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Diagnosing autoimmune limbic encephalitis | CMAJ

Diagnosing autoimmune limbic encephalitis | CMAJ | AntiNMDA | Scoop.it
KEY POINTS Autoimmune limbic encephalitis is an inflammatory disease involving the medial temporal lobes; it classically presents with the subacute onset of short-term memory deficits, seizures or psychiatric symptoms. Brain magnetic resonance imaging can show medial temporal lobe abnormalities typical of autoimmune limbic encephalitis in suspected cases, but clinicians should be aware of other diseases that may have a similar imaging appearance. Analysis of both electroencephalogram (EEG) and cerebrospinal fluid can provide supportive evidence of neuro-inflammation in patients with suspected autoimmune limbic encephalitis, but a normal EEG or cerebrospinal fluid profile does not exclude the diagnosis. Testing for antibodies to onconeural, cell-surface and synaptic proteins represents a major advancement in the diagnosis of autoimmune limbic encephalitis, although false-positives are possible. Autoimmune limbic encephalitis (ALE) is an inflammatory disease involving the medial temporal lobes; it classically presents with rapid neuropsychiatric decline. Patients with ALE have, and may present with, a diverse array of neuropsychiatric symptoms, which means that they may initially be assessed by any one of a range of medical practitioners. The condition was first described as a paraneoplastic phenomenon, but subsequently, with the discovery of disease-causing antibodies, was shown to be nonparaneoplastic in many cases.1,2 Although ALE is uncommon (an epidemiologic study of encephalitis found the prevalence of ALE without antibody positivity to be only 2 cases per 100 000 people), the incidence of autoimmune encephalitides has risen over the last decade, driven largely by improved antibody detection.3 Autoimmune limbic encephalitis is commonly misdiagnosed, yet early diagnosis and treatment can improve outcomes. We review the approach to diagnosis of ALE, drawing on findings of large cohort and case-control studies, which represent the highest level of evidence in this field (Box 1). We discuss diagnostic criteria for ALE presented in a 2016 position paper by Graus and colleagues (hereafter referred to as the Graus criteria; Box 2),4 which aim to prevent overdiagnosis of ALE and are highly specific.5 These criteria serve as an excellent resource for both specialists and generalists. The treatment of ALE is best coordinated by a specialist in autoimmune neurologic diseases and is beyond the scope of this review. Box 1: Search strategy for this review We screened titles of all publications via PubMed pertaining to the diagnosis of autoimmune limbic encephalitis and/or exclusion of its mimics, dating back to 1964, and reviewed those that were relevant to the subject. We also reviewed the references of all relevant publications for potential inclusion. We emphasized larger cohort and case-control studies over case reports, as well as publications within the last 10 years, given the recent advancements in antibody testing. Box 2: Diagnostic criteria for definite autoimmune limbic encephalitis4 Diagnosis can be made when all 4* of the following criteria have been met: Subacute onset (rapid progression of less than 3 mo) of working memory deficits, seizures, or psychiatric symptoms suggesting involvement of the limbic system. Bilateral brain abnormalities on T2-weighted fluid-attenuated inversion recovery MRI highly restricted to the medial temporal lobes† At least one of the following: CSF pleocytosis (white blood cell count of more than 5 cells per mm3) EEG with epileptic or slow-wave activity involving the temporal lobes Reasonable exclusion of alternative causes Reprinted from Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404, with permission from Elsevier. Note: CSF = cerebrospinal fluid, EEG = electroencephalogram, MRI = magnetic resonance imaging. ↵* If one of the first 3 criteria is not met, a diagnosis of definite limbic encephalitis can be made only with the detection of antibodies against cell-surface, synaptic, or onconeural proteins. ↵† 18 Fluorodeoxyglucose (18 F-FDG) PET can be used to fulfil this criterion. Results from studies from the past 5 years suggest that 18 F-FDG-PET imaging might be more sensitive than MRI to show an increase in FDG uptake in normal-appearing medial temporal lobes. What are the clinical features of autoimmune limbic encephalitis? Typical symptoms of ALE reflect dysfunction of the limbic structures of the brain and include short-term memory deficits, behavioural changes, anxiety, depression, psychosis and seizures. 1,6,7 Autoimmune limbic encephalitis most often occurs in middle-aged adults, but it can affect people of all ages, ranging from children to older people.1,6–8 Pace of disease progression In retrospective studies of patients with ALE, the median time from symptom onset to clinical assessment was usually several weeks;6,9 this subacute presentation of the disease is highlighted in the Graus criteria and is a hallmark of the disorder.4 Although ALE should be considered in any patient who presents with rapidly progressive memory difficulties, behavioural changes, psychiatric symptoms or seizures of unclear cause, an individual who presents with sudden-onset neurologic symptoms is more likely to have suffered an acute neurologic or systemic insult such as a stroke or toxic ingestion. However, it is important not to classify a patient’s illness as acute before questioning family, friends or caregivers about subtle memory problems or behavioural changes in the preceding days or weeks. Conversely, an individual may seem to have a precipitous deterioration concerning for ALE, but after further history-taking, it becomes apparent that there has been milder cognitive impairment over many months, or even years. Although certain antibodies have been associated with a more insidious presentation of ALE,10 a protracted disease course should alert the physician to the possibility of an alternative diagnosis such as a neurodegenerative disease. Involuntary movements Clinicians should ask caregivers about any hemi-body jerking leading up to presentation, which may represent faciobrachial dystonic seizures. These involuntary movements consist of brief contractions that affect the ipsilateral face, arm and sometimes leg; last a few seconds; can occur up to hundreds of times a day; and are often refractory to treatment with anti-epileptic drugs.11 They are seen with anti–leucine-rich glioma inactivated 1 (LGI1) antibodies, the most common antibody causing ALE.9 Other symptoms likely resulting from focal seizure activity may occur in anti-LGI1 encephalitis, including thermal sensations, piloerection and paroxysmal dizziness