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Autoimmune Encephalitis Resembling Dementia Syndromes | Neurology Neuroimmunology & Neuroinflammation

Autoimmune Encephalitis Resembling Dementia Syndromes | Neurology Neuroimmunology & Neuroinflammation | AntiNMDA | Scoop.it
Abstract Objective As autoimmune encephalitis (AIE) can resemble neurodegenerative dementia syndromes, and patients do not always present as encephalitis, this study evaluates how frequently AIE mimics dementia and provides red flags for AIE in middle-aged and older patients. Methods In this nationwide observational cohort study, patients with anti–leucine-rich glioma-inactivated 1 (LGI1), anti–NMDA receptor (NMDAR), anti–gamma-aminobutyric acid B receptor (GABABR), or anti–contactin-associated protein-like 2 (CASPR2) encephalitis were included. They had to meet 3 additional criteria: age ≥45 years, fulfillment of dementia criteria, and no prominent seizures early in the disease course (≤4 weeks). Results Two-hundred ninety patients had AIE, of whom 175 were 45 years or older. Sixty-seven patients (38%) fulfilled criteria for dementia without prominent seizures early in the disease course. Of them, 42 had anti-LGI1 (48%), 13 anti-NMDAR (52%), 8 anti-GABABR (22%), and 4 anti-CASPR2 (15%) encephalitis. Rapidly progressive cognitive deterioration was seen in 48 patients (76%), whereas a neurodegenerative dementia syndrome was suspected in half (n = 33). In 17 patients (27%; 16/17 anti-LGI1), subtle seizures had been overlooked. Sixteen patients (25%) had neither inflammatory changes on brain MRI nor CSF pleocytosis. At least 1 CSF biomarker, often requested when dementia was suspected, was abnormal in 27 of 44 tested patients (61%), whereas 8 had positive 14-3-3 results (19%). Most patients (84%) improved after immunotherapy. Conclusions Red flags for AIE in patients with suspected dementia are: (1) rapidly progressive cognitive decline, (2) subtle seizures, and (3) abnormalities in ancillary testing atypical for neurodegeneration. Physicians should be aware that inflammatory changes are not always present in AIE, and that biomarkers often requested when dementia was suspected (including 14-3-3) can show abnormal results. Diagnosis is essential as most patients profit from immunotherapy. Glossary Aβ42=amyloid-beta-42; AD=Alzheimer dementia; ADL=activity of daily living; AIE=autoimmune encephalitis; CASPR2=contactin-associated protein-like 2; CBA=cell-based assay; CJD=Creutzfeldt-Jakob disease; DWI=diffusion-weighted imaging; FBDS=faciobrachial dystonic seizures; FDG-PET=18fluorodeoxyglucose PET; GABABR=gamma-aminobutyric acid B receptor; Ig=immunoglobulin; IQR=interquartile range; ISO=International Organization for Standardization; LGI1=leucine-rich glioma-inactivated 1; mRS=modified Rankin scale; NMDAR=NMDA receptor; p-tau=phosphorylated tau; RPD=rapidly progressive dementia; RT-QuIC=real‐time quaking-induced conversion; t-tau=total tau Autoimmune encephalitis (AIE) comprises a group of antibody-mediated inflammatory brain diseases. Binding of these antibodies to extracellular epitopes of neuronal structures leads to cerebral dysfunction. Diagnostic criteria for AIE help to select patients for antibody testing. These criteria are characterized by a subacute deterioration of cognition, altered mental status, or psychiatric symptoms. These symptoms should be accompanied by seizures, new findings of focal involvement of the CNS, or inflammatory changes in the CSF (pleocytosis) or on brain MRI.1 Anti–leucine-rich glioma-inactivated 1 (LGI1), anti–NMDA receptor (NMDAR), anti–gamma-aminobutyric acid B receptor (GABABR), or anti–contactin-associated protein-like 2 (CASPR2) antibodies are the most common antibodies causing AIE, and cognition is frequently affected in all these AIE subtypes.2,-,5 Diagnosing AIE can be challenging because patients can present with less notable encephalitis signs. The disease course can mimic neurodegenerative dementia syndromes. Rapid progression is often expected, but slower progression has also been described, resulting in misdiagnosis or treatment delay leading to a worse outcome.5,-,10 It is unknown how often AIE resembles dementia syndromes.11,12 In patients presenting with a possible dementia, clinical clues are essential for physicians to avoid misdiagnosis and inadvertently withhold patients from immunotherapy. The study aim was to evaluate possible dementia diagnosis and to describe red flags for AIE in middle-aged and older patients with anti-LGI1, anti-NMDAR, anti-CASPR2, and anti-GABABR encephalitis. Methods Patients We performed a nationwide observational cohort study in middle-aged and older patients with anti-LGI1, anti-NMDAR, anti-GABABR, and anti-CASPR2 encephalitis. The Department of Neurology of the Erasmus University Medical Center is the national referral site for patients with suspected AIE, and the Laboratory of Medical Immunology is the International Organization for Standardization (ISO) 15189-accredited national referral site for antineuronal antibody testing. Patients were identified between August 1999 and September 2019, although 87% were identified after 2010. All Dutch patients with AIE with anti-LGI1, anti-NMDAR, anti-GABABR, or anti-CASPR2 antibodies were asked to participate.3,-,5,13 Antibodies were detected in serum, or in the CSF using validated commercial cell-based assays (CBAs), and were confirmed with in-house CBA, immunohistochemistry, or live hippocampal neurons as described before.3,5,14,15 Only patients who were 45 years or older at disease onset were included, as the main challenge to discriminate between AIE and neurodegenerative dementia is within this age group (Figure 1). Figure 1 Patient Inclusion In total, 290 patients with autoimmune encephalitis were identified. At disease onset, 175 of the patients had an age of ≥45 years. Sixty-seven patients fulfilled the dementia criteria including the additional condition that no prominent seizures were present at early disease course (≤4 weeks). *Percentage of the patients ≥45 years of age. AIE = autoimmune encephalitis; CASPR2 = contactin-associated protein-like 2; GABABR = gamma-aminobutyric acid B receptor; LGI1 = leucine-rich glioma-inactivated 1; NMDAR = NMDA receptor. In addition to the tests that were performed in the diagnostic workup, CSF markers that often requested when dementia was suspected (total tau [t-tau], phosphorylated tau-181 [p-tau], and 14-3-3) were determined in all patients with sufficient available CSF (n = 12), in the ISO 15189-accredited laboratory at the Radboud UMC.16 Levels of t-tau and p-tau were measured using ELISAs (Fujirebio, Ghent, Belgium). From February 2019, a semiautomated version of the same ELISAs using Lumipulse (Fujirebio, Ghent, Belgium) was used. 14-3-3 was analyzed using Western blotting as previously described.17 Furthermore, patients with a positive 14-3-3 and sufficient available CSF were post hoc tested for real‐time quaking-induced conversion (RT-QuIC).18 All values were scored according to the reference values at the time of testing and adjusted to current cutoff values in the figure for ease of comparison. Cutoff values to be considered abnormal were t-tau > 400 pg/mL, p-tau > 64 pg/mL, amyloid-beta-42 (Aβ42) < 500 pg/mL, a t-tau/p-tau ratio > 30, and a t-tau/Aβ42 ratio > 0.52. A positive 14-3-3 or RT-QuIC was also abnormal. Based on these CSF markers, patients had a Creutzfeldt-Jakob disease (CJD) profile if the t-tau/p-tau ratio was abnormal, and an Alzheimer dementia (AD) profile was assigned when Aβ42 was lowered or the t-tau/Aβ42 ratio was abnormal.19 MRIs were reviewed at our site by neuroradiologists in most cases visiting our center, whereas in patients with LGI1 antibodies MRIs were scored by an independent neuroradiologist as published before.3 In the remaining patients, radiographic outcomes were based on the radiology reports. Clinical Phenotype and Dementia Criteria Clinical patient data were retrieved during a visit to our clinic in 48%, from telephone interviews with patients or relatives in 31%, and from medical files in 21%. The clinical disease course was assessed for fulfillment of the 2011 NINCDS-ADRDA criteria for dementia.20 These internationally accepted core clinical criteria can be used for the diagnosis of all-cause dementia. Dementia is diagnosed when there are cognitive or behavioral symptoms that (1) interfere with the ability to function at work or at usual activities; (2) represent a decline from previous levels of functioning and performing; (3) are not explained by delirium or major psychiatric disorder; (4) cognitive impairment is detected and diagnosed through a combination of history-taking and a cognitive assessment; and (5) the cognitive or behavioral impairment involves a minimum of 2 of the following domains: (a) impaired ability to acquire and remember new information; (b) impaired executive functions; (c) impaired visuospatial abilities; (d) impaired language functions; and (e) changes in personality, behavior, or comportment.20 Rapidly progressive dementia (RPD) was defined as fulfillment of the dementia criteria within 12 months or death within 2 years after the appearance of the first cognitive symptoms.21 In addition, we excluded patients with prominent seizures early in the disease course (≤4 weeks) because this is less likely in neurodegenerative dementia syndromes, and physicians will already suspect inflammatory causes. Subtle seizures that remained unnoticed by the treating physician were not covered by these additional criteria. Level of functioning was measured with the modified Rankin scale (mRS),22 and in most patients, we had direct contact to obtain mRS scores. Cognitive domains were assessed by 2 persons independently reviewing all clinical charts, using neuropsychological assessments, Mini-Mental State Examinations, and Montreal Cognitive Assessments when available. Statistics Categorical data were compared using the Fisher-Freeman-Halton test. Continuous data were analyzed using one-way analysis of variance with log-transformation because of skewed distribution (age at disease onset and delay until initiation of treatment after disease onset) and the Kruskal-Wallis test (days between the onset and start of seizures, days to cognitive decline after disease onset, duration of follow-up, and mRS at follow-up). To assess multiple testing, p values below 0.005 were considered significant. Values between 0.05 and 0.005 should be interpreted carefully and considered exploratory. Post hoc analysis to evaluate differences between antibody types was assessed using the same statistical tests, corrected by the Holm method. We used SPSS 25.0 (SPSS Inc., Chicago, IL) for Windows for statistical analysis, as well as Prism 8.4.3 (GraphPad, San Diego, CA). Standard Protocol Approvals, Registrations, and Patient Consents This study was approved by the Institutional Review Board of the Erasmus MC. Written informed consent was obtained from all patients. Data Availability Any data not published within this article are available at the Erasmus MC University Medical Center. Patient-related data will be shared on reasonable request from any qualified investigator, maintaining anonymization of the individual patients. Results Patient Characteristics In total, 290 patients with AIE were identified, of whom 95 patients harbored LGI1 antibodies, 132 NMDAR antibodies, 37 GABABR antibodies, and 26 CASPR2 antibodies. At disease onset, 175 of the patients (60%) had an age of ≥45 years, including 88 LGI1 (93%), 25 NMDAR (19%), 36 GABABR (97%), and 26 CASPR2 (100%) encephalitis patients. These patients were assessed for fulfillment of the dementia criteria including the additional condition that no prominent seizures were present at early disease course. Sixty-seven patients fulfilled these criteria (39%): 42 LGI1 (48%), 13 NMDAR (52%), 8 GABABR (22%), and 4 CASPR2 (15%) encephalitis patients (Figure 1). Patients who had no very rapid onset (only fulfilling dementia criteria beyond 3 months) and had neither MRI abnormalities nor CSF pleocytosis were highlighted in eFigure 1 and eTable 1 (links.lww.com/NXI/A535), as these pose the largest challenge. The patients with CASPR2 encephalitis were excluded from statistical analysis (because of the small number) and described exploratively in the supplementary text. Of the remaining 63 patients with anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis, 37 were male (58%; Table 1). In anti-LGI1 encephalitis, there was a trend toward a male predominance compared with the higher frequency of females in anti-NMDAR encephalitis (puncorrected = 0.047). The median age at onset was 64 years (interquartile range [IQR] 58–72, range 48–85). View inline View popup Table 1 Patient Characteristics Almost all patients had cognitive deterioration (n = 62, 98%) and behavioral changes (n = 55, 87%). Cognitive decline was the presenting symptom in most patients (n = 48, 76%; median time to cognitive decline 0 days). There was a rapidly progressive deterioration of cognitive symptoms in 48 patients (76%), and 5 patients were admitted to a closed psychogeriatric ward. In half of the patients (n = 33, 52%), a neurodegenerative dementia syndrome was suspected by the treating physician. Cognitive domains were affected differently in the various AIE subtypes (Figure 2). Patients with anti-LGI1 or anti-GABABR encephalitis had similarities with more prominent and more frequently severe impairment of visuospatial and executive functions (∼70% in LGI1 and 55% in GABABR encephalitis). By contrast, patients with anti-NMDAR encephalitis more frequently had impaired language functions (85%, p < 0.0001), and behavioral changes were more prominent. Figure 2 Cognitive Domains in Autoimmune Encephalitis For patients with anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis, cognitive symptoms were divided into 5 cognitive domains. The domains for memory and behavior were divided into 4 categories (not present, mildly present, present, and prominent), and the speech, visuospatial, and executive domains were divided into 3 categories (not present, present, and prominent). ***p < 0.0001 and **p = 0.001 between anti-NMDAR and, respectively, anti-LGI1 and anti-GABABR. GABABR = gamma-aminobutyric acid B receptor; LGI1 = leucine-rich glioma-inactivated 1; NMDAR = NMDA receptor. Sleep-related problems were most frequent in anti-LGI1 encephalitis (57%, p = 0.004). In anti-NMDAR encephalitis, patients experienced, besides the speech problems, more movement disorders (46%, puncorrected = 0.009; eTable 1 and eTable 2, links.lww.com/NXI/A535). There were no prominent seizures early (≤4 weeks) in the disease course (exclusion criterion). If prominent seizures were present, these occurred after a median of 3 months (IQR 42–181 days). However, 40 patients (64%) developed seizures during the course of the disease. Looking scrutinously, actually 11 of 40 patients with seizures (28%) had developed subtle seizures within 2 weeks after disease onset. However, in all patients, these were initially missed faciobrachial dystonic seizures (FBDS) or nonmotor subtle focal seizures. In total, subtle seizures were overlooked in a quarter of the patients (n = 17). Most subtle seizures were seen in anti-LGI1 encephalitis (n = 16) compared with the other AIE subtypes (puncorrected = 0.011). Ancillary Testing Ancillary testing showed normal routine CSF results (white blood cell count, total protein, and, if performed, immunoglobulin (Ig) G index and oligoclonal bands) and no abnormalities related to AIE (hyperintensities of the mesial temporal lobe) on MRI T2/fluid-attenuated inversion recovery in half of the patients (53% and 54%, respectively). In 16 of 61 patients (25%), neither CSF pleocytosis nor MRI inflammatory changes were found. In anti-LGI1, CSF was even more frequently normal (76%, p < 0.0001). In all patients, atrophy was rarely seen on initial MRI (n = 4), and no abnormalities on diffusion-weighted imaging (DWI) were reported. EEG showed epileptic discharges in 13 patients (23%), and in 25 patients (45%), the EEG was normal, similar between AIE subtypes. Tumor screening resulted in malignancies in 10 patients (17%), and as expected, in patients with GABABR antibodies, this was most frequent (57%; p = 0.004). Only 2 patients underwent 18fluorodeoxyglucose PET (FDG-PET) of the brain: one showed hypometabolism in the right caudate area, whereas the other was normal. CSF biomarkers (t-tau, p-tau, and Aβ42) were tested in 44 patients (Aβ42 only in 29; Figure 3). A high t-tau was seen in 19 patients (45%), a high p-tau in 6 patients (16%), and a low Aβ42 in 12 patients (41%). A high t-tau/p-tau ratio (>30; suggestive for CJD) was present in 6 of 38 patients (16%), and 14-3-3 was (weakly) positive in 8 of 42 patients (19%). Five patients with a positive 14-3-3 had been tested by RT-QuIC, and all tested negative. In anti-GABABR encephalitis, the 14-3-3 test was most often found positive, but this was not significantly different compared with other AIE subtypes. The clinical profile of the patients with AIE with a high t-tau or high t-tau/Aβ42 is shown in eTable 3 (links.lww.com/NXI/A535). Based on these CSF markers that are often requested when dementia was suspected, 14 patients were considered to have a CSF profile suitable for Alzheimer disease or CJD. Figure 3 Dementia Biomarkers in Patients With Autoimmune Encephalitis Dementia CSF biomarkers in 44 patients with autoimmune encephalitis cutoff values to be considered abnormal were (A) t-tau > 400 pg/mL, (B) p-tau > 64 pg/mL, (C) a t-tau/p-tau ratio of >30, (D) Aβ42 < 500 pg/mL, and (E) a t-tau/Aβ42 ratio of >0.52. (F) A positive 14-3-3 is abnormal. Two patients with t-tau values of 14,720 and 2,800 were maximized at 2001. Five patients with a positive 14-3-3 had been tested by RT-QuIC, all negative. Filled diamond symbols represent abnormal results, and half-filled symbols represent normal results. Aβ42 = amyloid-beta-42; CASPR2 = contactin-associated protein-like 2; GABABR = gamma-aminobutyric acid B receptor; LGI1 = leucine-rich glioma-inactivated 1; NMDAR = NMDA receptor; p-tau = phosphorylated tau; RT-QuIC = real‐time quaking-induced conversion; t-tau = total tau. We could not identify significant differences between patients with and without RPD, except for the obvious time to dementia (data not shown). Treatment and Outcome The median mRS at onset was 3 (IQR 3–4; 3% activity of daily living [ADL] independent), and patients were admitted to the ICU in 16% of the total cohort (Table 2). Most patients (n = 59, 94%) were treated with first-line immunotherapy (combination of IV methylprednisolone or IVIgs). Nine patients (14%) received additional second-line immunotherapy (rituximab or cyclophosphamide). In 4 of 8 patients with anti-GABABR encephalitis, no immunotherapy was administered. Two of these patients received chemotherapy for small cell lung carcinoma, and the remaining 2 were postmortem diagnosed as anti-GABABR encephalitis. In patients with anti-NMDAR encephalitis, second-line immunotherapy was administered more frequently (39%, p = 0.005). View inline View popup Table 2 Treatment and Outcome The median delay until initiation of treatment after disease onset was 99 days (IQR 32–219). To analyze the effects of treatment delay, without interference of the antibody subtype, we assessed treatment in the largest AIE subtype (anti-LGI encephalitis). Patients with a longer delay until the start of immunotherapy after disease onset (>60 days, n = 28/41) had a higher mRS at 6 and 12 months (mRS 3 [IQR 2–3] vs mRS 2 [IQR 1–2], p = 0.012; and mRS 2 [IQR 2–3] vs mRS 1 [IQR 1–2], p = 0.027, respectively). Similarly, more cognitive problems remained after 6 months in those treated later (96% vs 67%, p = 0.02), whereas a similar trend was seen at 12 months of follow-up (92% vs 67%, p = 0.10). Patients improved after therapy indicated by a lower mRS score after treatment (median mRS 2; 67% ADL independent). Only in anti-GABABR encephalitis, patients tended to remain dependent more frequently, whereas in the other AIE subtypes the majority became independent (puncorrected = 0.019). Cognitive deficits were still present after 12 months in most patients (81%) and were similar between AIE subtypes. In total, encephalitis relapses were seen in 11 patients (17%), and 14 patients had died (22%). Discussion This nationwide observational cohort study evaluated cognitive characteristics in middle-aged or older patients with anti-LGI1, anti-NMDAR, anti-GABABR, and anti-CASPR2 encephalitis. We show that AIE can resemble dementia frequently, especially as RPD. Ancillary testing can be misleading, lacking an inflammatory signature (in the CSF or on brain MRI), whereas the CSF biomarker profile that is often requested for dementia workup might mimic a neurodegenerative syndrome. Seizures are often present both early and late in the disease course. These can be very subtle and therefore easily overlooked. Our study shows that a neurodegenerative dementia syndrome is frequently suspected initially in patients with AIE. The cognitive deterioration has a rapidly progressive character in most patients, which is much larger than the prevalence of RPD in reported studies of dementia cohorts (4%–30%).23,-,25 Literature on pure cognitive decline in patients with antineuronal autoantibodies is sparse,26,27 and in our experience, many patients with RPD are not investigated for neuronal autoantibodies. Our results emphasize that part of the (older) patients with a possible dementia diagnosis should be tested for extracellular neuronal antibodies. In all AIE subtypes, we identified patients with cognitive deterioration fulfilling the criteria for dementia. Encephalitis with anti-LGI1 antibodies is the most common subtype in this age category, and the clinical picture mimics dementia most often. Fewer patients with anti-NMDAR encephalitis were included in this study, as this disease predominantly affects young adults.28 Patients with anti-GABABR encephalitis are characterized by severe seizures in many29 but can present as RPD.5 Most patients with anti-CASPR2 encephalitis had other symptoms, such as (painful) polyneuropathy, cerebellar dysfunction, or epilepsy.4 Anti-IgLON5 encephalopathy has broad clinical phenotypes, including manifestations that can resemble dementia,30 but as this disease is still evolving, we have not included these patients. Anti-AMPAR can occasionally present with cognitive decline without other symptoms but is very rare.31 Similarly, a recent publication also showed the even rarer AK5 antibodies to be associated frequently with cognitive decline, although MRI and CSF testing was very abnormal in almost all.32 Seizures are generally better known within AIE and less likely in dementia, although 10%–22% of early-onset AD patients develop seizures in all disease stages.33 Our study shows that a high percentage (∼two-third of the cohort) developed seizures, despite (arbitrarily) excluding patients with prominent seizures within the first 4 weeks. The seizures within this study appeared late in the disease course or were subtle seizures (FBDS or nonmotor subtle focal seizures), often overlooked. Altogether, it indicates that seizures are an important red flag differentiating between a possible AIE when patients present with dementia symptoms. There should be more awareness for FBDS and nonmotor focal seizures because missing leads to a delay, incorrect diagnosis, and more important inadvertently withholding of immunotherapy resulting in worse outcomes,3,6 also seen in our cohort. These subtle seizures were almost exclusively seen in anti-LGI1 encephalitis. FBDS, 1 subtype, are known to be pathognomonic for anti-LGI1 encephalitis and are defined as frequent attacks (>8 per day) lasting less than 30 seconds with a dystonic posture of the arm, often combined with a facial contraction.34 Frequently, ancillary testing showed no clues suggesting an autoimmune etiology: no abnormalities in the CSF (e.g., pleocytosis) or no typical mesiotemporal hyperintensities on brain MRI, consistent with previous studies.1,26,35 Patients with LGI1 or CASPR2 antibodies had more frequently normal CSF results, also in line with previous studies.4,36 In addition, EEG results were normal or only showing some encephalopathy in many patients with AIE, similar to patterns seen in patients with neurodegenerative dementia. Noteworthy, regular ictal EEG generally shows no abnormalities during FBDS. Similarly, EEG is unrevealing if patients have an epileptic focus deep in the temporal lobe.37,38 Finally, tumors can be present in AIE, but in general, patients are only screened for tumors after antibody positivity. Therefore, in clinical practice, this rarely points toward an autoimmune etiology in patients with cognitive deterioration. Differentiating between AIE and a neurodegenerative cause becomes more complex when CSF markers that are often requested when dementia is suspected are abnormal. In almost half of our tested AIE patients (in whom Aβ42 was also tested), the combination of biomarkers was fitting a neurodegenerative dementia profile. Few cases had positive 14-3-3 results, sometimes attributed to CJD, but none had abnormalities on MRI-DWI. Unfortunately, we did not have data to evaluate the discriminatory value of FDG-PET. A selection of the 14-3-3 positive samples was analyzed by RT-QuIC, considered a more specific marker for CJD, and all had negative test results confirming the higher specificity compared with 14-3-3.39 Some of the CSF markers are known to be not highly specific for dementia (t-tau and 14-3-3), as these represent neuronal injury. The explanation for abnormal Aβ42 is currently unknown. Although we cannot exclude that patients were developing concomitant AD, the improvement to immunotherapy and lack of cognitive