Encephalitis associated with antibodies against the NMDA receptor

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La gráfica muestra la forma de presentación habitual y el curso clínico multifásico y progresivo característico en una mujer joven con una encefalitis anti-NMDA en su forma de expresión completa. En la población pediátrica y en hombres jóvenes, los síntomas de presentación inicial suelen ser movimientos anormales, crisis epilépticas, alteración conductual o insomnio. No obstante, los síntomas suelen evolucionar de manera similar en la mayoría de los pacientes. Las formas clínicas más leves, sin trastornos que requieran medidas de soporte vital avanzado, son cada vez más frecuentes conforme la enfermedad va siendo mejor conocida y se logran un diagnóstico y un tratamiento precoces. 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An example is shown by drawings made by a 56-year-old female patient with autoimmune post–herpes simplex encephalitis at the time of symptoms onset (tree, family and home: A, D and G), 3 weeks after immunotherapy (B, E, H) and at 6 months of follow-up (C, F and I). At the onset of the disease, the patient had severe anterograde amnesia, disorientation, confusion and disorganized thinking. After treatment, the patient improved, and most symptoms resolved, except for amnesia and temporary disorientation." ] ] ] "textoCompleto" => "IntroductionThe syndrome and antibodies associated with anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDAR encephalitis) were initially described in 2005 in 4 young women who had subacute behaviour disorders and psychosis in the context of encephalitis associated with decreased level of consciousness and central hypoventilation.<a class="elsevierStyleCrossRef" href="#bib0285">1</a> The 4 patients had an ovarian teratoma and 3 of them improved with immunotherapy, which increased the suspicion that it was the same disease. Studies were initiated, resulting in the identification of antibodies to a neuronal surface antigen that, in 2007, was recognized as NMDAR.<a class="elsevierStyleCrossRef" href="#bib0290">2</a> Since then, this disease has become the most frequent and best-studied neuronal surface antibody-mediated autoimmune encephalitis.<a class="elsevierStyleCrossRefs" href="#bib0295">3–5</a>NMDAR is composed of 4 subunits (2 GluN1 and 2 GluN2) and acts as an excitatory post-synaptic ionotropic receptor. It has a crucial role in the mechanisms of synaptic plasticity necessary for learning, memory and cognition. The GluN1 subunit is mandatory, while the GluN2 subunits (A, B, C, D) vary according to the brain region, synaptic or extrasynaptic localization, and brain development.<a class="elsevierStyleCrossRef" href="#bib0310">6</a> An important aspect of anti-NMDAR encephalitis is that the antibodies are specifically directed against an extracellular region of the GluN1 subunit, have pathogenic effects, demonstrated in in vitro and in vivo models<a class="elsevierStyleCrossRefs" href="#bib0315">7–10</a> and result in a highly specific and recognizable syndrome.<a class="elsevierStyleCrossRef" href="#bib0335">11</a> These characteristics differentiate them from the antibodies described in a wide variety of processes (systemic lupus erythematosus, neurodegeneration, viral processes, among others), in which the target is the GluN2 subunits.<a class="elsevierStyleCrossRefs" href="#bib0340">12,13</a> These antibodies are not associated with any specific syndrome and in most cases their clinical and pathogenic value is uncertain.This review focuses on the clinical manifestations, the differential diagnosis and the treatment of anti-NMDAR encephalitis.EpidemiologyBecause the discovery of anti-NMDAR encephalitis is recent, knowledge of its incidence is still limited. Studies in the Netherlands estimate it at 2–3 cases per million inhabitants; however, our experience in a prospective study which we are currently conducting in Spain suggests a higher incidence. A study on the aetiology of encephalitis in the United Kingdom showed that anti-NMDAR encephalitis was the second most frequent cause of autoimmune encephalitis (behind acute disseminated encephalomyelitis (ADEM)) and the first cause of antineuronal antibody-mediated encephalitis. In a US center (California Encephalitis Project) dedicated to the study of causes and epidemiology of encephalitis, anti-NMDAR encephalitis was more frequent than any individual form of viral encephalitis.<a class="elsevierStyleCrossRef" href="#bib0350">14</a>Patients with anti-NMDAR encephalitis are usually young (mean age of presentation is 23 years) and predominantly females (4:1).<a class="elsevierStyleCrossRef" href="#bib0305">5</a> The disease can also affect men and the age range can vary between a few months (the youngest of the patients studied so far was 2 months) and over 85 years of age.<a class="elsevierStyleCrossRef" href="#bib0355">15</a> It is estimated that 40% of patients are under 18 years of age; on the other hand, only 5% are over 45 years of age.<a class="elsevierStyleCrossRef" href="#bib0360">16</a>EtiopathogenesisThe histopathological study of brain biopsies and necropsies of patients with anti-NMDAR encephalitis shows mild inflammatory infiltrates, absence or discrete neuronal loss, microglial activation and deposits of immunoglobulin G (IgG) without complement.<a class="elsevierStyleCrossRefs" href="#bib0290">2,17</a> In addition, the IgG immunohistochemical pattern present in the brain of these patients resembles antibody immunoreactivity in rat brain studies (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). These findings, together with the resolution of the disease with immunotherapy, demonstrated that the antibodies produced a neuronal dysfunction without irreversible abnormalities,<a class="elsevierStyleCrossRefs" href="#bib0315">7,9,18</a> which contrasted with the irreversible neuronal degeneration mediated by T-cell-dependent cytotoxicity observed in classic paraneoplastic syndromes.<a class="elsevierStyleCrossRefs" href="#bib0375">19,20</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>Antibodies act selectively against conformational extracellular NMDAR epitopes, which explains why only techniques that preserve the antigen's native structure (brain tissue, neuron cultures, cells transfected with the receptor) allow the detection of antibodies.<a class="elsevierStyleCrossRef" href="#bib0295">3</a> Studies carried out in neuron cultures show that the antibodies cause the internalization of the NMDAR in both excitatory and inhibitory neurons, which is associated with a reduction of NMDAR-dependent synaptic currents.<a class="elsevierStyleCrossRefs" href="#bib0315">7,8</a> These in vitro effects correlate strongly and inversely with antibody titers in CSF, are reversible after their culture medium elimination and do not modify the dendritic complexity or affect neuronal survival.<a class="elsevierStyleCrossRefs" href="#bib0315">7,9</a> At synapses, antibodies alter the interaction between NMDAR and the Ephrin type-B receptor 2 (EphB2, a member of the tyrosine kinase receptor superfamily<a class="elsevierStyleCrossRefs" href="#bib0330">10,21</a>), responsible for stabilizing the NMDAR in the postsynaptic membrane and facilitating long-term potentiation mechanisms (LTP) and synaptic plasticity.<a class="elsevierStyleCrossRefs" href="#bib0390">22,23</a> These functions are in turn critical in learning and memory processes.<a class="elsevierStyleCrossRef" href="#bib0400">24</a> On the other hand, there is an animal model in which the infusion of patient CSF antibodies in the cerebral ventricular system of mice has demonstrated in vivo replication of some symptoms of the disease and has conclusively established the antibody's pathogenic mechanism.<a class="elsevierStyleCrossRef" href="#bib0325">9</a> The same animal model was recently replicated using a recombinant human monoclonal antibody generated from the patient's CSF plasma cells.<a class="elsevierStyleCrossRef" href="#bib0405">25</a>In addition to systemically produced antibodies, all patients have intrathecal antibody synthesis produced by plasma cell infiltrates in the brain.<a class="elsevierStyleCrossRef" href="#bib0365">17</a> Antibodies are detectable during the disease and, even though at low levels, can also be identified after the patient has recovered.<a class="elsevierStyleCrossRefs" href="#bib0410">26,27</a> Therefore, the detection of antibodies, although very important to establish the diagnosis of the disease, should not be used for decisions related to treatment maintenance or discontinuation.<a class="elsevierStyleCrossRef" href="#bib0415">27</a>Clinical manifestationsMany patients begin with viral-like prodromal symptoms which include headache or fever, which progresses in the following days towards a multi-phase and progressive syndrome that mimics that caused by the non-competitive NMDAR antagonist drugs (such as ketamine or phencyclidine<a class="elsevierStyleCrossRefs" href="#bib0420">28,29</a>), which facilitates its recognition (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>A few days after the prodromal symptoms, most patients develop psychiatric symptoms that include anxiety, insomnia, personality changes, hallucinations, paranoid ideas, aberrant behaviour, extreme agitation or psychosis.<a class="elsevierStyleCrossRefs" href="#bib0295">3,16,30</a> Speech may be accelerated, but more often than not there is a progressive reduction of verbal language to a situation of mutism.These psychiatric manifestations can manifest in isolation for days or weeks, but in general they become associated with movement disorders such as dyskinesias (typically orofacial, trunk and limbs), choreoathetosis, dystonia, stiffness and, sometimes, opisthotonos. In most patients, these symptoms are accompanied by autonomic abnormalities that may include hyperthermia, tachycardia, sialorrhea, blood pressure fluctuations and, less frequently, bradycardia (with heart pauses that may require a temporary pacemaker<a class="elsevierStyleCrossRef" href="#bib0435">31</a>). Agitation episodes tend to alternate with catatonic states during the condition, with the possibility of ending up in a coma. 50% of patients need mechanical ventilatory support due to central hypoventilation.<a class="elsevierStyleCrossRefs" href="#bib0360">16,32</a>Cognitive and memory abnormalities start manifesting during the early stages of the disease but may be difficult to evaluate due to episodes of agitation and lack of patient collaboration. Epileptic seizures, partial or generalized, may occur at any time during the initial phases of the disease.<a class="elsevierStyleCrossRef" href="#bib0430">30</a>During the neurological examination it is common to detect dissociated responses to diverse stimuli; for example, the catatonic patient seems to oppose the ocular opening, but does not respond to intense painful stimuli. These responses are similar to those produced by NMDAR-antagonists.In younger children, the initial symptoms of the disease are usually insomnia, irritability, movement disorders or epileptic seizures, while psychiatric disorders are less common or recognizable. However, most patients tend to progress towards the same group of symptoms, so that within a few weeks disease onset, the symptoms are very similar in both children and adults.<a class="elsevierStyleCrossRefs" href="#bib0360">16,33,34</a>Complementary tests and antibody studyOnly 35% of patients have brain MRI abnormalities, which are visible in Fluid-Attenuated Inversion Recovery (FLAIR) sequences, affect cortical (brain, cerebellar) or subcortical regions, with a discreet or transient contrast uptake.<a class="elsevierStyleCrossRefs" href="#bib0295">3,16</a> Although not performed routinely, PET studies show a fronto-occipital gradient of cerebral glucose metabolism characteristically increased in the fronto-limbic and parietal regions, and reduced in the occipital region, which correlates with the severity of the disease.<a class="elsevierStyleCrossRef" href="#bib0455">35</a>CSF shows moderate pleocytosis in 80% of patients, high spinal fluid protein concentration in 30% and oligoclonal bands in 60%. In the early stages of the disease, routine CSF studies may be apparently normal; however, all patients have high levels of anti-NMDAR antibodies.