Reduced serial dependence suggests deficits in synaptic potentiation in anti-NMDAR encephalitis and schizophrenia

A mechanistic understanding of core cognitive processes, such as working memory, is crucial to addressing psychiatric symptoms in brain disorders. We propose a combined psychophysical and biophysical account of two symptomatologically related diseases, both linked to hypofunctional NMDARs: schizophrenia and autoimmune anti-NMDAR encephalitis. We first quantified shared working memory alterations in a delayed-response task. In both patient groups, we report a markedly reduced influence of previous stimuli on working memory contents, despite preserved memory precision. We then simulated this finding with NMDAR-dependent synaptic alterations in a microcircuit model of prefrontal cortex. Changes in cortical excitation destabilized within-trial memory maintenance and could not account for disrupted serial dependence in working memory. Rather, a quantitative fit between data and simulations supports alterations of an NMDAR-dependent memory mechanism operating on longer timescales, such as short-term potentiation

Placental transfer of NMDAR antibodies causes reversible alterations in mice

Objective: To determine whether maternofetal transfer of NMDA receptor (NMDAR) antibodies has pathogenic effects on the fetus and offspring, we developed a model of placental transfer of antibodies. Methods: Pregnant C57BL/6J mice were administered via tail vein patients' or controls' immunoglobulin G (IgG) on days 14-16 of gestation, when the placenta is able to transport IgG and the immature fetal blood-brain barrier is less restrictive to IgG crossing. Immunohistochemical and DiOlistic (gene gun delivery of fluorescent dye) staining, confocal microscopy, standardized developmental and behavioral tasks, and hippocampal long-term potentiation were used to determine the antibody effects. Results: In brains of fetuses, patients' IgG, but not controls' IgG, bound to NMDAR, causing a decrease in NMDAR clusters and cortical plate thickness. No increase in neonatal mortality was observed, but offspring exposed in utero to patients' IgG had reduced levels of cell-surface and synaptic NMDAR, increased dendritic arborization, decreased density of mature (mushroom-shaped) spines, microglial activation, and thinning of brain cortical layers II-IV with cellular compaction. These animals also had a delay in innate reflexes and eye opening and during follow-up showed depressive-like behavior, deficits in nest building, poor motor coordination, and impaired social-spatial memory and hippocampal plasticity. Remarkably, all these paradigms progressively improved (becoming similar to those of controls) during follow-up until adulthood. Conclusions: In this model, placental transfer of patients' NMDAR antibodies caused severe but reversible synaptic and neurodevelopmental alterations. Reversible antibody effects may contribute to the infrequent and limited number of complications described in children of patients who develop anti-NMDAR encephalitis during pregnancy

Neurological syndromes associated with antibodies against the glutamic acid decarboxylase (GAD)

