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Rituximab Treatment and Long-term Outcome of Patients With Autoimmune Encephalitis | Neurology Neuroimmunology & Neuroinflammation

Rituximab Treatment and Long-term Outcome of Patients With Autoimmune Encephalitis | Neurology Neuroimmunology & Neuroinflammation | AntiNMDA | Scoop.it
From nn.neurology.org - October 6, 2021 8:44 AM
Abstract Background and Objectives To determine the real-world use of rituximab in autoimmune encephalitis (AE) and to correlate rituximab treatment with the long-term outcome. Methods Patients with NMDA receptor (NMDAR)-AE, leucine-rich glioma-inactivated-1 (LGI1)- AE, contactin-associated protein-like-2 (CASPR2)-AE, or glutamic acid decarboxylase 65 (GAD65) disease from the GErman Network for Research on AuToimmune Encephalitis who had received at least 1 rituximab dose and a control cohort of non–rituximab-treated patients were analyzed retrospectively. Results Of the 358 patients, 163 (46%) received rituximab (NMDAR-AE: 57%, CASPR2-AE: 44%, LGI1-AE: 43%, and GAD65 disease: 37%). Rituximab treatment was initiated significantly earlier in NMDAR- and LGI1-AE (median: 54 and 155 days from disease onset) compared with CASPR2-AE or GAD65 disease (median: 632 and 1,209 days). Modified Rankin Scale (mRS) scores improved significantly in patients with NMDAR-AE, both with and without rituximab treatment. Although being more severely affected at baseline, rituximab-treated patients with NMDAR-AE more frequently reached independent living (mRS score ≤2) (94% vs 88%). In LGI1-AE, rituximab-treated and nontreated patients improved, whereas in CASPR2-AE, only rituximab-treated patients improved significantly. No improvement was observed in patients with GAD65 disease. A significant reduction of the relapse rate was observed in rituximab-treated patients (5% vs 13%). Detection of NMDAR antibodies was significantly associated with mRS score improvement. A favorable outcome was also observed with early treatment initiation. Discussion We provide real-world data on immunosuppressive treatments with a focus on rituximab treatment for patients with AE in Germany. We suggest that early and short-term rituximab therapy might be an effective and safe treatment option in most patients with NMDAR-, LGI1-, and CASPR2-AE. Class of Evidence This study provides Class IV evidence that rituximab is an effective treatment for some types of AE. Glossary abs=antibodies; AE=autoimmune encephalitis; CA=cerebellar ataxia; CASPR2=contactin-associated protein-like-2; CBA=cell-based assay; GAD65=glutamic acid decarboxylase 65; GENERATE=GErman Network for Research on AuToimmune Encephalitis; IHC=immunohistochemistry; IVIG=IV immunoglobulin; LE=limbic/autoimmune encephalitis; LGI1=leucine-rich glioma-inactivated-1; mRS=Modified Rankin Scale; NMDAR=NMDA receptor; RIA=radioimmunoassay; SPS=stiff-person syndrome Autoimmune encephalitis (AE) is an umbrella term for an emerging spectrum of immune-mediated neuropsychiatric disorders often associated with antibodies (abs) against neuronal cell surface, synaptic, or intracellular proteins.1,2 Anti-NMDA receptor (NMDAR)-AE, anti–leucine-rich glioma-inactivated-1 (LGI1)-AE, anti–contactin-associated protein-like-2 (CASPR2)-AE, and anti–glutamic acid decarboxylase-65 (GAD65) disease together make up the majority of seropositive AE subtypes. NMDAR-AE affects young adults and children with female preponderance, is frequently associated with ovarian teratomas, and causes psychiatric symptoms, movement disorders, decreased consciousness, autonomic dysregulation, epileptic seizures, and central apnea.3,4 LGI1-AE affects middle-aged or elderly patients, causes short-term memory deficits, confusion, and epileptic seizures,5,6 and is sometimes preceded by faciobrachial dystonic or tonic seizures.7 CASPR2-AE predominantly affects elderly men and causes encephalitis and neuromyotonia, neuropathic pain, ataxia, myoclonus, autonomic dysfunction, or a combination thereof (e.g., Morvan syndrome).8,9 GAD65 disease is considerably more heterogeneous, affects predominantly women of all ages, and may cause cerebellar ataxia (CA), limbic/AE (LE), stiff-person syndrome (SPS), isolated temporal lobe epilepsy, and overlap forms of the aforementioned manifestations.10,-,13 Early diagnosis and prompt initiation of immunotherapy is crucial and often leads to substantial or complete recovery from these severe disorders.8 However, treatment data from randomized trials are scarce.14,15 Empiric treatment of AE usually consists of a step-wise escalation of immunotherapy including first-line therapy with steroids, plasma exchange, IV immunoglobulin (IVIG), or combinations, followed by second-line therapy with cyclophosphamide, rituximab, or combinations.2 Rituximab is a B cell–depleting monoclonal ab directed against CD20 with established efficacy in many neurologic autoimmune diseases including MS,16 and neuromyelitis optica spectrum disorders.17 Rituximab was shown to be effective in AE associated with different auto-abs.4,18,19 By contrast, 1 randomized placebo-controlled trial with rituximab did not show efficacy in patients with SPS.15 Detailed and comparative evaluations of rituximab use and the long-term outcome between AE subtypes in a real-world setting are missing. In this study, we evaluated demographic and clinical characteristics, laboratory