<a class="elsevierStyleCrossRefs" href="#bib0295">3,16,27,36</a>Electroencephalographic (EEG) studies show a slow and disorganized activity, which does not correlate with most abnormal movements or improve with antiepileptic drugs. In addition to this slowed-down activity (theta or delta waves), the records may show epileptic activity. Due to the complexity of the disease manifestations, EEG monitoring is recommended. Approximately one-third of patients develop a pattern known as extreme delta brush (continuous rhythmic delta activity at 1–3Hz with beta activity at 20–30Hz superimposed on each delta wave, in a symmetric, synchronous and diffuse way), which is associated with longer and more severe clinical symptoms.<a class="elsevierStyleCrossRef" href="#bib0465">37</a>All patients with anti-NMDAR encephalitis have antibodies in the CSF; on the other hand, 10% do not have detectable antibodies in serum.<a class="elsevierStyleCrossRef" href="#bib0415">27</a> The antibodies are IgG-type and are specifically directed against the GluN1 subunit (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). On the other hand, there is a growing number of patients who are wrongly diagnosed with anti-NMDAR encephalitis due to falsely positive serum results.<a class="elsevierStyleCrossRef" href="#bib0470">38</a> The error is due to several factors that have been previously described, including the serum analysis (without considering the CSF) through a commercially available test (cell-based assay [CBA]) which includes cells that recombinantly express NMDAR, but without additional confirmation tests. These confirmation tests (immunohistochemistry with brain tissue or neuron cultures) are essential if only serum is used.<a class="elsevierStyleCrossRef" href="#bib0300">4</a> In our experience, these errors are avoided using CSF, which is the definitive test for this disease.<a class="elsevierStyleCrossRef" href="#bib0415">27</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>IgM and IgA isoforms of NMDAR antibodies have been described in some patients with chronic primary psychiatric disorders, cerebral infarcts, neurodegenerative processes or even in healthy controls. These antibodies do not provide any additional value to the diagnosis of encephalitis and lack clinical significance.<a class="elsevierStyleCrossRef" href="#bib0475">39</a>Differential diagnosisThe diagnosis of anti-NMDAR encephalitis is usually delayed in many patients, possibly because the disease is still poorly understood, or because the differential diagnosis is wide and varies throughout the process (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). Considering the patient's symptoms, the differential diagnosis should be established with primary psychiatric disorders (acute psychotic episode, first episode of schizophrenia), especially in adults.<a class="elsevierStyleCrossRef" href="#bib0480">40</a> Other equally important entities are the infectious causes of encephalitis (especially viral ones and, among them, herpes virus encephalitis<a class="elsevierStyleCrossRef" href="#bib0485">41</a>) and the use of psychotropic drugs (phencyclidine, ketamine, amphetamine<a class="elsevierStyleCrossRef" href="#bib0425">29</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Other processes to be considered in the differential diagnosis are neuroleptic malignant syndrome and lethal catatonia, in which the symptomatic triad of altered mental status, stiffness and dysautonomia can also be observed, frequently accompanied by hyperthermia, metabolic acidosis, rhabdomyolysis (with elevation of the creatine phosphokinase enzyme), acute renal failure and epileptic seizures.<a class="elsevierStyleCrossRef" href="#bib0435">31</a> Anti-NMDAR encephalitis can mimic these conditions without having taken antipsychotic drugs, but the diagnostic confusion is increased by the fact that many of the patients with anti-NMDAR encephalitis are treated with these drugs, so it is important to consider the overall clinical context to differentiate both entities. In addition, a recent study showed greater intolerance to antipsychotics in the population with anti-NMDAR encephalitis.<a class="elsevierStyleCrossRef" href="#bib0490">42</a>It should be taken into account that, in approximately 3% of patients, anti-NMDAR encephalitis coexists with demyelinating diseases, such as ADEM, myelitis or neuromyelitis optica spectrum disorders (NMOSD) associated with anti-AQP4 or anti-MOG antibodies. The overlapping of syndromes, either concomitantly or sequentially in time, can occur with clinical expression or only demyelinating process neuroimaging.<a class="elsevierStyleCrossRef" href="#bib0495">43</a> The identification of these conditions is important because it can imply a change in prognosis and, therefore, in therapeutic approach.There is currently evidence that several syndromes previously defined in a partial or purely descriptive way in adults and children are probably cases of anti-NMDAR encephalitis. In this sense, the search for antibodies in idiopathic forms described as “lethargic encephalitis” or “idiopathic encephalitis with dyskinesias” is recommended. For example, one study retrospectively identified anti-NMDAR antibodies in CSF samples from 50% of patients who had been classified as suffering from “lethargic encephalitis”.<a class="elsevierStyleCrossRef" href="#bib0500">44</a>Association with tumoursThe association of anti-NMDAR encephalitis with tumours depends on age and sex, with ovarian teratoma being the most common tumor.<a class="elsevierStyleCrossRef" href="#bib0445">33</a> 56% of patients over 18 years of age have uni or bilateral ovarian teratomas that contain nerve tissue.<a class="elsevierStyleCrossRef" href="#bib0360">16</a> However, less than 9% of patients under the age of 14 have ovarian teratomas. Consequently, systematic screening for ovarian teratomas is recommended through abdominopelvic MRI or computed tomography studies or transvaginal ultrasound in young women with this type of encephalitis. Whole-body PET screening is usually negative, since 70% of teratomas are benign.In male patients or those over 45 years of age, tumour detection is uncommon, and its histology is different.<a class="elsevierStyleCrossRefs" href="#bib0355">15,45</a> Cases associated with testicular germ cell tumours, mediastinal teratomas, small cell lung carcinoma, Hodgkin's lymphoma and neuroblastoma have been described.If no tumour is detected, annual tumour screening is recommended for a period of 2–3 years, particularly in young women. The prognosis is similar in patients with or without tumour, provided they are treated with immunotherapy and tumour removal when necessary.<a class="elsevierStyleCrossRef" href="#bib0360">16</a>Association with herpes simplex encephalitisApproximately 25% of the patients affected by herpes simplex virus (HSE) encephalitis develop autoimmune encephalitis (post-HSE immune-mediated encephalitis) during the following weeks, which in most cases is associated with antibodies to several synaptic proteins, especially NMDAR.<a class="elsevierStyleCrossRef" href="#bib0510">46</a> Some of these proteins are other synaptic receptors (anti-GABAaR, anti-dopamine receptor) and others remain to be discovered.In this group of patients, the symptoms of autoimmune encephalitis generally appear between 2 and 6 weeks after the onset of HSE, although they may manifest contiguously or following a time interval (usually less than 2 months) after recovery from HSE. In the paediatric population, motor symptoms predominate, such as choreoathetosis and orofacial dyskinesias, associated with behavioural abnormalities, determining the condition previously known as “post-HSE choreoathetosis”.<a class="elsevierStyleCrossRefs" href="#bib0515">47–49</a> On the other hand, psychiatric and cognitive abnormalities are more prevalent in adolescents and young adults, which, although significant and highly disruptive, are often underdiagnosed due to being after-effects of the infectious process<a class="elsevierStyleCrossRef" href="#bib0530">50</a> (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). Post-HSE autoimmune encephalitis tends to respond less satisfactorily to immunotherapy than classical anti-NMDAR encephalitis.<elsevierMultimedia ident="fig0015"></elsevierMultimedia>TreatmentGiven the lack of prospective and randomized studies, therapeutic decisions should be individualized and consider aspects such as the age of the patient, the presence of tumour and the severity of the disease. Based on observational studies and the clinical experience of expert groups,<a class="elsevierStyleCrossRef" href="#bib0360">16</a> it is recommended to start the treatment as soon as possible with intravenous methylprednisolone (1g daily for 5 days in adults) associated with intravenous IgG (IVIG; 400mg/kg of weight per day for 5 days) or plasma exchange, together with the complete surgical resection of the tumour when found. Although it is unknown which of the two, IVIG or plasma exchange, has greater effectiveness, IVIG tends to be prescribed due to its greater administration convenience, preferably at paediatric ages with severe dyskinesias, agitation states or in critically ill patients with autonomic instability.If a favourable response is not achieved, it is recommended to proceed with second-line immunosuppressive therapies, including rituximab (375mg/m2 weekly for 4 weeks, or 1g 2 times separated by 2 weeks), cyclophosphamide (750mg/m2 monthly for 4–6 months depending on progression), or a combination of both.An increasingly popular approach, not only for severe cases, but systematically supported in all patients, consists of the inclusion of rituximab in first-line therapies (glucocorticoids, IVIG or plasma exchange) as a result of the beneficial effect observed on recurrence rates.<a class="elsevierStyleCrossRef" href="#bib0360">16</a>In children, a similar step strategy is also used, although the doses are not so clearly agreed upon and guidelines adapted from other autoimmune disorders, such as those established for systemic lupus erythematosus, are normally used. In the same way, in the paediatric population, the early use of rituximab along with first-line therapies is recommended, given the good results observed.<a class="elsevierStyleCrossRefs" href="#bib0450">34,51</a>In cases of post-HSE autoimmune encephalitis, early diagnosis and immunomodulatory treatment also improve prognosis, despite the persistence of residual deficits to viral encephalitis.<a class="elsevierStyleCrossRef" href="#bib0530">50</a> Antiviral treatment in this phase has not proven useful.The largest published study on treatment and outcome in patients with anti-NMDAR encephalitis is based on a descriptive and retrospective analysis of a 501-patient cohort.<a class="elsevierStyleCrossRef" href="#bib0360">16</a> By way of illustration, the clear majority (94%) were treated according to the strategy outlined above, by surgical intervention on the tumour along with first-line immunotherapy, including glucocorticoids, IVIG and/or plasma exchange. 50% of patients improved during the first 4 weeks of first-line treatment and 97% of patients had a good functional status (defined by a score between 0 and 2 on the modified Rankin scale [mRS]) at 24 months of follow-up. Of the 221 patients who did not show improvement after first-line therapies, 125 (57%) were treated with rituximab, cyclophosphamide or both. Patients who received these second-line therapies were more likely to experience a favourable course (mRS of 0–2) than those who did not. It was observed that clinical recovery was slow in many patients; at 24 months, 80% achieved a good functional recovery (mRS 0–2), including adults and children. Thirty patients died, most of them in the acute phase of the disease (during their stay in intensive care units). 12% of the patients had recurrences in the first 2 years of the initial episode, with cases not associated with tumour and those who did not receive second-line therapies being the most at risk.Outcome and prognosisRecovery usually occurs in reverse order of the presentation of symptoms: first, as autonomic functions stabilize, patients come out of coma, spontaneous breathing is recovered and dyskinesias cease; then the level of consciousness is progressively recovered, improving the interaction with the environment parallel to the recovery of verbal functions. During this period, patients may present agitation or isolated psychiatric episodes like those described in the beginning.