[eng] This thesis focuses on antibodies against the glutamic acid decarboxylase (GAD-ab) in neurological disorders. GAD-ab were first identified in 1988 in the serum and CSF from one patient with stiff-person syndrome (SPS) and diabetes mellitus (T1DM). Since then, GAD-ab have become excellent biomarkers in several autoimmune conditions affecting the endocrine system, the CNS or both simultaneously. High serum GAD-ab levels have expanded the neurological spectrum and have been described in patients with cerebellar ataxia (CA), epilepsy and limbic encephalitis (LE) of autoimmune origin. Even though all the syndromes share the same autoimmune biomarker, it may well be that GAD-ab have a different role in each syndrome. Whether all GAD-associated syndromes share the same pathogenic mechanisms, or what renders certain brain regions vulnerable to autoantibody attack is not clear. In recent years, other antibodies have been found in patients with neurological syndromes attributed to GAD-ab, such as antibodies directed against the alpha subunit of the glycine receptor (GlyRα1) in patients with syndromes of the stiff-person spectrum, or antibodies against GABA receptors (GABAA in patients with severe epilepsy, and GABAB in patients with limbic encephalitis, GAD-ab and an unknown lung cancer), yielding the possibility of an alternative immunological response coexisting with GAD autoimmunity that might be more relevant in certain neurological conditions. In this thesis we explored the immunological determinants linked to the different neurological phenotypes with state-of-the-art techniques, and investigated the prognostic value of GAD-ab in neurological disorders. After studying the largest cohort of patients (121) with neurological syndromes and GAD-ab, we found that: 1) the presence of additional antibodies against antigens of the inhibitory synapse or a different reactivity against particular GAD isoforms or sites of GAD65 do not explain the diversity of the clinical phenotype in non-paraneoplastic neurological syndromes associated with GAD-ab; 2) the immunological response against GAD is different in serum and CSF, indicating a process of antigen-driven intrathecal maturation in patients with non-paraneoplastic syndromes; 3) patients with cerebellar ataxia and GAD-ab may respond to immunotherapy, and maintain good functional status at long-term. Early initiation of treatment likely offers a greater chance of improvement; 4) neurological syndromes with paraneoplastic criteria in the context of GAD autoimmunity have a different clinical presentation and humoral immunity profile. Patients presenting neurological syndromes not typically associated with GAD-ab should be screened for an underlying cancer; 5) among patients with stiff-person spectrum disorders, the immunological classification is an independent predictor of outcome. Those patients with GAD-ab have worse prognosis than antibody-negative patients and patients with GlyR-ab. Our results confirmed that autoimmunity regarding the humoral response is similar among different neurological syndromes, and that GAD-ab is still the most important biomarker in these diseases. From a clinical perspective we contributed to fill some clinical gaps, like the value of GAD-ab in SPS, the management of patients with GAD-associated CA, and he clues to suspect paraneoplastic neurological syndromes.[spa] Esta tesis se centra en síndromes neurológicos asociados a anticuerpos contra el enzima descarboxilasa del ácido glutámico (anti-GAD), descritos asociados a multitud de síndromes neurológicos y enfermedades endocrinológicas. El rol de estos anticuerpos en cada una de estas entidades no está perfectamente establecido. Los resultados de esta tesis contribuyen a clarificar qué valor tiene el hallazgo de anticuerpos anti-GAD en pacientes con determinados síndromes neurológicos y a caracterizar el perfil de algunos de los grupos grupos clínicos asociados a anti-GAD más desconocidos, como son pacientes con ataxia cerebelosa (AC) o síndromes paraneoplásicos. Algunas de las conclusiones más relevantes, recogidas en las 4 publicaciones principales que conforman esta tesis, son: 1) la presencia adicional de anticuerpos contra antígenos de la sinapsis inhibitoria, una reactividad diferente contra alguna de las isoformas de GAD o contra algún epítopo particular de GAD65, no determinan la diversidad fenotípica en síndromes neurológicos asociados a anti-GAD ; 2) la respuesta inmune contra GAD difiere en suero y líquido cefalorraquídeo; 3) los pacientes con AC y anti-GAD pueden responder a la inmunoterapia y mantener un buen estado funcional a largo plazo, pero es importante la instauración del tratamiento de forma precoz; 4) los síndromes neurológicos paraneoplásicos asociados a anti-GAD tienen una presentación clínica y un perfil inmunológico diferente; 5) En pacientes con síndromes del espectro de la persona rígida, la clasificación inmunológica es un factor pronóstico independiente. Aquellos pacientes con anticuerpos anti-GAD tienen un peor pronóstico

Neurological syndromes associated with antibodies against the glutamic acid decarboxylase (GAD)