findings, and immunotherapies in patients with NMDAR-, LGI1-, CASPR2-AE, or GAD65 disease in a cohort from the GErman NEtwork for Research on AuToimmune Encephalitis (GENERATE) registry and compared patients who had received at least 1 rituximab dose with non–rituximab-treated patients. In the rituximab cohort, we specifically correlated early, high-dose, or prolonged rituximab treatment with the long-term outcome. Methods Standard Protocol Approvals, Registrations, and Patient Consents All data were collected from the GENERATE registry, which is a noninterventional retrospective and prospective multicentric database for patients with AE in Germany, Austria, and Switzerland (generate-net.de). GENERATE was approved by the institutional review boards of all actively recruiting centers. Patients from participating centers entered into the registry until June 30, 2019, were analyzed. The study was performed according to the Declaration of Helsinki. All enrolled patients or their legal representatives gave written informed consent before enrollment in the registry. Study Population The following patients were included: (1) patients with detection of NMDAR-, LGI1-, CASPR2-, or GAD65 abs according to the ab criteria below; (2) clinical diagnosis of AE based on the consensus criteria published in reference 2, or for patients with GAD abs, alternatively diagnosis of CA or SPS; (3) any documented treatment with rituximab; and (4) available information on the number, dosage, and timing of rituximab infusions. In addition, a control cohort with consistent inclusion criteria except for rituximab treatment was included. Analysis of Clinical, Laboratory, and Immunotherapy Profiles Ab testing was performed in the respective GENERATE centers using cell-based assays (CBAs) and confirmation by immunofluorescence (commercial test kit panels Euroimmun, Lübeck) and/or immunohistochemistry (IHC) for NMDAR, LGI1, and CASPR2, and ELISA, radioimmunoassay (RIA), or CBA for GAD65. Patients fulfilling the following ab criteria in earliest available samples were included: NMDAR abs detected in serum by CBA confirmed by IHC (in the absence of confirmatory IHC in serum, only CBA serum titers of >1:500 were considered specific) and/or CSF positive; GAD abs >1:500 in CBA or >2000IE/mL in ELISA or RIA in serum and/or CSF positive; LGI1 abs at any titer in CSF and/or serum; CASPR2 abs >1:128 in serum and/or CSF positive.20 Only IgG abs were considered relevant. Data on any immunotherapy were recorded. First-line immunotherapy was defined as treatment with corticosteroids, plasma exchange/immunoabsorption, and IVIG; second-line therapy included rituximab in the rituximab cohort and all other immunotherapies except reapplied corticosteroids, IVIG, and plasma exchange in both cohorts. The occurrence of relapses during follow-up was based on the overall clinical impression of the treating physician. Functional status was assessed using the modified Rankin Scale (mRS) at the peak of disease and then throughout disease course. Side effects of rituximab treatment were queried from all participating centers. Primary Research Question Do rituximab-treated patients with NMDAR-AE, LGI1-AE, CASPR2-AE, and GAD65 disease have a better outcome than non–rituximab-treated patients? Classification of Evidence This study provides Class IV evidence that rituximab is an effective treatment for some types of AE. Statistics Statistical tests were performed using Prism Software (GraphPad). Normality testing was performed using the D'Agostino-Pearson omnibus test. Continuous variables with >2 subgroups were compared using the Kruskal-Wallis test followed by the Dunn multiple comparisons test and with 2 subgroups using the Mann-Whitney test. Ordinal variables were compared using the χ2 test or the Fisher exact test. The Benjamini-Hochberg procedure was performed to control for multiple testing. Multivariate analysis was performed by ordinal logistic fit using JMP software (Version 16, JMP, A Business Unit of SAS, Cary, NC). Data Availability No deidentified patient data will be shared. No study-related documents will be shared. Reasonable requests from any qualified investigator for anonymized data will be considered by the corresponding author. Results Patient Characteristics We identified 358 patients with NMDAR-AE, GAD65 disease, LGI1-AE, or CASPR2-AE. One hundred sixty-three patients (46%) were treated with rituximab. Based on the inclusion criteria, 14 patients in the rituximab cohort and 32 patients in the control cohort were excluded from further analysis (Figure 1, eFigure 1, links.lww.com/NXI/A595). Our final study cohort comprised 149 patients in the rituximab cohort (NMDAR-AE: n = 81, GAD65 disease: n = 31, LGI1-AE: n = 26, and CASPR2-AE: n = 11) and 163 patients in the control cohort (NMDAR-AE: n = 61, GAD65 disease: n = 53, LGI1-AE: n = 35, and CASPR2-AE: n = 14) (Figure 1). Overall, rituximab was administered most frequently in NMDAR-AE (57%), followed by CASPR2-AE (44%), LG1-1-AE (43%), and GAD65 disease (37%). Clinical characteristics as well as CSF and MRI parameters, as expected, varied considerably between the ab subgroups (Table 1). Differences between the rituximab cohort and the control cohort indicating severity bias were observed for patients with NMDAR-AE and GAD65 disease: patients with NMDAR-AE treated with rituximab had a significantly