deterioration over time, despite extended follow-up, make this highly improbable. Overall, physicians should be aware that ancillary testing can be deceivingly normal in many cases, and dementia biomarkers can be “falsely” positive. IgG index and oligoclonal bands in the CSF can be helpful and should be routinely tested to investigate an autoimmune etiology. The dementia syndrome shows distinctive cognitive profiles in different AIE subtypes. Both anti-LGI1 and anti-GABABR encephalitis are associated with visuospatial and executive dysfunction. This is consistent with cognitive dysfunction seen in dementia with Lewy bodies,40 and the regularly accompanied hallucinations and sleep problems are also known in AIE. Anti-NMDAR encephalitis is more reminiscent of frontotemporal dementia because language impairments and behavioral problems are more prominent in both diseases.41,42 Contrary to neurodegenerative dementia syndromes, patients with AIE can be treated and generally respond well to immunotherapy. In this study looking at elderly patients with AIE, in which most were initially suspected of having an untreatable dementia syndrome, many patients improved with immunotherapy. This improvement was seen despite the relatively long delay until treatment (median 99 days). This delay is witness to the difficulties in diagnosing AIE in older patients, as shown for anti-NMDAR encephalitis.8 Nevertheless, patients became independent in their daily activities again (best mRS after treatment ≤2). However, better treatments and targeted guidance are necessary to reduce long-lasting cognitive dysfunction because a high percentage of patients in all subtypes of AIE still experience problems 1 year after disease onset. Research evaluating neuropsychological assessments is still sparse.3,13,43 In patients with anti-LGI1 encephalitis, long-term cognitive deficits were attributed to hippocampal damage43 and to reduced connectivity in anti-NMDAR encephalitis,44 but direct links with poorer cognitive recovery are needed. Although this study is nationwide, including 4 types of AIE, there are some limitations associated with the retrospective design of this study. First, detailed cognitive symptoms were not always accurately documented, especially during follow-up. Second, because of the low incidence of anti-GABABR and anti-CASPR2 encephalitis and because of our restrictive selection criteria (mainly for anti-NMDAR and anti-CASPR2 encephalitis), we describe modest group sizes, especially compared with anti-LGI1 encephalitis. A large study examining antibodies in unselected patients with presumed dementia, without suspicion of autoimmunity, as well as patients with RPD would be most useful to consolidate our findings. In conclusion, AIE can mimic dementia. Antibody testing should be considered more often and sooner in the disease course, especially if red flags are present. Red flags for AIE in patients aged 45 years or older are a rapidly progressive cognitive decline, abnormalities in ancillary testing (inflammatory changes in the CSF or on MRI), easily missed subtle seizures early in the disease course, and prominent seizures later in the disease. Extensive brain atrophy early in the disease course argues in favor of neurodegeneration, whereas abnormalities on MRI-DWI are more suggestive for CJD in patients with RPD. CSF markers that are often requested when dementia is suspected (including t-tau, p-tau, Aβ42, and 14-3-3) can be positive in AIE. However, physicians should be aware that ancillary testing of the CSF and brain MRI can be entirely normal in AIE, necessitating antibody testing when in doubt. Study Funding M.J. Titulaer was supported by an Erasmus MC fellowship and has received funding from the Netherlands Organization for Scientific Research (NWO, Veni incentive), ZonMw (Memorabel program), and the Dutch Epilepsy Foundation (NEF 14-19 and 19-08). Disclosure A.E.M. Bastiaansen, R.W. van Steenhoven, M.A.A.M. de Bruijn, Y.S. Crijnen, A. van Sonderen, M.H. van Coevorden-Hameete, and M.M. Nühn report no disclosures relevant to the manuscript. M.M. Verbeek receives grant support from the NIH, USA (CAFÉ project, grant number 5R01NS104147-02), the Selfridges Group Foundation, and the BIONIC project (no. 733050822), which has been made possible by ZonMw. The BIONIC project is part of “Memorabel,” the research and innovation program for dementia, as part of the Dutch national “Deltaplan for Dementia”: zonmw.nl/dementiaresearch. M.W.J. Schreurs reports no disclosures relevant to the manuscript. P.A.E. Sillevis Smitt holds a patent for the detection of anti-DNER and received research support from Euroimmun. J.M. de Vries and F.J. de Jong report no disclosures relevant to the manuscript. M.J. Titulaer has filed a patent, on behalf of the Erasmus MC, for methods for typing neurologic disorders and cancer, and devices for use therein, and has received research funds for serving on a scientific advisory board of MedImmune LLC, for consultation at Guidepoint Global LLC, for consultation at UCB, and for teaching colleagues by Novartis. M.J. Titulaer has received an unrestricted research grant from Euroimmun AG and from CSL Behring. Go to Neurology.org/NN for full disclosures. Acknowledgment The authors thank all patients for their participation, and they thank all referring physicians. The authors thank Esther Hulsenboom and Mariska Nagtzaam for their technical assistance. M.W.J. Schreurs, P.A.E. Sillevis Smitt, J.M. de Vries, and M.J. Titulaer of this publication are members of the European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases—Project ID No. 739543 (ERN-RITA). Appendix Authors Footnotes Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article. The Article Processing Charge was funded by Erasmus MC University Medical Center/ZonMw (Memorabel program). Infographic: http://links.lww.com/NXI/A561 Received February 25, 2021. Accepted in final form May 19, 2021. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. References 1.↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.OpenUrlCrossRefPubMed 2.↵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(2):157-165.OpenUrlCrossRefPubMed 3.↵van Sonderen A, Thijs RD, Coenders EC, et al. Anti-LGI1 encephalitis: clinical syndrome and long-term follow-up. Neurology. 2016;87(14):1449-1456.OpenUrlPubMed 4.↵van Sonderen A, Arino H, Petit-Pedrol M, et al. The clinical spectrum of Caspr2 antibody-associated disease. Neurology. 2016;87(5):521-528.OpenUrlCrossRefPubMed 5.↵van Coevorden-Hameete MH, de Bruijn M, de Graaff E, et al. The expanded clinical spectrum of anti-GABABR encephalitis and added value of KCTD16 autoantibodies. Brain. 2019;142(6):1631-1643.OpenUrl 6.↵Arino H, Armangue T, Petit-Pedrol M, et al. Anti-LGI1-associated cognitive impairment: presentation and long-term outcome. Neurology. 2016;87(8):759-765.OpenUrlCrossRefPubMed 7.↵Maat P, de Beukelaar JW, Jansen C, et al. Pathologically confirmed autoimmune encephalitis in suspected Creutzfeldt-Jakob disease. Neurol Neuroimmunol Neuroinflamm. 2015;2(6):e178. 8.↵Titulaer MJ, McCracken L, Gabilondo I, et al. Late-onset anti-NMDA receptor encephalitis. Neurology. 2013;81(12):1058-1063.OpenUrlCrossRefPubMed 9.↵Geschwind MD, Tan KM, Lennon VA, et al. Voltage-gated potassium channel autoimmunity mimicking Creutzfeldt-Jakob disease. Arch Neurol. 2008;65(10):1341-1346.OpenUrlCrossRefPubMed 10.↵Grau-Rivera O, Sanchez-Valle R, Saiz A, et al. Determination of neuronal antibodies in suspected and definite Creutzfeldt-Jakob disease. JAMA Neurol. 2014;71(1):74-78.OpenUrl 11.↵Baumgartner A, Rauer S, Hottenrott T, et al. Admission diagnoses of patients later diagnosed with autoimmune encephalitis. J Neurol. 2019;266(1):124-132.OpenUrl 12.↵Flanagan EP, McKeon A, Lennon VA, et al. Autoimmune dementia: clinical course and predictors of immunotherapy response. Mayo Clin Proc. 2010;85(10):881-897.OpenUrlCrossRefPubMed 13.↵de Bruijn M, Aarsen FK, van Oosterhout MP, et al. Long-term neuropsychological outcome following pediatric anti-NMDAR encephalitis. Neurology. 2018;90(22):e1997-e2005.OpenUrl 14.↵Ances BM, Vitaliani R, Taylor RA, et al. Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain. 2005;128(pt 8):1764-1777.OpenUrlCrossRefPubMed 15.↵Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol. 2014;13(2):167-177.OpenUrlCrossRefPubMed 16.↵Herbert MK, Eeftens JM, Aerts MB, et al. CSF levels of DJ-1 and tau distinguish MSA patients from PD patients and controls. Parkinsonism Relat Disord. 2014;20(1):112-115.OpenUrl 17.↵van Eijk JJ, van Everbroeck B, Abdo WF, Kremer BP, Verbeek MM. CSF neurofilament proteins levels are elevated in sporadic Creutzfeldt-Jakob disease. J Alzheimers Dis. 2010;21(2):569-576.OpenUrlCrossRefPubMed 18.↵McGuire LI, Peden AH, Orru CD, et al. Real time quaking-induced conversion analysis of cerebrospinal fluid in sporadic Creutzfeldt-Jakob disease. Ann Neurol. 2012;72(2):278-285.OpenUrlCrossRefPubMed 19.↵Duits FH, Teunissen CE, Bouwman FH, et al. The cerebrospinal fluid “Alzheimer profile”: easily said, but what does it mean? Alzheimers Dement. 2014;10(6):713-723.e2.OpenUrlCrossRefPubMed 20.↵McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):263-269.OpenUrlCrossRefPubMed 21.↵Geschwind MD. Rapidly progressive dementia. Continuum (Minneap Minn). 2016;22(2 dementia):510-537.OpenUrl 22.↵van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19(5):604-607. 23.↵Schmidt C, Wolff M, Weitz M, et al. Rapidly progressive Alzheimer disease. Arch Neurol. 2011;68(9):1124-1130.OpenUrlCrossRefPubMed 24.↵Studart Neto A, Soares Neto HR, Simabukuro MM, et al. Rapidly progressive dementia: prevalence and causes in a neurologic unit of a tertiary hospital in Brazil. Alzheimer Dis Assoc Disord. 2017;31(3):239-243.OpenUrl 25.↵Anuja P, Venugopalan V, Darakhshan N, et al. Rapidly progressive dementia: an eight year (2008–2016) retrospective study. PLoS One. 2018;13(1):e0189832.OpenUrl 26.↵Escudero D, Guasp M, Arino H, et al. Antibody-associated CNS syndromes without signs of inflammation in the elderly. Neurology. 2017;89(14):1471-1475.OpenUrlCrossRefPubMed 27.↵Geschwind MD, Haman A, Miller BL. Rapidly progressive dementia. Neurol Clin. 2007;25(3):783-807, vii.OpenUrlCrossRefPubMed 28.↵Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):1091-1098.OpenUrlCrossRefPubMed 29.↵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(1):67-76.OpenUrlCrossRefPubMed 30.↵Gaig C, Graus F, Compta Y, et al. Clinical manifestations of the anti-IgLON5 disease. Neurology. 2017;88(18):1736-1743.OpenUrlCrossRefPubMed 31.↵Joubert B, Kerschen P, Zekeridou A, et al. Clinical spectrum of encephalitis associated with antibodies against the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor: case series and review of the literature. JAMA Neurol. 2015;72(10):1163-1169.OpenUrl 32.↵Muniz-Castrillo S, Hedou JJ, Ambati A, et al. Distinctive clinical presentation and pathogenic specificities of anti-AK5 encephalitis. Brain. 2021;2021:awab153.OpenUrl 33.↵Vossel KA, Tartaglia MC, Nygaard HB, Zeman AZ, Miller BL. Epileptic activity in Alzheimer's disease: causes and clinical relevance. Lancet Neurol. 2017;16(4):311-322.OpenUrlCrossRefPubMed 34.↵Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol. 2011;69(5):892-900.OpenUrlCrossRefPubMed 35.↵Hebert J, Gros P, Lapointe S, et al. Searching for autoimmune encephalitis: beware of normal CSF. J Neuroimmunol. 2020;345:577285.OpenUrl 36.↵Jarius S, Hoffmann L, Clover L, Vincent A, Voltz R. CSF findings in patients with voltage gated potassium channel antibody associated limbic encephalitis. J Neurol Sci. 2008;268(1–2):74-77.OpenUrlPubMed 37.↵Schmitt SE, Pargeon K, Frechette ES, et al. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology. 2012;79(11):1094-1100.OpenUrlCrossRefPubMed 38.↵Navarro V, Kas A, Apartis E, et al. Motor cortex and hippocampus are the two main cortical targets in LGI1-antibody encephalitis. Brain. 2016;139(pt 4):1079-1093.OpenUrlCrossRefPubMed 39.↵Fairfoul G, McGuire LI, Pal S, et al. Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies. Ann Clin Transl Neurol. 2016;3(10):812-818.OpenUrl 40.↵McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology. 2017;89(1):88-100.OpenUrlCrossRefPubMed 41.↵Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134(pt 9):2456-2477.OpenUrlCrossRefPubMed 42.↵Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011;76(11):1006-1014.OpenUrlCrossRefPubMed 43.↵Finke C, Pruss H, Heine J, et al. Evaluation of cognitive deficits and structural hippocampal damage in encephalitis with leucine-rich, glioma-inactivated 1 antibodies. JAMA Neurol. 2017;74(1):50-59.OpenUrl 44.↵Finke C, Kopp UA, Scheel M, et al. Functional and structural brain changes in anti-N-methyl-D-aspartate receptor encephalitis. Ann Neurol. 2013;74(2):284-296.OpenUrlCrossRefPubMed
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Josep Dalmau receives the “Scientific Breakthrough 2023” Award from the American Brain Foundation