spells, but faciobrachial dystonic seizures are especially helpful diagnostically as they are nearly pathognomonic of this disease.11–14 Importantly, a normal electroencephalogram (EEG) during faciobrachial dystonic seizures should not dissuade practitioners, as coincident epileptiform discharges are seen only in the minority.11 A retrospective study of 26 patients with such seizures found that they preceded cognitive impairment typical of ALE in 20 patients (77%);11 thus, faciobrachial dystonic seizures may be a clue to prodromal autoimmune neurologic disease in a patient who appears to present acutely. Why is prompt, correct diagnosis essential? A retrospective study examining admission diagnoses of 50 patients with autoimmune encephalitides such as ALE found that two-thirds were initially thought to have conditions other than encephalitis, including primary psychiatric disorders, idiopathic epilepsy, cerebral ischemia or neurodegeneration.15 Even among the one-third of patients in whom encephalitis was considered, an infectious rather than autoimmune cause was more commonly assumed.15 The potential symptom overlap between these 2 disease processes was highlighted in a prospective study of 203 patients with encephalitis, which found that many traditionally infectious symptoms such as fever did not readily distinguish between an infectious and immune-mediated cause.16 Identification of ALE is important because it facilitates prompt use of immunotherapy which, in observational studies, has been associated with reduced seizure frequency, recovery of cognition and likely even improved survival.12,17 Recognition of ALE also triggers malignancy screening, especially among patients with antibodies that strongly predict the presence of a tumour (discussed later; Table 1). Detection of any occult neoplasm is critical as the malignancy may ultimately determine clinical outcome.1 Table 1: Antibodies that may be found in autoimmune limbic encephalitis, and their tumour associations What tests aid in the diagnosis of ALE? Magnetic resonance imaging Magnetic resonance imaging (MRI) of the brain can show medial temporal lobe changes typical of the disease (Figure 1) and is recommended by expert consensus in suspected cases.4 18-Fluorodeoxyglucose positron emission tomography (18-FDG PET) of the brain may be even more sensitive for temporal lobe abnormalities;29 because this modality is not as accessible to many Canadian practitioners, MRI remains a first-line neuroimaging technique. Bilateral imaging abnormalities restricted to the medial temporal lobes are required for a definitive diagnosis of ALE in the absence of antibody positivity. It is important to bear in mind that other diseases — such as other infectious and inflammatory encephalitides, as well as vascular or neoplastic conditions — may involve these structures (Appendix 1, available at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.181548/-/DC1). Figure 1: Brain magnetic resonance imaging in autoimmune limbic encephalitis. On coronal fluid-attenuated inversion recovery (FLAIR) image, bilateral T2-hyperintensity of the medial temporal lobes is seen (A, arrows). (B) Bilateral T2-hyperintensity of the medial temporal lobes is also shown on an axial FLAIR image (arrows). Antibodies targeting contactin-associated protein-like 2 were identified in serum by cell-based assay. Differential diagnosis of temporal lobe changes on MRI In a retrospective review of 251 suspected cases of encephalitis with temporal lobe abnormalities on MRI, nearly 25% were due to herpes simplex virus encephalitis; it is therefore important to rule out this potentially devastating infection in patients with suspected ALE.30 Unilateral rather than bilateral temporal lobe changes, insular involvement and absence of basal ganglia involvement are neuroimaging clues that suggest herpes simplex virus encephalitis rather than ALE (Figure 2A, 2B).30,31 Other major infectious considerations are varicella zoster virus, tuberculosis and neurosyphilis; appropriate testing for these entities should be considered early in the disease course.30,32 Figure 2: Magnetic resonance imaging (MRI) mimics of autoimmune limbic encephalitis. (A, B) Herpes simplex virus encephalitis: On axial T2-weighted image, diffuse T2-hyperintensity of the right anteromedial temporal lobe with swelling is seen (A, arrow). There is also T2-hyperintensity of the right insula (B, arrow) that spares the adjacent basal ganglia (red line demarcating separation). (C, D) Temporal lobe glioma: On axial T2-weighted image, diffuse T2-hyperintensity of the right anteromedial temporal lobe is seen (C, arrow). On follow-up MRI 6 months later, there is heterogenous enhancement with local edema on axial T1-weighted post-gadolinium image, concerning for transformation into high-grade glioma (D, arrow). (E) Status epilepticus: On axial T2-weighted image, there is focal T2-hyperintensity of the medial temporal lobes bilaterally (arrows). (F) Acute ischemic stroke: On axial diffusion–weighted image, there is a diffusion-bright lesion of the left medial temporal lobe within the territory of the left posterior cerebral artery (arrow). There is no extension of the lesion into the more anterior or lateral temporal lobe supplied by the left middle cerebral artery (red line demarcating separation), in keeping with acute infarction restricted to a vascular territory. Several noninfectious diseases may involve the temporal lobes and be mistaken for ALE. Gliomas may cause diffuse temporal lobe changes on MRI, while imaging features of high-grade neoplasm such as necrosis, irregular enhancement and vasogenic edema are absent early on. Although classically thought to present unilaterally, in one retrospective series, bilateral medial temporal lobe involvement was seen in 54% cases of patients with suspected ALE who later developed glioblastoma.33 Follow-up with magnetic resonance imaging is therefore recommended in any patient with possible ALE who progresses atypically, as malignant transformation indicative of high-grade neoplasm may occur (Figure 2C, 2D). Seizures can also cause temporal lobe imaging abnormalities34 (Figure 2E), but early control of seizures with anti-epileptic drugs alone, lack of prodromal neuropsychiatric symptoms and the resolution of temporal lobe changes after cessation of seizure activity are all supportive of seizure-related MRI changes rather than ALE. Ischemic stroke involving the medial temporal lobe usually presents acutely but sometimes causes only mild neurocognitive deficits; patients may delay seeking medical attention. Careful history-taking is needed to differentiate a subacute progression of symptoms over days from a static neurologic insult that occurred days earlier. On MRI, signal abnormality restricted to a vascular territory