OBJECTIVE:This nationwide study gives a detailed description of the clinical features and long-term outcome of anti–leucine-rich glioma-inactivated 1 (LGI1) encephalitis.
METHODS:We collected ...patients prospectively from October 2013, and retrospectively from samples sent to our laboratory from January 2007. LGI1 antibodies were confirmed with both cell-based assay and immunohistochemistry. Clinical information was obtained in interviews with patients and their relatives and from medical records. Initial MRI and follow-up MRI were revised blindly. Neuropsychological assessment was performed in those patients with follow-up over 2 years.
RESULTS:Annual incidence in the Netherlands was 0.83/million. A total of 34/38 patients had a limbic encephalitis. Subtle focal seizures (66%, autonomic or dyscognitive) and faciobrachial dystonic seizures (FBDS, 47%) mostly occurred before onset of memory disturbance. Later in the disease course, 63% had tonic-clonic seizures. Initial MRI showed hippocampal T2 hyperintensity in 74% of the patients. These lesions evolved regularly into mesial temporal sclerosis (44%). Substantial response to immunotherapy was seen in 80%, with early response of seizures and slow recovery of cognition. At follow-up ≥2 years, most surviving patients reported mild residual cognitive deficit with spatial disorientation. A total of 86% had persistent amnesia for the disease period. Relapses were common (35%) and presented up to 8 years after initial disease. Two-year case fatality rate was 19%.
CONCLUSIONS:Anti-LGI1 encephalitis is a homogenous clinical syndrome, showing early FBDS and other focal seizures with subtle clinical manifestations, followed by memory disturbances. Better recognition will lead to earlier diagnosis, essential for prompt start of treatment. Long-term outcome of surviving patients is mostly favorable, but relapses are common.
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). Twenty patients (3.4%) had AES, of whom 3 had anti–leucine‐rich glioma inactivated 1, 3 had anti–contactin‐associated protein‐like 2, 1 had anti–N‐methyl‐D‐aspartate receptor, and 13 had anti–glutamic acid decarboxylase 65 (enzyme‐linked immunosorbent assay concentrations >10,000IU/ml). Risk factors for AES were temporal magnetic resonance imaging hyperintensities (odds ratio OR = 255.3, 95% confidence interval CI = 19.6–3332.2, p < 0.0001), autoimmune diseases (OR = 13.31, 95% CI = 3.1–56.6, p = 0.0005), behavioral changes (OR 12.3, 95% CI = 3.2–49.9, p = 0.0003), autonomic symptoms (OR = 13.3, 95% CI = 3.1–56.6, p = 0.0005), cognitive symptoms (OR = 30.6, 95% CI = 2.4–382.7, p = 0.009), and speech problems (OR = 9.6, 95% CI = 2.0–46.7, p = 0.005). The internally validated C statistic was 0.95, and 0.92 in the validation cohort (n = 128). Assigning each factor 1 point, an antibodies contributing to focal epilepsy signs and symptoms (ACES) score ≥ 2 had a sensitivity of 100% to detect AES, and a specificity of 84.9%.
Interpretation
Specific signs point toward AES in focal epilepsy of unknown etiology. The ACES score (cutoff ≥ 2) is useful to select patients requiring antibody testing. ANN NEUROL 2021;89:698–710
OBJECTIVEThis 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.
METHODSAnti-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.
RESULTSOf 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.
CONCLUSIONEpilepsy 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.
OBJECTIVE:To assess the clinical relevance of a positive voltage-gated potassium channel (VGKC) test in patients lacking antibodies to LGI1 and Caspr2.
METHODS:VGKC-positive patients were tested for ...LGI1 and Caspr2 antibodies. Patients lacking both antibodies were matched (1:2) to VGKC-negative patients. Clinical and paraclinical criteria were used to blindly determine evidence for autoimmune inflammation in both groups. Patients with an inconclusive VGKC titer were analyzed in the same way.
RESULTS:A total of 1,455 patients were tested by VGKC radioimmunoassay. Fifty-six patients tested positive, 50 of whom were available to be included. Twenty-five patients had antibodies to LGI1 (n = 19) or Caspr2 (n = 6) and 25 patients lacked both antibodies. Evidence for autoimmune inflammation was present in 7 (28%) of the VGKC-positive patients lacking LGI1 and Caspr2, compared to 9 (18%) of the VGKC-negative controls (p = 0.38). Evidence for autoimmune inflammation was mainly found in patients with limbic encephalitis/encephalomyelitis (57%), but not in other clinical phenotypes (5%, p < 0.01). VGKC titers were significantly higher in patients with antibodies to LGI1 or Caspr2 (p < 0.001). However, antibodies to Caspr2 could also be detected in patients with inconclusive low VGKC titer, while many VGKC-positive patients had no evidence for autoimmune inflammation.
CONCLUSIONS:VGKC positivity in the absence of antibodies to LGI1 and Caspr2 is not a clear marker for autoimmune inflammation and seems not to contribute in clinical practice. No cutoff value for the VGKC titer was appropriate to discriminate between patients with and without autoimmune inflammation.
OBJECTIVETo 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).
METHODSAll 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 includedattention, 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.
RESULTSTwenty-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).