higher mRS score at peak of disease (rituximab cohort: median: 4.0; control cohort: median: 3.0) and a significantly higher frequency of decreased consciousness (Table 1). In patients with GAD65 disease, the mRS score at the peak of disease was also higher in the rituximab cohort (median: 3.0) compared with the control cohort (median: 2.0) (Table 1). Figure 1 Study Population Profile Patient numbers in the different study subpopulations are depicted. *Patients excluded because of insufficient data on rituximab dosing (n = 2), concomitant diagnosis of MS (n = 2), retraction of consent for the GENERATE registry (n = 1), or not fulfilling the ab criteria for inclusion (n = 9). **Patients excluded because of insufficient data on immunosuppressive treatment (n = 1) or not fulfilling the ab criteria for inclusion (n = 31). CA, cerebellar ataxia; CASPR2 = contactin-associated protein-like-2; Enc. = encephalitis; GAD65 = glutamic acid decarboxylase 65; GENERATE = GErman Network for Research on AuToimmune Encephalitis; LGI1 = leucine-rich glioma-inactivated-1; NMDAR = NMDA receptor; SPS = stiff-person syndrome. View inline View popup Table 1 Characterization of the Patient Cohort First-Line and Second-Line Treatments All patients with rituximab treatment received prior first-line immunotherapy. In the control cohort, 4 patients (7%) with NMDAR-AE, 5 patients (9%) with GAD65 disease, and 1 patient (7%) with CASPR2-AE had no prior first-line immunotherapy (Table 2). Time to initiation of first-line therapy was shortest in patients with NMDAR-AE, and the therapy was started significantly earlier in patients with NMDAR-AE treated with rituximab (median: 16 days) compared with patients with NMDAR-AE not receiving rituximab (median: 33 days) (Table 2). In all subgroups, the majority of patients received a combination of different first-line treatments with steroids and plasma exchange being the most frequent combination in the overall cohort (n = 103; 33%) (Figure 2, A–H). As expected, because of severity bias, patients in the rituximab cohort were treated significantly more often with combinations of first-line therapy (Figure 2, A–H). Physicians reported some improvement following first-line therapy in the majority of patients independent of the subgroup. Of interest, the frequency of this observation was similar between patients later receiving rituximab and patients who were treated differently (Table 2). View inline View popup Table 2 Immunotherapy and Follow-up of Patients Figure 2 Venn/Euler Diagrams Showing Applied Mono- and Combination First-Line and Second-Line Immunotherapies The numbers of patients treated with the respective prior first-line immunotherapies (A–H) and second-line immunotherapies (I–P) in the rituximab cohort (A–D) and in the control cohort (E–H) are depicted for the different ab subgroups (A, E, I, and M: NMDAR-AE; B, F, J, and N: GAD65 disease; C, G, K, and O: LGI1-AE; and D, H, L, and P: CASPR2-AE). Other second-line therapies included bortezomib (n = 6 in patients with NMDAR-AE treated with rituximab), daratumumab (n = 1 in patients with NMDAR-AE treated with rituximab), tacrolimus (n = 1 in patients with GAD65 disease treated with rituximab and n = 1 in patients with GAD65 disease not treated with rituximab), and basiliximab (n = 1 in patients with GAD65 disease treated with rituximab). Areas of Venn diagrams are proportional to the case numbers relative to the respective subgroup. (A–H) Proportions of combination first-line therapy relative to none/monotherapy were compared using the Fisher exact test. ***p < 0.001, **p < 0.01, and *p < 0.05. (I–P) Proportions of treatment with cyclophosphamide or other therapies relative to steroid-sparing therapies and no treatment were compared using the Fisher exact test. ***p < 0.001, **p < 0.01, and *p < 0.05. AZA = azathioprine; CASPR2 = contactin-associated protein-like-2; cyc = cyclophosphamide; GAD65 = glutamic acid decarboxylase 65; IVIG = IV immunoglobulin; MMF = mycophenolate mofetil; MTX = methotrexate; NMDAR = NMDA receptor; LGI1 = leucine-rich glioma-inactivated-1; PLEX = plasma exchange. Forty patients (25%) in the control cohort and 38 patients (26%) in the rituximab cohort received a second-line immunotherapy other than rituximab. The frequency of application of second-line immunotherapies other than rituximab did not differ between the rituximab cohort and the control cohort (Table 2). These second-line immunotherapies included cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate, bortezomib, daratumumab, tacrolimus, and basiliximab (Figure 2, I–P) and were applied before, parallel to, or after rituximab therapy. In patients with NMDAR-AE and GAD65 disease, more aggressive second-line therapies such as cyclophosphamide, bortezomib, or daratumumab were applied more frequently in the rituximab cohort compared with the control cohort (Figure 2, I–P). Other than this and the above-mentioned severity bias, we did not observe significant selection bias between patients treated with and without rituximab. Description of Rituximab Treatments A wide spectrum of rituximab treatment regimens was observed in our rituximab cohort. In detail, patients with GAD65 disease and CASPR2-AE received rituximab significantly later (GAD65: median 1,209 days, CASPR2: 632 days) than patients with NMDAR-AE (median: 54 days) and LGI1-AE (median: 155 