Maarten Titulaer - Academia.edu (original) (raw)

Papers by Maarten Titulaer

Research paper thumbnail of Predicting Functional Outcome and Response to Therapy of Anti-NMDAR Encephalitis, Already at Diagnosis: The NEOS2 Model. (P5-5.009)

Research paper thumbnail of Reply: To PMID 24700511

Annals of neurology, 2014

We thank Drs Kaneko and colleagues for their comments. These authors describe a patient with over... more We thank Drs Kaneko and colleagues for their comments. These authors describe a patient with overlapping N-methyl-D-aspartate receptor (NMDAR) and myelin oligodendrocyte glycoprotein (MOG) antibodies and the longitudinal follow-up of antibody titers and brain magnetic resonance imaging (MRI) that is reminiscent of several cases of our recently reported series of 23 patients and subsequent cases described by others. Since the discovery of anti-NMDAR encephalitis, publications describing hundreds of patients have shown that this disorder is a specific clinical entity distinct from limbic encephalitis. Although partial phenotypes and atypical symptoms can occur, these are uncommon. Among them, pyramidal symptoms or prominent ocular movement abnormalities are rarely seen outside of young children. In these atypical clinical cases, MRI abnormalities suggesting demyelination are more likely to be seen, and these are the cases that more often have MOG or aquaporin 4 (AQP4) antibodies. This finding suggests the presence of 2 different immune mechanisms, each with its own set of symptoms and outcome. The case of Kaneko et al also suggests this association; their patient developed 3 episodes of neurological dysfunction, the first and third compatible with anti-NMDAR encephalitis, whereas the second was more suggestive of a demyelinating disorder. Unfortunately, the limited clinical description and single images of the MRIs provided do not allow for further assessment. However, the interpretation made by these authors would be in agreement with the findings of our study, where we showed the follow-up MRI of multiple cases, and the longitudinal clinical, antibody, and MRI follow-up of 1 (Fig 3, 4 and 5 in Titulaer et al), which were apparently overlooked by Kaneko and colleagues. These cases, although rare, have important implications: 1. Patients with anti-NMDAR encephalitis and atypical symptoms (spinal cord, brainstem) or MRI features of demyelination should be examined for MOG or AQP4 antibodies; conversely, patients with NMO spectrum disorders and atypical symptoms (dyskinesias, psychiatric manifestations) should be tested for NMDAR antibodies (immunoglobulin G against GluN1). 2. It is difficult to correlate the titer of each antibody to different clinical episodes, especially if the number of samples is limited. It is even more difficult to use only cell-based assays for these correlations. In the case of Kaneko and colleagues, it is unknown whether the antibody titers changed between 4 and 45 months (not studied), and how quickly each of the antibody titers decreased after therapy. Given that association does not mean causation, the improvement of an inflammatory contrast-enhancing lesion after steroids does not necessarily establish a correlation with a decrease of MOG antibody titers, as the authors imply. 3. Serum NMDAR antibodies are less sensitive and specific than cerebrospinal fluid antibodies. The case of Kaneko and colleagues confirms this by showing that the antibody levels in serum did not reflect any of the relapses. 4. After a first relapse of anti-NMDAR encephalitis, patients have a 3-fold increased risk of subsequent relapses; these patients should receive more intense immunotherapy than steroids. In this setting, there are data showing that treatment with second-line immunotherapy (rituximab and/or cyclophosphamide) associates with a lower rate of subsequent relapses. It is currently unclear whether azathioprine and mycophenolate mofetil are effective at preventing relapses.

Research paper thumbnail of Investigations on CXCL13 in Anti–N-Methyl-D-Aspartate Receptor Encephalitis

JAMA Neurology, 2015

IMPORTANCE Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe but treatable auto... more IMPORTANCE Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe but treatable autoimmune encephalitis affecting mainly young adults and children. The lack of suitable biomarkers of disease activity makes treatment decisions and identification of relapses challenging. OBJECTIVE To determine the levels of the B-cell-attracting C-X-C motif chemokine 13 (CXCL13) in serum samples and cerebrospinal fluid (CSF) of patients with anti-NMDAR encephalitis and whether they can be used as biomarkers of treatment response and outcome. DESIGN, SETTINGS, AND PARTICIPANTS Retrospective cohort study of 167 patients consecutively diagnosed as having anti-NMDAR encephalitis between May 1, 2008, and January 31, 2013. Concentration of CXCL13 was determined with enzyme-linked immunosorbent assay in all available patients' samples (272 CSF and 55 serum samples). Samples from 25 patients with noninflammatory neurological disorders and 9 with neuroborreliosis served as controls. Expression of CXCL13 in the brain biopsy of a patient with anti-NMDAR encephalitis was determined by immunohistochemistry. MAIN OUTCOMES AND MEASURES Percentage of patients with anti-NMDAR encephalitis and elevated CXCL13 in CSF. RESULTS Compared with control individuals, 70% of patients with early-stage anti-NMDAR encephalitis had increased CXCL13 in CSF (>7 pg/mL; P < .001) but none in serum samples (>1047 pg/mL; P > .99). High concentration of CSF CXCL13 was associated with the presence of prodromal fever or headache (P = .01), limited response to therapy (P = .003), clinical relapses (P = .03), and intrathecal NMDAR-antibody synthesis (P < .001). Among patients with monophasic disease assessed 2 to 6 months after starting treatment, 10 of 15 with limited treatment response vs 0 of 13 with favorable response had increased CSF CXCL13 (specificity, 100%; 95% CI, 75-100 and sensitivity, 67%; 95% CI, 38-88; P = .02). Six of 12 patients had elevated CSF CXCL13 at relapse including 3 with previously normal levels. In brain, abundant mononuclear cells in perivascular infiltrates and scattered intraparenchymal microglia expressed CXCL13. CONCLUSIONS AND RELEVANCE Seventy percent of patients with early-stage anti-NMDAR encephalitis had increased CSF CXCL13 concentration that correlated with intrathecal NMDAR-antibody synthesis. Prolonged or secondary elevation of CXCL13 was associated with limited response to treatment and relapses. CXCL13 is a potentially useful biomarker of treatment response and outcome in anti-NMDAR encephalitis.