helps distinguish ischemic stroke from ALE35 (Figure 2F). Electroencephalography Patients with ALE may occasionally have a normal EEG, which does not rule out the diagnosis.9,36 Usually, however, EEG shows slow-wave activity or epileptiform discharges from the temporal lobes of patients with ALE — a clue to brain inflammation. In a retrospective analysis of 19 patients with autoimmune encephalitis and seizures, 10 of 16 patients with ictal EEGs (63%) had seizure onset over the temporal lobe region, which closely mirrored the medial temporal lobe abnormalities seen on MRI in three-quarters of those studied.37 Importantly, EEG abnormalities of the temporal lobes without any observed changes on imaging are not sufficient to make a diagnosis of ALE in the absence of a positive antibody, according to the Graus criteria4 outlined in Box 2. In clinical practice, an EEG that shows slow-wave activity or epileptiform discharges from the temporal lobes in a patient with possible ALE should raise suspicion of the condition even if the initial MRI is normal; in such cases, repeat MRI may be considered, to look for the interval development of medial temporal lobe abnormalities.38 Cerebrospinal fluid analysis Analysis of cerebrospinal fluid can provide evidence of neuro-inflammation in patients with possible ALE. In a retrospective study of 50 patients with paraneoplastic ALE, about 50% had a modest leukocyte pleocytosis in cerebrospinal fluid (< 100 cells/μL), while three-quarters of samples tested for oligoclonal bands were positive. 1 In a larger retrospective pooled-data analysis of 205 patients with ALE, however, leukocyte pleocytosis and oligoclonal bands were each noted in only about 25% of tested cerebrospinal fluid samples.39 These findings suggest that although the presence of leukocyte pleocytosis and oligoclonal bands in cerebrospinal fluid supports a diagnosis of ALE in the appropriate clinical context, their diagnostic sensitivity is low. This is reflected in the Graus criteria, which do not require leukocyte pleocytosis or oligoclonal bands in cerebrospinal fluid for a diagnosis of definite ALE even in the absence of antibody positivity. Testing of the cerebrospinal fluid is also helpful to exclude mimics of ALE, in particular herpes simplex virus encephalitis. A retrospective study found that the cerebrospinal fluid profile alone (leukocyte count, erythrocyte count, protein and glucose) could not reliably differentiate between herpes simplex virus encephalitis and autoimmune encephalitis with temporal lobe abnormalities.30 Polymerase chain reaction (PCR) testing for herpes simplex virus in the cerebrospinal fluid has high diagnostic sensitivity and specificity, but clinicians should be aware that it may be negative early in the disease course.40 If a patient has a negative PCR result but herpes simplex virus encephalitis remains a concern clinically or on neuroimaging, continuing antiviral treatment while awaiting a second lumbar puncture for repeat PCR testing is wise.40 Antibody testing Testing for antibodies to onconeural, cell-surface or synaptic proteins is very helpful in suspected ALE, as a positive disease-specific antibody can make the diagnosis in patients who would not otherwise satisfy Graus criteria.4 The recognition that ALE may be associated with malignancy was followed by the discovery of antineuronal antibodies that supported an immune-mediated disease mechanism.1,41 In a retrospective study of paraneoplastic ALE, antibodies to neural antigens expressed by a tumour (referred to as onconeural antibodies) were identified in 30 of 50 (60%) of patients.1 These were most often anti-Hu or Ma2 antibodies, which are classically found with small-cell lung cancer and testicular tumour, respectively.1 Onconeural antibodies bind intracellular antigens and are therefore of unclear pathogenic significance in ALE; they may simply be an epiphenomenon of a primarily cytotoxic T-cell–mediated process that can lead to irreversible neuronal damage and poor clinical outcomes.42,43 Antibodies to the intracellular antigen glutamic acid decarboxylase may also be associated with ALE, but at much higher titres than are typically seen in type 1 diabetes mellitus.44 More recently, antibodies targeting neuronal cell-surface or synaptic proteins have been discovered in patients with ALE; they bind extracellular antigens and are thus more likely to be pathogenic.6,7,45 These antibodies are variably associated with malignancy, and patients often improve with immunotherapy, owing to reversal of antibody-mediated neuronal dysfunction.2 In a retrospective study of 163 patients with ALE, antibodies were found in 93%, the majority of which targeted neuronal cell-surface or synaptic proteins: LGI1 in 44%, γ-aminobutyric acid B receptor (GABABR) in 16%, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in 7%, and contactin-associated protein-like 2 (CASPR2) in 6%.9 Of note, antibodies to the voltage-gated potassium channel were initially reported in ALE but later found to target the associated proteins LGI1 and CASPR2, rather than the voltage-gated potassium channel itself.46 Antibodies to the N-methyl-d-aspartate receptor (NMDAR) may be identified in ALE, but more often are found in patients with a normal MRI and a characteristic clinical syndrome (anti-NMDAR encephalitis), consisting of abnormal behaviour, speech dysfunction, seizures, dyskinesias or dysautonomia.20,47 Approach to antibody testing Both serum and cerebrospinal fluid testing for the most commonly identified antibodies in ALE (anti-LGI1, GABABR, AMPAR, CASPR2, Hu, Ma2 and GAD) should be considered, to maximize diagnostic yield, as some antibodies (e.g., anti-LGI1) are more sensitive in serum and others (e.g., anti-GABABR) may be identified only in cerebrospinal fluid.14,17 Antibody testing is also worthwhile even in a patient who already meets Graus criteria for definite ALE, as a positive antibody may indicate the likelihood of a specific tumour (Table 1) and inform malignancy screening. The presence of an antibody with a strong tumour association should prompt repeated screening for malignancy if an initial screen is negative, to ensure an occult neoplasm is not missed.48 Even if a patient is ultimately determined to have a diagnosis other than ALE, a positive antibody still requires investigation if it strongly associates with an underlying tumour (e.g., anti-Hu).49 Further detail regarding screening for tumours in paraneoplastic neurologic syndromes such as ALE is beyond the scope of this review, but a comprehensive guideline has been published.48 If a positive antibody is reported in a patient deemed unlikely to have ALE, inquiry should be made into whether the testing laboratory can perform a confirmatory assay to exclude false-positives.10,50 Conclusion Accurate