The accolade recognises the commitment of this Clínic Barcelona-IDIBAPS researcher to deepening our understanding of autoimmune neurological diseases such...
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IDIBAPS creates three multidisciplinary research programs to encourage collaboration among its groups

They are the Translational cancer research program, the Synaptic autoimmunity in neurology, psychiatry and cognitive neuroscience program and the Lymphoid...
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ExTINGUISH: A Beacon of Hope for NMDAR Encephalitis

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MR Imaging Findings in a Large Population of Autoimmune Encephalitis | American Journal of Neuroradiology

MR Imaging Findings in a Large Population of Autoimmune Encephalitis | American Journal of Neuroradiology | AntiNMDA | Scoop.it
Research ArticleAdult Brain MR Imaging Findings in a Large Population of Autoimmune Encephalitis S. Gillon, M. Chan, J. Chen, E.L. Guterman, X. Wu, C.M. Glastonbury and Y. Li American Journal of Neuroradiology July 2023, 44 (7) 799-806; DOI: https://doi.org/10.3174/ajnr.A7907 ArticleFigures & DataInfo & MetricsReferences PDF This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased. AbstractBACKGROUND AND PURPOSE: Autoimmune encephalitis is a rare condition in which autoantibodies attack neuronal tissue, causing neuropsychiatric disturbances. This study sought to evaluate MR imaging findings associated with subtypes and categories of autoimmune encephalitis.MATERIALS AND METHODS: Cases of autoimmune encephalitis with specific autoantibodies were identified from the medical record (2009–2019). Cases were excluded if no MR imaging of the brain was available, antibodies were associated with demyelinating disease, or >1 concurrent antibody was present. Demographics, CSF profile, antibody subtype and group (group 1 intracellular antigen or group 2 extracellular antigen), and MR imaging features at symptom onset were reviewed. Imaging and clinical features were compared across antibody groups using χ2 and Wilcoxon rank-sum tests.RESULTS: Eighty-five cases of autoimmune encephalitis constituting 16 distinct antibodies were reviewed. The most common antibodies were anti-N-methyl-D-aspartate (n = 41), anti-glutamic acid decarboxylase (n = 7), and anti-voltage-gated potassium channel (n = 6). Eighteen of 85 (21%) were group 1; and 67/85 (79%) were group 2. The median time between MR imaging and antibody diagnosis was 14 days (interquartile range, 4–26 days). MR imaging had normal findings in 33/85 (39%), and 20/33 (61%) patients with normal MRIs had anti-N-methyl-D-aspartate receptor antibodies. Signal abnormality was most common in the limbic system (28/85, 33%); 1/68 (1.5%) had susceptibility artifacts. Brainstem and cerebellar involvement were more common in group 1, while leptomeningeal enhancement was more common in group 2.CONCLUSIONS: Sixty-one percent of patients with autoimmune encephalitis had abnormal brain MR imaging findings at symptom onset, most commonly involving the limbic system. Susceptibility artifact is rare and makes autoimmune encephalitis less likely as a diagnosis. Brainstem and cerebellar involvement were more common in group 1, while leptomeningeal enhancement was more common in group 2.ABBREVIATIONS:AIEautoimmune encephalitisanti-Gq1banti-ganglioside Q1banti-LGI1anti-leucine-rich glioma inactivated 1CASPR2contactin-associated protein-like 2GABAgamma-aminobutyric acidGADglutamic acid decarboxylaseGFAPglial fibrillary acidic proteinNMDAN-methyl-D-aspartatePD-1programmed cell death protein 1VGCCvoltage gated calcium channelVGKCvoltage-gated potassium channel© 2023 by American Journal of NeuroradiologyView Full Text Log in using your username and password Username * Password * Forgot your user name or password? PreviousNext Back to top In this issue American Journal of Neuroradiology Vol. 44, Issue 7 1 Jul 2023 Table of ContentsIndex by authorComplete Issue (PDF) Print Download PDF Email Article Citation Tools Share Tweet WidgetFacebook LikeGoogle Plus One Purchase Related ArticlesNo related articles found.PubMedGoogle Scholar Cited By...No citing articles found.CrossrefGoogle Scholar More in this TOC Section Cost-Effectiveness Analysis of 68Ga-DOTATATE PET/MRI in Radiotherapy Planning in Patients with Intermediate-Risk Meningioma Choroid Plexus Calcification Correlates with Cortical Microglial Activation in Humans: A Multimodal PET, CT, MRI Study Show more ADULT BRAIN Similar Articles
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Elevated blood and cerebrospinal fluid biomarkers of microglial activation and blood‒brain barrier disruption in anti-NMDA receptor encephalitis | Journal of Neuroinflammation | Full Text