Research paper thumbnail of Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study

The Lancet Neurology, 2014

Background-We aimed to assess the sensitivity/specificity of serum and CSF antibody-testing in pa... more Background-We aimed to assess the sensitivity/specificity of serum and CSF antibody-testing in patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, and the correlation between titers, relapses, outcome, and epitope repertoire. Methods-In this observational study, brain immunohistochemistry and cell-based assays (CBA) with fixed and live NMDAR-expressing cells were used to determine the sensitivity/specificity of antibody-testing in paired serum/CSF obtained at diagnosis of 250 patients with anti-NMDAR

Research paper thumbnail of The ExTINGUISH Trial: A Phase-2B Randomized Placebo-Controlled Trial of Inebilizumab in Anti-NMDA Receptor Encephalitis

Neurology

ObjectiveTo assess the safety and efficacy of inebilizumab in patients with anti-N-methyl-D-aspar... more ObjectiveTo assess the safety and efficacy of inebilizumab in patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.BackgroundThe lack of approved therapies for NMDAR encephalitis has led to substantial variability in treatment. High-quality data is needed to guide treatment and optimize long-term outcomes in recovering patients. Inebilizumab is a humanized anti-CD19 monoclonal antibody that can be administered intravenously with good CSF penetration and high target engagement. Inebilizumab may be an efficacious treatment for NMDAR encephalitis, with the potential to achieve early robust and sustained suppression of NMDAR autoantibodies and CD19+ plasmablasts and plasma cells leading to better long-term outcomes.Design/MethodsThe ExTINGUISH trial is a Phase 2B randomized double-blind placebo-controlled trial designed to evaluate the safety and efficacy of inebilizumab 300 mg for the acute treatment of moderate-to-severe NMDAR encephalitis. 120 participants will be en...

Research paper thumbnail of Genetic factors in myasthenia gravis and Lambert-Eaton myasthenic syndrome

Journal of the Neurological Sciences, 2009

Research paper thumbnail of The role of antibody indexes in clinical virology

Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2021

BACKGROUND Serological techniques are an essential part of the diagnostic tools used in clinical ... more BACKGROUND Serological techniques are an essential part of the diagnostic tools used in clinical virology. Among these techniques, antibody indexes are not novel, but do require specific expertise. Their niche has expanded substantially in recent years due to increasing evidence of their performance to diagnose viral infections. OBJECTIVES This narrative review describes the background and clinical applications of antibody indexes. The first objective is to provide an overview of the theoretical background, insights for implementation, limitations and pitfalls. The second objective is to review the available evidence for the diagnostic performance, with a specific focus on viral encephalitis and uveitis. SOURCES A comprehensive literature search was performed in PubMed, including original studies as well as reviews, with no time limit on the studies included. The following search terms were used: antibody index, Goldmann-Witmer coefficient, Reibergram, viral encephalitis, viral uvei...

Research paper thumbnail of Diagnosis and significance of antibody titers in anti-NMDA receptor encephalitis, a retrospective study

1Department of Neurology at Hospital ClinicInstitut d'Investigacions Biomèdiques August Pi i ... more 1Department of Neurology at Hospital ClinicInstitut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain 2Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands 3Biostatistics and Data Management Platform, IDIBAPS, Hospital Clinic, Barcelona, Spain 4Department of Neurology, University of Pennsylvania, Philadelphia, PA 5Department of Neurology, University of California – Los Angeles, Los Angeles, CA 6Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 7Department of Neurology, University of Pennsylvania, Philadelphia, PA 8Department of Neurology, Children’s Hospital of Philadelphia (CHOP), Philadelphia, PA 9Institució Catalana de Recerca i Estudis Avançats (ICREA)

Research paper thumbnail of Anti-NMDAR encefalitis als oorzaak van epilepsie bij een zesjarige jongen

Epilepsie, periodiek voor professionals

Nieuw ontstane epilepsie bij kinderen en volwassenen kan wijzen op een auto-immuun oorzaak, met n... more Nieuw ontstane epilepsie bij kinderen en volwassenen kan wijzen op een auto-immuun oorzaak, met name als de epilepsie voorkomt in combinatie met neuropsychiatrische klachten of therapieresistent blijkt. Het is belangrijk om auto-immuun epilepsie snel te herkennen omdat de klinische uitkomst verbetert naarmate er sneller gestart wordt met behandeling. Vanwege de variatie in mogelijke klachten is het stellen van de diagnose vaak een uitdaging.

