From VGKC to LGI1 and Caspr2 encephalitis: The evolution of a disease entity over time

AbstractA wide variety of clinical syndromes has been associated with antibodies to voltage-gated potassium channels (VGKCs). Six years ago, it was discovered that patients do not truly have antibodies to potassium channels, but to associated proteins. This enabled the distinction of three VGKC-positive subgroups: anti-LGI1 patients, anti-Caspr2 patients and VGKC-positive patients lacking both antibodies. Patients with LGI1-antibodies have a limbic encephalitis, often with hyponatremia, and about half of the patients have typical faciobrachial dystonic seizures. Caspr2-antibodies cause a more variable syndrome of peripheral or central nervous system symptoms, almost exclusively affecting older males. Immunotherapy seems to be beneficial in patients with antibodies to LGI1 or Caspr2, stressing the need for early diagnosis. Half of the VGKC-positive patients lack antibodies to both LGI1 and Caspr2. This is a heterogeneous group of patients with a wide variety of clinical syndromes, raising the question whether VGKC-positivity is truly a marker of disease in these patients. Data regarding this issue are limited, but a recent study did not show any clinical relevance of VGKC-positivity in the absence of antibodies to LGI1 and Caspr2. The three VGKC-positive subgroups are essentially different, therefore, the lumping term ‘VGKC-complex antibodies’ should be abolished

From VGKC to LGI1 and Caspr2 encephalitis: The evolution of a disease entity over time

A wide variety of clinical syndromes has been associated with antibodies to voltage-gated potassium channels (VGKCs). Six years ago, it was discovered that patients do not truly have antibodies to potassium channels, but to associated proteins. This enabled the distinction of three VGKC-positive subgroups: anti-LGI1 patients, anti-Caspr2 patients and VGKC-positive patients lacking both antibodies. Patients with LGI1-antibodies have a limbic encephalitis, often with hyponatremia, and about half of the patients have typical faciobrachial dystonic seizures. Caspr2-antibodies cause a more variable syndrome of peripheral or central nervous system symptoms, almost exclusively affecting older males. Immunotherapy seems to be beneficial in patients with antibodies to LGI1 or Caspr2, stressing the need for early diagnosis. Half of the VGKC-positive patients lack antibodies to both LGI1 and Caspr2. This is a heterogeneous group of patients with a wide variety of clinical syndromes, raising the question whether VGKC-positivity is truly a marker of disease in these patients. Data regarding this issue are limited, but a recent study did not show any clinical relevance of VGKC-positivity in the absence of antibodies to LGI1 and Caspr2. The three VGKC-positive subgroups are essentially different, therefore, the lumping term ‘VGKC-complex antibodies’ should be abolished

Pediatric autoimmune encephalitis: Recognition and diagnosis

OBJECTIVE: The aims of this study were (1) to describe the incidence of autoimmune encephalitis (AIE) and acute dissemi

Neurologic syndromes related to anti-GAD65: Clinical and serologic response to treatment

OBJECTIVE: Antibodies against glutamic acid decarboxylase 65 (anti-GAD65) are associated with a number of neurologic syndromes. However, their pathogenic role is controversial. Our objective was to describe clinical and paraclinical characteristics of anti-GAD65 patients and analyze their response to immunotherapy. METHODS: Retrospectively, we studied patients (n = 56) with positive anti-GAD65 and any neurologic symptom. We tested serum and CSF with ELISA, immunohistochemistry, and cell-based assay. Accordingly, we set a cutoff value of 10,000 IU/mL in serum by ELISA to group patients into high-concentration (n = 36) and low-concentration (n = 20) groups. We compared clinical and immunologic features and analyzed response to immunotherapy. RESULTS: Classical anti-GAD65-associated syndromes were seen in 34/36 patients with high concentration (94%): stiff-person syndrome (7), cerebellar ataxia (3), chronic epilepsy (9), limbic encephalitis (9), or an overlap of 2 or more of the former (6). Patients with low concentrations had a broad, heterogeneous symptom spectrum. Immunotherapy was effective in 19/27 treated patients (70%), although none of them completely recovered. Antibody concentration reduction occurred in 15/17 patients with available pre- and post-treatment samples (median reduction 69%; range 27%-99%), of which 14 improved clinically. The 2 patients with unchanged concentrations showed no clinical improvement. No differences in treatment responses were observed between specific syndromes. CONCLUSION: Most patients with high anti-GAD65 concentrations (>10,000 IU/mL) showed some improvement after immunotherapy, unfortunately without complete recovery. Serum antibody concen