Elevated blood and cerebrospinal fluid biomarkers of microglial activation and blood‒brain barrier disruption in anti-NMDA receptor encephalitis | Journal of Neuroinflammation | Full Text | AntiNMDA | Scoop.it
Background Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disease characterized by complex neuropsychiatric syndrome and cerebrospinal fluid (CSF) NMDAR antibodies. Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to be associated with inflammation of the...
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Anti-N-methyl-d-aspartate receptor encephalitis and positive human herpesvirus-7 deoxyribonucleic acid in cerebrospinal fluid: a case report | Journal of Medical Case Reports | Full Text

Anti-N-methyl-d-aspartate receptor encephalitis and positive human herpesvirus-7 deoxyribonucleic acid in cerebrospinal fluid: a case report | Journal of Medical Case Reports | Full Text | AntiNMDA | Scoop.it
Background Anti-N-methyl-d-aspartate receptor encephalitis is a neuroautoimmune syndrome typically presenting with seizures, psychiatric symptoms, and autonomic dysfunction. Human herpesvirus-7 is often found with human herpesvirus-6 and infects leukocytes such as T-cells, monocytes–macrophages,...
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We have a winner! - The Anti-NMDA Receptor Encephalitis Foundation Prize, 2023

We have a winner! - The Anti-NMDA Receptor Encephalitis Foundation Prize, 2023 | AntiNMDA | Scoop.it
It’s that time of year again, when the Foundation is delighted to offer its annual Anti-NMDA Receptor Encephalitis Foundation Prize to a promising neurology trainee ...Read More...
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Antibodies Associated With Autoimmune Encephalitis in Patients With Presumed Neurodegenerative Dementia | Neurology Neuroimmunology & Neuroinflammation