Research paper thumbnail of Autoimmune Encephalitis in First Episode Psychoses

Neurology

The discovery of patients with prominent psychosis and subacute decline in neurologic function as... more The discovery of patients with prominent psychosis and subacute decline in neurologic function associated with immunoglobulin G (IgG) autoantibodies against CNS NMDA receptors (NMDAR) established anti-NMDAR encephalitis as a novel cause of new-onset psychoses.1 Although patients may be severely affected at presentation (earning the moniker “brain on fire”), remarkable improvement is noted after early induction of appropriate immunotherapies.2 The importance of early treatment has highlighted the need to improve recognition of patients early in the disease course when psychiatric symptoms predominate and most patients are likely to meet criteria for first episode psychoses (FEP).

Research paper thumbnail of Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management

Journal of Neurology, Neurosurgery & Psychiatry

The objective of this paper is to evaluate available evidence for each step in autoimmune encepha... more The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. The most popular bridging therapy was oral prednisone taper chosen by 38% of responders while rituximab was the most popular maintenance therapy chosen by 46%. Most responders considered maintenance immunosuppression after a second relapse in patients with neuronal surface antibodies (70%) or seronegative autoimmune encephalitis (61%) as opposed to those with onconeuronal antibodies (29%). Mos...

Research paper thumbnail of Phase II trial of natalizumab for the treatment of anti-Hu associated paraneoplastic neurological syndromes

Neuro-Oncology Advances

Background Paraneoplastic neurological syndromes with anti-Hu antibodies (Hu-PNS) have a very poo... more Background Paraneoplastic neurological syndromes with anti-Hu antibodies (Hu-PNS) have a very poor prognosis: more than half of the patients become bedridden and median survival is less than 12 months. Several lines of evidence suggest a pathogenic T cell-mediated immune response. Therefore, we conducted a prospective open-label phase II trial with natalizumab. Methods Twenty Hu-PNS patients with progressive disease were treated with a maximum of three monthly natalizumab cycles (300 mg). The primary outcome measure was functional improvement, this was defined as at least one point decrease in modified Rankin Scale (mRS) score at the last treatment visit. In addition, treatment response was assessed wherein a mRS score ≤3 after treatment was defined as treatment responsive. Results The median age at onset was 67.8 years (SD 8.4) with a female predominance (n=17, 85%). The median time from symptom onset to Hu-PNS diagnosis was 5 months (IQR 2-11). Most patients had subacute sensory n...

Research paper thumbnail of Encephalitis with Autoantibodies against the Glutamate Kainate Receptors GluK2

Annals of Neurology

The objective of this study was to report the identification of antibodies against the glutamate ... more The objective of this study was to report the identification of antibodies against the glutamate kainate receptor subunit 2 (GluK2‐abs) in patients with autoimmune encephalitis, and describe the clinical‐immunological features and antibody effects.

Research paper thumbnail of Autoimmune Encephalitis Resembling Dementia Syndromes

Neurology - Neuroimmunology Neuroinflammation

ObjectiveAs autoimmune encephalitis (AIE) can resemble neurodegenerative dementia syndromes, and ... more ObjectiveAs autoimmune encephalitis (AIE) can resemble neurodegenerative dementia syndromes, and patients do not always present as encephalitis, this study evaluates how frequently AIE mimics dementia and provides red flags for AIE in middle-aged and older patients.MethodsIn this nationwide observational cohort study, patients with anti–leucine-rich glioma-inactivated 1 (LGI1), anti–NMDA receptor (NMDAR), anti–gamma-aminobutyric acid B receptor (GABABR), or anti–contactin-associated protein-like 2 (CASPR2) encephalitis were included. They had to meet 3 additional criteria: age ≥45 years, fulfillment of dementia criteria, and no prominent seizures early in the disease course (≤4 weeks).ResultsTwo-hundred ninety patients had AIE, of whom 175 were 45 years or older. Sixty-seven patients (38%) fulfilled criteria for dementia without prominent seizures early in the disease course. Of them, 42 had anti-LGI1 (48%), 13 anti-NMDAR (52%), 8 anti-GABABR (22%), and 4 anti-CASPR2 (15%) encephali...

Research paper thumbnail of Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes

Neurology - Neuroimmunology Neuroinflammation

ObjectiveThe contemporary diagnosis of paraneoplastic neurologic syndromes (PNSs) requires an inc... more ObjectiveThe contemporary diagnosis of paraneoplastic neurologic syndromes (PNSs) requires an increasing understanding of their clinical, immunologic, and oncologic heterogeneity. The 2004 PNS criteria are partially outdated due to advances in PNS research in the last 16 years leading to the identification of new phenotypes and antibodies that have transformed the diagnostic approach to PNS. Here, we propose updated diagnostic criteria for PNS.MethodsA panel of experts developed by consensus a modified set of diagnostic PNS criteria for clinical decision making and research purposes. The panel reappraised the 2004 criteria alongside new knowledge on PNS obtained from published and unpublished data generated by the different laboratories involved in the project.ResultsThe panel proposed to substitute “classical syndromes” with the term “high-risk phenotypes” for cancer and introduce the concept of “intermediate-risk phenotypes.” The term “onconeural antibody” was replaced by “high ri...