<a class="elsevierStyleCrossRef" href="#bib0480">40</a> When a significant clinical improvement is achieved, most patients experience a favourable progression over a variable period of time until complete recovery (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). However, social behaviour and executive functions are usually the last ones to improve, their resolution may be incomplete or prolonged over time, and are more common and serious the more the treatment of the disease is delayed.<a class="elsevierStyleCrossRefs" href="#bib0360">16,52</a> Cases of recovery after 10–14 months of severe disease have been described, even requiring prolonged mechanical ventilation and hemodynamic support.<a class="elsevierStyleCrossRefs" href="#bib0545">53,54</a>No unambiguous biological marker is currently available to monitor the progression of the disease. After the treatment and during the recovery phase, CSF antibodies usually continue to be detected for months, while the serum antibodies may be present or absent, unrelated to the clinical response.<a class="elsevierStyleCrossRefs" href="#bib0410">26,27</a> In some patients, antibodies remain detectable in serum and CSF (even though at low titers) for several months or even years after clinical recovery.<a class="elsevierStyleCrossRef" href="#bib0415">27</a> Therefore, antibody titres in CSF are those that best correlate with clinical outcome but cannot be used to decide long-term immunotherapy management.Most studies describe the early onset of immunotherapy and the absence of admission to intensive care units as predictors of good prognosis (pointing to the less severe forms of the disease)<a class="elsevierStyleCrossRef" href="#bib0360">16</a>). The disease is less aggressive in the over-45 years of age group, but the prognosis is not usually as favourable as in the younger patients, which has been attributed to greater diagnostic delays and, possibly, to a smaller reserve of cognitive recovery in elderly patients.<a class="elsevierStyleCrossRef" href="#bib0360">16</a>The most persistent or last symptoms to improve are those related to executive functions, such as attention and planning, working memory, impulsivity, apathy and behavioural disinhibition, which frequently delay the incorporation of the patient in social activities. For symptomatic treatment, drugs such as quetiapine, chlorpromazine, valproic acid or benzodiazepines are better tolerated than classical neuroleptics such as haloperidol, which has a higher risk of inducing a neuroleptic malignant syndrome in this disease.<a class="elsevierStyleCrossRef" href="#bib0490">42</a>One still unresolved problem is the duration of immunotherapy. In general, immunotherapy is not necessary during the last phases of recovery. In our experience, it is not clear that prolonged immunotherapy (with drugs such as azathioprine or mycophenolate) is useful after second-line treatments (rituximab or cyclophosphamide) to accelerate recovery or prevent recurrence.There is a risk of encephalitis recurrence, estimated at 10–25%, several years after resolution of the first episode.<a class="elsevierStyleCrossRefs" href="#bib0360">16,55</a> Recurrences are more common in those cases that did not receive treatment of the tumour or early immunotherapy during the first episode and its therapeutic approach is similar to that of the initial episodes.<a class="elsevierStyleCrossRef" href="#bib0360">16</a>Future perspectivesThe discovery of anti-NMDAR encephalitis has led to the identification of a new category of diseases associated with antibodies to neuronal surface proteins or synaptic receptors. Currently, 16 diseases associated with different types of neuronal surface antibodies are known, most of which show direct effects on the corresponding antigen, altering synaptic transmission, modifying the integration of somatodendritic signals, or interfering with the development of synapses, among other identified pathogenic mechanisms.<a class="elsevierStyleCrossRef" href="#bib0305">5</a>The study of the mechanisms involved in anti-NMDAR encephalitis, especially the internalization of NMDARs resulting in a reduction of synaptic levels, as well as psychiatric symptoms (positive and negative) have revealed points of convergence with one of the most influential theories of schizophrenia, which associates this disease with a reduction of NMDAR levels in several brain nodes and inhibitory circuits.<a class="elsevierStyleCrossRef" href="#bib0560">56</a> The most commonly used animal models for the study of psychosis are based on NMDAR antagonists or on the genetic ablation of this receptor in fronto-limbic regions.<a class="elsevierStyleCrossRef" href="#bib0425">29</a> Anti-NMDAR encephalitis provides a natural human model that results from the immunoablation of said receptor.There remain many unanswered questions in the field of basic research. Future studies should improve our knowledge about how antibodies alter the function of brain circuits, causing abnormalities in memory, behaviour, cognition or psychosis. At the immunological level, it is important to better understand the environmental, systemic or genetic factors that trigger the immune response. For example, the mechanisms by which a viral encephalitis leads to a process of synaptic autoimmunity and, more specifically, where and how the B-lymphocytes are activated, reach the central nervous system and differentiate into plasma cells producing antibodies are still unknown.A greater understanding of the synaptic mechanisms associated with the symptoms would favour a therapeutic approach combining immunotherapy with drugs that antagonize the effects of antibodies, in the same way as knowledge of the pathophysiology of Myasthenia gravis or Lambert-Eaton syndrome led to the use of anticholinesterase or 3–4 diaminopyridine, respectively. Those advances are expected in the near future; for example, it has been observed that the stimulation of EphB2-R with a soluble form of its ligand (ephrin-like molecules) antagonizes the pathogenic effect of anti-NMDAR antibodies.<a class="elsevierStyleCrossRefs" href="#bib0330">10,21</a>Finally, the development of multicenter prospective studies is essential to help us better understand how we should treat patients in the slower stages of recovery, in order to accelerate them and minimize the sequelae, as well as the role that long-term immunotherapy maintenance could play.FundingThe present study was partly financed with a grant from the Carlos III Institute/FEDER (FIS PI14/00203) and the CELLEX Foundation (Josep Dalmau).Conflict of interestsDr. Dalmau receives royalties from Athena Diagnostics for the use of Ma2 as a diagnostic test and from Euroimmun for the use of diagnostic tests related to the detection of antibodies to NMDAR, GABABR, GABAAR, DPPX, and IgLON5. He has also received a research grant without restrictions from Euroimmun." "textoCompletoSecciones" => array:1 [ "secciones" => array:19 [ 0 => array:3 [ "identificador" => "xres1063465" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1011668" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1063466" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1011669" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Epidemiology" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Etiopathogenesis" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Clinical manifestations" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Complementary tests and antibody study" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Differential diagnosis" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Association with tumours" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Association with herpes simplex encephalitis" ] 12 => array:2 [ "identificador" => "sec0045" "titulo" => "Treatment" ] 13 => array:2 [ "identificador" => "sec0050" "titulo" => "Outcome and prognosis" ] 14 => array:2 [ "identificador" => "sec0055" "titulo" => "Future perspectives" ] 15 => array:2 [ "identificador" => "sec0060" "titulo" => "Funding" ] 16 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflict of interests" ] 17 => array:2 [ "identificador" => "xack359943" "titulo" => "Acknowledgements" ] 18 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-07-28" "fechaAceptado" => "2017-10-07" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1011668" "palabras" => array:5 [ 0 => "Antibodies" 1 => "Autoimmune" 2 => "Encephalitis" 3 => "NMDA" 4 => "Receptor" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1011669" "palabras" => array:5 [ 0 => "Anticuerpo" 1 => "Autoinmune" 2 => "Encefalitis" 3 => "NMDA" 4 => "Receptor" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The encephalitis associated with antibodies against the N-methyl-d-aspartate receptor (NMDAR) is characterized by the presence of antibodies against the GluN1 subunit of this receptor, resulting in symptoms that are similar to those observed in models of genetic or pharmacologic reduction of NMDARs. Patients are usually young adults, predominantly women, and children who develop, in a sequential manner, rapidly progressive symptoms including psychosis, abnormal movements, autonomic dysfunction, and coma. Epileptic seizures are variable and can occur throughout the course of the disease. The disease is often mistaken as viral encephalitis, primary psychiatric disorders, drug abuse, or neuroleptic malignant syndrome. About 50% of young women have an ovarian teratoma; in young girls and men the presence of a tumour is infrequent. In some patients, the disease is triggered by herpes simplex encephalitis. The recognition of anti-NMDAR encephalitis is important because, despite its severity, most patients respond to immunotherapy." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La encefalitis asociada a anticuerpos contra el receptor N-metil-D-aspartato (NMDAR) se caracteriza por la presencia de anticuerpos contra la subunidad GluN1 del NMDAR, resultando en síntomas parecidos a los observados en modelos de alteración genética o antagonistas farmacológicos del receptor. Los pacientes suelen ser adultos jóvenes, predominantemente mujeres, y niños/as que presentan de manera rápida y secuencial: psicosis, movimientos anormales, disfunción autonómica y coma. Las crisis epilépticas son variables y pueden ocurrir en cualquier momento de la evolución. La enfermedad suele confundirse con encefalitis virales, procesos psiquiátricos primarios, ingesta de drogas y síndrome neuroléptico maligno. El 50% de las mujeres jóvenes tienen un teratoma de ovario; en niñas y varones, la presencia de un tumor es infrecuente. En algunos pacientes la enfermedad es iniciada por una encefalitis herpética. El reconocimiento de la encefalitis anti-NMDAR es importante porque, a pesar de su gravedad, la mayoría de los pacientes responden a la inmunoterapia." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Guasp M, Dalmau J. Encefalitis por anticuerpos contra el receptor de NMDA. Med Clin (Barc). 2018;151:71–79." ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1660 "Ancho" => 2499 "Tamanyo" => 342945 ] ] "descripcion" => array:1 [ "en" => "Reactivity of anti-NMDAR antibodies with brain and rat neuronal cultures. Coronal section of rat brain showing the cerebrospinal fluid (CSF) reactivity of a patient with anti-NMDAR encephalitis (A). A contiguous brain section has been incubated with the CSF of a person without NMDAR antibodies (B). Anti-NMDAR antibodies show an intense and highly characteristic staining of the neuropil of the brain, especially in the hippocampi. Panel (C) shows that in cultures of living neurons (without permeabilization), the CSF of the patient reacts with the neuronal surface; panel (D) shows the same experiment using the control CSF (without antibodies). The nuclei of the neurons are shown stained with DAPI (4′,6-diamidino-2-phenylindole). Scale in B=2mm, and scale in D=10μm." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Modified from Kayser and Dalmau.