CONCLUSIONSAlthough follow-up is often reported as “good” following pediatric anti-NMDAR encephalitis, many patients have cognitive problems and fatigue, even up until adolescence, resulting in academic achievement problems and lower QoL. For physicians, it is essential to be aware of these problems, to provide valuable advice to patients and caregivers in the acute and follow-up phase, and to consider early neuropsychological counseling.
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 cell lung carcinoma and optimize laboratory methods for the detection of GABABR antibodies. Patients (n = 3225) were tested for the presence of GABABR antibodies using cell-based assay, immunohistochemistry and live hippocampal neurons. Clinical data were obtained retrospectively. Potassium channel tetramerization domain-containing (KCTD)16 antibodies were identified by immunoprecipitation, mass spectrometry analysis and cell-based assays. KCTD16 antibodies were identified in 23/32 patients with anti-GABABR encephalitis, and in 1/26 patients with small cell lung carcinoma and Hu antibodies, but not in 329 healthy subjects and disease controls. Of the anti-GABABR encephalitis patients that were screened sufficiently, 18/19 (95%) patients with KCTD16 antibodies had a tumour versus 3/9 (33%) anti-GABABR encephalitis patients without KCTD16 antibodies (P = 0.001). In most cases this was a small cell lung carcinoma. Patients had cognitive or behavioural changes (97%) and prominent seizures (90%). Thirteen patients developed a refractory status epilepticus with intensive care unit admittance (42%). Strikingly, 4/32 patients had a rapidly progressive dementia. The addition of KCTD16 to the GABABR cell-based assay improved sensitivity of the in-house fixed cell-based assay, without loss of specificity. Twenty-two of 26 patients improved (partially) to immunotherapy or chemotherapy. Anti-GABABR encephalitis is a limbic encephalitis with prominent, severe seizures, but patients can also present with rapidly progressive dementia. The co-occurrence of KCTD16 antibodies points towards a paraneoplastic origin. The addition of KCTD16 improves the sensitivity of the cell-based assay.
Joint decision-making entails that you sometimes have to go along with the other's choice even though you disagree. In this situation, a resulting negative outcome may, however, elicit a feeling of ...satisfaction and an impulse to say "I told you so". Using fMRI, we investigated the neural correlates of this complex process comprised of both positive and negative outcomes. During a social visual search task, 19 participants gave their advice to a co-actor who then made the decision resulting in a mutual loss or gain. This design allowed direct comparisons of situations that resulted in the same monetary outcome but that differed with respect to the correctness of the initial advice of the participant. Increased striatal activations were found for gains compared to losses and for correct compared to incorrect advice. Importantly, ROI analyses also showed enhanced striatum activation for monetary losses that were preceded by correct compared to incorrect advices. The current study therefore suggests that reward-related neural mechanisms may be involved when being right even in situations that end in monetary losses.
OBJECTIVEAntibodies 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.
METHODSRetrospectively, 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.
RESULTSClassical 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.
CONCLUSIONMost patients with high anti-GAD65 concentrations (>10,000 IU/mL) showed some improvement after immunotherapy, unfortunately without complete recovery. Serum antibody concentrationsʼ course might be useful to monitor response. In patients with low anti-GAD65 concentrations, especially in those without typical clinical phenotypes, diagnostic alternatives are more likely.
Several studies have associated physical activity with the risk of dementia, but mostly did so during short follow-up. It remains unclear whether physical activity also affects dementia during longer ...follow-up. We examined the association between physical activity and risk of dementia during a follow-up period up to 14 years. From 1997 to 1999, physical activity was assessed using a validated questionnaire in 4,406 elderly persons (age range 61–97) from the prospective, population-based Rotterdam Study. Follow-up for dementia was complete until January 1, 2011. We used Cox proportional hazards models to assess the association between physical activity and incident dementia. Next, we stratified follow-up time using a cut-off of 4 years. We separately investigated dementia due to Alzheimer disease. During 38,631 person-years, 583 participants developed dementia. When adjusting for age and sex, we found a borderline significant association between higher physical activity and lower risk of dementia (HR 0.95; 95 % CI 0.87–1.04). This association was confined to follow-up up to 4 years (HR 0.82; 95 % CI 0.71–0.95), and not to follow-up of at least 4 years (HR 1.04; 95 % CI 0.93–1.16). Additional adjustments only slightly attenuated the associations. A similar pattern was present for Alzheimer disease. We found a higher level of physical activity to be associated with a lower risk of dementia. This association was confined to follow-up for up to 4 years and not to longer follow-up, suggesting either a role for reverse causality or only a short term effect of late-life physical activity in an elderly population.
In social contexts, errors have a special significance and often bear consequences for others. Thinking about others and drawing social inferences in interpersonal games engages the mentalizing ...system. We used neuroimaging to investigate the differences in brain activations between errors that affect only agents themselves and errors that additionally influence the payoffs of interaction partners. Activation in posterior medial frontal cortex (pMFC) and bilateral insula was increased for all errors, whereas errors that implied consequences for others specifically activated medial prefrontal cortex (mPFC), an important part of the mentalizing system. The results demonstrate that performance monitoring in social contexts involves additional processes and brain structures compared with individual performance monitoring where errors only have consequences for the person committing them. Taking into account how one’s behavior may affect others is particularly crucial for adapting behavior in interpersonal interactions and joint action.
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