diagnosis of ALE is critical to ensure appropriate management of the disease and to maximize the likelihood of a good patient outcome. Although recently published criteria provide a valuable diagnostic framework for ALE, it is important to understand the rationale behind using conventional diagnostic tools (MRI, EEG and analysis of cerebrospinal fluid), as well as their limitations. While questions remain (Box 3), the ongoing discovery of antibodies to onconeural, cell-surface and synaptic proteins represents a major advancement in the refined diagnosis of ALE, and, as such testing becomes more accessible, a thoughtful diagnostic approach will help to balance patient care with resource management in Canada. Box 3: Unanswered questions Should 18-fluorodeoxyglucose positron emission tomography routinely be performed in patients with suspected autoimmune limbic encephalitis who have a normal magnetic resonance imaging scan? Should more extensive antibody testing be performed in patients who already meet criteria for definite autoimmune limbic encephalitis, but are negative for the most common antibodies associated with this disease? What is the threshold of suspicion for autoimmune limbic encephalitis above which antibody testing should be sent, so as to avoid indiscriminate ordering and minimize the risk of false-positive results? Should methods of antibody testing be standardized across Canadian institutions? Footnotes Competing interests: Jorge Burneo reports receiving grants from the Rick Berg Legacy Fund, the Ontario Brain Institute and Western University, and other support through the Jack Cowin Chair in Epilepsy Research (a Western University Research Chair), outside the submitted work. No other competing interests were declared. This article has been peer reviewed. Contributors: All of the authors contributed to the conception and design of the work, and the acquisition, analysis, and interpretation of data. Adrian Budhram drafted the manuscript. Andrew Leung, Michael Nicolle and Jorge Burneo revised it critically for important intellectual content. All authors gave final approval of the version to be published and agreed to be accountable for all aspects of the work. References ↵Gultekin SH, Rosenfeld MR, Voltz R, et al. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain 2000;123:1481–94.OpenUrlCrossRefPubMed ↵Dalmau J, Graus F. Antibody-mediated encephalitis. N Engl J Med 2018;378:840–51.OpenUrlCrossRefPubMed ↵Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol 2018;83:166–77.OpenUrlCrossRefPubMed ↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 2016;15:391–404.OpenUrlCrossRefPubMed ↵Li L, Sun L, Du R, et al. Application of the 2016 diagnostic approach for autoimmune encephalitis from Lancet Neurology to Chinese patients. BMC Neurol 2017;17:195.OpenUrl ↵Höftberger R, Titulaer MJ, Sabater L, et al. Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology 2013;81:1500–6.OpenUrlCrossRefPubMed ↵Lai M, Huijbers MG, Lancaster E, et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol 2010;9:776–85.OpenUrlCrossRefPubMed ↵Honnorat J, Didelot A, Karantoni E, et al. Autoimmune limbic encephalopathy and anti-Hu antibodies in children without cancer. Neurology 2013;80:2226–32.OpenUrlCrossRefPubMed ↵Graus F, Escudero D, Oleaga L, et al. 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Admission diagnoses of patients later diagnosed with autoimmune encephalitis. J Neurol 2019;266:124–32.OpenUrl ↵Granerod J, Ambrose HE, Davies NW, et al.UK Health Protection Agency (HPA) Aetiology of Encephalitis Study Group. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis 2010;10:835–44.OpenUrlCrossRefPubMed ↵Lancaster E, Lai M, Peng X, et al. Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol 2010;9:67–76.OpenUrlCrossRefPubMed Höftberger R, van Sonderen A, Leypoldt F, et al. Encephalitis and AMPA receptor antibodies: novel findings in a case series of 22 patients. Neurology 2015;84: 2403–12.OpenUrlPubMed Laurido-Soto O, Brier MR, Simon LE, et al. Patient characteristics and outcome associations in AMPA receptor encephalitis. J Neurol 2019;266:450–60.OpenUrl ↵Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013;12:157–65.OpenUrlCrossRefPubMed Spatola M, Sabater L, Planagumà J, et al. Encephalitis with mGluR5 antibodies: symptoms and antibody effects. Neurology 2018;90:e1964–72.OpenUrl Gresa-Arribas N, Planagumà J, Petit-Pedrol M, et al. Human neurexin-3α antibodies associate with encephalitis and alter synapse development. Neurology 2016;86:2235–42.OpenUrl Graus F, Keime-Guibert F, Reñe R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001;124:1138–48.OpenUrlCrossRefPubMed Dalmau J, Graus F, Villarejo A, et al. Clinical analysis of anti-Ma2-associated encephalitis. Brain 2004;127:1831–44.OpenUrlCrossRefPubMed Ariño H, Höftberger R, Gresa-Arribas N, et al. Paraneoplastic neurological syndromes and glutamic acid decarboxylase antibodies. JAMA Neurol 2015;72: 874–81.OpenUrl Pittock SJ, Lucchinetti CF, Parisi JE, et al. Amphiphysin autoimmunity: paraneoplastic accompaniments. Ann Neurol 2005;58:96–107.OpenUrlCrossRefPubMed Yu Z, Kryzer TJ, Griesmann GE, et al. CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol 2001; 49: 146–54.OpenUrlCrossRefPubMed Do L-D, Chanson E, Desestret V, et al. Characteristics in limbic encephalitis with anti–adenylate kinase 5 autoantibodies. Neurology 2017;88:514–24.OpenUrl ↵Newey CR, Sarwal A, Hantus S. [(18)F]-fluoro-deoxy-glucose positron emission tomography scan should be obtained early in cases of autoimmune encephalitis. Autoimmune Dis 2016;2016:9450452. ↵Chow FC, Glaser CA, Sheriff H, et al. Use of clinical and neuroimaging characteristics to distinguish temporal lobe herpes simplex encephalitis from its mimics. 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Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 2004;127:701–12.OpenUrlCrossRefPubMed ↵Steriade C, Moosa ANV, Hantus S, et al. Electroclinical features of seizures associated with autoimmune encephalitis. Seizure 2018;60:198–204.OpenUrl ↵Pessa ME, Janes F, Gigli GL. Electroencephalographic evaluation for early diagnosis of limbic encephalitis. Clin EEG Neurosci 2016;47:207–10.OpenUrlCrossRefPubMed ↵Malter MP, Elger CE, Surges R. Diagnostic value of CSF findings in antibody-associated limbic and anti-NMDAR-encephalitis. Seizure 2013;22:136–40.OpenUrlCrossRefPubMed ↵Weil AA, Glaser CA, Amad Z, et al. Patients with suspected herpes simplex encephalitis: rethinking an initial negative polymerase chain reaction result. Clin Infect Dis 2002;34:1154–7.OpenUrlCrossRefPubMed ↵Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. 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Neural Antibody Testing for Autoimmune Encephalitis: A Canadian Single-Centre Experience | Canadian Journal of Neurological Sciences