Research paper thumbnail of Antibodies Contributing to Focal Epilepsy Signs and Symptoms Score

Annals of Neurology

Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases su... more Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases such as epilepsy. However, recognition is important, as patients require immunotherapy. This study aims to identify antibodies in patients with focal epilepsy of unknown etiology, and to create a score to preselect patients requiring testing.

Research paper thumbnail of Diagnostic Criteria for Primary Autoimmune Cerebellar Ataxia—Guidelines from an International Task Force on Immune-Mediated Cerebellar Ataxias

The Cerebellum

Aside from well-characterized immune-mediated ataxias with a clear trigger and/or association wit... more Aside from well-characterized immune-mediated ataxias with a clear trigger and/or association with specific neuronal antibodies, a large number of idiopathic ataxias are suspected to be immune mediated but remain undiagnosed due to lack of diagnostic biomarkers. Primary autoimmune cerebellar ataxia (PACA) is the term used to describe this later group. An International Task Force comprising experts in the field of immune ataxias was commissioned by the Society for Research on the Cerebellum and Ataxias (SRCA) in order to devise diagnostic criteria aiming to improve the diagnosis of PACA. The proposed diagnostic criteria for PACA are based on clinical (mode of onset, pattern of cerebellar involvement, presence of other autoimmune diseases), imaging findings (MRI and if available MR spectroscopy showing preferential, but not exclusive involvement of vermis) and laboratory investigations (CSF pleocytosis and/or CSF-restricted IgG oligoclonal bands) parameters. The aim is to enable clini...

Research paper thumbnail of Pediatric autoimmune encephalitis

Neurology - Neuroimmunology Neuroinflammation

ObjectiveThe aims of this study were (1) to describe the incidence of autoimmune encephalitis (AI... more ObjectiveThe aims of this study were (1) to describe the incidence of autoimmune encephalitis (AIE) and acute disseminated encephalomyelitis (ADEM) in children, (2) to validate the currently used clinical criteria to diagnose AIE, and (3) to describe pitfalls in the diagnosis of pediatric autoimmune (AI) and inflammatory neurologic disorders.MethodsThis study cohort consists of 3 patient categories: (1) children with antibody-mediated AIE (n = 21), (2) children with ADEM (n = 32), and (3) children with suspicion of an AI etiology of their neurologic symptoms (n = 60). Baseline and follow-up clinical data were used to validate the current guideline to diagnose AIE. In addition, patient files and final diagnoses were reviewed.ResultsOne-hundred three of the 113 included patients fulfilled the criteria of possible AIE. Twenty-one children had antibody-mediated AIE, of whom 19 had anti-N-methyl-D-aspartate receptor (NMDAR), 1 had anti–α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid...

Research paper thumbnail of Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis

Neurology

ObjectiveThis nationwide cohort study evaluates seizure responses to immunotherapy and antiepilep... more ObjectiveThis nationwide cohort study evaluates seizure responses to immunotherapy and antiepileptic drugs (AEDs) in patients with anti-leucine-rich glioma-inactivated 1 (LGI1), anti-NMDA receptor (NMDAR), and anti-gamma-aminobutyric-acid B receptor (GABABR) encephalitis.MethodsAnti-LGI1, anti-NMDAR, and anti-GABABR encephalitis patients with new-onset seizures were included. Medical information about disease course, AEDs and immunotherapies used, effects, and side effects were collected. Outcome measures were (1) seizure freedom while using AEDs or immunotherapy, (2) days to seizure freedom from start of AEDs or immunotherapy, and (3) side effects.ResultsOf 153 patients with autoimmune encephalitis (AIE) (53 LGI1, 75 NMDAR, 25 GABABR), 72% (n = 110) had epileptic seizures, and 89% reached seizure freedom. At least 53% achieved seizure freedom shortly after immunotherapy, and 14% achieved seizure freedom while using only AEDs (p < 0.0001). This effect was similar in all types (p ...

Research paper thumbnail of Predictive value of electroencephalography in anti-NMDA receptor encephalitis

Journal of Neurology, Neurosurgery & Psychiatry

ObjectivesAnti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is a severe, but treatabl... more ObjectivesAnti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is a severe, but treatable disease. This study aims to give a detailed description of electroencephalogram (EEG) results in paediatric and adult patients to improve disease recognition, and analyses the predictive value of the first EEG for the final clinical outcome.MethodsThis nationwide cohort study includes patients with N-methyl-D-aspartate receptor antibodies confirmed with cell-based assay and immunohistochemistry in serum and cerebrospinal fluid. EEG recordings were re-evaluated by two experienced neurophysiologists, mixed with control EEGs for blinding. Initial EEG as well as follow-up registrations were analysed.Results35 adults and 18 children were included. Only two patients (4%) had a normal EEG. During the first recording, the majority of the patients had normal posterior rhythm (71%), which was associated with better modified Rankin Scale at final outcome (OR 4.74; 95% CI 1.56 to 14.47; p=0.006). ...