days) (Figure 3A; Table 2). Time from initiation of first-line treatment to rituximab treatment was shortest in NMDAR-AE (median: 30 days) and longest in GAD65 disease (median: 141 days) (Figure 3B; Table 2). Sixteen (20%) patients with NMDAR-AE received rituximab very early within 2 weeks after first-line immunotherapy. The median number of infusions and total rituximab dose did not differ significantly among the subgroups (Figure 3C, D; Table 2). The duration of rituximab treatment, defined as the time from first to last infusion, was shortest in NMDAR-AE (median: 24 days) and longest in GAD65 disease (median: 454 days) (Figure 3E and Table 2). The percentage of patients who received only induction therapy defined as time between first to last rituximab treatment of less than 6 months was highest in patients with NMDAR-AE (54%) and lowest in patients with GAD65 abs (27%); patients with LGI1- and CASPR2-AE were in between (35% and 46%, respectively) (Figure 3F; Table 2). Side effects after rituximab treatment were rare (n = 5, 3.4%); however, they were not systematically registered in this study. In detail, we observed n = 2 infusion-related reactions (n = 1: urticaria with, however, simultaneous IVIG application; n = 1: tremor, tachycardia, and fear); n = 1 lymphopenia leading to a reduction of the rituximab dose; n = 1 frequent infections; and n = 1 unknown side effect. Figure 3 Rituximab Regimens Used in Patients With AE and the Outcome According to Subtypes of AE (A–F) In different subgroups (NMDAR-AE, GAD65 disease, LGI1-AE, and CASPR2-AE), the duration in days from disease onset to initiation of rituximab treatment (A), the duration in days from initiation of first-line therapy to initiation of rituximab treatment (B), the number of rituximab infusions (C), the total cumulative rituximab dose (D), the duration in days from the first to the last rituximab infusion (E), and the number of patients receiving induction therapy (rituximab treatment <6 months) or induction + maintenance therapy (rituximab treatment ≥6 months) (F) are depicted. Bars indicate the median. Normality testing was performed using the D'Agostino-Pearson omnibus test. Continuous variables were compared using the Kruskal-Wallis test followed by the Dunn multiple comparisons test, and ordinal variables were compared using the Fisher exact test. ****p<0.0001 ***p < 0.001, **p < 0.01, and *p < 0.05. (G) mRS scores in the different ab subgroups were compared in the rituximab cohort and in the control cohort. The distribution of mRS scores is depicted at 4 time points: I, maximal mRS at symptom onset; II, mRS at initiation of rituximab treatment (from −2 months to +4 months from rituximab onset); III, mRS 4–12 months after initiation of rituximab treatment; IV, mRS at last follow-up with at least >12 months after rituximab treatment. The line represents the change in mRS scores dividing favorable mRS scores (0–2) and nonfavorable mRS scores (≥3). The ordinal χ2 test was applied to compare the distribution of mRS scores. ****p<0.0001 ***p < 0.001, **p < 0.01, and *p < 0.05. CASPR2, contactin-associated protein-like-2; GAD65 = glutamic acid decarboxylase 65; mRS = modified Rankin Scale; NMDAR = NMDA receptor; LGI1 = leucine-rich glioma-inactivated-1. Follow-up and Treatment Response Follow-up data were available for 282 patients (90%) with a median follow-up duration of 41 months with no significant differences between rituximab-treated patients and controls regarding follow-up data availability and duration (Table 2). The distribution of mRS scores at the peak of disease and at last follow-up improved significantly in patients with NMDAR-AE and in patients with LGI1-AE both in the rituximab cohort and in the control cohort. In patients with CASPR2-AE, a significant improvement was observed only in the rituximab cohort, but not in the control cohort. No significant improvement was observed in patients with GAD65 disease (Figure 3G). In addition, in patients with GAD65 disease, no significant improvement was observed when mRS scores were analyzed in the different disease subentities (encephalitis/overlap syndrome, CA, and SPS) (eFigure 2A, links.lww.com/NXI/A596). Although patients with NMDAR-AE treated with rituximab were affected more severely at baseline (Table 1), at final follow-up, 94% of rituximab-treated patients compared with 88% of nontreated patients had reached independent living (mRS score ≤2, p = 0.33). Patients with LGI1-AE reached independent living in 83% of cases treated with rituximab and in 78% of cases without rituximab treatment (p = 0.74). In CASPR2-AE, independent living was observed in 80% of cases treated with rituximab vs 57% of cases who did not receive B-cell depletion (p = 0.60). In contrast, patients with GAD65 disease treated with rituximab, who were more severely affected at baseline, continued to have a lower rate of independent living compared with the non–rituximab-treated control cohort at last follow-up (52% vs 75%, p = 0.07). When we analyzed the mRS scores in the rituximab cohort throughout follow-up in more detail, we found patients with NMDAR-AE to improve significantly already before rituximab initiation (Figure 3, G.a I-II), presumably because of first-line treatments. After initiation of rituximab treatment, patients continued to improve significantly (Figure 3G.a II-III). No significant