Neural Antibody Testing for Autoimmune Encephalitis: A Canadian Single-Centre Experience - Volume 48 Issue 6
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Autoimmune encephalitis with coexistent LGI1 and GABABR1 antibodies: case report | BMC Neurology | Full Text

Autoimmune encephalitis with coexistent LGI1 and GABABR1 antibodies: case report | BMC Neurology | Full Text | AntiNMDA | Scoop.it
Background Autoimmune encephalitis (AE) with multiple auto-antibodies is of great clinical significance because its complex clinical manifestations and atypical imaging increase the difficulty of diagnosis, differential diagnosis and treatment, which may aggravate the disease, increase the recurrence rate and mortality. The coexistence of anti-Leucinie-rich Glioma Inactivated 1 (LGI1) and anti-γ-aminobutyric acid-beta-receptor 1 (GABABR1) has not been published before. Case presentation We herein present the case of a 60-year-old man with slow response, behavioral changes, psychosis and sleep disorders. Laboratory test included serum hyponatremia, positive serum LGI1 and GABABR1 antibodies using transfected cell-based assays. Electroencephalogram exhibited moderate diffusion abnormality. The patient responded well to steroid impulse treatment and sodium supplement therapy, and did not recur during the follow-up. Conclusions Here we report the first AE characterized by positive LGI1 and GABABR1 antibodies, as well as summarizing AE with multiple auto-antibodies reported so far, hopefully to provide experience for clinical practice.
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EEG Contribution to the Diagnosis of Antibody-Negative Autoimmune Encephalitis: A Case Report - FullText - Case Reports in Neurology 2021, Vol. 13, No. 3 - Karger Publishers

