Autoimmune encephalitis : The clinical value of antibodies directed to extracellular antigens

Het doel van dit proefschrift is om meer inzicht te geven in de meest voorkomende ziekten die geassocieerd zijn met antistoffen tegen extracellulaire antigenen. Vroege herkenning van subtiele epileptische aanvallen is essentieel voor de vlotte herkenning en behandeling van een anti-LGI1 encefalitis. Anti-LGI1 encefalitis is sterk geassocieerd met HLA-DR7 en HLA-DRB4. De syndromen geassocieerd met Caspr2-antistoffen zijn gevarieerd, waaronder encefalitis, het syndroom van Morvan, en neuromyotonie, maar er zijn opvallend sterke overeenkomsten tussen patiënten wat betreft epidemiologische kenmerken en kernsymptomen. VGKC-positiviteit in afwezigheid van antistoffen tegen LGI1 en Caspr2 is geen marker voor een auto-immuun ontsteking en is in de klinische praktijk niet bijdragend. Het eerste EEG bij patienten met een anti-NMDAR encefalitis heeft een voorspellende waarde voor de uiteindelijke klinische uitkomst

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

Mimics of Autoimmune Encephalitis:Validation of the 2016 Clinical Autoimmune Encephalitis Criteria

BACKGROUND AND OBJECTIVES: The clinical criteria for autoimmune encephalitis (AE) were proposed by Graus et al. in 2016. In this study, the AE criteria were validated in the real world, and common AE mimics were described. In addition, criteria for probable anti-LGI1 encephalitis were proposed and validated. METHODS: In this retrospective cohort study, patients referred to our national referral center with suspicion of AE and specific neuroinflammatory disorders with similar clinical presentations were included from July 2016 to December 2019. Exclusion criteria were pure cerebellar or peripheral nerve system disorders. All patients were evaluated according to the AE criteria. RESULTS: In total, 239 patients were included (56% female; median age 42 years, range 1-85). AE was diagnosed in 104 patients (44%) and AE mimics in 109 patients (46%). The most common AE mimics and misdiagnoses were neuroinflammatory CNS disorders (26%), psychiatric disorders (19%), epilepsy with a noninflammatory cause (13%), CNS infections (7%), neurodegenerative diseases (7%), and CNS neoplasms (6%). Common confounding factors were mesiotemporal lesions on brain MRI (17%) and false-positive antibodies in serum (12%). Additional mesiotemporal features (involvement extralimbic structures, enhancement, diffusion restriction) were observed more frequently in AE mimics compared with AE (61% vs 24%; p = 0.005). AE criteria showed the following sensitivity and specificity: possible AE, 83% (95% CI 74-89) and 27% (95% CI 20-36); definite autoimmune limbic encephalitis (LE), 10% (95% CI 5-17) and 98% (95% CI 94-100); and probable anti-NMDAR encephalitis, 50% (95% CI 26-74) and 96% (95% CI 92-98), respectively. Specificity of the criteria for probable seronegative AE was 99% (95% CI 96-100). The newly proposed criteria for probable anti-LGI1 encephalitis showed a sensitivity of 66% (95% CI 47-81) and specificity of 96% (95% CI 93-98). DISCUSSION: AE mimics occur frequently. Common pitfalls in AE misdiagnosis are mesiotemporal lesions (predominantly with atypical features) and false-positive serum antibodies. As expected, the specificity of the criteria for possible AE is low because these criteria represent the minimal requirements for entry in the diagnostic algorithm for AE. Criteria for probable AE (-LGI1, -NMDAR, seronegative) and definite autoimmune LE are applicable for decisions on immunotherapy in early disease stage, as specificity is high.</p

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)

Autoimmune encephalitis

This chapter gives an overview of the syndromes associated with antibodies directed to membrane-bound or synaptic proteins. In contrast to the classical syndromes, disease occurs in younger patients as well; patients are also seen by non-neurologists like psychiatrists and pediatricians, and patients tend to have a more favorable response to immunotherapy. The focus in this chapter is on the clinical characteristics which distinguishes these disorders and on the relevance of cerebrospinal fl uid (CSF) analysis. Comparison of sensitivity and specifi city for serum and CSF is extensively discussed. N -methyl-D-aspartate receptor (NMDAR) encephalitis is relatively common and discussed fi rst. Alpha-amino- 3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) encephalitis and encephalitis associated with antibodies to the metabotropic glutamate receptors mGluR1 and mGluR5 are rare and will be reviewed briefl y. Subsequently, syndromes associated with antibodies to the glycine receptor, VGKC complex, and dipeptidyl-peptidase-like protein-6 (DPP6) are described. Encephalitis with antibodies directed to the a-aminobutyric acid (GABA) receptor type B and type A are reviewed last.</p

Encephalitis and AMPA receptor antibodies: Novel findings in a case series of 22 patients.

ObjectiveWe report the clinical features, comorbidities, and outcome of 22 newly identified patients with antibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR).MethodsThis was a retrospective review of patients diagnosed between May 2009 and March 2014. Immunologic techniques have been reported previously.ResultsPatients' median age was 62 years (range 23-81; 14 female). Four syndromes were identified: 12 (55%) patients presented with distinctive limbic encephalitis (LE), 8 (36%) with limbic dysfunction along with multifocal/diffuse encephalopathy, one with LE preceded by motor deficits, and one with psychosis with bipolar features. Fourteen patients (64%) had a tumor demonstrated pathologically (5 lung, 4 thymoma, 2 breast, 2 ovarian teratoma) or radiologically (1 lung). Additional antibodies occurred in 7 patients (3 onconeuronal, 1 tumor-related, 2 cell surface, and 1 tumor-related and cell surface), all with neurologic symptoms or tumor reflecting the concurrent autoimmunity. Treatment and outcome were available from 21 patients (median follow-up 72 weeks, range 5-266): 5 had good response to immunotherapy and tumor therapy, 10 partial response, and 6 did not improve. Eventually 5 patients died; all had a tumor or additional paraneoplastic symptoms related to onconeuronal antibodies. Coexistence of onconeuronal antibodies predicted a poor outcome (p = 0.009).ConclusionAnti-AMPAR encephalitis usually manifests as LE, can present with other symptoms or psychosis, and is paraneoplastic in 64% of cases. Complete and impressive neurologic improvement can occur, but most patients have partial recovery. Screening for a tumor and onconeuronal antibodies is important because their detection influences outcome