This thesis focuses on antibodies against the glutamic acid decarboxylase (GAD-ab) in neurological disorders. GAD-ab were first identified in 1988 in the serum and CSF from one patient with stiff-person syndrome (SPS) and diabetes mellitus (T1DM). Since then, GAD-ab have become excellent biomarkers in several autoimmune conditions affecting the endocrine system, the CNS or both simultaneously. High serum GAD-ab levels have expanded the neurological spectrum and have been described in patients with cerebellar ataxia (CA), epilepsy and limbic encephalitis (LE) of autoimmune origin. Even though all the syndromes share the same autoimmune biomarker, it may well be that GAD-ab have a different role in each syndrome. Whether all GAD-associated syndromes share the same pathogenic mechanisms, or what renders certain brain regions vulnerable to autoantibody attack is not clear. In recent years, other antibodies have been found in patients with neurological syndromes attributed to GAD-ab, such as antibodies directed against the alpha subunit of the glycine receptor (GlyRα1) in patients with syndromes of the stiff-person spectrum, or antibodies against GABA receptors (GABAA in patients with severe epilepsy, and GABAB in patients with limbic encephalitis, GAD-ab and an unknown lung cancer), yielding the possibility of an alternative immunological response coexisting with GAD autoimmunity that might be more relevant in certain neurological conditions. In this thesis we explored the immunological determinants linked to the different neurological phenotypes with state-of-the-art techniques, and investigated the prognostic value of GAD-ab in neurological disorders. After studying the largest cohort of patients (121) with neurological syndromes and GAD-ab, we found that: 1) the presence of additional antibodies against antigens of the inhibitory synapse or a different reactivity against particular GAD isoforms or sites of GAD65 do not explain the diversity of the clinical phenotype in non-paraneoplastic neurological syndromes associated with GAD-ab; 2) the immunological response against GAD is different in serum and CSF, indicating a process of antigen-driven intrathecal maturation in patients with non-paraneoplastic syndromes; 3) patients with cerebellar ataxia and GAD-ab may respond to immunotherapy, and maintain good functional status at long-term. Early initiation of treatment likely offers a greater chance of improvement; 4) neurological syndromes with paraneoplastic criteria in the context of GAD autoimmunity have a different clinical presentation and humoral immunity profile. Patients presenting neurological syndromes not typically associated with GAD-ab should be screened for an underlying cancer; 5) among patients with stiff-person spectrum disorders, the immunological classification is an independent predictor of outcome. Those patients with GAD-ab have worse prognosis than antibody-negative patients and patients with GlyR-ab. Our results confirmed that autoimmunity regarding the humoral response is similar among different neurological syndromes, and that GAD-ab is still the most important biomarker in these diseases. From a clinical perspective we contributed to fill some clinical gaps, like the value of GAD-ab in SPS, the management of patients with GAD-associated CA, and he clues to suspect paraneoplastic neurological syndromes.Esta tesis se centra en síndromes neurológicos asociados a anticuerpos contra el enzima descarboxilasa del ácido glutámico (anti-GAD), descritos asociados a multitud de síndromes neurológicos y enfermedades endocrinológicas. El rol de estos anticuerpos en cada una de estas entidades no está perfectamente establecido. Los resultados de esta tesis contribuyen a clarificar qué valor tiene el hallazgo de anticuerpos anti-GAD en pacientes con determinados síndromes neurológicos y a caracterizar el perfil de algunos de los grupos grupos clínicos asociados a anti-GAD más desconocidos, como son pacientes con ataxia cerebelosa (AC) o síndromes paraneoplásicos. Algunas de las conclusiones más relevantes, recogidas en las 4 publicaciones principales que conforman esta tesis, son: 1) la presencia adicional de anticuerpos contra antígenos de la sinapsis inhibitoria, una reactividad diferente contra alguna de las isoformas de GAD o contra algún epítopo particular de GAD65, no determinan la diversidad fenotípica en síndromes neurológicos asociados a anti-GAD ; 2) la respuesta inmune contra GAD difiere en suero y líquido cefalorraquídeo; 3) los pacientes con AC y anti-GAD pueden responder a la inmunoterapia y mantener un buen estado funcional a largo plazo, pero es importante la instauración del tratamiento de forma precoz; 4) los síndromes neurológicos paraneoplásicos asociados a anti-GAD tienen una presentación clínica y un perfil inmunológico diferente; 5) En pacientes con síndromes del espectro de la persona rígida, la clasificación inmunológica es un factor pronóstico independiente. Aquellos pacientes con anticuerpos anti-GAD tienen un peor pronóstico