Research paper thumbnail of Predicting Functional Outcome and Response to Therapy of Anti-NMDAR Encephalitis, Already at Diagnosis: The NEOS2 Model. (P5-5.009)

Research paper thumbnail of Reply: To PMID 24700511

Annals of neurology, 2014

We thank Drs Kaneko and colleagues for their comments. These authors describe a patient with over... more We thank Drs Kaneko and colleagues for their comments. These authors describe a patient with overlapping N-methyl-D-aspartate receptor (NMDAR) and myelin oligodendrocyte glycoprotein (MOG) antibodies and the longitudinal follow-up of antibody titers and brain magnetic resonance imaging (MRI) that is reminiscent of several cases of our recently reported series of 23 patients and subsequent cases described by others. Since the discovery of anti-NMDAR encephalitis, publications describing hundreds of patients have shown that this disorder is a specific clinical entity distinct from limbic encephalitis. Although partial phenotypes and atypical symptoms can occur, these are uncommon. Among them, pyramidal symptoms or prominent ocular movement abnormalities are rarely seen outside of young children. In these atypical clinical cases, MRI abnormalities suggesting demyelination are more likely to be seen, and these are the cases that more often have MOG or aquaporin 4 (AQP4) antibodies. This finding suggests the presence of 2 different immune mechanisms, each with its own set of symptoms and outcome. The case of Kaneko et al also suggests this association; their patient developed 3 episodes of neurological dysfunction, the first and third compatible with anti-NMDAR encephalitis, whereas the second was more suggestive of a demyelinating disorder. Unfortunately, the limited clinical description and single images of the MRIs provided do not allow for further assessment. However, the interpretation made by these authors would be in agreement with the findings of our study, where we showed the follow-up MRI of multiple cases, and the longitudinal clinical, antibody, and MRI follow-up of 1 (Fig 3, 4 and 5 in Titulaer et al), which were apparently overlooked by Kaneko and colleagues. These cases, although rare, have important implications: 1. Patients with anti-NMDAR encephalitis and atypical symptoms (spinal cord, brainstem) or MRI features of demyelination should be examined for MOG or AQP4 antibodies; conversely, patients with NMO spectrum disorders and atypical symptoms (dyskinesias, psychiatric manifestations) should be tested for NMDAR antibodies (immunoglobulin G against GluN1). 2. It is difficult to correlate the titer of each antibody to different clinical episodes, especially if the number of samples is limited. It is even more difficult to use only cell-based assays for these correlations. In the case of Kaneko and colleagues, it is unknown whether the antibody titers changed between 4 and 45 months (not studied), and how quickly each of the antibody titers decreased after therapy. Given that association does not mean causation, the improvement of an inflammatory contrast-enhancing lesion after steroids does not necessarily establish a correlation with a decrease of MOG antibody titers, as the authors imply. 3. Serum NMDAR antibodies are less sensitive and specific than cerebrospinal fluid antibodies. The case of Kaneko and colleagues confirms this by showing that the antibody levels in serum did not reflect any of the relapses. 4. After a first relapse of anti-NMDAR encephalitis, patients have a 3-fold increased risk of subsequent relapses; these patients should receive more intense immunotherapy than steroids. In this setting, there are data showing that treatment with second-line immunotherapy (rituximab and/or cyclophosphamide) associates with a lower rate of subsequent relapses. It is currently unclear whether azathioprine and mycophenolate mofetil are effective at preventing relapses.

Research paper thumbnail of Investigations on CXCL13 in Anti–N-Methyl-D-Aspartate Receptor Encephalitis

JAMA Neurology, 2015

IMPORTANCE Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe but treatable auto... more IMPORTANCE Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe but treatable autoimmune encephalitis affecting mainly young adults and children. The lack of suitable biomarkers of disease activity makes treatment decisions and identification of relapses challenging. OBJECTIVE To determine the levels of the B-cell-attracting C-X-C motif chemokine 13 (CXCL13) in serum samples and cerebrospinal fluid (CSF) of patients with anti-NMDAR encephalitis and whether they can be used as biomarkers of treatment response and outcome. DESIGN, SETTINGS, AND PARTICIPANTS Retrospective cohort study of 167 patients consecutively diagnosed as having anti-NMDAR encephalitis between May 1, 2008, and January 31, 2013. Concentration of CXCL13 was determined with enzyme-linked immunosorbent assay in all available patients' samples (272 CSF and 55 serum samples). Samples from 25 patients with noninflammatory neurological disorders and 9 with neuroborreliosis served as controls. Expression of CXCL13 in the brain biopsy of a patient with anti-NMDAR encephalitis was determined by immunohistochemistry. MAIN OUTCOMES AND MEASURES Percentage of patients with anti-NMDAR encephalitis and elevated CXCL13 in CSF. RESULTS Compared with control individuals, 70% of patients with early-stage anti-NMDAR encephalitis had increased CXCL13 in CSF (>7 pg/mL; P < .001) but none in serum samples (>1047 pg/mL; P > .99). High concentration of CSF CXCL13 was associated with the presence of prodromal fever or headache (P = .01), limited response to therapy (P = .003), clinical relapses (P = .03), and intrathecal NMDAR-antibody synthesis (P < .001). Among patients with monophasic disease assessed 2 to 6 months after starting treatment, 10 of 15 with limited treatment response vs 0 of 13 with favorable response had increased CSF CXCL13 (specificity, 100%; 95% CI, 75-100 and sensitivity, 67%; 95% CI, 38-88; P = .02). Six of 12 patients had elevated CSF CXCL13 at relapse including 3 with previously normal levels. In brain, abundant mononuclear cells in perivascular infiltrates and scattered intraparenchymal microglia expressed CXCL13. CONCLUSIONS AND RELEVANCE Seventy percent of patients with early-stage anti-NMDAR encephalitis had increased CSF CXCL13 concentration that correlated with intrathecal NMDAR-antibody synthesis. Prolonged or secondary elevation of CXCL13 was associated with limited response to treatment and relapses. CXCL13 is a potentially useful biomarker of treatment response and outcome in anti-NMDAR encephalitis.