<a class="elsevierStyleCrossRef" href="#bib0440">32</a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1617 "Ancho" => 2470 "Tamanyo" => 240588 ] ] "descripcion" => array:1 [ "en" => "Typical clinical progression of anti-NMDAR encephalitis. The graph shows the usual form of presentation and the characteristic multiphase and progressive clinical course in a young woman with an anti-NMDA encephalitis in its full expression form. In the paediatric population and in young men, the symptoms of initial presentation are usually abnormal movements, epileptic seizures, behavioural disturbance or insomnia. However, symptoms usually evolve in a similar way in most patients. The milder clinical forms, without disorders that require advanced life support measures, are increasingly frequent as the disease becomes better known and early diagnosis and treatment are achieved." ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Modified by Armangue et al.<a class="elsevierStyleCrossRef" href="#bib0530">50</a>" "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2237 "Ancho" => 3000 "Tamanyo" => 327002 ] ] "descripcion" => array:1 [ "en" => "Drawings made by a patient with autoimmune post–herpes simplex encephalitis, comparing the initial phase of the disease with the post-immunotherapy phase. An example is shown by drawings made by a 56-year-old female patient with autoimmune post–herpes simplex encephalitis at the time of symptoms onset (tree, family and home: A, D and G), 3 weeks after immunotherapy (B, E, H) and at 6 months of follow-up (C, F and I). At the onset of the disease, the patient had severe anterograde amnesia, disorientation, confusion and disorganized thinking. After treatment, the patient improved, and most symptoms resolved, except for amnesia and temporary disorientation." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Probable diagnosis<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">The diagnosis of anti-NMDAR encephalitis is considered probable if the following three criteria are met: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1. Quick onset (in less than 3 months) of a minimum of 4 of the following 6 major groups of symptoms: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cognitive-behavioural abnormalities or psychiatric symptoms \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Language disorder (logorrhoea, verbal reduction or mutism) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Epileptic seizures \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Abnormal movements, dyskinesias, stiffness or dystonic postures \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Decreased level of consciousness \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Autonomic dysfunction or central hypoventilation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2. At least one of the following results in the complementary tests: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Abnormal EEG (slow or focal disorganized or diffuse activity, epileptic activity or extreme delta brush) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cerebrospinal fluid with pleocytosis or oligoclonal bands \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3. Reasonable exclusion of other disorders \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Established diagnosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">The diagnosis of anti-NMDAR encephalitis is considered established in the presence of one or more of the 6 major groups of symptoms and anti-GluN1 IgG antibodies in cerebrospinal fluid<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a>, after reasonable exclusion of other disorders \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1813195.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Alternatively, the probable diagnosis can also be made in 3 of the groups of symptoms mentioned, associated with a teratoma." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "The determination of antibodies should be made in the cerebrospinal fluid. If only serum is available, confirmatory tests should be performed (brain immunohistochemistry or neuron cultures, in addition to CBA).Adapted from Graus et al.<a class="elsevierStyleCrossRef" href="#bib0300">4</a>" ] ] ] "descripcion" => array:1 [ "en" => "Diagnostic criteria for anti-NMDAR encephalitis." ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "ADEM: acute disseminated encephalomyelitis; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; RA: rheumatoid arthritis; CASPR2: contactin-associated protein-like 2; DPPX: dipeptidyl-peptidase-like protein-6; EEG: electroencephalogram; MS: multiple sclerosis; FIRES: febrile infection-related epilepsy syndrome; GABAaR: gamma-aminobutyric acid type A receptor; GABAbR: gamma-aminobutyric acid type B receptor; CSF: cerebrospinal fluid; SLE: systemic lupus erythematosus; LGI-1: leucine-rich glioma inactivated-1; MDMA: 3,4-methylenedioxymethamphetamine; NMDAR: N-methyl-d-aspartate receptor; NMO: neuromyelitis optica; NORSE: new onset refractory status epilepticus; PCR: polymerase chain reaction; NMS: neuroleptic malignant syndrome." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Disorder \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Keys for differential diagnosis \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Viral encephalitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">It is usually the first presumptive diagnosis in the face of an acute neurological syndrome with fever and pleocytosis in CSF. The majority have higher levels of pleocytosis and increased CSF protein concentrations. Psychosis and dyskinesias are less common \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Herpes simplex virus (1 and 2), varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, enterovirus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Detection of viral genetic material by PCR in CSF \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Herpes simplex virus 6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Detection of viral genetic material by PCR in CSF. It usually affects immunosuppressed patients \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rabies \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">It occurs with mild pleocytosis. Corneal smear for antigen detection; antibodies in serum and CSF \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Arbovirus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Antibodies in CSF \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Primary psychiatric disorders \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">They can be confused with the isolated psychiatric symptoms that occur at the onset of anti-NMDAR encephalitis. It is common for patients with this type of encephalitis to be initially admitted to psychiatric units. Unlike patients with anti-NMDAR encephalitis, the results of complementary examinations in patients with primary psychiatric disorders are normal \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Acute psychotic episode/onset of psychotic or affective disorder \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Conversion disorder \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Consumption of recreational drugs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Especially in adolescents and young adults, with acute personality and behaviour changes associated with dopaminergic hyperactivation symptoms \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ketamine, phencyclidine, cocaine, amphetamines (MDMA), cannabinoids \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Toxicological screening in emergency services \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Neuroleptic malignant syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The use of neuroleptics in early phases of encephalitis adds a confounding factor. It can occur from the first dose of medication, it is more frequently related to rapid dose escalation, high doses and classic neuroleptics. The presence of dyskinesias and catatonic features indicates an anti-NMDAR encephalitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Serotonin syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">In addition to the triad of altered mental status, stiffness and dysautonomia, mydriasis, hyperreflexia, clonus, diaphoresis and increased peristalsis are typical \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lethal catatonia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">History of schizophrenia, major depression or mania (may be indistinguishable from NMS) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Autoimmune encephalitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Associated with other antibodies to neuronal surface proteins \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Limbic encephalitis (anti-LGI-1, anti-CASPR2, anti-AMPAR, anti-GABAbR) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Although anti-NMDAR encephalitis is clinically and radiologically different from limbic encephalitis, the differential diagnosis is sometimes raised. Limbic encephalitis criteria are well defined. Each autoantibody is associated with a characteristic clinical syndrome. They do not usually present dyskinesias or central hypoventilation. Any abnormalities observed in neuroimaging and EEG are generally restricted to the medial temporal lobes, something very uncommon in anti-NMDAR encephalitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Anti-GABAaR encephalitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">It can affect the paediatric age group. Refractory epileptic seizures are typical; sometimes there are movement abnormalities. It is frequently associated with extensive multifocal cortical and subcortical abnormalities in neuroimaging \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Anti-DPPX encephalitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Movement disorders (myoclonus, tremor), hyperekplexia, cognitive deficits and epileptic seizures are also common. It is usually associated with diarrheal syndrome and weight loss. The course tends to be more insidious \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Antiphospholipid syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">A chorea-type presentation is typical. Antiphospholipid antibodies. Frequent association with systemic lupus erythematosus and rheumatoid arthritis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lethargic encephalitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ill-defined entity probably includes multiple disorders. Its criteria include acute or subacute encephalitis with at least 3 of the following signs: basal ganglia involvement, oculogyric crisis, ophthalmoplegia, obsessive-compulsive behaviour, akinetic mutism, central respiratory dysfunction, sleepiness/sleep cycle reversal. One study showed that 50% of patients classified as hyperkinetic lethargic encephalitis had anti-NMDAR encephalitis<a class="elsevierStyleCrossRef" href="#bib0500">44</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Overlapping syndrome between anti-NMDAR and NMO \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Demyelinating diseases (either clinical or radiological episodes of MS, NMO, ADEM) can coexist with anti-NMDAR encephalitis (anti-NMDAR-NMO overlap) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Epileptic syndromes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NORSE, FIRES. Mainly in the paediatric age. Epileptic activity in EEG. They are not associated with psychiatric symptoms or movement disorders. They respond little to treatment \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kleine-Levin syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypersomnia, cognitive and affective abnormalities, hyperphagia and hypersexuality are symptoms that may appear transiently during the recovery phase of anti-NMDAR encephalitis, or remain as sequelae \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1813194.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Differential diagnosis of anti-NMDAR encephalitis." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:56 [ 0 => array:3 [ "identificador" => "bib0285" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "R. 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Encephalitis associated with antibodies against the NMDA receptor

Encefalitis por anticuerpos contra el receptor de NMDA

Mar Guaspa, Josep Dalmaua,b,c,d,

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Jdalmau@clinic.cat

Corresponding author.