Antibodies Associated With Autoimmune Encephalitis in Patients With Presumed Neurodegenerative Dementia | Neurology Neuroimmunology & Neuroinflammation | AntiNMDA | Scoop.it
AbstractBackground & Objectives Autoimmune encephalitis (AIE) may present with prominent cognitive disturbances without overt inflammatory changes in MRI and CSF. Identification of these neurodegenerative dementia diagnosis mimics is important because patients generally respond to immunotherapy. The objective of this study was to determine the frequency of neuronal antibodies in patients with presumed neurodegenerative dementia and describe the clinical characteristics of the patients with neuronal antibodies.Methods In this retrospective cohort study, 920 patients were included with neurodegenerative dementia diagnosis from established cohorts at 2 large Dutch academic memory clinics. In total, 1,398 samples were tested (both CSF and serum in 478 patients) using immunohistochemistry (IHC), cell-based assays (CBA), and live hippocampal cell cultures (LN). To ascertain specificity and prevent false positive results, samples had to test positive by at least 2 different research techniques. Clinical data were retrieved from patient files.Results Neuronal antibodies were detected in 7 patients (0.8%), including anti-IgLON5 (n = 3), anti-LGI1 (n = 2), anti-DPPX, and anti-NMDAR. Clinical symptoms atypical for neurodegenerative diseases were identified in all 7 and included subacute deterioration (n = 3), myoclonus (n = 2), a history of autoimmune disease (n = 2), a fluctuating disease course (n = 1), and epileptic seizures (n = 1). In this cohort, no patients with antibodies fulfilled the criteria for rapidly progressive dementia (RPD), yet a subacute deterioration was reported in 3 patients later in the disease course. Brain MRI of none of the patients demonstrated abnormalities suggestive for AIE. CSF pleocytosis was found in 1 patient, considered as an atypical sign for neurodegenerative diseases. Compared with patients without neuronal antibodies (4 per antibody-positive patient), atypical clinical signs for neurodegenerative diseases were seen more frequently among the patients with antibodies (100% vs 21%, p = 0.0003), especially a subacute deterioration or fluctuating course (57% vs 7%, p = 0.009).Discussion A small, but clinically relevant proportion of patients suspected to have neurodegenerative dementias have neuronal antibodies indicative of AIE and might benefit from immunotherapy. In patients with atypical signs for neurodegenerative diseases, clinicians should consider neuronal antibody testing. Physicians should keep in mind the clinical phenotype and confirmation of positive test results to avoid false positive results and administration of potential harmful therapy for the wrong indication.GlossaryAD=Alzheimer dementia; AIE=autoimmune encephalitis; CBA=cell-based assays; DLB=dementia with Lewy bodies; IHC=immunohistochemistry; LN=live hippocampal cell cultures; PPA=primary progressive aphasia; PSP=progressive supranuclear palsy; RPD=rapidly progressive dementia; VGCC=voltage-gated calcium channelCognitive dysfunction can be the presenting and most prominent symptom in patients with autoimmune encephalitis (AIE).1,2 In contrast to neurodegenerative diseases, patients with antibody-mediated encephalitis might benefit from immunotherapy and improve considerably.3,4 The presence of neuronal antibodies has been reported predominantly in rapidly progressive dementia (RPD).5,6 However, AIE can present less fulminantly and is therefore potentially missed, resulting in diagnosis and treatment delay or even misdiagnosis.7,8 We hypothesized that a small—but not insignificant—part of dementia syndromes is indeed caused by antibody-mediated encephalitis and underdiagnosed, withholding these patients' available treatments. The wish to diagnose every single patient with autoimmune encephalitis is in opposition with the risk for false positive tests.9 Therefore, we strictly adhere to confirmation of positive test results with 2 different test techniques. In this study, we describe the frequency of neuronal antibodies in a cohort of patients diagnosed with various dementia syndromes in a memory clinic. In addition, we present clues to improve clinical recognition of AIE in dementia syndromes.MethodsPatients and Laboratory StudiesIn this retrospective multicenter study, we tested for the presence of neuronal antibodies in serum and CSF samples from patients diagnosed with neurodegenerative dementia diagnosis, included earlier prospectively in established cohorts at 2 large Dutch academic memory clinics (Erasmus University Medical Center, Amsterdam University Medical Centers, location VUmc)10 between 1998 and 2016 (84% last 10 years). All patients fulfilled the core clinical criteria for dementia, as defined by the National Institutes of Aging-Alzheimer Association workgroups.11 Patients were classified into 4 subgroups (based on diagnostic criteria): Alzheimer dementia (AD), frontotemporal dementia (FTD; both behavioral variant and primary progressive aphasia [PPA]), dementia with Lewy bodies (DLB), and other dementia syndromes.11,-,14 Rapidly progressive dementia was defined as dementia within 12 months or death within 2 years after the appearance of the first cognitive symptoms.15 Patients with vascular dementia were not included. Clinic information was retrieved from the prospectively collected data. A subacute deterioration was defined as a marked progression of symptoms in 3 months and a fluctuating course as a disease course fluctuating over a longer period (e.g., weeks to months; different from the fluctuations within a day as seen in some patients with DLB). Dementia markers were scored according to the reference values (per year and per center; included in Table 1).View inline View popup Table 1 Patient Characteristics of Auto-antibody Positive PatientsAll samples, stored in both cohorts' biobanks, were screened for immunoreactivity with immunohistochemistry (IHC), as previously described.16 Preferably, paired serum and CSF were tested for optimal sensitivity and specificity. Samples that were showing a positive or questionable staining pattern were tested more extensively using validated commercial cell-based assays (CBA) and in-house CBA (eTable 1, links.lww.com/NXI/A869). In addition, these samples were tested with live hippocampal cell cultures (LN).16,17 To ascertain specificity, only samples that could be confirmed by CBA or LN were scored as positive because there is a higher risk for false-positive test results in this population with a low a priori chance to have encephalitis.9,18 If IHC was suggestive for antibodies against intracellular (paraneoplastic) targets, this was explored by a different IHC technique.19 Anti-thyroid peroxidase (TPO), voltage-gated calcium channel (VGCC), or low titer glutamic acid decarboxylase antibodies were not tested for because these are generally nonspecific at these ages and are not associated with dementia syndromes.Antibody-positive patients were described exploratory and compared with a randomly selected antibody-negative group (ratio 1:4) matched for memory clinic, dementia subtype, sex, and age (±5 years). For these comparisons, medical records were additionally assessed for both the antibody-positive and antibody-negative patients. All antibody-positive patients were reviewed by a panel consisting of neurologists specialized in neurodegenerative (F.J., H.S., J.S.) or autoimmune diseases (J.V., P.S.S., M.T.), and a consensus classification of AIE vs AIE with a neurodegenerative dementia comorbidity was reached.Statistical AnalysisWe used IBM SPSS 25.0 (SPSS Inc) and Prism 8.4.3 (GraphPad) for statistical analysis. Baseline characteristics were analyzed using the Fisher exact test, the Fisher-Freeman-Halton test, or the Kruskal-Wallis test, when appropriate. For group comparisons, encompassing categorical data, we used the Pearson χ2 test or the Fisher-Freeman-Halton test, when appropriate. Continuous data were analyzed using the Mann-Whitney U test. All p-values were two-sided and considered statistically significant when below 0.05. We applied no correction for multiple testing, and therefore, p values between 0.05 and 0.005 should be interpreted carefully.Standard Protocol Approvals, Registrations, and Patient ConsentsThe study was approved by The Institutional Review Boards of Erasmus University Medical Center Rotterdam and Amsterdam University Medical Center, location VUmc. Written informed consent was obtained from all patients.Data AvailabilityAny data not published within this article are available at the Erasmus MC University Medical Center. Patient-related data will be shared on reasonable request from any qualified investigator, maintaining anonymization of the individual patients.ResultsIn total, 1,398 samples from 920 patients were tested (Figure; in 478, both CSF and serum [52%]). Three-hundred fifty-eight patients were classified as AD (39%), 283 FTD (31%), and 161 DLB (17%). The fourth subgroup with other dementia syndromes consisted of 118 patients (13%), including progressive supranuclear palsy (n = 48, 5%) and corticobasal syndrome (n = 29, 3%). The median age at disease onset was 62 years (range 16–90 years). Male patients were overrepresented (n = 542, 59%), and 60 patients (7%) fulfilled the criteria for rapidly progressive dementia (RPD; eTable 2, links.lww.com/NXI/A869).<img class="highwire-fragment fragment-image" alt="Figure" width="440" height="305" src="https://nn.neurology.org/content/nnn/10/5/e200137/F1.medium.gif">Download figure Open in new tab Download powerpoint Figure Flowchart of Patient Inclusion With Antibody ResultsIn total, 920 patients (1,398 samples) with a presumed neurodegenerative dementia syndrome were tested for the presence of neuronal antibodies in serum and CSF. Neuronal antibodies were detected in 7 patients (0.8%, 95% CI 0.2–1.3); five among the 358 Alzheimer disease patients. Subclassification of the ‘other’ group is provided in supplementary table eTable 2 (links.lww.com/NXI/A869). AD = Alzheimer disease; DLB = diffuse Lewy body dementia; DPPX = dipeptidyl aminopeptidase-like protein 6; FTD = frontotemporal dementia; IgLON5 = Ig-like domain-containing protein family member 5; LGI1 = leucin-rich glioma inactivated protein 1; NMDAR = N-methyl-d-aspartate receptor; S = serum.Neuronal antibodies were detected in 7 patients (0.8%; 5 in the AD group: 1.4%; Figure), including anti-IgLON5 (n = 3), anti-LGI1 (n = 2), anti-DPPX (n = 1), and anti-NMDAR antibodies (n = 1; Table 1). Among these 7, 4 patients were diagnosed retrospectively with an exclusive diagnosis of AIE, while 3 patients were classified to have AIE (anti-IgLON5 [n = 2] and anti-NMDAR antibodies [n = 1]) with a neurodegenerative dementia comorbidity. No patients with antibodies fulfilled the criteria for RPD, yet a subacute deterioration later in the disease was reported in 3 patients. Atypical clinical signs for neurodegenerative diseases were present in 7 of 7 antibody-positive patients (100% vs 21% in antibody-negative patients, p = 0.0003; Table 2). These included a subacute deterioration (n = 3), myoclonus (n = 2), a fluctuating disease course over months (n = 1), a history of autoimmune disease (n = 2), and epileptic seizures (n = 1; Table 1). Brain MRI of none of the patients demonstrated abnormalities suggestive for active AIE, in particular no hippocampal swelling nor increased T2-signal intensity. CSF pleocytosis was found in 1 patient. CSF biomarkers (t-tau, p-tau, and Aβ42) were tested in 5 of 7 patients, and t-tau and p-tau were increased in 4, while a low Aβ42 was seen in 2. Of note, only 1 patient had the combination of reduced Aβ42 and increased p-tau/t-tau, and was diagnosed with a comorbid AD. No patient received immunotherapy. Two patients still alive (1 anti-LG1, 1 anti-DPPX positive) were contacted but refused to visit our clinic to try very delayed immunotherapy trials. It is of interest that the patient with anti-DPPX antibodies showed spontaneous improvement of cognitive disturbances, atypical for a pure neurodegenerative disease.View inline View popup Table 2 Comparisons Between Patients With Neuronal Auto-antibodies and Antibody-Negative PatientsCompared with the patients without neuronal antibodies, subacute cognitive deterioration or fluctuating course was present more frequently (4/7 [57%] vs 2/28 [7%], p = 0.009). Although movement disorders (myoclonus) and autoimmune disorders were present in 2 of 7 patients each, this did not reach significance (Table 2).DiscussionIn this large, multicenter, cohort study consisting of patients with a presumed neurodegenerative dementia diagnosis, we show that a small, but clinically relevant proportion (0.8%) have neuronal antibodies. In this particular group, 4 of 7 antibody-positive patients presented with an atypical clinical course (subacute deterioration or fluctuating disease course), which is considered as a clinical clue (‘red flag’) for an antibody-mediated etiology of dementia.4 It is important that a fluctuating disease course was observed over a longer period (e.g., weeks or months) in AIE and should not be confused with shorter fluctuations of cognition or alertness (over the day) in DLB. Other known red flags, which we observed in these 7 patients, were myoclonus, epilepsy, pleocytosis, or a history of autoimmune disorders, as described earlier.1,4,-,6 Compared with antibody-negative patients, no significant difference was found related to these symptoms alone, probably due to the low number of positive patients and related low power. However, atypical clinical signs for neurodegenerative diseases together were seen significantly more frequently in the antibody-positive group. Within this cohort mostly devoid of patients with RPD, none of the antibody-positive patients fulfilled the criteria for RPD, nor ancillary testing showed specific signs for AIE in most patients. This implicates that AIE can resemble more protracted, progressive neurodegenerative dementia syndromes, as we reported earlier.1Three antibody-positive patients had IgLON5 antibodies, which is a very rare and known to have heterogeneous (chronic) clinical manifestations, including pronounced sleep problems, cognitive dysfunction, and movement disorders.20,21 Misdiagnosis with progressive supranuclear palsy (PSP) is reported, mainly associated with the preceding movement disorders. In addition, half of the patients have cognitive impairment of whom 20% fulfilled clinical criteria for dementia.21 It is of interest that IgLON5 disease shares features with neurodegeneration because autopsy studies showed tau deposits.22 However, there is a strong HLA association,20 and studies show that antibodies directly bind to surface IgLON5 on neurons and directly alter neuronal function and structure,23 suggesting a primary inflammatory disease.In previous research, a notably higher frequency (14%) of neuronal antibodies in patients with dementia was reported by