Autoimmune encephalitis (AE) is a group of inflammatory brain diseases that are characterized by prominent neuropsychiatric symptoms. Early therapeutic intervention is important for AE.Therefore, wit...
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Author Response: Clinical, Neuroimmunologic, and CSF Investigations in First Episode Psychosis | Neurology

Author Response: Clinical, Neuroimmunologic, and CSF Investigations in First Episode Psychosis | Neurology | AntiNMDA | Scoop.it
We appreciate the interest in our research.1 According to Pollak and colleagues,2 criteria of possible autoimmune psychosis (AP) are fulfilled if a patient has abrupt onset psychotic symptoms with at least one of the following: the presence of a tumor, movement disorder (dyskinesias, catatonia), adverse response to antipsychotics, “severe or disproportionate” cognitive dysfunction, decreased level of consciousness, unexplained seizures, and significant autonomic dysfunction.2 Fulfilment of these criteria should lead to additional tests such as EEG, MRI, and serum or CSF investigations. In our series of 105 patients with first episode of psychosis (FEP), 20% fulfilled these criteria but never developed AP.1 We confirm that 2 of 3 patients with anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis presenting with FEP did not fulfill any of these criteria, including catatonia, which is a complex syndrome with its own set of 12 criteria that include echolalia.3 Thus, catatonia and echolalia should not be used as interchangeable terms.
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Autoantibody-associated psychiatric symptoms and syndromes in adults: A narrative review and proposed diagnostic approach

Autoantibody-associated psychiatric symptoms and syndromes in adults: A narrative review and proposed diagnostic approach | AntiNMDA | Scoop.it
Autoimmune-mediated encephalitis is a disease that often encompasses psychiatric symptoms as its first clinical manifestation’s predominant and isolated characteristic. Novel guidelines even distinguish autoimmune psychosis from autoimmune encephalitis.
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Vennada's Story: Recovery from Anti-NMDA Receptor Encephalitis

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The grey zone between autoimmune encephalitis and autoimmune‐associated epilepsy - Morano - - Epilepsia Open

The grey zone between autoimmune encephalitis and autoimmune‐associated epilepsy - Morano - - Epilepsia Open | AntiNMDA | Scoop.it
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The role of dendritic cells and their interactions in the pathogenesis of antibody-associated autoimmune encephalitis | Journal of Neuroinflammation | Full Text