a Servei de Neurologia, Institut Clínic de Neurociències, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain

b Laboratori d’Immunologia Clínica i Experimental, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

c Department of Neurology, University of Pennsylvania, Philadelphia, United States

d Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

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have pathogenic effects&#44; demonstrated in in vitro and in vivo models<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">7&#8211;10</span></a> and result in a highly specific and recognizable syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">11</span></a> These characteristics differentiate them from the antibodies described in a wide variety of processes &#40;systemic lupus erythematosus&#44; neurodegeneration&#44; viral processes&#44; among others&#41;&#44; in which the target is the GluN2 subunits&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">12&#44;13</span></a> These antibodies are not associated with any specific syndrome and in most cases their clinical and pathogenic value is uncertain&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">This review focuses on the clinical manifestations&#44; the differential diagnosis and the treatment of anti-NMDAR encephalitis&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Epidemiology</span><p id="par0020" class="elsevierStylePara elsevierViewall">Because the discovery of anti-NMDAR encephalitis is recent&#44; knowledge of its incidence is still limited&#46; Studies in the Netherlands estimate it at 2&#8211;3 cases per million inhabitants&#59; however&#44; our experience in a prospective study which we are currently conducting in Spain suggests a higher incidence&#46; A study on the aetiology of encephalitis in the United Kingdom showed that anti-NMDAR encephalitis was the second most frequent cause of autoimmune encephalitis &#40;behind acute disseminated encephalomyelitis &#40;ADEM&#41;&#41; and the first cause of antineuronal antibody-mediated encephalitis&#46; In a US center &#40;California Encephalitis Project&#41; dedicated to the study of causes and epidemiology of encephalitis&#44; anti-NMDAR encephalitis was more frequent than any individual form of viral encephalitis&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">14</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Patients with anti-NMDAR encephalitis are usually young &#40;mean age of presentation is 23 years&#41; 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microglial activation and deposits of immunoglobulin G &#40;IgG&#41; without complement&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">2&#44;17</span></a> In addition&#44; the IgG immunohistochemical pattern present in the brain of these patients resembles antibody immunoreactivity in rat brain studies &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; These findings&#44; together with the resolution of the disease with immunotherapy&#44; demonstrated that the antibodies produced a neuronal dysfunction without irreversible abnormalities&#44;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">7&#44;9&#44;18</span></a> which contrasted with the irreversible neuronal degeneration mediated by T-cell-dependent cytotoxicity observed in classic paraneoplastic syndromes&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">19&#44;20</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Antibodies act selectively against conformational extracellular NMDAR epitopes&#44; which explains why only techniques that preserve the antigen&#39;s native structure &#40;brain tissue&#44; neuron cultures&#44; cells transfected with the receptor&#41; allow the detection of antibodies&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">3</span></a> Studies carried out in neuron cultures show that the antibodies cause the internalization of the NMDAR in both excitatory and inhibitory neurons&#44; which is associated with a reduction of NMDAR-dependent synaptic currents&#46;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">7&#44;8</span></a> These <span class="elsevierStyleItalic">in vitro</span> effects correlate strongly and inversely with antibody titers in CSF&#44; are reversible after their culture medium elimination and do not modify the dendritic complexity or affect neuronal survival&#46;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">7&#44;9</span></a> At synapses&#44; antibodies alter the interaction between NMDAR and the Ephrin type-B receptor 2 &#40;EphB2&#44; a member of the tyrosine kinase receptor superfamily<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">10&#44;21</span></a>&#41;&#44; responsible for stabilizing the NMDAR in the postsynaptic membrane and facilitating long-term potentiation mechanisms &#40;LTP&#41; and synaptic plasticity&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">22&#44;23</span></a> These functions are in turn critical in learning and memory processes&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">24</span></a> On the other hand&#44; there is an animal model in which the infusion of patient CSF antibodies in the cerebral ventricular system of mice has demonstrated <span class="elsevierStyleItalic">in vivo</span> replication of some symptoms of the disease and has conclusively established the antibody&#39;s pathogenic mechanism&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">9</span></a> The same animal model was recently replicated using a recombinant human monoclonal antibody generated from the patient&#39;s CSF plasma cells&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">25</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">In addition to systemically produced antibodies&#44; all patients have intrathecal antibody synthesis produced by plasma cell infiltrates in the brain&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">17</span></a> Antibodies are detectable during the disease and&#44; even though at low levels&#44; can also be identified after the patient has recovered&#46;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">26&#44;27</span></a> Therefore&#44; the detection of antibodies&#44; although very important to establish the diagnosis of the disease&#44; should not be used for decisions related to treatment maintenance or discontinuation&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">27</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Clinical manifestations</span><p id="par0045" class="elsevierStylePara elsevierViewall">Many patients begin with viral-like prodromal symptoms which include headache or fever&#44; which progresses in the following days towards a multi-phase and progressive syndrome that mimics that caused by the non-competitive NMDAR antagonist drugs &#40;such as ketamine or phencyclidine<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">28&#44;29</span></a>&#41;&#44; which facilitates its recognition &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">A few days after the prodromal symptoms&#44; most patients develop psychiatric symptoms that include anxiety&#44; insomnia&#44; personality changes&#44; hallucinations&#44; paranoid ideas&#44; aberrant behaviour&#44; extreme agitation or psychosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">3&#44;16&#44;30</span></a> Speech may be accelerated&#44; but more often than not there is a progressive reduction of verbal language to a situation of mutism&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">These psychiatric manifestations can manifest in isolation for days or weeks&#44; but in general they become associated with movement disorders such as dyskinesias &#40;typically orofacial&#44; trunk and limbs&#41;&#44; choreoathetosis&#44; dystonia&#44; stiffness and&#44; sometimes&#44; opisthotonos&#46; In most patients&#44; these symptoms are accompanied by autonomic abnormalities that may include hyperthermia&#44; tachycardia&#44; sialorrhea&#44; blood pressure fluctuations and&#44; less frequently&#44; bradycardia &#40;with heart pauses that may require a temporary pacemaker<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">31</span></a>&#41;&#46; Agitation episodes tend to alternate with catatonic states during the condition&#44; with the possibility of ending up in a coma&#46; 50&#37; of patients need mechanical ventilatory support due to central hypoventilation&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">16&#44;32</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Cognitive and memory abnormalities start manifesting during the early stages of the disease but may be difficult to evaluate due to episodes of agitation and lack of patient collaboration&#46; Epileptic seizures&#44; partial or generalized&#44; may occur at any time during the initial phases of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">30</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">During the neurological examination it is common to detect dissociated responses to diverse stimuli&#59; for example&#44; the catatonic patient seems to oppose the ocular opening&#44; but does not respond to intense painful stimuli&#46; These responses are similar to those produced by NMDAR-antagonists&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">In younger children&#44; the initial symptoms of the disease are usually insomnia&#44; irritability&#44; movement disorders or epileptic seizures&#44; while psychiatric disorders are less common or recognizable&#46; However&#44; most patients tend to progress towards the same group of symptoms&#44; so that within a few weeks disease onset&#44; the symptoms are very similar in both children and adults&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">16&#44;33&#44;34</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Complementary tests and antibody study</span><p id="par0075" class="elsevierStylePara elsevierViewall">Only 35&#37; of patients have brain MRI abnormalities&#44; which are visible in Fluid-Attenuated Inversion Recovery &#40;FLAIR&#41; sequences&#44; affect cortical &#40;brain&#44; cerebellar&#41; or subcortical regions&#44; with a discreet or transient contrast uptake&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">3&#44;16</span></a> Although not performed routinely&#44; PET studies show a fronto-occipital gradient of cerebral glucose metabolism characteristically increased in the fronto-limbic and parietal regions&#44; and reduced in the occipital region&#44; which correlates with the severity of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">35</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">CSF shows moderate pleocytosis in 80&#37; of patients&#44; high spinal fluid protein concentration in 30&#37; and oligoclonal bands in 60&#37;&#46; In the early stages of the disease&#44; routine CSF studies may be apparently normal&#59; however&#44; all patients have high levels of anti-NMDAR antibodies&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">3&#44;16&#44;27&#44;36</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Electroencephalographic &#40;EEG&#41; studies show a slow and disorganized activity&#44; which does not correlate with most abnormal movements or improve with antiepileptic drugs&#46; In addition to this slowed-down activity &#40;theta or delta waves&#41;&#44; the records may show epileptic activity&#46; Due to the complexity of the disease manifestations&#44; EEG monitoring is recommended&#46; Approximately one-third of patients develop a pattern known as <span class="elsevierStyleItalic">extreme delta brush</span> &#40;continuous rhythmic delta activity at 1&#8211;3<span class="elsevierStyleHsp" style=""></span>Hz with beta activity at 20&#8211;30<span class="elsevierStyleHsp" style=""></span>Hz superimposed on each delta wave&#44; in a symmetric&#44; synchronous and diffuse way&#41;&#44; which is associated with longer and more severe clinical symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">37</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">All patients with anti-NMDAR encephalitis have antibodies in the CSF&#59; on the other hand&#44; 10&#37; do not have detectable antibodies in serum&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">27</span></a> The antibodies are IgG-type and are specifically directed against the GluN1 subunit &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; On the other hand&#44; there is a growing number of patients who are wrongly diagnosed with anti-NMDAR encephalitis due to falsely positive serum results&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">38</span></a> The error is due to several factors that have been previously described&#44; including the serum analysis &#40;without considering the CSF&#41; through a commercially available test &#40;cell-based assay &#91;CBA&#93;&#41; which includes cells that recombinantly express NMDAR&#44; but without additional confirmation tests&#46; These confirmation tests &#40;immunohistochemistry with brain tissue or neuron cultures&#41; are essential if only serum is used&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">4</span></a> In