Neurological syndromes associated with antibodies against the glutamic acid decarboxylase (GAD)

This thesis focuses on antibodies against the glutamic acid decarboxylase (GAD-ab) in neurological disorders. GAD-ab were first identified in 1988 in the serum and CSF from one patient with stiff-person syndrome (SPS) and diabetes mellitus (T1DM). Since then, GAD-ab have become excellent biomarkers in several autoimmune conditions affecting the endocrine system, the CNS or both simultaneously. High serum GAD-ab levels have expanded the neurological spectrum and have been described in patients with cerebellar ataxia (CA), epilepsy and limbic encephalitis (LE) of autoimmune origin. Even though all the syndromes share the same autoimmune biomarker, it may well be that GAD-ab have a different role in each syndrome. Whether all GAD-associated syndromes share the same pathogenic mechanisms, or what renders certain brain regions vulnerable to autoantibody attack is not clear. In recent years, other antibodies have been found in patients with neurological syndromes attributed to GAD-ab, such as antibodies directed against the alpha subunit of the glycine receptor (GlyRα1) in patients with syndromes of the stiff-person spectrum, or antibodies against GABA receptors (GABAA in patients with severe epilepsy, and GABAB in patients with limbic encephalitis, GAD-ab and an unknown lung cancer), yielding the possibility of an alternative immunological response coexisting with GAD autoimmunity that might be more relevant in certain neurological conditions. In this thesis we explored the immunological determinants linked to the different neurological phenotypes with state-of-the-art techniques, and investigated the prognostic value of GAD-ab in neurological disorders. After studying the largest cohort of patients (121) with neurological syndromes and GAD-ab, we found that: 1) the presence of additional antibodies against antigens of the inhibitory synapse or a different reactivity against particular GAD isoforms or sites of GAD65 do not explain the diversity of the clinical phenotype in non-paraneoplastic neurological syndromes associated with GAD-ab; 2) the immunological response against GAD is different in serum and CSF, indicating a process of antigen-driven intrathecal maturation in patients with non-paraneoplastic syndromes; 3) patients with cerebellar ataxia and GAD-ab may respond to immunotherapy, and maintain good functional status at long-term. Early initiation of treatment likely offers a greater chance of improvement; 4) neurological syndromes with paraneoplastic criteria in the context of GAD autoimmunity have a different clinical presentation and humoral immunity profile. Patients presenting neurological syndromes not typically associated with GAD-ab should be screened for an underlying cancer; 5) among patients with stiff-person spectrum disorders, the immunological classification is an independent predictor of outcome. Those patients with GAD-ab have worse prognosis than antibody-negative patients and patients with GlyR-ab. Our results confirmed that autoimmunity regarding the humoral response is similar among different neurological syndromes, and that GAD-ab is still the most important biomarker in these diseases. From a clinical perspective we contributed to fill some clinical gaps, like the value of GAD-ab in SPS, the management of patients with GAD-associated CA, and he clues to suspect paraneoplastic neurological syndromes.Esta tesis se centra en síndromes neurológicos asociados a anticuerpos contra el enzima descarboxilasa del ácido glutámico (anti-GAD), descritos asociados a multitud de síndromes neurológicos y enfermedades endocrinológicas. El rol de estos anticuerpos en cada una de estas entidades no está perfectamente establecido. Los resultados de esta tesis contribuyen a clarificar qué valor tiene el hallazgo de anticuerpos anti-GAD en pacientes con determinados síndromes neurológicos y a caracterizar el perfil de algunos de los grupos grupos clínicos asociados a anti-GAD más desconocidos, como son pacientes con ataxia cerebelosa (AC) o síndromes paraneoplásicos. Algunas de las conclusiones más relevantes, recogidas en las 4 publicaciones principales que conforman esta tesis, son: 1) la presencia adicional de anticuerpos contra antígenos de la sinapsis inhibitoria, una reactividad diferente contra alguna de las isoformas de GAD o contra algún epítopo particular de GAD65, no determinan la diversidad fenotípica en síndromes neurológicos asociados a anti-GAD ; 2) la respuesta inmune contra GAD difiere en suero y líquido cefalorraquídeo; 3) los pacientes con AC y anti-GAD pueden responder a la inmunoterapia y mantener un buen estado funcional a largo plazo, pero es importante la instauración del tratamiento de forma precoz; 4) los síndromes neurológicos paraneoplásicos asociados a anti-GAD tienen una presentación clínica y un perfil inmunológico diferente; 5) En pacientes con síndromes del espectro de la persona rígida, la clasificación inmunológica es un factor pronóstico independiente. Aquellos pacientes con anticuerpos anti-GAD tienen un peor pronóstico