Giannocaro et al.24 The discrepancy with our test results is probably explained by differences in patient selection and antibody testing methodology. First, 30% of the patients in the cohort described by Giannocaro et al. demonstrated CSF inflammatory abnormalities, indicating a relatively high pretest probability of antibody-positivity compared with our study.24 A lack of CSF pleocytosis probably better represents the population of memory clinics. Second, the previous study exclusively tested serum by cell-based assay without confirmatory tests nor testing antibodies in CSF.24 We only considered antibody test results positive when confirmed by additional techniques to avoid suboptimal specificity and false-positive test results.9Previous studies, including our own, suggested RPD as a relevant red flag for AIE,1,4,9,25 but we cannot determine this from our study based on the design of our study. We included patients at tertiary memory clinics without overt signs or symptoms suggestive for encephalitis. Therefore, the amount of patients with RPD included was very limited (7%), comparable with other large dementia cohort studies, as was the amount of patients with abnormal ancillary testing suggestive for AIE because this would have prompted a different approach than referral to a tertiary memory clinic. These patients with RPD and ancillary testing suggestive of AIE were not included in our study. Inclusion of those patients would have likely increased our rate of positivity.The strength of our study is the large number of paired samples (serum and CSF combined) from a cohort with various presumed neurodegenerative diseases without AIE suspicion, representative for academic memory clinics. A limitation is the lack of neuropathologic data to support our findings and make diagnoses of neurodegeneration or inflammation definite. To confirm if the symptoms are related to the presence of antibodies, we tried to overcome this concern in different ways. First, the presence of antibodies in serum and CSF was confirmed by different techniques (cell-based assay, tissue immunohistochemistry, and cultured live neurons), indicating optimal test specificity. Second, afterward patients were thoroughly reviewed by a panel of neurologists specialized in neurodegenerative or autoimmune disease to detect atypical signs and symptoms related to AIE. This is a very large cohort of patients with dementia examined for the presence of neuronal antibodies. Nevertheless, an important limitation of this study is the small number of antibody-positive patients, underpowering the probability to identify significant differences between antibody-positive and antibody-negative patients. The low number of patients with RPD has probably added to this small number, and a prospective study including patients with RPD is recommended. Nevertheless, several probable red flags could be identified. Diagnosing AIE in patients with dementia is highly relevant because these patients might respond to immunotherapy. Therefore, clinicians should test for neuronal antibody in patients demonstrating red flags suggestive for an autoimmune etiology, if possible early in disease course. When profound temporal lobe atrophy already has developed, little effect is to be expected. Red flags identified in this study are subacute deterioration or fluctuating course. Other red flags described previously, we also see reflected in our study, are autoimmune disorders, myoclonus, seizures, and pleocytosis,1,4,-,6 Preferably, both serum and CSF should be tested and confirmed by additional techniques. Always consider the possibility of a false positive test result, especially when only using a single technique (like the commercial cell-based assay). If the clinical phenotype is atypical, confirmation in a research laboratory should be mandatory. The use of antibody panels is discouraged, especially including the paraneoplastic blots, because these are associated with higher risks of lack of clinical relevance.26 This caution is even more warranted for tests not associated with neurodegenerative syndromes, but with a history of nonspecificity, including VGKC (in the absence of LGI1 or CASPR2), VGCC, anti-TPO, and low-titer anti-GAD65.27,-,30 Further research should focus on improving clinical recognition of AIE in patients with dementia determining the effect of immunotherapy in this specific patient category and assessing the frequency of AIE in RPD.In conclusion, we have shown that a clinically relevant, albeit small proportion of patients with a suspected neurodegenerative disease and nonrapidly progressive course have neuronal antibodies indicative of AIE.Study FundingM.J. Titulaer was supported by an Erasmus MC fellowship and has received funding from the Netherlands Organization for Scientific Research (NWO, Veni incentive), ZonMw (Memorabel program), the Dutch Epilepsy Foundation (NEF 14-19 & 19-08), Dioraphte (2001 0403), and E-RARE JTC 2018 (UltraAIE, 90030376505). F. Leypoldt has received funding from the German Ministry of Education and Research (01GM1908A) and the Era-Net funding program (LE3064/2-1).DisclosureA.E.M. Bastiaansen reports no disclosures. R.W. van Steenhoven reports no disclosures. Research programs of Wiesje van der Flier have been funded by ZonMW, now, EUFP7, EU-JPND, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health∼Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, and Combinostics. W.M. van der Flier holds the Pasman chair. W.M. van der Flier is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). All funding is paid to her institution. WF has performed contract research for Biogen MA Inc and Boehringer Ingelheim. All funding is paid to her institution. W.M. van der Flier has been an invited speaker at Boehringer Ingelheim, Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), and Springer Healthcare. All funding is paid to her institution. W.M. van der Flier is consultant to Oxford Health Policy Forum CIC, Roche, and Biogen MA Inc. All funding is paid to her institution. W.M. van der Flier participated in advisory boards of Biogen MA Inc and Roche. All funding is paid to her institution. W.M. van der Flier is a member of the steering committee of PAVE and Think Brain Health. W.M. van der Flier was an associate editor of Alzheimer, Research & Therapy in 2020/2021. W.M. van der Flier is an associate editor at Brain. Research of C. Teunissen was supported by the European Commission (Marie Curie International Training Network, Grant Agreement No. 860197 (MIRIADE)), Innovative Medicines Initiatives 3TR (Horizon 2020, Grant No. 831434), EPND (IMI 2 Joint Undertaking (JU) under Grant Agreement No. 101034344) and JPND (bPRIDE), National MS Society (Progressive MS alliance) and Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands, and Alzheimer Association. C. Teunissen is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP-allowance, #LSHM20106). ABOARD also receives funding from Edwin Bouw Fonds and Gieskes-Strijbisfonds. C. Teunissen has a collaboration contract with ADx Neurosciences, Quanterix, and Eli Lilly, performed contract research or received grants from AC-Immune, Axon Neurosciences, Bioconnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Grifols, Novo Nordisk, PeopleBio, Roche, Toyama, and Vivoryon. She serves on editorial boards of Medidact Neurologie/Springer, Alzheimer Research and Therapy, and Neurology: Neuroimmunology & Neuroinflammation and is an editor of a Neuromethods book Springer. She had speaker contracts for Roche, Grifols, and Novo Nordisk. E. de Graaff holds a patent for the detection of anti-DNER antibodies. M.M.P. Nagtzaam reports no disclosures. M. Paunovic reports no disclosures. S. Franken reports no disclosures. M.W.J. Schreurs reports no disclosures. F. Leypoldt has received speakers honoraria from Grifols, Roche, Novartis, Alexion, and Biogen and serves on an advisory board for Roche and Biogen. He works for an academic institution (University Hospital Schleswig-Holstein) which offers commercial autoantibody testing. P.A.E. Sillevis Smitt holds a patent for the detection of anti-DNER and received research support from Euroimmun. J.M. de Vries reports no disclosures. H. Seelaar reports no disclosures. J.C. van Swieten reports no disclosures. F.J. de Jong reports no disclosures. Y.A.L. Pijnenburg Research of Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The chair of Wiesje van der Flier is supported by the Pasman stichting. M.J. Titulaer has filed a patent, on behalf of the Erasmus MC, for methods for typing neurologic disorders and cancer, and devices for use therein, and has received research funds for serving on a scientific advisory board of Horizon Therapeutics, for consultation at Guidepoint Global LLC, for consultation at UCB, for teaching colleagues by Novartis. MT has received an unrestricted research grant from Euroimmun AG and from CSL Behring. Go to Neurology.org/NN for full disclosure.AcknowledgmentThe authors thank all patients for their participation. The authors also thank Esther Hulsenboom and Ashraf Jozefzoon-Aghai for their technical assistance. M.W.J. Schreurs, F. Leypoldt, P.A.E. Sillevis Smitt, J.M. de Vries, and M.J. Titulaer of this publication are members of the European Reference Network for Rare Immunodeficiency, Autoinflammatory, and Autoimmune Diseases—Project ID No. 739543 (ERN-RITA; HCP Erasmus MC and University Hospital Schleswig-Holstein). H. Seelaar, J.C. van Swieten, and F.J. de Jong of this publication are members of the European Reference Network for Rare Neurological Diseases—Project ID 73910. Research of the VUmc Alzheimer center is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center VUmc is supported by Alzheimer Nederland and Stichting VUmc Fonds. The clinical database structure was developed with funding from Stichting Dioraphte.Appendix Authors<img class="highwire-fragment fragment-image" alt="Table" src="https://nn.neurology.org/content/nnn/10/5/e200137/T3.medium.gif"; width="599" height="2531">FootnotesGo to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.The Article Processing Charge was funded the authors.Submitted and externally peer reviewed. The handling editor was Editor Josep O. Dalmau, MD, PhD, FAAN.Received December 8, 2022.Accepted in final form May 8, 2023.Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.References1.↵Bastiaansen AEM, van Steenhoven RW, de Bruijn M, et al. Autoimmune encephalitis resembling dementia syndromes. Neurol Neuroimmunol Neuroinflamm. 2021;8(5):e1039.OpenUrlAbstract/FREE Full Text2.↵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(1):67-76.OpenUrlCrossRefPubMed3.↵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(2):157-165.OpenUrlCrossRefPubMed4.↵Flanagan EP, McKeon A, Lennon VA, et al. Autoimmune dementia: clinical course and predictors of immunotherapy response. Mayo Clin Proc. 2010;85(10):881-897.OpenUrlCrossRefPubMed5.↵Geschwind MD, Tan KM, Lennon VA, et al. Voltage-gated potassium channel autoimmunity mimicking creutzfeldt-jakob disease. Arch Neurol. 2008;65(10):1341-1346.OpenUrlCrossRefPubMed6.↵Grau-Rivera O, Sanchez-Valle R, Saiz A, et al. Determination of neuronal antibodies in suspected and definite Creutzfeldt-Jakob disease. JAMA Neurol. 2014;71(1):74-78.OpenUrl7.↵Titulaer MJ, McCracken L, Gabilondo I, et al. Late-onset anti-NMDA receptor encephalitis. Neurology. 2013;81(12):1058-1063.OpenUrlAbstract/FREE Full Text8.↵Gaig C, Graus F, Compta Y, et al. Clinical manifestations of the anti-IgLON5 disease. Neurology. 2017;88(18):1736-1743.OpenUrlAbstract/FREE Full Text9.↵Bastiaansen AEM, de Bruijn M, Schuller SL, et al. Anti-NMDAR encephalitis in The Netherlands, focusing on late-onset patients and antibody test accuracy. Neurol Neuroimmunol Neuroinflamm. 2022;9(2):e1127.OpenUrl10.↵van der Flier WM, Scheltens P. Amsterdam dementia cohort: performing research to optimize care. J Alzheimers Dis. 2018;62(3):1091-1111.OpenUrl11.↵McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):263-269.OpenUrlCrossRefPubMed12.↵Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134(Pt 9):2456-2477.OpenUrlCrossRefPubMed13.↵Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011;76(11):1006-1014.OpenUrlAbstract/FREE Full Text14.↵McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology. 2017;89(1):88-100.OpenUrlAbstract/FREE Full Text15.↵Geschwind MD. Rapidly progressive dementia. Continuum (Minneap Minn). 2016;22(2 Dementia):510-537.OpenUrl16.↵Ances BM, Vitaliani R, Taylor RA, et al. Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain. 2005;128(Pt 8):1764-1777.OpenUrlCrossRefPubMed17.↵Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol. 2014;13(2):167-177.OpenUrlCrossRefPubMed18.↵Martinez-Martinez P, Titulaer MJ. Autoimmune psychosis. Lancet Psychiatry. 2020;7(2):122-123.OpenUrl19.↵van Coevorden-Hameete MH, Titulaer MJ, Schreurs MW, et al. Detection and characterization of autoantibodies to neuronal cell-surface antigens in the central nervous system. Front Mol Neurosci. 2016;9:37.OpenUrl20.↵Sabater L, Gaig C, Gelpi E, et al. A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study. Lancet Neurol. 2014;13(6):575-586.OpenUrlCrossRefPubMed21.↵Gaig C, Compta Y, Heidbreder A, et al. Frequency and characterization of movement disorders in anti-IgLON5 disease. Neurology. 2021;97(14):e1367–e1381.OpenUrlAbstract/FREE Full Text22.↵Gelpi E, Hoftberger R, Graus F, et al. Neuropathological criteria of anti-IgLON5-related tauopathy. Acta Neuropathol. 2016;132(4):531-543.OpenUrlCrossRefPubMed23.↵Landa J, Gaig C, Plaguma J, et al. Effects of IgLON5 antibodies on neuronal cytoskeleton: a link between autoimmunity and neurodegeneration. Ann Neurol. 2020;88(5):1023-1027.OpenUrlCrossRefPubMed24.↵Giannoccaro MP, Gastaldi M, Rizzo G, et al. Antibodies to neuronal surface antigens in patients with a clinical diagnosis of neurodegenerative disorder. Brain Behav Immun. 2021;96:106-112.OpenUrl25.↵Hermann P, Zerr I. Rapidly progressive dementias - aetiologies, diagnosis and management. Nat Rev Neurol. 2022;18(6):363-376.OpenUrl26.↵Dechelotte B, Muniz-Castrillo S, Joubert B, et al. Diagnostic yield of commercial immunodots to diagnose paraneoplastic neurologic syndromes. Neurol Neuroimmunol Neuroinflamm. 2020;7(3):e701.OpenUrlAbstract/FREE Full Text27.↵van Sonderen A, Schreurs MW, de Bruijn MA, et al. The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. Neurology. 2016;86(18):1692-1699.OpenUrlCrossRefPubMed28.↵Muñoz Lopetegi A, Boukhrissi S, Bastiaansen A, et al. Neurological syndromes related to anti-GAD65: clinical and serological response to treatment. Neurol Neuroimmunol Neuroinflamm. 2020;7(3):e696.OpenUrlAbstract/FREE Full Text29.↵Mattozzi S, Sabater L, Escudero D, et al. Hashimoto encephalopathy in the 21st century. Neurology. 2020;94(2):e217-e224.OpenUrlAbstract/FREE Full Text30.↵Flanagan EP, Geschwind MD, Lopez-Chiriboga AS, et al. Autoimmune encephalitis misdiagnosis in adults. JAMA Neurol. 2023;80(1):30-39.OpenUrl
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Research study - can you help?