our experience&#44; these errors are avoided using CSF&#44; which is the definitive test for this disease&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">27</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">IgM and IgA isoforms of NMDAR antibodies have been described in some patients with chronic primary psychiatric disorders&#44; cerebral infarcts&#44; neurodegenerative processes or even in healthy controls&#46; These antibodies do not provide any additional value to the diagnosis of encephalitis and lack clinical significance&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">39</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Differential diagnosis</span><p id="par0100" class="elsevierStylePara elsevierViewall">The diagnosis of anti-NMDAR encephalitis is usually delayed in many patients&#44; possibly because the disease is still poorly understood&#44; or because the differential diagnosis is wide and varies throughout the process &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Considering the patient&#39;s symptoms&#44; the differential diagnosis should be established with primary psychiatric disorders &#40;acute psychotic episode&#44; first episode of schizophrenia&#41;&#44; especially in adults&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">40</span></a> Other equally important entities are the infectious causes of encephalitis &#40;especially viral ones and&#44; among them&#44; herpes virus encephalitis<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">41</span></a>&#41; and the use of psychotropic drugs &#40;phencyclidine&#44; ketamine&#44; amphetamine<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">29</span></a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">Other processes to be considered in the differential diagnosis are neuroleptic malignant syndrome and lethal catatonia&#44; in which the symptomatic triad of altered mental status&#44; stiffness and dysautonomia can also be observed&#44; frequently accompanied by hyperthermia&#44; metabolic acidosis&#44; rhabdomyolysis &#40;with elevation of the creatine phosphokinase enzyme&#41;&#44; acute renal failure and epileptic seizures&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">31</span></a> Anti-NMDAR encephalitis can mimic these conditions without having taken antipsychotic drugs&#44; but the diagnostic confusion is increased by the fact that many of the patients with anti-NMDAR encephalitis are treated with these drugs&#44; so it is important to consider the overall clinical context to differentiate both entities&#46; In addition&#44; a recent study showed greater intolerance to antipsychotics in the population with anti-NMDAR encephalitis&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">42</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">It should be taken into account that&#44; in approximately 3&#37; of patients&#44; anti-NMDAR encephalitis coexists with demyelinating diseases&#44; such as ADEM&#44; myelitis or neuromyelitis optica spectrum disorders &#40;NMOSD&#41; associated with anti-AQP4 or anti-MOG antibodies&#46; The overlapping of syndromes&#44; either concomitantly or sequentially in time&#44; can occur with clinical expression or only demyelinating process neuroimaging&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">43</span></a> The identification of these conditions is important because it can imply a change in prognosis and&#44; therefore&#44; in therapeutic approach&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">There is currently evidence that several syndromes previously defined in a partial or purely descriptive way in adults and children are probably cases of anti-NMDAR encephalitis&#46; In this sense&#44; the search for antibodies in idiopathic forms described as &#8220;lethargic encephalitis&#8221; or &#8220;idiopathic encephalitis with dyskinesias&#8221; is recommended&#46; For example&#44; one study retrospectively identified anti-NMDAR antibodies in CSF samples from 50&#37; of patients who had been classified as suffering from &#8220;lethargic encephalitis&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">44</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Association with tumours</span><p id="par0120" class="elsevierStylePara elsevierViewall">The association of anti-NMDAR encephalitis with tumours depends on age and sex&#44; with ovarian teratoma being the most common tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">33</span></a> 56&#37; of patients over 18 years of age have uni or bilateral ovarian teratomas that contain nerve tissue&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">16</span></a> However&#44; less than 9&#37; of patients under the age of 14 have ovarian teratomas&#46; Consequently&#44; systematic screening for ovarian teratomas is recommended through abdominopelvic MRI or computed tomography studies or transvaginal ultrasound in young women with this type of encephalitis&#46; Whole-body PET screening is usually negative&#44; since 70&#37; of teratomas are benign&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">In male patients or those over 45 years of age&#44; tumour detection is uncommon&#44; and its histology is different&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">15&#44;45</span></a> Cases associated with testicular germ cell tumours&#44; mediastinal teratomas&#44; small cell lung carcinoma&#44; Hodgkin&#39;s lymphoma and neuroblastoma have been described&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">If no tumour is detected&#44; annual tumour screening is recommended for a period of 2&#8211;3 years&#44; particularly in young women&#46; The prognosis is similar in patients with or without tumour&#44; provided they are treated with immunotherapy and tumour removal when necessary&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Association with herpes simplex encephalitis</span><p id="par0135" class="elsevierStylePara elsevierViewall">Approximately 25&#37; of the patients affected by herpes simplex virus &#40;HSE&#41; encephalitis develop autoimmune encephalitis &#40;post-HSE immune-mediated encephalitis&#41; during the following weeks&#44; which in most cases is associated with antibodies to several synaptic proteins&#44; especially NMDAR&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">46</span></a> Some of these proteins are other synaptic receptors &#40;anti-GABAaR&#44; anti-dopamine receptor&#41; and others remain to be discovered&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">In this group of patients&#44; the symptoms of autoimmune encephalitis generally appear between 2 and 6 weeks after the onset of HSE&#44; although they may manifest contiguously or following a time interval &#40;usually less than 2 months&#41; after recovery from HSE&#46; In the paediatric population&#44; motor symptoms predominate&#44; such as choreoathetosis and orofacial dyskinesias&#44; associated with behavioural abnormalities&#44; determining the condition previously known as &#8220;post-HSE choreoathetosis&#8221;&#46;<a class="elsevierStyleCrossRefs" href="#bib0515"><span class="elsevierStyleSup">47&#8211;49</span></a> On the other hand&#44; psychiatric and cognitive abnormalities are more prevalent in adolescents and young adults&#44; which&#44; although significant and highly disruptive&#44; are often underdiagnosed due to being after-effects of the infectious process<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">50</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; Post-HSE autoimmune encephalitis tends to respond less satisfactorily to immunotherapy than classical anti-NMDAR encephalitis&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Treatment</span><p id="par0145" class="elsevierStylePara elsevierViewall">Given the lack of prospective and randomized studies&#44; therapeutic decisions should be individualized and consider aspects such as the age of the patient&#44; the presence of tumour and the severity of the disease&#46; Based on observational studies and the clinical experience of expert groups&#44;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">16</span></a> it is recommended to start the treatment as soon as possible with intravenous methylprednisolone &#40;1<span class="elsevierStyleHsp" style=""></span>g daily for 5 days in adults&#41; associated with intravenous IgG &#40;IVIG&#59; 400<span class="elsevierStyleHsp" style=""></span>mg&#47;kg of weight per day for 5 days&#41; or plasma exchange&#44; together with the complete surgical resection of the tumour when found&#46; Although it is unknown which of the two&#44; IVIG or plasma exchange&#44; has greater effectiveness&#44; IVIG tends to be prescribed due to its greater administration convenience&#44; preferably at paediatric ages with severe dyskinesias&#44; agitation states or in critically ill patients with autonomic instability&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">If a favourable response is not achieved&#44; it is recommended to proceed with second-line immunosuppressive therapies&#44; including rituximab &#40;375<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> weekly for 4 weeks&#44; or 1<span class="elsevierStyleHsp" style=""></span>g 2 times separated by 2 weeks&#41;&#44; cyclophosphamide &#40;750<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> monthly for 4&#8211;6 months depending on progression&#41;&#44; or a combination of both&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">An increasingly popular approach&#44; not only for severe cases&#44; but systematically supported in all patients&#44; consists of the inclusion of rituximab in first-line therapies &#40;glucocorticoids&#44; IVIG or plasma exchange&#41; as a result of the beneficial effect observed on recurrence rates&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">16</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">In children&#44; a similar step strategy is also used&#44; although the doses are not so clearly agreed upon and guidelines adapted from other autoimmune disorders&#44; such as those established for systemic lupus erythematosus&#44; are normally used&#46; In the same way&#44; in the paediatric population&#44; the early use of rituximab along with first-line therapies is recommended&#44; given the good results observed&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">34&#44;51</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">In cases of post-HSE autoimmune encephalitis&#44; early diagnosis and immunomodulatory treatment also improve prognosis&#44; despite the persistence of residual deficits to viral encephalitis&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">50</span></a> Antiviral treatment in this phase has not proven useful&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">The largest published study on treatment and outcome in patients with anti-NMDAR encephalitis is based on a descriptive and retrospective analysis of a 501-patient cohort&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">16</span></a> By way of illustration&#44; the clear majority &#40;94&#37;&#41; were treated according to the strategy outlined above&#44; by surgical intervention on the tumour along with first-line immunotherapy&#44; including glucocorticoids&#44; IVIG and&#47;or plasma exchange&#46; 50&#37; of patients improved during the first 4 weeks of first-line treatment and 97&#37; of patients had a good functional status &#40;defined by a score between 0 and 2 on the modified Rankin scale &#91;mRS&#93;&#41; at 24 months of follow-up&#46; Of the 221 patients who did not show improvement after first-line therapies&#44; 125 &#40;57&#37;&#41; were treated with rituximab&#44; cyclophosphamide or both&#46; Patients who received these second-line therapies were more likely to experience a favourable course &#40;mRS of 0&#8211;2&#41; than those who did not&#46; It was observed that clinical recovery was slow in many patients&#59; at 24 months&#44; 80&#37; achieved a good functional recovery &#40;mRS 0&#8211;2&#41;&#44; including adults and children&#46; Thirty patients died&#44; most of them in the acute phase of the disease &#40;during their stay in intensive care units&#41;&#46; 12&#37; of the patients had recurrences in the first 2 years of the initial episode&#44; with cases not associated with tumour and those who did not receive second-line therapies being the most at risk&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Outcome and prognosis</span><p id="par0175" class="elsevierStylePara elsevierViewall">Recovery usually occurs in reverse order of the presentation of symptoms&#58; first&#44; as autonomic functions stabilize&#44; patients come out of coma&#44; spontaneous breathing is recovered and dyskinesias cease&#59; then the level of consciousness is progressively recovered&#44; improving the interaction with the environment parallel to the recovery of verbal functions&#46; During this period&#44; patients may present agitation or isolated psychiatric episodes like those described in the beginning&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">40</span></a> When a