Antibodies to inhibitory synaptic proteins in neurological syndromes associated with glutamic acid decarboxylase autoimmunity

Antibodies to glutamic acid decarboxylase (GAD-ab) associate to different neurological syndromes. It is unknown if the diversity in syndrome association represents epitopes in different immunodominant domains or co-existence of antibodies to other proteins of the inhibitory synapsis. We examined the serum and CSF of 106 patients with anti-GAD related syndromes (39 cerebellar ataxia, 32 stiff-person syndrome [SPS], 18 epilepsy, and 17 limbic encephalitis [LE]). GAD65-ab titres were quantified by ELISA. Immunoblot was used to determine if the antibody-targeted epitopes of GAD65 and GAD67 were linear. A cell-based assay (CBA) with HEK293 cells expressing the GAD65 N-terminal, central catalytic domain, or C-terminal was used to investigate the immunodominant domains. Antibodies to GAD67, gamma-aminobutyric acid A receptor (GABAaR), glycine receptor (GlyR), GABAaR-associated protein (GABARAP), and gephyrin were determined with CBA. GAD-ab internalization was investigated using cultured rat hippocampal neurons. CSF GAD65-ab titres were higher in patients with cerebellar ataxia and LE compared to those with SPS (p = 0.02). GAD67-ab were identified in 81% of sera and 100% of CSF. GAD65-ab recognized linear epitopes in 98% of the patients and GAD67-ab in 42% (p<0.001). The GAD65 catalytic domain was recognized by 93% of sera, and the three domains by 22% of sera and 74% of CSF (p<0.001). Six patients had GABAaR-ab and another 6 had GlyR-ab without association to distinctive symptoms. None of the patients had gephyrin- or GABARAP-ab. GAD65-ab were not internalized by live neurons. Overall, these findings show that regardless of the neurological syndrome, the CSF immune response against GAD is more widespread than that of the serum and that there is no specific association between clinical phenotype and the presence of antibodies against other proteins of the inhibitory synapsis

Antibodies to inhibitory synaptic proteins in neurological syndromes associated with glutamic acid decarboxylase autoimmunity