difference in the mRS score was observed in patients with NMDAR-AE exhibiting a tumor compared with those without a tumor both regarding mRS score at worst status and mRS score at last follow-up (eFigure 2B, links.lww.com/NXI/A596). In LGI1 patients, a significant improvement was also already observed before rituximab treatment was initiated (Figure 3G.c I-II). After initiation of rituximab treatment, the mRS scores continued to drop; however, this improvement did not reach statistical significance (Figure 3G.c II-IV). In patients with CASPR2-AE, mRS scores decreased after initiation of rituximab treatment (Figure 3G.d II-IV) without reaching significance presumably because of small patient numbers. Nineteen relapses (14%) were reported during follow-up in the rituximab cohort (NMDAR-AE: n = 13, 19%; LGI1-AE: n = 5, 20%; and CASPR2-AE: n = 1, 11%). Of note, only 6 relapses (5%) in the rituximab cohort occurred after rituximab treatment was started (NDMAR-AE: n = 3, 4%; LGI1-AE: n = 3; 12%) (Table 2). The other 13 relapses occurred before rituximab initiation. In the control cohort, 19 relapses (13%) occurred (NMDAR-AE: n = 7, 13%; LGI1-AE: n = 10, 31%; CASPR2-AE: n = 2, 14%), which was more frequent than those observed in the rituximab group after initiation of rituximab (p = 0.02) (Table 2). Finally, we performed a multivariate analysis for the rituximab cohort to identify factors associated with the extent of improvement as measured by the change in the mRS score from baseline to last follow-up. Most significantly, the AE subtype (NMDAR-AE) was associated with mRS score improvement, whereas rituximab dosage and duration were not significantly associated with an improved mRS score (Table 3). MRS score improvement was also observed for early initiation of rituximab treatment (≤60 days after initiation of first-line treatment), and a trend was observed for early initiation of first-line treatment (≤30 days after symptom onset). View inline View popup Table 3 Multivariate Analysis of the Outcome Discussion This study describes real-world data on rituximab usage in a large German cohort of patients with the most common AE subtypes. We confirm the following: (1) Rituximab is the most frequent second-line immunotherapy that is used in nearly half of all patients with AE in Germany. (2) Rituximab usage differs within AE subtypes with patients with NMDAR-AE most frequently and patients with GAD65 disease least frequently receiving rituximab. Treatment was in all cases initiated following prior first-line immunotherapy. Patients with NMDAR-AE and GAD65 disease were more likely to be treated with rituximab if they presented with more severe disease (decreased levels of consciousness and higher mRS). (3) Patients with NMDAR-AE were treated earlier and more often (54%) received a short-term rituximab treatment (<6 months) without repeated maintenance reinfusion than other AE subgroups. (4) The long-term outcome in patients with NMDAR-, LGI1-, and CASPR2-AE in the overall cohort was favorable with 91%, 80%, and 63% of the patients being able to function independently at last follow-up, respectively. (5) Although comparison of patients with and without rituximab treatment is prone to severity bias, we found some hints of a better outcome and fewer relapses in the former group: patients with NMDAR-AE treated with rituximab more often reached independent living at last follow-up although being affected more severely at baseline; patients with CASPR2-AE improved significantly better under rituximab treatment; patients with NMDAR-E and LGI1-AE experienced fewer relapses if treated with rituximab. (6) No significant improvement during follow-up of patients with GAD65 disease was observed both in the rituximab cohort and in the control cohort. However, although we did not observe a group effect in GAD65 disease, some individuals showed a remarkable response associated with B cell–depleting treatment. In NMDAR-AE, treatment with rituximab is widely accepted. It has been used empirically since the first description of NMDAR-AE, and a large prospective case series4 and a systematic review21 could add further evidence that early second-line immunotherapy in patients not responding sufficiently to first-line immunotherapy was associated with better outcomes and fewer relapses. Recently, a meta-analysis of 14 retrospective and prospective case series summarizing 277 patients with AE (88.8% NMDAR-AE) concluded that rituximab is an effective second-line agent with an acceptable toxicity profile.19 Our data confirm and extend these observations. We found patients with NMDAR-AE treated with rituximab to have a favorable outcome. As patients treated with induction or maintenance therapy did not significantly differ in the outcome, our data support the notion that in many patients with NMDAR-AE, short-term rituximab treatment might be sufficient to control the disease. In a recent position paper by the Autoimmune Encephalitis Alliance Clinicians Network,22 this is reflected by the recommendation to consider long-term rituximab treatment mainly in relapsing disease. Compared with NMDAR-AE, considerably less information on long-term immunosuppression and especially rituximab is available in other AE subtypes. For LGI1-AE, early initiation of any immune therapy was associated with better outcomes in studies with 297 and 13 patients,23 