significant clinical improvement is achieved&#44; most patients experience a favourable progression over a variable period of time until complete recovery &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; However&#44; social behaviour and executive functions are usually the last ones to improve&#44; their resolution may be incomplete or prolonged over time&#44; and are more common and serious the more the treatment of the disease is delayed&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">16&#44;52</span></a> Cases of recovery after 10&#8211;14 months of severe disease have been described&#44; even requiring prolonged mechanical ventilation and hemodynamic support&#46;<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">53&#44;54</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">No unambiguous biological marker is currently available to monitor the progression of the disease&#46; After the treatment and during the recovery phase&#44; CSF antibodies usually continue to be detected for months&#44; while the serum antibodies may be present or absent&#44; unrelated to the clinical response&#46;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">26&#44;27</span></a> In some patients&#44; antibodies remain detectable in serum and CSF &#40;even though at low titers&#41; for several months or even years after clinical recovery&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">27</span></a> Therefore&#44; antibody titres in CSF are those that best correlate with clinical outcome but cannot be used to decide long-term immunotherapy management&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Most studies describe the early onset of immunotherapy and the absence of admission to intensive care units as predictors of good prognosis &#40;pointing to the less severe forms of the disease&#41;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">16</span></a>&#41;&#46; The disease is less aggressive in the over-45 years of age group&#44; but the prognosis is not usually as favourable as in the younger patients&#44; which has been attributed to greater diagnostic delays and&#44; possibly&#44; to a smaller reserve of cognitive recovery in elderly patients&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">16</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">The most persistent or last symptoms to improve are those related to executive functions&#44; such as attention and planning&#44; working memory&#44; impulsivity&#44; apathy and behavioural disinhibition&#44; which frequently delay the incorporation of the patient in social activities&#46; For symptomatic treatment&#44; drugs such as quetiapine&#44; chlorpromazine&#44; valproic acid or benzodiazepines are better tolerated than classical neuroleptics such as haloperidol&#44; which has a higher risk of inducing a neuroleptic malignant syndrome in this disease&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">42</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">One still unresolved problem is the duration of immunotherapy&#46; In general&#44; immunotherapy is not necessary during the last phases of recovery&#46; In our experience&#44; it is not clear that prolonged immunotherapy &#40;with drugs such as azathioprine or mycophenolate&#41; is useful after second-line treatments &#40;rituximab or cyclophosphamide&#41; to accelerate recovery or prevent recurrence&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">There is a risk of encephalitis recurrence&#44; estimated at 10&#8211;25&#37;&#44; several years after resolution of the first episode&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">16&#44;55</span></a> Recurrences are more common in those cases that did not receive treatment of the tumour or early immunotherapy during the first episode and its therapeutic approach is similar to that of the initial episodes&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Future perspectives</span><p id="par0205" class="elsevierStylePara elsevierViewall">The discovery of anti-NMDAR encephalitis has led to the identification of a new category of diseases associated with antibodies to neuronal surface proteins or synaptic receptors&#46; Currently&#44; 16 diseases associated with different types of neuronal surface antibodies are known&#44; most of which show direct effects on the corresponding antigen&#44; altering synaptic transmission&#44; modifying the integration of somatodendritic signals&#44; or interfering with the development of synapses&#44; among other identified pathogenic mechanisms&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">5</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">The study of the mechanisms involved in anti-NMDAR encephalitis&#44; especially the internalization of NMDARs resulting in a reduction of synaptic levels&#44; as well as psychiatric symptoms &#40;positive and negative&#41; have revealed points of convergence with one of the most influential theories of schizophrenia&#44; which associates this disease with a reduction of NMDAR levels in several brain nodes and inhibitory circuits&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">56</span></a> The most commonly used animal models for the study of psychosis are based on NMDAR antagonists or on the genetic ablation of this receptor in fronto-limbic regions&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">29</span></a> Anti-NMDAR encephalitis provides a natural human model that results from the immunoablation of said receptor&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">There remain many unanswered questions in the field of basic research&#46; Future studies should improve our knowledge about how antibodies alter the function of brain circuits&#44; causing abnormalities in memory&#44; behaviour&#44; cognition or psychosis&#46; At the immunological level&#44; it is important to better understand the environmental&#44; systemic or genetic factors that trigger the immune response&#46; For example&#44; the mechanisms by which a viral encephalitis leads to a process of synaptic autoimmunity and&#44; more specifically&#44; where and how the B-lymphocytes are activated&#44; reach the central nervous system and differentiate into plasma cells producing antibodies are still unknown&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">A greater understanding of the synaptic mechanisms associated with the symptoms would favour a therapeutic approach combining immunotherapy with drugs that antagonize the effects of antibodies&#44; in the same way as knowledge of the pathophysiology of <span class="elsevierStyleItalic">Myasthenia gravis</span> or Lambert-Eaton syndrome led to the use of anticholinesterase or 3&#8211;4 diaminopyridine&#44; respectively&#46; Those advances are expected in the near future&#59; for example&#44; it has been observed that the stimulation of EphB2-R with a soluble form of its ligand &#40;<span class="elsevierStyleItalic">ephrin-like</span> molecules&#41; antagonizes the pathogenic effect of anti-NMDAR antibodies&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">10&#44;21</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">Finally&#44; the development of multicenter prospective studies is essential to help us better understand how we should treat patients in the slower stages of recovery&#44; in order to accelerate them and minimize the sequelae&#44; as well as the role that long-term immunotherapy maintenance could play&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Funding</span><p id="par0230" class="elsevierStylePara elsevierViewall">The present study was partly financed with a grant from the <span class="elsevierStyleGrantSponsor" id="gs1">Carlos <span class="elsevierStyleSmallCaps">III</span> Institute&#47;FEDER</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs1">FIS PI14&#47;00203</span>&#41; and the <span class="elsevierStyleGrantSponsor" id="gs2">CELLEX Foundation</span> &#40;Josep Dalmau&#41;&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflict of interests</span><p id="par0235" class="elsevierStylePara elsevierViewall">Dr&#46; Dalmau receives <span class="elsevierStyleItalic">royalties</span> from Athena Diagnostics for the use of Ma2 as a diagnostic test and from Euroimmun for the use of diagnostic tests related to the detection of antibodies to NMDAR&#44; GABA<span class="elsevierStyleInf">B</span>R&#44; GABA<span class="elsevierStyleInf">A</span>R&#44; DPPX&#44; and IgLON5&#46; He has also received a research grant without restrictions from Euroimmun&#46;</p></span></span>"
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          "titulo" => "Etiopathogenesis"
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          "titulo" => "Association with tumours"
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          "titulo" => "Association with herpes simplex encephalitis"
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    "fechaAceptado" => "2017-10-07"
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            2 => "Encephalitis"
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            1 => "Autoinmune"
            2 => "Encefalitis"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The encephalitis associated with antibodies against the N-methyl-<span class="elsevierStyleSmallCaps">d</span>-aspartate receptor &#40;NMDAR&#41; is characterized by the presence of antibodies against the GluN1 subunit of this receptor&#44; resulting in symptoms that are similar to those observed in models of genetic or pharmacologic reduction of NMDARs&#46; Patients are usually young adults&#44; predominantly women&#44; and children who develop&#44; in a sequential manner&#44; rapidly progressive symptoms including psychosis&#44; abnormal movements&#44; autonomic dysfunction&#44; and coma&#46; Epileptic seizures are variable and can occur throughout the course of the disease&#46; The disease is often mistaken as viral encephalitis&#44; primary psychiatric disorders&#44; drug abuse&#44; or neuroleptic malignant syndrome&#46; About 50&#37; of young women have an ovarian teratoma&#59; in young girls and men the presence of a tumour is infrequent&#46; In some patients&#44; the disease is triggered by herpes simplex encephalitis&#46; The recognition of anti-NMDAR encephalitis is important because&#44; despite its severity&#44; most patients respond to immunotherapy&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La encefalitis asociada a anticuerpos contra el receptor <span class="elsevierStyleItalic">N-metil-D-aspartato</span> &#40;NMDAR&#41; se caracteriza por la presencia de anticuerpos contra la subunidad GluN1 del NMDAR&#44; resultando en s&#237;ntomas parecidos a los observados en modelos de alteraci&#243;n gen&#233;tica o antagonistas farmacol&#243;gicos del receptor&#46; Los pacientes suelen ser adultos j&#243;venes&#44; predominantemente mujeres&#44; y ni&#241;os&#47;as que presentan de manera r&#225;pida y secuencial&#58; psicosis&#44; movimientos anormales&#44; disfunci&#243;n auton&#243;mica y coma&#46; Las crisis epil&#233;pticas son variables y pueden ocurrir en cualquier momento de la evoluci&#243;n&#46; La enfermedad suele confundirse con encefalitis virales&#44; procesos psiqui&#225;tricos primarios&#44; ingesta de drogas y s&#237;ndrome neurol&#233;ptico maligno&#46; El 50&#37; de las mujeres j&#243;venes tienen un teratoma de ovario&#59; en ni&#241;as y varones&#44; la presencia de un tumor es infrecuente&#46; En algunos pacientes la enfermedad es iniciada por una encefalitis herp&#233;tica&#46; El reconocimiento de la encefalitis anti-NMDAR es importante porque&#44; a pesar de su gravedad&#44; la mayor&#237;a de los pacientes responden a la inmunoterapia&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as&#58; Guasp M&#44; Dalmau J&#46; Encefalitis por anticuerpos contra el receptor de NMDA&#46; Med Clin &#40;Barc&#41;&#46; 2018&#59;151&#58;71&#8211;79&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Reactivity of anti-NMDAR antibodies with brain and rat neuronal cultures&#46; Coronal section of rat brain showing the cerebrospinal fluid &#40;CSF&#41; reactivity of a patient with anti-NMDAR encephalitis &#40;A&#41;&#46; A contiguous brain section has been incubated with the CSF of a person without NMDAR antibodies &#40;B&#41;&#46; Anti-NMDAR antibodies show an intense and highly characteristic staining of the neuropil of the brain&#44; especially in the hippocampi&#46; Panel &#40;C&#41; shows that in cultures of living neurons &#40;without permeabilization&#41;&#44; the CSF of the patient reacts with the neuronal surface&#59; panel &#40;D&#41; shows the same experiment using the control CSF &#40;without antibodies&#41;&#46; The nuclei of the neurons are shown stained with DAPI &#40;4&#8242;&#44;6-diamidino-2-phenylindole&#41;&#46; Scale in <span class="elsevierStyleItalic">B</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>mm&#44; and scale in <span class="elsevierStyleItalic">D</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>&#956;m&#46;</p>"