Research paper thumbnail of Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study

The Lancet Neurology, 2014

Background-We aimed to assess the sensitivity/specificity of serum and CSF antibody-testing in pa... more Background-We aimed to assess the sensitivity/specificity of serum and CSF antibody-testing in patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, and the correlation between titers, relapses, outcome, and epitope repertoire. Methods-In this observational study, brain immunohistochemistry and cell-based assays (CBA) with fixed and live NMDAR-expressing cells were used to determine the sensitivity/specificity of antibody-testing in paired serum/CSF obtained at diagnosis of 250 patients with anti-NMDAR

Research paper thumbnail of The ExTINGUISH Trial: A Phase-2B Randomized Placebo-Controlled Trial of Inebilizumab in Anti-NMDA Receptor Encephalitis

Neurology

ObjectiveTo assess the safety and efficacy of inebilizumab in patients with anti-N-methyl-D-aspar... more ObjectiveTo assess the safety and efficacy of inebilizumab in patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.BackgroundThe lack of approved therapies for NMDAR encephalitis has led to substantial variability in treatment. High-quality data is needed to guide treatment and optimize long-term outcomes in recovering patients. Inebilizumab is a humanized anti-CD19 monoclonal antibody that can be administered intravenously with good CSF penetration and high target engagement. Inebilizumab may be an efficacious treatment for NMDAR encephalitis, with the potential to achieve early robust and sustained suppression of NMDAR autoantibodies and CD19+ plasmablasts and plasma cells leading to better long-term outcomes.Design/MethodsThe ExTINGUISH trial is a Phase 2B randomized double-blind placebo-controlled trial designed to evaluate the safety and efficacy of inebilizumab 300 mg for the acute treatment of moderate-to-severe NMDAR encephalitis. 120 participants will be en...

Research paper thumbnail of Genetic factors in myasthenia gravis and Lambert-Eaton myasthenic syndrome

Journal of the Neurological Sciences, 2009

Research paper thumbnail of The role of antibody indexes in clinical virology

Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2021

BACKGROUND Serological techniques are an essential part of the diagnostic tools used in clinical ... more BACKGROUND Serological techniques are an essential part of the diagnostic tools used in clinical virology. Among these techniques, antibody indexes are not novel, but do require specific expertise. Their niche has expanded substantially in recent years due to increasing evidence of their performance to diagnose viral infections. OBJECTIVES This narrative review describes the background and clinical applications of antibody indexes. The first objective is to provide an overview of the theoretical background, insights for implementation, limitations and pitfalls. The second objective is to review the available evidence for the diagnostic performance, with a specific focus on viral encephalitis and uveitis. SOURCES A comprehensive literature search was performed in PubMed, including original studies as well as reviews, with no time limit on the studies included. The following search terms were used: antibody index, Goldmann-Witmer coefficient, Reibergram, viral encephalitis, viral uvei...

Research paper thumbnail of Diagnosis and significance of antibody titers in anti-NMDA receptor encephalitis, a retrospective study

1Department of Neurology at Hospital ClinicInstitut d'Investigacions Biomèdiques August Pi i ... more 1Department of Neurology at Hospital ClinicInstitut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain 2Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands 3Biostatistics and Data Management Platform, IDIBAPS, Hospital Clinic, Barcelona, Spain 4Department of Neurology, University of Pennsylvania, Philadelphia, PA 5Department of Neurology, University of California – Los Angeles, Los Angeles, CA 6Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 7Department of Neurology, University of Pennsylvania, Philadelphia, PA 8Department of Neurology, Children’s Hospital of Philadelphia (CHOP), Philadelphia, PA 9Institució Catalana de Recerca i Estudis Avançats (ICREA)

Research paper thumbnail of Anti-NMDAR encefalitis als oorzaak van epilepsie bij een zesjarige jongen

Epilepsie, periodiek voor professionals

Nieuw ontstane epilepsie bij kinderen en volwassenen kan wijzen op een auto-immuun oorzaak, met n... more Nieuw ontstane epilepsie bij kinderen en volwassenen kan wijzen op een auto-immuun oorzaak, met name als de epilepsie voorkomt in combinatie met neuropsychiatrische klachten of therapieresistent blijkt. Het is belangrijk om auto-immuun epilepsie snel te herkennen omdat de klinische uitkomst verbetert naarmate er sneller gestart wordt met behandeling. Vanwege de variatie in mogelijke klachten is het stellen van de diagnose vaak een uitdaging.