respectively. Only few patients were treated with rituximab in retrospective case series19,24,25 and a small open-label trial.26 In our cohort, we observed a surprisingly favorable outcome in patients with LGI1-AE, with 80% reaching independent living (mRS score ≤2) (83% in the rituximab cohort and 78% in the control cohort). A systematic review21 showed full recovery or an mRS score of 0 in 27.8% of patients, with 8% of patients treated with rituximab and 18% of patients receiving second-line treatment. In light of these findings, we believe that rituximab treatment can be considered early in patients with LGI1-AE as 1 possible immunosuppressive treatment, although the duration of therapy is unclear. Relapses occurred in 16% of patients with NMDAR-AE and 26% with LGI1-AE in our overall cohort. Previously, relapses were reported in 11.2% (85/758) of patients with NMDAR-AE and 18.8% (16/85) with LGI1-AE.21 However, we did observe a reduced rate of relapses in patients with NMDAR-AE and LGI1-AE treated with rituximab compared with patients without (independent of other second-line immunotherapies) suggesting better efficacy of rituximab in preventing relapses compared with other regimens. Nevertheless, this should be interpreted with caution because absolute patient numbers are small and controlled studies missing. For the treatment of CASPR2-AE, even less evidence exists. In our series, 44% of patients with CASPR2-AE (n = 11) were treated with rituximab albeit considerably later than patients with NMDAR-AE. We could show significant improvement in patients with CASPR2-AE treated with rituximab, which was not observed in the control group. Although patient numbers were small, our results suggest an effect of rituximab treatment in CASPR2-AE but also indicate the need for larger numbers. Immunotherapeutic strategies for GAD65-AE remain highly controversial.27 Most patients are considered to require immunotherapy, and early immunotherapy has been found to be associated with a better outcome.10,28 However, the different neurologic manifestations of SPS, CA, and LE appear to respond differently to treatments.27 Treatment of SPS with IVIG has been examined in a small crossover placebo-controlled trial in 16 patients with SPS11 and showed efficacy in approximately 80% of patients. The use of plasma exchange and corticosteroids was linked to ambiguous clinical responses,29,30 and immunosuppressive agents such as azathioprine, methotrexate, cyclophosphamide, and mycophenolate mofetil are currently used in clinical practice, however, with insufficient evidence from larger clinical trials.30,31 Rituximab was examined in a randomized, placebo-controlled trial in 24 patients with GAD65-SPS yet surprisingly did not show significant effects, possibly because of the long disease duration at the time of treatment initiation (8.0 years).15 The long-term outcome in SPS in general was poor, with 40% of patients not responding to immunotherapy.32 Although small case series show a benefit from immunotherapy including rituximab in GAD65-CA in 41%–48% of cases,33,34 the long-term outcome is poor in approximately 65% of patients.10 Similarly, most patients with GAD65-LE continue to have seizures with or without immunotherapy.35,36 Our data are in line with these observations. Rituximab treatment was initiated very late after onset of symptoms in our patients, and we did not find a significant association with a better outcome in these patients. Yet, the functional level was better than expected with 67% of patients being able to live independently (mRS score ≤2) (52% in the rituximab group and 75% in the control group). In summary, our data support the notion that long-standing GAD65 disease does not respond to rituximab therapy. However, patients in early disease stages might be more likely to respond to rituximab treatment; however, response is difficult to predict, and a lack of response should trigger benefit-risk reevaluation of rituximab therapy. We analyzed data acquired by the GENERATE network, a multicenter registry for AE in Germany. Of note, all participating centers had experience in treatment of AE, and thus, our study is not necessarily representative for nonexpert centers or centers outside Germany. Further limitations of our study are the observational character going along with a severity bias when patients with and without rituximab treatment are compared and the difficulty to differentiate rituximab treatment effects from spontaneous improvements or improvements due to concomitant treatments, the incomplete follow-up data with potential selection bias, and the lack of clinical criteria defining response to first-line therapies. Nevertheless, because randomized trials are difficult to conduct in rare diseases such as AE, real-world data from registries add important information on treatment profiles and sequences and may lead to standardized treatment protocols. In addition, single-center bias is unlikely due to the multicenter approach. Analysis of auto-ab levels, B-cell counts, and biomarkers like serum neurofilament light chain concentration throughout treatment course could add to future studies investigating the response to rituximab treatment in AE. In addition, safety data should be captured systematically. Our results support the efficacy of early rituximab treatment in NMDAR-, LGI1-, and CASPR2-AE and