The role of dendritic cells and their interactions in the pathogenesis of antibody-associated autoimmune encephalitis | Journal of Neuroinflammation | Full Text | AntiNMDA | Scoop.it
Autoimmune encephalitis (AE) is an inflammatory brain disease which is frequently associated with antibodies (Abs) against cell-surface, synaptic or intracellular neuronal proteins. There is increasing evidence that dendritic cells (DCs) are implicated as key modulators in keeping the balance...
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Unraveling the enigma of new-onset refractory status epilepticus: a systematic review of aetiologies | Read by QxMD

Unraveling the enigma of new-onset refractory status epilepticus: a systematic review of aetiologies | Read by QxMD | AntiNMDA | Scoop.it
RESULTS: Four hundred and fifty records were initially identified, of which 197 were included in the review. The selected studies were retrospective case-control (n=11), case series (n=83), and case reports (n=103) and overall described 1334 patients both of paediatric and adult age. Aetiology remains unexplained in about half of the cases, representing the so-called "cryptogenic NORSE". Among adult patients without cryptogenic NORSE, the most often identified cause is autoimmune encephalitis, either non-paraneoplastic or paraneoplastic. Infections are the prevalent aetiology of paediatric non-cryptogenic NORSE. Genetic and congenital disorders can have a causative role in NORSE, and toxic, vascular, and degenerative conditions have been also described.
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Screening for pathogenic neuronal autoantibodies in serum and CSF of patients with first-episode psychosis

Screening for pathogenic neuronal autoantibodies in serum and CSF of patients with first-episode psychosis | AntiNMDA | Scoop.it
Patients with autoimmune encephalitides, especially those with antibodies to the N-methyl-d-aspartate receptor (NMDAR), often present with prominent psychosis and respond well to immunotherapies. Although most patients progress to develop various neurological symptoms, it has been hypothesised...
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Rituximab Treatment and Long-term Outcome of Patients With Autoimmune Encephalitis | Neurology Neuroimmunology & Neuroinflammation

Rituximab Treatment and Long-term Outcome of Patients With Autoimmune Encephalitis | Neurology Neuroimmunology & Neuroinflammation | AntiNMDA | Scoop.it
Immunotherapeutic strategies for GAD65-AE remain highly controversial.27 Most patients are considered to require immunotherapy, and early immunotherapy has been found to be associated with a better outcome.10,28 However, the different neurologic manifestations of SPS, CA, and LE appear to respond...
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Anti-NMDAR Encephalitis: Multidisciplinary Development of a Clinical Practice Guideline | American Academy of Pediatrics

Anti-NMDAR Encephalitis: Multidisciplinary Development of a Clinical Practice Guideline | American Academy of Pediatrics | AntiNMDA | Scoop.it
Knowledge about the diagnosis of autoimmune encephalitis (AE) is rapidly expanding. In the last 15 years, multiple new antibodies have been described. Anti-N-methyl-D-aspartate receptor (NMDAR)–antibody-mediated encephalitis, in particular, has been found to be common among teenagers and young adults1 and accounts for up to 86% of AE in patients aged <18 years.2 Other antibodies associated with AE (leucine-rich glioma-inactivated 1, contactin-associated protein-like 2, glutamic acid decarboxylase 65-kilodalton isoform, γ-aminobutyric acid A, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) are reported in children as case reports or series and with less clear typical clinical syndromes.3–9
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Comprehensive B-Cell Immune Repertoire Analysis of Anti-NMDAR Encephalitis and Anti-LGI1 Encephalitis

Comprehensive B-Cell Immune Repertoire Analysis of Anti-NMDAR Encephalitis and Anti-LGI1 Encephalitis | AntiNMDA | Scoop.it
Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) and anti-leucine-rich glioma-inactivated 1 encephalitis (anti-LGI1E) are the two most common types of antibody-mediated autoimmune encephalitis.
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Meet Ambassador Jayden Liuzza

The Foundation is very proud to introduce our first and the world’s youngest Ambassador for Anti-NMDA receptor encephalitis, Jayden Liuzza. You may remember seeing Jayden ...Read More...
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Dysfunction of the Autonomic Nervous System and its Role in the Pathogenesis of Septic Critical Illness (Review)

Dysfunction of the Autonomic Nervous System and its Role in the Pathogenesis of Septic Critical Illness (Review) | AntiNMDA | Scoop.it
Dysfunction of the autonomic nervous system (ANS) of the brain in sepsis can cause severe systemic inflammation and even death. Numerous data confirmed the role of ANS dysfunction in the occurrence, course, and outcome of systemic sepsis.
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Frontiers | Risk Factors and Brain Metabolic Mechanism of Sleep Disorders in Autoimmune Encephalitis | Immunology