Research paper thumbnail of Autoimmune Encephalitis in First Episode Psychoses

Neurology

The discovery of patients with prominent psychosis and subacute decline in neurologic function as... more The discovery of patients with prominent psychosis and subacute decline in neurologic function associated with immunoglobulin G (IgG) autoantibodies against CNS NMDA receptors (NMDAR) established anti-NMDAR encephalitis as a novel cause of new-onset psychoses.1 Although patients may be severely affected at presentation (earning the moniker “brain on fire”), remarkable improvement is noted after early induction of appropriate immunotherapies.2 The importance of early treatment has highlighted the need to improve recognition of patients early in the disease course when psychiatric symptoms predominate and most patients are likely to meet criteria for first episode psychoses (FEP).

Research paper thumbnail of Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management

Journal of Neurology, Neurosurgery & Psychiatry

The objective of this paper is to evaluate available evidence for each step in autoimmune encepha... more The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. The most popular bridging therapy was oral prednisone taper chosen by 38% of responders while rituximab was the most popular maintenance therapy chosen by 46%. Most responders considered maintenance immunosuppression after a second relapse in patients with neuronal surface antibodies (70%) or seronegative autoimmune encephalitis (61%) as opposed to those with onconeuronal antibodies (29%). Mos...

Research paper thumbnail of Phase II trial of natalizumab for the treatment of anti-Hu associated paraneoplastic neurological syndromes

Neuro-Oncology Advances

Background Paraneoplastic neurological syndromes with anti-Hu antibodies (Hu-PNS) have a very poo... more Background Paraneoplastic neurological syndromes with anti-Hu antibodies (Hu-PNS) have a very poor prognosis: more than half of the patients become bedridden and median survival is less than 12 months. Several lines of evidence suggest a pathogenic T cell-mediated immune response. Therefore, we conducted a prospective open-label phase II trial with natalizumab. Methods Twenty Hu-PNS patients with progressive disease were treated with a maximum of three monthly natalizumab cycles (300 mg). The primary outcome measure was functional improvement, this was defined as at least one point decrease in modified Rankin Scale (mRS) score at the last treatment visit. In addition, treatment response was assessed wherein a mRS score ≤3 after treatment was defined as treatment responsive. Results The median age at onset was 67.8 years (SD 8.4) with a female predominance (n=17, 85%). The median time from symptom onset to Hu-PNS diagnosis was 5 months (IQR 2-11). Most patients had subacute sensory n...

Research paper thumbnail of Encephalitis with Autoantibodies against the Glutamate Kainate Receptors GluK2

Annals of Neurology

The objective of this study was to report the identification of antibodies against the glutamate ... more The objective of this study was to report the identification of antibodies against the glutamate kainate receptor subunit 2 (GluK2‐abs) in patients with autoimmune encephalitis, and describe the clinical‐immunological features and antibody effects.

Research paper thumbnail of Autoimmune Encephalitis Resembling Dementia Syndromes

Neurology - Neuroimmunology Neuroinflammation

ObjectiveAs autoimmune encephalitis (AIE) can resemble neurodegenerative dementia syndromes, and ... more ObjectiveAs autoimmune encephalitis (AIE) can resemble neurodegenerative dementia syndromes, and patients do not always present as encephalitis, this study evaluates how frequently AIE mimics dementia and provides red flags for AIE in middle-aged and older patients.MethodsIn this nationwide observational cohort study, patients with anti–leucine-rich glioma-inactivated 1 (LGI1), anti–NMDA receptor (NMDAR), anti–gamma-aminobutyric acid B receptor (GABABR), or anti–contactin-associated protein-like 2 (CASPR2) encephalitis were included. They had to meet 3 additional criteria: age ≥45 years, fulfillment of dementia criteria, and no prominent seizures early in the disease course (≤4 weeks).ResultsTwo-hundred ninety patients had AIE, of whom 175 were 45 years or older. Sixty-seven patients (38%) fulfilled criteria for dementia without prominent seizures early in the disease course. Of them, 42 had anti-LGI1 (48%), 13 anti-NMDAR (52%), 8 anti-GABABR (22%), and 4 anti-CASPR2 (15%) encephali...

Research paper thumbnail of Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes

Neurology - Neuroimmunology Neuroinflammation

ObjectiveThe contemporary diagnosis of paraneoplastic neurologic syndromes (PNSs) requires an inc... more ObjectiveThe contemporary diagnosis of paraneoplastic neurologic syndromes (PNSs) requires an increasing understanding of their clinical, immunologic, and oncologic heterogeneity. The 2004 PNS criteria are partially outdated due to advances in PNS research in the last 16 years leading to the identification of new phenotypes and antibodies that have transformed the diagnostic approach to PNS. Here, we propose updated diagnostic criteria for PNS.MethodsA panel of experts developed by consensus a modified set of diagnostic PNS criteria for clinical decision making and research purposes. The panel reappraised the 2004 criteria alongside new knowledge on PNS obtained from published and unpublished data generated by the different laboratories involved in the project.ResultsThe panel proposed to substitute “classical syndromes” with the term “high-risk phenotypes” for cancer and introduce the concept of “intermediate-risk phenotypes.” The term “onconeural antibody” was replaced by “high ri...