suggest that short-term therapy could be a treatment option. They also suggest that patients with long-standing GAD65 disease are less likely to benefit from B-cell depletion than the other AE subgroups. Nevertheless, future controlled, randomized, and prospective studies in addition to national and supranational registries with collaborative research efforts are in dire need in the field of AE. As an example of such collaborative research, the multicentric, double-blinded, and placebo-controlled phase II study GENERATE-BOOST is currently investigating the response to bortezomib in patients with severe AE. Study Funding This work was supported by the Else Kröner Fresenius Stiftung (2011_A154), the Gemeinnützige Hertie Stiftung, the Bundesministerium für Bildung und Forschung (CONNECT-GENERATE, 01GM1908), and the Munich Cluster for Systems Neurology (SyNergy). Disclosure The authors report no disclosures relevant to the manuscript. Go to Neurology.org/NN for full disclosures. Acknowledgment The authors thank the patients and relatives contributing by donating their pseudonymized data and biomaterials to the GENERATE network. Appendix 1 Authors Appendix 2 Coinvestigators Footnotes Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article. F. Leypoldt and T. Kümpfel contributed equally to this work as co–senior authors. German Network for Research on Autoimmune Encephalitis (GENERATE) coinvestigators are listed in Appendix 2 at the end of the article. The Article Processing Charge was funded by the authors. Class of Evidence: NPub.org/coe Received February 12, 2021. Accepted in final form August 23, 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.↵Leypoldt F, Armangue T, Dalmau J. Autoimmune encephalopathies. Ann N Y Acad Sci. 2015;1338(1):94-114.OpenUrlCrossRefPubMed 2.↵Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.OpenUrlCrossRefPubMed 3.↵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 4.↵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 5.↵Irani SR, Alexander S, Waters P, et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia. Brain. 2010;133(9):2734-2748.OpenUrlCrossRefPubMed 6.↵Lai M, Huijbers MG, Lancaster E, et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol. 2010;9(8):776-785.OpenUrlCrossRefPubMed 7.↵Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol. 2011;69(5):892-900.OpenUrlCrossRefPubMed 8.↵Lancaster E, Martinez-Hernandez E, Dalmau J. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology. 2011;77(2):179-189.OpenUrlCrossRefPubMed 9.↵Irani SR, Pettingill P, Kleopa KA, et al. Morvan syndrome: clinical and serological observations in 29 cases. Ann Neurol. 2012;72(2):241-255.OpenUrlCrossRefPubMed 10.↵Arino H, Gresa-Arribas N, Blanco Y, et al. Cerebellar ataxia and glutamic acid decarboxylase antibodies: immunologic profile and long-term effect of immunotherapy. JAMA Neurol. 2014;71(8):1009-1016.OpenUrl 11.↵Dalakas MC, Li M, Fujii M, Jacobowitz DM. Stiff person syndrome: quantification, specificity, and intrathecal synthesis of GAD65 antibodies. Neurology. 2001;57(5):780-784.OpenUrlCrossRefPubMed 12.↵Giometto B, Miotto D, Faresin F, Argentiero V, Scaravilli T, Tavolato B. Anti-gabaergic neuron autoantibodies in a patient with stiff-man syndrome and ataxia. J Neurol Sci. 1996;143(1−2):57-59.OpenUrlCrossRefPubMed 13.↵Gresa-Arribas N, Arino H, Martinez-Hernandez E, et al. Antibodies to inhibitory synaptic proteins in neurological syndromes associated with glutamic acid decarboxylase autoimmunity. PLoS One. 2015;10(3):e0121364.OpenUrlCrossRefPubMed 14.↵Dubey D, Britton J, McKeon A, et al. Randomized placebo-controlled trial of intravenous immunoglobulin in autoimmune LGI1/CASPR2 epilepsy. Ann Neurol. 2020;87(2):313-323.OpenUrlCrossRefPubMed 15.↵Dalakas MC, Rakocevic G, Dambrosia JM, Alexopoulos H, McElroy B. A double-blind, placebo-controlled study of rituximab in patients with stiff person syndrome. Ann Neurol. 2017;82(2):271-277.OpenUrl 16.↵Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676-688.OpenUrlCrossRefPubMed 17.↵Trebst C, Jarius S, Berthele A, et al. Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol. 2014;261(1):1-16.OpenUrlCrossRefPubMed 18.↵Lee WJ, Lee ST, Byun JI, et al. Rituximab treatment for autoimmune limbic encephalitis in an institutional cohort. Neurology. 2016;86(18):1683-1691.OpenUrl 19.↵Nepal G, Shing YK, Yadav JK, et al. Efficacy and safety of rituximab in autoimmune encephalitis: a meta-analysis. Acta Neurol Scand. 2020;142(5):449-459.OpenUrl 20.↵Bien CG, Bien CI, Dogan Onugoren M, et al. Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome. J Neurol. 2020;267(7):2101-2114.OpenUrl 21.↵Nosadini M, Mohammad SS, Ramanathan S, Brilot F, Dale RC. Immune therapy in autoimmune encephalitis: a systematic review. Expert Rev Neurother. 2015;15(12):1391-1419.OpenUrlCrossRefPubMed 22.↵Abboud H, Probasco J, Irani SR, et al. Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management. J Neurol Neurosurg Psychiatry. 2015;15(12):1391-1419.OpenUrl 23.↵Shin YW, Lee ST, Shin JW, et al. VGKC-complex/LGI1-antibody encephalitis: clinical manifestations and response to immunotherapy. J Neuroimmunol. 2013;265(1-2):75-81.OpenUrlCrossRefPubMed 24.↵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 25.↵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.OpenUrlCrossRefPubMed 26.