Research study - can you help? | AntiNMDA | Scoop.it
Researchers at Kings College London are looking for young people to travel to London and help with an encephalitis study...
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Sociocultural Influences in Autoimmune Encephalitis Without Neurologic Symptoms

Sociocultural Influences in Autoimmune Encephalitis Without Neurologic Symptoms | AntiNMDA | Scoop.it
This complex case highlights barriers to identifying autoimmune encephalitis when no neurologic symptoms are present, which are normally central to disease detection.
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Anti N-Methyl-D-Aspartate receptor antibody associated Acute Demyelinating Encephalomyelitis in a patient with COVID-19: a case report | Journal of Medical Case Reports | Full Text

Anti N-Methyl-D-Aspartate receptor antibody associated Acute Demyelinating Encephalomyelitis in a patient with COVID-19: a case report | Journal of Medical Case Reports | Full Text | AntiNMDA | Scoop.it
Background Anti N-Methyl-D-Aspartate (NMDA) receptor antibody associated ADEM is a diagnosis that was first described relatively recently in 2007 by Dalmau et al. The recent COVID-19 pandemic has resulted in multiple neurological complications being reported.
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Autoimmune Encephalitis Consensus Criteria | Neurology Clinical Practice

Autoimmune Encephalitis Consensus Criteria | Neurology Clinical Practice | AntiNMDA | Scoop.it
June 2023; 13 (3) Editorial Autoimmune Encephalitis Consensus CriteriaLessons Learned From Real-World Practice View ORCID ProfileJeffrey M. Gelfand, Chu-Yueh Guo First published April 25, 2023, DOI: https://doi.org/10.1212/CPJ.0000000000200155 Full PDF Citation Permissions Make Comment See Comments Downloads133 Share Article Info & Disclosures This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased. Autoimmune encephalitis (AE) encompasses a spectrum of neurologic disorders caused by brain inflammation, a subset of which is associated with autoantibodies to neuronal cell-surface antigens such as anti-N-methyl-d-aspartate (NMDA) receptor AE or anti-leucine-rich glioma-inactivated 1 (LGI1) AE.1 Up to half of patients with AE, however, do not have abnormal neuronal or glial autoantibodies identified and are classified as having “seronegative” AE.2 Clinical antibody testing can take several days to result, a time in which clinicians caring for patients with suspected AE may wish to initiate empiric immunosuppressive therapy. Antibody testing is also not readily accessible in some health care settings and, even when technically available, may require time-consuming advocacy with local clinical laboratories to justify relatively costly send-out testing. To add further complexity, some patients with immunoreactive (e.g., laboratory true-positive) antibodies do not have clinical AE, and over-reliance and misapplication of antibody testing were identified as important contributors to AE misdiagnosis in a 2023 multicenter analysis.3FootnotesFunding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.See page e200151© 2023 American Academy of NeurologyView Full Text AAN Members We have changed the login procedure to improve access between AAN.com and the Neurology journals. If you are experiencing issues, please log out of AAN.com and clear history and cookies. (For instructions by browser, please click the instruction pages below). After clearing, choose preferred Journal and select login for AAN Members. You will be redirected to a login page where you can log in with your AAN ID number and password. When you are returned to the Journal, your name should appear at the top right of the page. Google Safari Microsoft Edge Firefox Click here to login AAN Non-Member Subscribers Click here to login Purchase access For assistance, please contact: AAN Members (800) 879-1960 or (612) 928-6000 (International) Non-AAN Member subscribers (800) 638-3030 or (301) 223-2300 option 3, select 1 (international) Sign Up Information on how to subscribe to Neurology and Neurology: Clinical Practice can be found here Purchase Individual access to articles is available through the Add to Cart option on the article page. Access for 1 day (from the computer you are currently using) is US$ 39.00. Pay-per-view content is for the use of the payee only, and content may not be further distributed by print or electronic means. The payee may view, download, and/or print the article for his/her personal, scholarly, research, and educational use. Distributing copies (electronic or otherwise) of the article is not allowed. You May Also be Interested in Back to top Safety and Efficacy of Tenecteplase and Alteplase in Patients With Tandem Lesion Stroke: A Post Hoc Analysis of the EXTEND-IA TNK Trials Dr. Nicole Sur and Dr. Mausaminben Hathidara ► Watch Related Articles Autoimmune Encephalitis Criteria in Clinical Practice Topics Discussed All Clinical Neurology Autoimmune diseases Encephalitis Alert Me Alert me when eletters are published
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Predictive Value of Serum Neurofilament Light Chain Levels in Anti-NMDA Receptor Encephalitis

Predictive Value of Serum Neurofilament Light Chain Levels in Anti-NMDA Receptor Encephalitis | AntiNMDA | Scoop.it
Increased serum NfL levels reflect neuroaxonal damage in anti-NMDAR encephalitis. No relationship was identified with disease severity, whereas the association with outcome was confounded by age.The implied role of sampling timing on NfL levels also limits the applicability of NfL as a prognostic...
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Frontiers | The MOG antibody associated encephalitis preceded by COVID-19 infection; a case study and systematic review of the literature

Frontiers | The MOG antibody associated encephalitis preceded by COVID-19 infection; a case study and systematic review of the literature | AntiNMDA | Scoop.it
BackgroundNew neurological complications of COVID-19 infection have been reported in recent research. Among them, the spectrum of anti-MOG positive diseases, defined as anti-MOG antibody associated disease (MOGAD), is distinguished, which can manifest as optic neuritis, myelitis, or various forms...
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Enceph-IG Study - Institute of Infection, Veterinary and Ecological Sciences - University of Liverpool

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A Rare Presentation of Steroid-responsive Encephalopathy Associated with Autoimmune Thyroiditis with Neuropsychiatric Symptoms: A Case Report

A Rare Presentation of Steroid-responsive Encephalopathy Associated with Autoimmune Thyroiditis with Neuropsychiatric Symptoms: A Case Report | AntiNMDA | Scoop.it
A 42-year-old woman presented in the emergency department with acute onset whole-body myoclonic jerks for 1 day.On enquiry, the patient’s parents advised...
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Pioneering Research in Autoimmune Neurology: Vanda Lennon, M.D., Ph.D.

Pioneering Research in Autoimmune Neurology: Vanda Lennon, M.D., Ph.D. | AntiNMDA | Scoop.it
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New center to spotlight neurological autoimmune disorders

New center to spotlight neurological autoimmune disorders | AntiNMDA | Scoop.it
How do neurological disorders arise that are caused, triggered, or influenced by antibodies? What better possibilities are there for diagnosis – and above all for treatment? These are the questions addressed by the new Clinical Research Unit “BecauseY” headed by Charité – Universitätsmedizin Berlin.
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Progressive alliance advances science through patient-powered research

Progressive alliance advances science through patient-powered research | AntiNMDA | Scoop.it
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ENCEPH-IG Trial: The Challenges Of Running A Rare Disease Trial - Centre for Trials Research

ENCEPH-IG Trial: The Challenges Of Running A Rare Disease Trial - Centre for Trials Research | AntiNMDA | Scoop.it
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30 neurological disorders every doctor should know about –

30 neurological disorders every doctor should know about – | AntiNMDA | Scoop.it
Neurology is a jungle of disorders and syndromes. This creates a challenge for doctors and medical students... What to prioritise for learning and practice? *** To solve this conundrum... We combed the extensive database of Neurochecklists...
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A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis

A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis | AntiNMDA | Scoop.it
The NEOS score accurately predicts 1-year functional status in patients with anti-NMDAR encephalitis. This score could help estimate the clinical course following diagnosis and may aid in identifying patients who could benefit from novel therapies.
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Canadian Blood Services needs thousands more donors to roll up their sleeves | CBC News

Canadian Blood Services needs thousands more donors to roll up their sleeves | CBC News | AntiNMDA | Scoop.it
Canadian Blood Services is looking to fill 150,000 appointments for people willing to donate their blood or plasma to tackle a shortage.
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A catatonic woman awakened after 20 years. Her story may change psychiatry – My Health CRM

A catatonic woman awakened after 20 years. Her story may change psychiatry – My Health CRM | AntiNMDA | Scoop.it
New research suggests that a subset of patients with psychiatric conditions such as schizophrenia may actually have autoimmune disease that attacks the brain...
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Case Report: Paroxysmal weakness of unilateral limb as an initial symptom in anti-LGI1 encephalitis: a report of five cases

Case Report: Paroxysmal weakness of unilateral limb as an initial symptom in anti-LGI1 encephalitis: a report of five cases | AntiNMDA | Scoop.it
Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis is the second most common kind of autoimmune encephalitis following anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis.Anti-LGI1 encephalitis is characterized by cognitive impairment or rapid progressive dementia, psychiatric disorders...
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Medical Moment: The signs of ‘brain-on-fire’ disease

Medical Moment: The signs of ‘brain-on-fire’ disease | AntiNMDA | Scoop.it
(WNDU) - Imagine being totally fine one day, then the next, you’re having hallucinations, seizures, memory loss, and even trouble talking.It’s called “brain-on-fire” disease or anti-NMDA receptor encephalitis. It’s a rare neurological disorder that can cause inflammation in the brain.It occurs when the body’s immune system mistakenly attacks the NMDA receptors in the brain, which are responsible for regulating communication between nerve cells. Brain-on-fire disease is often misdiagnosed as other neurological disorders or psychiatric illnesses because its symptoms are similar to those of many other conditions.However, a blood or cerebrospinal fluid test can help diagnose the disease by detecting the presence of antibodies that attack the NMDA receptors in the brain. The disease is rare as it affects one in 1.5 million people a year.Katie Miller would be one of those people.Hunting, mountain biking, horseback riding - you name it, Katie Miler would do it... until she couldn’t.“I just didn’t feel like myself, like normal,” Katie recalled.“Katie said, ‘Mom, I feel like my brain snapped,’” said Colleen Miller, Katie’s mother.Local doctors admitted Katie into a psychiatric ward, but what was happening to Katie wasn’t mental; it was physical.“What happens is you’re perfectly normal one day, and suddenly overnight, this person can become paranoid, can start having visual hallucinations, auditory hallucinations,” explained Stacy Clardy, MD, PhD, an autoimmune neurologist at the University of Utah.Anti-NMDA receptor encephalitis is misdiagnosed as a psychiatric disorder in up to 40% of patients.“So, for many of the females, especially after puberty, they can develop what’s called an ovarian dermoid cyst or an ovarian teratoma,” Dr. Clardy said.These cysts often have hair and teeth in them. The immune system sees it as foreign and attacks it, but...“In these cysts, there is a component of tissue that really is brain tissue,” Dr. Clardy continued.Within four days, Katie was catatonic and needed a ventilator to breathe. There is no single approved treatment. That’s why a five-year, nationwide clinical trial is testing whether a drug called Inebilizumab will stop the assault on the brain. It has the potential to improve outcomes for patients who are not responding to other treatments and may also lead to fewer long-term neurological effects.Katie had her cyst removed; she can’t remember three months of her life. But now, with various medications, Katie is on her way to recovery.Up to 50% of patients can suffer long-term consequences, especially cognitive and mood symptoms.Copyright 2023 WNDU. All rights reserved.
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