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

Objective This nationwide cohort study evaluates seizure responses to immunotherapy and antiepileptic drugs (AEDs) in patients with anti-leucine-rich glioma-inactivated 1 (LGI1), anti-NMDA receptor (NMDAR), and anti-gamma-aminobutyric-acid B receptor (GABABR) encephalitis. Methods Anti-LGI1, anti-NMDAR, and anti-GABABR encephalitis patients with new-onset seizures were included. Medical information about disease course, AEDs and immunotherapies used, effects, and side effects were collected. Outcome measures were (1) seizure freedom while using AEDs or immunotherapy, (2) days to seizure freedom from start of AEDs or immunotherapy, and (3) side effects. Results Of 153 patients with autoimmune encephalitis (AIE) (53 LGI1, 75 NMDAR, 25 GABABR), 72% (n = 110) had epileptic seizures, and 89% reached seizure freedom. At least 53% achieved seizure freedom shortly after immunotherapy, and 14% achieved seizure freedom while using only AEDs (p < 0.0001). This effect was similar in all types (p = 0.0001; p = 0.0005; p = 0.013, respectively). Median time to seizure freedom from AEDs start was 59 days (interquartile range [IQR] 27–160), and 28 days from start of immunotherapy (IQR 9–71, p < 0.0001). Side effects were psychotic behavior and suicidal thoughts by the use of levetiracetam, and rash by the use of carbamazepine. Carbamazepine was more effective than levetiracetam in reducing seizures in anti-LGI1 encephalitis (p = 0.031). Only 1 patient, of 86 surviving patients, developed epilepsy after resolved encephalitis. Conclusion Epilepsy after resolved encephalitis was rare in our cohort of patients with AIE treated with immunotherapy. In addition, seizure freedom is achieved faster and more frequently after immunotherapy. Therefore, AEDs should be considered as add-on treatment, and similar to treatment of other encephalitis symptoms, immunotherapy is crucial

Long-term neuropsychological outcome following pediatric anti-NMDAR encephalitis

Objective: To provide detailed long-term outcome data of children and adolescents following pediatric anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis, to identify neuropsychological impairments, and to evaluate the influence of these factors on quality of life (QoL). Methods: All Dutch children diagnosed with anti-NMDAR encephalitis were identified. Patients currently aged 4 years or older were included in the follow-up study, consisting of a visit to our clinic for a detailed interview and a standardized neuropsychological assessment. The following domains were included: attention, memory, language, executive functioning, QoL, and fatigue. Primary outcome measures were z scores on sustained attention, long-term verbal memory, QoL, fatigue, and working memory. Results: Twenty-eight patients were included. Median Pediatric Cerebral Performance Category at last visit was 1 (interquartile range 1-2, range 1-4), and 64% (18/28) of patients returned consistently to their previous school level. Twenty-two patients were included in the cross-sectional part of the long-term follow-up study. Median follow-up time was 31 months (interquartile range 15-49, range 5-91). There were problems with sustained attention (z = -2.10, 95% confidence interval = -2.71 to -1.46, p < 0.0001) and fatigue (z = -0.96, 95% confidence interval = -1.64 to -0.28, p = 0.008). Cognitive deficits were not correlated with QoL, while fatigue was strongly correlated with QoL (r = 0.82, p < 0.0001). Conclusions: Although follow-up is often reported as "good" following pediatric anti-NMDAR encephalitis, many patients have cognitive problems an

Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma

Background: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with 18F-Fluorodeoxyglucose (18F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of 18F-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. 18F-Fluoro-3'-deoxy-3'L-fluorothymidine (18F-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than 18F-FDG. Methods: This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F-FDG/18F-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks. Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo 18F-FDG PET/CT and in 25 patients additional 18F-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response.

The expanded clinical spectrum of anti-GABABR encephalitis and added value of KCTD16 autoantibodies

In this study we report the clinical features of 32 patients with gamma aminobutyric acid B receptor (GABABR) antibodies, identify additional autoantibodies in patients with anti-GABABR encephalitis that mark the presence of an underlying small cel

Antibodies Contributing to Focal Epilepsy Signs and Symptoms Score

Objective: Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases such as epilepsy. However, recognition is important, as patients require immunotherapy. This study aims to identify antibodies in patients with focal epilepsy of unknown etiology, and to create a score to preselect patients requiring testing. Methods: In this prospective, multicenter cohort study, adults with focal epilepsy of unknown etiology, without recognized AIE, were included, between December 2014 and December 2017, and followed for 1 year. Serum, and if available cerebrospinal fluid, were analyzed using different laboratory techniques. The ACES score was created using factors favoring an autoimmune etiology of seizures (AES), as determined by multivariate logistic regression. The model was externally validated and evaluated using the Concordance (C) statistic. Results: We included 582 patients, with median epilepsy duration of 8 years (interquartile range = 2–18)