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        "fuente" => "Modified from Kayser and Dalmau&#46;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">32</span></a>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Typical clinical progression of anti-NMDAR encephalitis&#46; The graph shows the usual form of presentation and the characteristic multiphase and progressive clinical course in a young woman with an anti-NMDA encephalitis in its full expression form&#46; In the paediatric population and in young men&#44; the symptoms of initial presentation are usually abnormal movements&#44; epileptic seizures&#44; behavioural disturbance or insomnia&#46; However&#44; symptoms usually evolve in a similar way in most patients&#46; The milder clinical forms&#44; without disorders that require advanced life support measures&#44; are increasingly frequent as the disease becomes better known and early diagnosis and treatment are achieved&#46;</p>"
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        "fuente" => "Modified by Armangue et al&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">50</span></a>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Drawings made by a patient with autoimmune post&#8211;herpes simplex encephalitis&#44; comparing the initial phase of the disease with the post-immunotherapy phase&#46; An example is shown by drawings made by a 56-year-old female patient with autoimmune post&#8211;herpes simplex encephalitis at the time of symptoms onset &#40;tree&#44; family and home&#58; A&#44; D and G&#41;&#44; 3 weeks after immunotherapy &#40;B&#44; E&#44; H&#41; and at 6 months of follow-up &#40;C&#44; F and <span class="elsevierStyleSmallCaps">I</span>&#41;&#46; At the onset of the disease&#44; the patient had severe anterograde amnesia&#44; disorientation&#44; confusion and disorganized thinking&#46; After treatment&#44; the patient improved&#44; and most symptoms resolved&#44; except for amnesia and temporary disorientation&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Probable diagnosis</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">The diagnosis of anti-NMDAR encephalitis is considered probable if the following three criteria are met&#58;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>1&#46; Quick onset &#40;in less than 3 months&#41; of a minimum of 4 of the following 6 major groups of symptoms&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Cognitive-behavioural abnormalities or psychiatric symptoms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Language disorder &#40;logorrhoea&#44; verbal reduction or mutism&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Epileptic seizures&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Abnormal movements&#44; dyskinesias&#44; stiffness or dystonic postures&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Decreased level of consciousness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Autonomic dysfunction or central hypoventilation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>2&#46; At least one of the following results in the complementary tests&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Abnormal EEG &#40;slow or focal disorganized or diffuse activity&#44; epileptic activity or extreme delta brush&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Cerebrospinal fluid with pleocytosis or oligoclonal bands&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>3&#46; Reasonable exclusion of other disorders&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Established diagnosis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">The diagnosis of anti-NMDAR encephalitis is considered established in the presence of one or more of the 6 major groups of symptoms and anti-GluN1 IgG antibodies in cerebrospinal fluid</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&#44; <span class="elsevierStyleItalic">after reasonable exclusion of other disorders</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Alternatively&#44; the probable diagnosis can also be made in 3 of the groups of symptoms mentioned&#44; associated with a teratoma&#46;</p>"
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              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">The determination of antibodies should be made in the cerebrospinal fluid&#46; If only serum is available&#44; confirmatory tests should be performed &#40;brain immunohistochemistry or neuron cultures&#44; in addition to CBA&#41;&#46;Adapted from Graus et al&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">4</span></a></p>"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Diagnostic criteria for anti-NMDAR encephalitis&#46;</p>"
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">ADEM&#58; acute disseminated encephalomyelitis&#59; AMPAR&#58; &#945;-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor&#59; RA&#58; rheumatoid arthritis&#59; CASPR2&#58; <span class="elsevierStyleItalic">contactin-associated protein-like 2</span>&#59; DPPX&#58; <span class="elsevierStyleItalic">dipeptidyl-peptidase-like protein-6</span>&#59; EEG&#58; electroencephalogram&#59; MS&#58; multiple sclerosis&#59; FIRES&#58; <span class="elsevierStyleItalic">febrile infection-related epilepsy syndrome</span>&#59; GABAaR&#58; gamma-aminobutyric acid type A receptor&#59; GABAbR&#58; gamma-aminobutyric acid type B receptor&#59; CSF&#58; cerebrospinal fluid&#59; SLE&#58; systemic lupus erythematosus&#59; LGI-1&#58; <span class="elsevierStyleItalic">leucine-rich glioma inactivated-1</span>&#59; MDMA&#58; 3&#44;4-methylenedioxymethamphetamine&#59; NMDAR&#58; N-methyl-<span class="elsevierStyleSmallCaps">d</span>-aspartate receptor&#59; NMO&#58; neuromyelitis optica&#59; NORSE&#58; <span class="elsevierStyleItalic">new onset refractory status epilepticus</span>&#59; PCR&#58; polymerase chain reaction&#59; NMS&#58; neuroleptic malignant syndrome&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Disorder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Keys for differential diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Viral encephalitis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">It is usually the first presumptive diagnosis in the face of an acute neurological syndrome with fever and pleocytosis in CSF&#46; The majority have higher levels of pleocytosis and increased CSF protein concentrations&#46; Psychosis and dyskinesias are less common&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Herpes simplex virus &#40;1 and 2&#41;&#44; varicella-zoster virus&#44; Epstein-Barr virus&#44; cytomegalovirus&#44; enterovirus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Detection of viral genetic material by PCR in CSF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Herpes simplex virus 6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Detection of viral genetic material by PCR in CSF&#46; It usually affects immunosuppressed patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Rabies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">It occurs with mild pleocytosis&#46; Corneal smear for antigen detection&#59; antibodies in serum and CSF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Arbovirus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Antibodies in CSF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Primary psychiatric disorders</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">They can be confused with the isolated psychiatric symptoms that occur at the onset of anti-NMDAR encephalitis&#46; It is common for patients with this type of encephalitis to be initially admitted to psychiatric units&#46; Unlike patients with anti-NMDAR encephalitis&#44; the results of complementary examinations in patients with primary psychiatric disorders are normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Acute psychotic episode&#47;onset of psychotic or affective disorder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Conversion disorder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Consumption of recreational drugs</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Especially in adolescents and young adults&#44; with acute personality and behaviour changes associated with dopaminergic hyperactivation symptoms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Ketamine&#44; phencyclidine&#44; cocaine&#44; amphetamines &#40;MDMA&#41;&#44; cannabinoids&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Toxicological screening in emergency services&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Neuroleptic malignant syndrome</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The use of neuroleptics in early phases of encephalitis adds a confounding factor&#46; It can occur from the first dose of medication&#44; it is more frequently related to rapid dose escalation&#44; high doses and classic neuroleptics&#46; The presence of dyskinesias and catatonic features indicates an anti-NMDAR encephalitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Serotonin syndrome</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">In addition to the triad of altered mental status&#44; stiffness and dysautonomia&#44; mydriasis&#44; hyperreflexia&#44; clonus&#44; diaphoresis and increased peristalsis are typical&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Lethal catatonia</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">History of schizophrenia&#44; major depression or mania &#40;may be indistinguishable from NMS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Autoimmune encephalitis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Associated with other antibodies to neuronal surface proteins&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Limbic encephalitis &#40;anti-LGI-1&#44; anti-CASPR2&#44; anti-AMPAR&#44; anti-GABAbR&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Although anti-NMDAR encephalitis is clinically and radiologically different from limbic encephalitis&#44; the differential diagnosis is sometimes raised&#46; Limbic encephalitis criteria are well defined&#46; Each autoantibody is associated with a characteristic clinical syndrome&#46; They do not usually present dyskinesias or central hypoventilation&#46; Any abnormalities observed in neuroimaging and EEG are generally restricted to the medial temporal lobes&#44; something very uncommon in anti-NMDAR encephalitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Anti-GABAaR encephalitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">It can affect the paediatric age group&#46; Refractory epileptic seizures are typical&#59; sometimes there are movement abnormalities&#46; It is frequently associated with extensive multifocal cortical and subcortical abnormalities in neuroimaging&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Anti-DPPX encephalitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Movement disorders &#40;myoclonus&#44; tremor&#41;&#44; hyperekplexia&#44; cognitive deficits and epileptic seizures are also common&#46; It is usually associated with diarrheal syndrome and weight loss&#46; The course tends to be more insidious&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Antiphospholipid syndrome</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A chorea-type presentation is typical&#46; Antiphospholipid antibodies&#46; Frequent association with systemic lupus erythematosus and rheumatoid arthritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Lethargic encephalitis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ill-defined entity probably includes multiple disorders&#46; Its criteria include acute or subacute encephalitis with at least 3 of the following signs&#58; basal ganglia involvement&#44; oculogyric crisis&#44; ophthalmoplegia&#44; obsessive-compulsive behaviour&#44; akinetic mutism&#44; central respiratory dysfunction&#44; sleepiness&#47;sleep cycle reversal&#46; One study showed that 50&#37; of patients classified as hyperkinetic lethargic encephalitis had anti-NMDAR encephalitis<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">44</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Overlapping syndrome between anti-NMDAR and NMO</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Demyelinating diseases &#40;either clinical or radiological episodes of MS&#44; NMO&#44; ADEM&#41; can coexist with anti-NMDAR encephalitis &#40;anti-NMDAR-NMO overlap&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Epileptic syndromes</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">NORSE&#44; FIRES&#46; Mainly in the paediatric age&#46; Epileptic activity in EEG&#46; They are not associated with psychiatric symptoms or movement disorders&#46; They respond little to treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Kleine-Levin syndrome</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hypersomnia&#44; cognitive and affective abnormalities&#44; hyperphagia and hypersexuality are symptoms that may appear transiently during the recovery phase of anti-NMDAR encephalitis&#44; or remain as sequelae&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Differential diagnosis of anti-NMDAR encephalitis&#46;</p>"
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