Antibodies to glutamic acid decarboxylase (GAD-ab) associate to different neurological syndromes. It is unknown if the diversity in syndrome association represents epitopes in different immunodominant domains or co-existence of antibodies to other proteins of the inhibitory synapsis. We examined the serum and CSF of 106 patients with anti-GAD related syndromes (39 cerebellar ataxia, 32 stiff-person syndrome [SPS], 18 epilepsy, and 17 limbic encephalitis [LE]). GAD65-ab titres were quantified by ELISA. Immunoblot was used to determine if the antibody-targeted epitopes of GAD65 and GAD67 were linear. A cell-based assay (CBA) with HEK293 cells expressing the GAD65 N-terminal, central catalytic domain, or C-terminal was used to investigate the immunodominant domains. Antibodies to GAD67, gamma-aminobutyric acid A receptor (GABAaR), glycine receptor (GlyR), GABAaR-associated protein (GABARAP), and gephyrin were determined with CBA. GAD-ab internalization was investigated using cultured rat hippocampal neurons. CSF GAD65-ab titres were higher in patients with cerebellar ataxia and LE compared to those with SPS (p = 0.02). GAD67-ab were identified in 81% of sera and 100% of CSF. GAD65-ab recognized linear epitopes in 98% of the patients and GAD67-ab in 42% (p<0.001). The GAD65 catalytic domain was recognized by 93% of sera, and the three domains by 22% of sera and 74% of CSF (p<0.001). Six patients had GABAaR-ab and another 6 had GlyR-ab without association to distinctive symptoms. None of the patients had gephyrin- or GABARAP-ab. GAD65-ab were not internalized by live neurons. Overall, these findings show that regardless of the neurological syndrome, the CSF immune response against GAD is more widespread than that of the serum and that there is no specific association between clinical phenotype and the presence of antibodies against other proteins of the inhibitory synapsis

Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis

Background Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. We aimed to assess the frequency, symptoms, risk factors, and outcomes of this complication. Methods We did a prospective observational study and retrospective analysis. In the prospective observational part of this study, we included patients with herpes simplex encephalitis diagnosed by neurologists, paediatricians, or infectious disease specialists in 19 secondary and tertiary Spanish centres (Cohort A). Outpatient follow-up was at 2, 6, and 12 months from onset of herpes simplex encephalitis. We studied another group of patients retrospectively, when they developed autoimmune encephalitis after herpes simplex encephalitis (Cohort B). We compared demographics and clinical features of patients who developed autoimmune encephalitis with those who did not, and in patients who developed autoimmune encephalitis we compared these features by age group (patients ≤4 years compared with patients >4 years). We also used multivariable binary logistic regression models to assess risk factors for autoimmune encephalitis after herpes simplex encephalitis. Findings Between Jan 1, 2014, and Oct 31, 2017, 54 patients with herpes simplex encephalitis were recruited to Cohort A, and 51 were included in the analysis (median age 50 years [IQR 5-68]). At onset of herpes simplex encephalitis, none of the 51 patients had antibodies to neuronal antigens; during follow-up, 14 (27%) patients developed autoimmune encephalitis and all 14 (100%) had neuronal antibodies (nine [64%] had NMDA receptor [NMDAR] antibodies and five [36%] had other antibodies) at or before onset of symptoms. The other 37 patients did not develop autoimmune encephalitis, although 11 (30%) developed antibodies (n=3 to NMDAR, n=8 to unknown antigens; p<0·001). Antibody detection within 3 weeks of herpes simplex encephalitis was a risk factor for autoimmune encephalitis (odds ratio [OR] 11·5, 95% CI 2·7-48·8; p<0·001). Between Oct 7, 2011, and Oct 31, 2017, there were 48 patients in Cohort B with new-onset or worsening neurological symptoms not caused by herpes simplex virus reactivation (median age 8·8 years [IQR 1·1-44·2]; n=27 male); 44 (92%) patients had antibody-confirmed autoimmune encephalitis (34 had NMDAR antibodies and ten had other antibodies). In both cohorts (n=58 patients with antibody-confirmed autoimmune encephalitis), patients older than 4 years frequently presented with psychosis (18 [58%] of 31; younger children not assessable). Compared with patients older than 4 years, patients aged 4 years or younger (n=27) were more likely to have shorter intervals between onset of herpes simplex encephalitis and onset of autoimmune encephalitis (median 26 days [IQR 24-32] vs 43 days [25-54]; p=0·0073), choreoathetosis (27 [100%] of 27 vs 0 of 31; p<0·001), decreased level of consciousness (26 [96%] of 27 vs seven [23%] of 31; p<0·001), NMDAR antibodies (24 [89%] of 27 vs 19 [61%] of 31; p=0·033), and worse outcome at 1 year (median modified Rankin Scale 4 [IQR 4-4] vs 2 [2-3]; p<0·0010; seizures 12 [63%] of 19 vs three [13%] of 23; p=0·001). Interpretation The results of our prospective study show that autoimmune encephalitis occurred in 27% of patients with herpes simplex encephalitis. It was associated with development of neuronal antibodies and usually presented within 2 months after treatment of herpes simplex encephalitis; the symptoms were age-dependent, and the neurological outcome was worse in young children. Prompt diagnosis is important because patients, primarily those older than 4 years, can respond to immunotherapy

Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis

Background Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. We aimed to assess the frequency, symptoms, risk factors, and outcomes of this complication. Methods We did a prospective observational study and retrospective analysis. In the prospective observational part of this study, we included patients with herpes simplex encephalitis diagnosed by neurologists, paediatricians, or infectious disease specialists in 19 secondary and tertiary Spanish centres (Cohort A). Outpatient follow-up was at 2, 6, and 12 months from onset of herpes simplex encephalitis. We studied another group of patients retrospectively, when they developed autoimmune encephalitis after herpes simplex encephalitis (Cohort B). We compared demographics and clinical features of patients who developed autoimmune encephalitis with those who did not, and in patients who developed autoimmune encephalitis we compared these features by age group (patients ≤4 years compared with patients >4 years). We also used multivariable binary logistic regression models to assess risk factors for autoimmune encephalitis after herpes simplex encephalitis. Findings Between Jan 1, 2014, and Oct 31, 2017, 54 patients with herpes simplex encephalitis were recruited to Cohort A, and 51 were included in the analysis (median age 50 years [IQR 5-68]). At onset of herpes simplex encephalitis, none of the 51 patients had antibodies to neuronal antigens; during follow-up, 14 (27%) patients developed autoimmune encephalitis and all 14 (100%) had neuronal antibodies (nine [64%] had NMDA receptor [NMDAR] antibodies and five [36%] had other antibodies) at or before onset of symptoms. The other 37 patients did not develop autoimmune encephalitis, although 11 (30%) developed antibodies (n=3 to NMDAR, n=8 to unknown antigens; p<0·001). Antibody detection within 3 weeks of herpes simplex encephalitis was a risk factor for autoimmune encephalitis (odds ratio [OR] 11·5, 95% CI 2·7-48·8; p<0·001). Between Oct 7, 2011, and Oct 31, 2017, there were 48 patients in Cohort B with new-onset or worsening neurological symptoms not caused by herpes simplex virus reactivation (median age 8·8 years [IQR 1·1-44·2]; n=27 male); 44 (92%) patients had antibody-confirmed autoimmune encephalitis (34 had NMDAR antibodies and ten had other antibodies). In both cohorts (n=58 patients with antibody-confirmed autoimmune encephalitis), patients older than 4 years frequently presented with psychosis (18 [58%] of 31; younger children not assessable). Compared with patients older than 4 years, patients aged 4 years or younger (n=27) were more likely to have shorter intervals between onset of herpes simplex encephalitis and onset of autoimmune encephalitis (median 26 days [IQR 24-32] vs 43 days [25-54]; p=0·0073), choreoathetosis (27 [100%] of 27 vs 0 of 31; p<0·001), decreased level of consciousness (26 [96%] of 27 vs seven [23%] of 31; p<0·001), NMDAR antibodies (24 [89%] of 27 vs 19 [61%] of 31; p=0·033), and worse outcome at 1 year (median modified Rankin Scale 4 [IQR 4-4] vs 2 [2-3]; p<0·0010; seizures 12 [63%] of 19 vs three [13%] of 23; p=0·001). Interpretation The results of our prospective study show that autoimmune encephalitis occurred in 27% of patients with herpes simplex encephalitis. It was associated with development of neuronal antibodies and usually presented within 2 months after treatment of herpes simplex encephalitis; the symptoms were age-dependent, and the neurological outcome was worse in young children. Prompt diagnosis is important because patients, primarily those older than 4 years, can respond to immunotherapy

Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis

Background Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. We aimed to assess the frequency, symptoms, risk factors, and outcomes of this complication. Methods We did a prospective observational study and retrospective analysis. In the prospective observational part of this study, we included patients with herpes simplex encephalitis diagnosed by neurologists, paediatricians, or infectious disease specialists in 19 secondary and tertiary Spanish centres (Cohort A). Outpatient follow-up was at 2, 6, and 12 months from onset of herpes simplex encephalitis. We studied another group of patients retrospectively, when they developed autoimmune encephalitis after herpes simplex encephalitis (Cohort B). We compared demographics and clinical features of patients who developed autoimmune encephalitis with those who did not, and in patients who developed autoimmune encephalitis we compared these features by age group (patients ≤4 years compared with patients >4 years). We also used multivariable binary logistic regression models to assess risk factors for autoimmune encephalitis after herpes simplex encephalitis. Findings Between Jan 1, 2014, and Oct 31, 2017, 54 patients with herpes simplex encephalitis were recruited to Cohort A, and 51 were included in the analysis (median age 50 years [IQR 5-68]). At onset of herpes simplex encephalitis, none of the 51 patients had antibodies to neuronal antigens; during follow-up, 14 (27%) patients developed autoimmune encephalitis and all 14 (100%) had neuronal antibodies (nine [64%] had NMDA receptor [NMDAR] antibodies and five [36%] had other antibodies) at or before onset of symptoms. The other 37 patients did not develop autoimmune encephalitis, although 11 (30%) developed antibodies (n=3 to NMDAR, n=8 to unknown antigens; p<0·001). Antibody detection within 3 weeks of herpes simplex encephalitis was a risk factor for autoimmune encephalitis (odds ratio [OR] 11·5, 95% CI 2·7-48·8; p<0·001). Between Oct 7, 2011, and Oct 31, 2017, there were 48 patients in Cohort B with new-onset or worsening neurological symptoms not caused by herpes simplex virus reactivation (median age 8·8 years [IQR 1·1-44·2]; n=27 male); 44 (92%) patients had antibody-confirmed autoimmune encephalitis (34 had NMDAR antibodies and ten had other antibodies). In both cohorts (n=58 patients with antibody-confirmed autoimmune encephalitis), patients older than 4 years frequently presented with psychosis (18 [58%] of 31; younger children not assessable). Compared with patients older than 4 years, patients aged 4 years or younger (n=27) were more likely to have shorter intervals between onset of herpes simplex encephalitis and onset of autoimmune encephalitis (median 26 days [IQR 24-32] vs 43 days [25-54]; p=0·0073), choreoathetosis (27 [100%] of 27 vs 0 of 31; p<0·001), decreased level of consciousness (26 [96%] of 27 vs seven [23%] of 31; p<0·001), NMDAR antibodies (24 [89%] of 27 vs 19 [61%] of 31; p=0·033), and worse outcome at 1 year (median modified Rankin Scale 4 [IQR 4-4] vs 2 [2-3]; p<0·0010; seizures 12 [63%] of 19 vs three [13%] of 23; p=0·001). Interpretation The results of our prospective study show that autoimmune encephalitis occurred in 27% of patients with herpes simplex encephalitis. It was associated with development of neuronal antibodies and usually presented within 2 months after treatment of herpes simplex encephalitis; the symptoms were age-dependent, and the neurological outcome was worse in young children. Prompt diagnosis is important because patients, primarily those older than 4 years, can respond to immunotherapy