensuing change in the prognosis and treatment., Conclusions: The literature describes abnormalities in cranial magnetic resonance imaging in 10-20% of diagnosed cases of PS in which a scan is performed, although the diagnosis of PS is not always changed (matching lesions). Both cases exemplify the importance of reaching a correct diagnosis through a detailed study that must include neuroimaging, since, in some patients, causal brain injuries will be detected and as a result the diagnosis, treatment and evolution will be significantly different.

It is estimated that about 70 million people all over the world suffer from epilepsy, half of which are children, in whom the prevalence is around 0.5 to 0.8%. Although there are several therapies, the treatment of epilepsy is based mainly on drugs, which, depending on the year of coming onto the market are classified as first, second, or third generation. In this article, a description is presented on the main characteristics of the latest generation of anti-epileptic drugs (lacosamide, eslicarbazepine acetate, brivaracetam, perampanel, retigabine, everolimus and cannabidiol). These, with the exception of retigabine (is not yet on the market), are considered safe and effective in the paediatric population. Everolimus and cannabidiol have very specific indications (tuberous sclerosis, Dravet syndrome, and Lennox Gastaut syndrome), while the rest are indicated in the management of seizures of focal origin in children from 4 years-old. These new molecules have been developed in order to provide a pharmaceutical profile and tolerance superior to the previously available drugs, and it is forecast that as their use increases, their true potential and profile will widen. Furthermore, for the first time in Paediatric Epileptology, the extrapolation of the efficacy data in adults have been used (together with specific safety and pharmacokinetic studies in the paediatric population), in order to speed up their approval for use in the child population., (Copyright © 2019 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.)

Autism spectrum disorders are a heterogeneous group of disorders that share the presence of two core symptoms: problems in social interaction / communication and the tendency to present restricted interests and repetitive behavior. Over the last years, several epidemiologic studies have been published by different authors in diverse countries, having all of them shown two common characteristics: a global increase in the prevalence rates of autism spectrum disorders, and the existence of a great geographical variability no only between geographical areas, but also within the same geographical areas. At the present manuscript, we analyze some of the most recent prevalence data published in USA and some European countries (including Spain). All of them show different prevalence rates, ranging from 1/59 children with autism spectrum disorders in the USA to 1/806 in Portugal. In a second part, we briefly describe some of the current scientific hypotheses that try to explain this variability.

The objective of this study was to gather evidence-based data on the educational needs of neuropediatricians. A needs assessment was conducted to identify the clinical challenges of physicians when diagnosing, medically treating, and managing pediatric patients with epilepsy; which could be addressed through educational interventions. A two-phase mixed-methods approach was used to conduct the needs assessment in Germany, Spain, and the US. Phase 1 consisted of qualitative data collection through multiple sources: a literature review, semi-structured interviews with clinicians and nurses working in pediatric epilepsy, and interpretation and input from faculty experts. Qualitative data were coded (NVivo) and analyzed using a thematic analysis, and findings were then used to design the second phase. Phase 2 consisted of quantitative data collection through an online survey that aimed to validate the identified challenges and underlying causes using a larger sample than in Phase 1. Data from the survey were analyzed using frequency tabulations and chi-square tests (SPSS). A total of 267 participants were included in the study. Phase 1 included 88 participants (neurologists, pediatricians, neuropediatricians, and nurses). Phase 2 included 179 participants (neurologists, pediatricians, and neuropediatricians). The main areas of challenge which emerged from the triangulated data included: the integration of guidelines into practice, identification of epilepsy and epilepsy events, integration of genetic testing into practice, integration of non-pharmacological treatments, transition from pediatric to adult care, and involvement and engagement with caregivers. Underlying causes of these challenges are reported, along with supporting qualitative findings. This study identified the educational needs of physicians working in pediatric epilepsy in Germany, Spain and the USA. Increasingly, educational interventions are required to be evidence-based. The results of this study could be used to design such interventions to support neuropediatricians who wish to specialize in pediatric epileptology, in order to manage the identified challenges.

Objective: To report 14 patients with immune-mediated relapsing symptoms post-herpes simplex encephalitis (HSE) and to compare the clinical and immunologic features of the teenage and adult group with those of young children., Methods: Prospective observational study of patients diagnosed between June 2013 and February 2015. Immunologic techniques have been reported previously., Results: Among the teenage and adult group (8 patients, median age 40 years, range 13-69; 5 male), 3 had an acute symptom presentation suggesting a viral relapse, and 5 a presentation contiguous with HSE suggesting a recrudescence of previous deficits. Seven patients developed severe psychiatric/behavioral symptoms disrupting all social interactions, and one refractory status epilepticus. Blepharospasm occurred in one patient. Five patients had CSF antibodies against NMDA receptor (NMDAR) and 3 against unknown neuronal cell surface proteins. In 5/6 patients, the brain MRI showed new areas of contrast enhancement that decreased after immunotherapy and clinical improvement. Immunotherapy was useful in 7/7 patients, sometimes with impressive recoveries, returning to their baseline HSE residual deficits. Compared with the 6 younger children (median age 13 months, range 6-20, all with NMDAR antibodies), the teenagers and adults were less likely to develop choreoathetosis (0/8 vs 6/6, p < 0.01) and decreased level of consciousness (2/8 vs 6/6, p < 0.01) and had longer delays in diagnosis and treatment (interval relapse/antibody testing 85 days, range 17-296, vs 4 days, range 0-33, p = 0.037)., Conclusion: In teenagers and adults, the immune-mediated relapsing syndrome post-HSE is different from that known in young children as choreoathetosis post-HSE and is underrecognized. Prompt diagnosis is important because immunotherapy can be highly effective., (© 2015 American Academy of Neurology.)