Research paper thumbnail of Antibodies Contributing to Focal Epilepsy Signs and Symptoms Score

Annals of Neurology

Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases su... more Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases such as epilepsy. However, recognition is important, as patients require immunotherapy. This study aims to identify antibodies in patients with focal epilepsy of unknown etiology, and to create a score to preselect patients requiring testing.

Research paper thumbnail of Diagnostic Criteria for Primary Autoimmune Cerebellar Ataxia—Guidelines from an International Task Force on Immune-Mediated Cerebellar Ataxias

The Cerebellum

Aside from well-characterized immune-mediated ataxias with a clear trigger and/or association wit... more Aside from well-characterized immune-mediated ataxias with a clear trigger and/or association with specific neuronal antibodies, a large number of idiopathic ataxias are suspected to be immune mediated but remain undiagnosed due to lack of diagnostic biomarkers. Primary autoimmune cerebellar ataxia (PACA) is the term used to describe this later group. An International Task Force comprising experts in the field of immune ataxias was commissioned by the Society for Research on the Cerebellum and Ataxias (SRCA) in order to devise diagnostic criteria aiming to improve the diagnosis of PACA. The proposed diagnostic criteria for PACA are based on clinical (mode of onset, pattern of cerebellar involvement, presence of other autoimmune diseases), imaging findings (MRI and if available MR spectroscopy showing preferential, but not exclusive involvement of vermis) and laboratory investigations (CSF pleocytosis and/or CSF-restricted IgG oligoclonal bands) parameters. The aim is to enable clini...

Research paper thumbnail of Pediatric autoimmune encephalitis

Neurology - Neuroimmunology Neuroinflammation

ObjectiveThe aims of this study were (1) to describe the incidence of autoimmune encephalitis (AI... more ObjectiveThe aims of this study were (1) to describe the incidence of autoimmune encephalitis (AIE) and acute disseminated encephalomyelitis (ADEM) in children, (2) to validate the currently used clinical criteria to diagnose AIE, and (3) to describe pitfalls in the diagnosis of pediatric autoimmune (AI) and inflammatory neurologic disorders.MethodsThis study cohort consists of 3 patient categories: (1) children with antibody-mediated AIE (n = 21), (2) children with ADEM (n = 32), and (3) children with suspicion of an AI etiology of their neurologic symptoms (n = 60). Baseline and follow-up clinical data were used to validate the current guideline to diagnose AIE. In addition, patient files and final diagnoses were reviewed.ResultsOne-hundred three of the 113 included patients fulfilled the criteria of possible AIE. Twenty-one children had antibody-mediated AIE, of whom 19 had anti-N-methyl-D-aspartate receptor (NMDAR), 1 had anti–α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid...

Research paper thumbnail of Evaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis

Neurology

ObjectiveThis nationwide cohort study evaluates seizure responses to immunotherapy and antiepilep... more ObjectiveThis nationwide cohort study evaluates seizure responses to immunotherapy and antiepileptic drugs (AEDs) in patients with anti-leucine-rich glioma-inactivated 1 (LGI1), anti-NMDA receptor (NMDAR), and anti-gamma-aminobutyric-acid B receptor (GABABR) encephalitis.MethodsAnti-LGI1, anti-NMDAR, and anti-GABABR encephalitis patients with new-onset seizures were included. Medical information about disease course, AEDs and immunotherapies used, effects, and side effects were collected. Outcome measures were (1) seizure freedom while using AEDs or immunotherapy, (2) days to seizure freedom from start of AEDs or immunotherapy, and (3) side effects.ResultsOf 153 patients with autoimmune encephalitis (AIE) (53 LGI1, 75 NMDAR, 25 GABABR), 72% (n = 110) had epileptic seizures, and 89% reached seizure freedom. At least 53% achieved seizure freedom shortly after immunotherapy, and 14% achieved seizure freedom while using only AEDs (p < 0.0001). This effect was similar in all types (p ...

Research paper thumbnail of Predictive value of electroencephalography in anti-NMDA receptor encephalitis

Journal of Neurology, Neurosurgery & Psychiatry

ObjectivesAnti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is a severe, but treatabl... more ObjectivesAnti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is a severe, but treatable disease. This study aims to give a detailed description of electroencephalogram (EEG) results in paediatric and adult patients to improve disease recognition, and analyses the predictive value of the first EEG for the final clinical outcome.MethodsThis nationwide cohort study includes patients with N-methyl-D-aspartate receptor antibodies confirmed with cell-based assay and immunohistochemistry in serum and cerebrospinal fluid. EEG recordings were re-evaluated by two experienced neurophysiologists, mixed with control EEGs for blinding. Initial EEG as well as follow-up registrations were analysed.Results35 adults and 18 children were included. Only two patients (4%) had a normal EEG. During the first recording, the majority of the patients had normal posterior rhythm (71%), which was associated with better modified Rankin Scale at final outcome (OR 4.74; 95% CI 1.56 to 14.47; p=0.006). ...