↵Irani SR, Gelfand JM, Bettcher BM, Singhal NS, Geschwind MD. Effect of rituximab in patients with leucine-rich, glioma-inactivated 1 antibody-associated encephalopathy. JAMA Neurol. 2014;71(7):896-900.OpenUrl 27.↵Graus F, Saiz A, Dalmau J. GAD antibodies in neurological disorders - insights and challenges. Nat Rev Neurol. 2020;16(7):353-365.OpenUrlPubMed 28.↵Di Giacomo R, Deleo F, Pastori C, et al. Predictive value of high titer of GAD65 antibodies in a case of limbic encephalitis. J Neuroimmunol. 2019;337:577063.OpenUrl 29.↵Vasconcelos OM, Dalakas MC. Stiff-person syndrome. Curr Treat Options Neurol. 2003;5(1):79-90.OpenUrlCrossRefPubMed 30.↵Tsiortou P, Alexopoulos H, Dalakas MC. GAD antibody-spectrum disorders: progress in clinical phenotypes, immunopathogenesis and therapeutic interventions. Ther Adv Neurol Disord. 2021;14:17562864211003486.OpenUrl 31.↵Hao W, Davis C, Hirsch IB, et al. Plasmapheresis and immunosuppression in stiff-man syndrome with type 1 diabetes: a 2-year study. J Neurol. 1999;246(8):731-735.OpenUrlCrossRefPubMed 32.↵McKeon A, Robinson MT, McEvoy KM, et al. Stiff-man syndrome and variants: clinical course, treatments, and outcomes. Arch Neurol. 2012;69(2):230-238.OpenUrlCrossRefPubMed 33.↵Mitoma H, Hadjivassiliou M, Honnorat J. Guidelines for treatment of immune-mediated cerebellar ataxias. Cerebellum Ataxias. 2015;2:14.OpenUrl 34.↵Jones AL, Flanagan EP, Pittock SJ, et al. Responses to and outcomes of treatment of autoimmune cerebellar ataxia in adults. JAMA Neurol. 2015;72(11):1304-1312.OpenUrl 35.↵Daif A, Lukas RV, Issa NP, et al. Antiglutamic acid decarboxylase 65 (GAD65) antibody-associated epilepsy. Epilepsy Behav. 2018;80:331-336.OpenUrl 36.↵Malter MP, Frisch C, Zeitler H, et al. Treatment of immune-mediated temporal lobe epilepsy with GAD antibodies. Seizure. 2015;30:57-63.OpenUrlCrossRefPubMed
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Josep Dalmau receives the “Scientific Breakthrough 2023” Award from the American Brain Foundation

From www.clinicbarcelona.org - May 23, 2023 2:38 PM
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

From www.clinicbarcelona.org - September 5, 2023 11:21 AM
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

From youtu.be - August 6, 2023 7:10 PM
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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
From www.ajnr.org - July 27, 2023 11:18 AM
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
From jneuroinflammation.biomedcentral.com - July 27, 2023 11:01 AM
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
From jmedicalcasereports.biomedcentral.com - July 14, 2023 2:17 PM
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
From www.antinmdafoundation.org - June 25, 2023 2:58 PM
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
From nn.neurology.org - June 19, 2023 9:45 PM
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
From www.encephalitis.info - June 19, 2023 9:38 PM
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
From www.psychiatrist.com - June 19, 2023 9:33 PM
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
From jmedicalcasereports.biomedcentral.com - June 19, 2023 9:27 PM
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
From cp.neurology.org - June 14, 2023 7:42 PM
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
From pubmed.ncbi.nlm.nih.gov - June 14, 2023 7:41 PM
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
From www.frontiersin.org - September 5, 2023 11:22 AM
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

Enceph-IG Study - Institute of Infection, Veterinary and Ecological Sciences - University of Liverpool | AntiNMDA | Scoop.it
From www.liverpool.ac.uk - August 6, 2023 7:27 PM
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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
From touchneurology.com - July 27, 2023 11:22 AM
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
From news.mayocliniclabs.com - July 27, 2023 11:05 AM
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New center to spotlight neurological autoimmune disorders

New center to spotlight neurological autoimmune disorders | AntiNMDA | Scoop.it
From bioengineer.org - July 14, 2023 2:19 PM
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
From news.mayocliniclabs.com - July 14, 2023 2:16 PM
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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
From blogs.cardiff.ac.uk - June 19, 2023 9:46 PM
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30 neurological disorders every doctor should know about –

30 neurological disorders every doctor should know about – | AntiNMDA | Scoop.it
From theneurologylounge.com - June 19, 2023 9:42 PM
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
From pubmed.ncbi.nlm.nih.gov - June 19, 2023 9:34 PM
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
From www.cbc.ca - June 19, 2023 9:28 PM
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
From myhealthcrm.com - June 14, 2023 7:43 PM
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
From pubmed.ncbi.nlm.nih.gov - June 14, 2023 7:41 PM
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
From www.wndu.com - June 14, 2023 7:40 PM
(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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jack henry's curator insight, April 2, 7:35 AM


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