Frontiers | Risk Factors and Brain Metabolic Mechanism of Sleep Disorders in Autoimmune Encephalitis | Immunology | AntiNMDA | Scoop.it
BackgroundSleep disorders (SDs) in autoimmune encephalitis (AE) have received little attention and are poorly understood. We investigated the clinical characteristics, risk factors, and cerebral metabolic mechanism of SD in AE.MethodsClinical, laboratory, and imaging data were retrospectively...
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A peculiar case of psychosis: anti-NMDAr encephalitis | International Journal of Emergency Medicine | Full Text

A peculiar case of psychosis: anti-NMDAr encephalitis | International Journal of Emergency Medicine | Full Text | AntiNMDA | Scoop.it
Background Psychosis in pregnancy is rare and could be life-threatening. It requires prompt evaluation and proper management accordingly. Anti-N-methyl-d-aspartate receptor (anti-NMDAr) encephalitis following herpes simplex virus (HSV) infection is a rare cause of psychosis during pregnancy.
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Acute Psychosis Due to Anti-N-Methyl D-Aspartate Receptor Encephalitis Following COVID-19 Vaccination: A Case Report - PMC

Acute Psychosis Due to Anti-N-Methyl D-Aspartate Receptor Encephalitis Following COVID-19 Vaccination: A Case Report - PMC | AntiNMDA | Scoop.it
Anti-N-methyl D-aspartate (NMDA) receptor (anti-NMDAR) encephalitis has been reported after SARS-CoV-2 infection, but not after SARS-CoV-2 vaccination. We report the first known case of anti-NMDAR encephalitis after SARS-CoV-2 immunization in a young ...
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Anti-NMDAR Autoantibodies Disrupt Ionotropic Receptor Signaling –

Anti-NMDAR Autoantibodies Disrupt Ionotropic Receptor Signaling – | AntiNMDA | Scoop.it
Vignesh Subramanian '24 Figure 1: The N-methyl-D-aspartate receptor (NMDAR) functions as an ion channel. N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels whose signaling enables higher-order functions, such as learning and memory, throughout the brain.
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A Brain on Fire: Laura's Battle with Autoimmune Encephalitis

A Brain on Fire: Laura's Battle with Autoimmune Encephalitis | AntiNMDA | Scoop.it
Laura Martin, a strong student and standout goalie at Transylvania University, hit a sudden wall as things turned worse. Diagnosis: Autoimmune Encephalitis.
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Frontiers | Case Report: Prominent Brainstem Involvement in Two Patients With Anti-CASPR2 Antibody-Associated Autoimmune Encephalitis | Immunology

Frontiers | Case Report: Prominent Brainstem Involvement in Two Patients With Anti-CASPR2 Antibody-Associated Autoimmune Encephalitis | Immunology | AntiNMDA | Scoop.it
Anti-contactin-associated protein-like 2 (CASPR2) antibody-associated autoimmune encephalitis is commonly characterized by limbic encephalitis with clinical symptoms of mental and behavior disorders, cognitive impairment, deterioration of memory, and epilepsy.
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Frontiers | Acute Psychosis Due to Anti-N-Methyl D-Aspartate Receptor Encephalitis Following COVID-19 Vaccination: A Case Report | Neurology

Frontiers | Acute Psychosis Due to Anti-N-Methyl D-Aspartate Receptor Encephalitis Following COVID-19 Vaccination: A Case Report | Neurology | AntiNMDA | Scoop.it
Anti-N-methyl D-aspartate (NMDA) receptor (anti-NMDAR) encephalitis has been reported after SARS-CoV-2 infection, but not after SARS-CoV-2 vaccination. We report the first known case of anti-NMDAR encephalitis after SARS-CoV-2 immunization in a young female presenting with acute psychosis,...
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Lauren's Healing Story (Autoimmune Encephalitis) - Phoenix Helix

Lauren's Healing Story (Autoimmune Encephalitis) - Phoenix Helix | AntiNMDA | Scoop.it
When you have a disease only recently discovered and most doctors don't know it exists, it takes strong self-advocacy to get the help you need.
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CSF Findings in Acute NMDAR and LGI1 Antibody–Associated Autoimmune Encephalitis

CSF Findings in Acute NMDAR and LGI1 Antibody–Associated Autoimmune Encephalitis | AntiNMDA | Scoop.it
CSF in antibody-defined autoimmune encephalitis (AE) subtypes shows subtype-dependent degrees of inflammation ranging from rare and often mild to frequent and often robust. AEs with NMDA receptor antibodies (NMDAR-E) and leucine-rich glioma-inactivated ...
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Physical Therapy Interventions and Outcome Measures for a Patient Diagnosed with Anti-NMDA Receptor Encephalitis

Physical Therapy Interventions and Outcome Measures for a Patient Diagnosed with Anti-NMDA Receptor Encephalitis | AntiNMDA | Scoop.it
Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is the most common cause of
autoimmune encephalitis after acute demyelinating encephalitis. Patients usually present
with acute behavioral changes, psychosis, and abnormal limb movements and can also
...
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