Distinct movement disorders in contactin-associated-protein-like-2 antibody-associated autoimmune encephalitis.

Autoimmune encephalitis can be classified into antibody-defined subtypes, which can manifest with immunotherapy-responsive movement disorders sometimes mimicking non-inflammatory aetiologies. In the elderly, anti-LGI1 and contactin associated protein like 2 (CASPR2) antibody-associated diseases compose a relevant fraction of autoimmune encephalitis. Patients with LGI1 autoantibodies are known to present with limbic encephalitis and additionally faciobrachial dystonic seizures may occur. However, the clinical spectrum of CASPR2 autoantibody-associated disorders is more diverse including limbic encephalitis, Morvan's syndrome, peripheral nerve hyperexcitability syndrome, ataxia, pain and sleep disorders. Reports on unusual, sometimes isolated and immunotherapy-responsive movement disorders in CASPR2 autoantibody-associated syndromes have caused substantial concern regarding necessity of autoantibody testing in patients with movement disorders. Therefore, we aimed to systematically assess their prevalence and manifestation in patients with CASPR2 autoimmunity. This international, retrospective cohort study included patients with CASPR2 autoimmunity from participating expert centres in Europe. Patients with ataxia and/or movement disorders were analysed in detail using questionnaires and video recordings. We recruited a comparator group with anti-LGI1 encephalitis from the GENERATE network. Characteristics were compared according to serostatus. We identified 164 patients with CASPR2 autoantibodies. Of these, 149 (90.8%) had only CASPR2 and 15 (9.1%) both CASPR2 and LGI1 autoantibodies. Compared to 105 patients with LGI1 encephalitis, patients with CASPR2 autoantibodies more often had movement disorders and/or ataxia (35.6 versus 3.8%; P < 0.001). This was evident in all subgroups: ataxia 22.6 versus 0.0%, myoclonus 14.6 versus 0.0%, tremor 11.0 versus 1.9%, or combinations thereof 9.8 versus 0.0% (all P < 0.001). The small group of patients double-positive for LGI1/CASPR2 autoantibodies (15/164) significantly more frequently had myoclonus, tremor, 'mixed movement disorders', Morvan's syndrome and underlying tumours. We observed distinct movement disorders in CASPR2 autoimmunity (14.6%): episodic ataxia (6.7%), paroxysmal orthostatic segmental myoclonus of the legs (3.7%) and continuous segmental spinal myoclonus (4.3%). These occurred together with further associated symptoms or signs suggestive of CASPR2 autoimmunity. However, 2/164 patients (1.2%) had isolated segmental spinal myoclonus. Movement disorders and ataxia are highly prevalent in CASPR2 autoimmunity. Paroxysmal orthostatic segmental myoclonus of the legs is a novel albeit rare manifestation. Further distinct movement disorders include isolated and combined segmental spinal myoclonus and autoimmune episodic ataxia.

Clinical relevance of distinguishing autoimmune nodopathies from CIDP: longitudinal assessment in a large cohort.

BACKGROUND: The aim of this study was to determine treatment response and whether it is associated with antibody titre change in patients with autoimmune nodopathy (AN) previously diagnosed as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and to compare clinical features and treatment response between AN and CIDP. METHODS: Serum IgG antibodies to neurofascin-155 (NF155), contactin-1 (CNTN1) and contactin-associated protein 1 (CASPR1) were detected with cell-based assays in patients diagnosed with CIDP. Clinical improvement was determined using the modified Rankin scale, need for alternative and/or additional treatments and assessment of the treating neurologist. RESULTS: We studied 401 patients diagnosed with CIDP and identified 21 patients with AN (10 anti-NF155, 6 anti-CNTN1, 4 anti-CASPR1 and 1 anti-NF155/anti-CASPR1 double positive). In patients with AN ataxia (68% vs 28%, p=0.001), cranial nerve involvement (34% vs 11%, p=0.012) and autonomic symptoms (47% vs 22%, p=0.025) were more frequently reported; patients with AN improved less often after intravenous immunoglobulin treatment (39% vs 80%, p=0.002) and required additional/alternative treatments more frequently (84% vs 34%, p<0.001), compared with patients with CIDP. Antibody titres decreased or became negative in patients improving on treatment. Treatment withdrawal was associated with a titre increase and clinical deterioration in four patients. CONCLUSIONS: Distinguishing CIDP from AN is important, as patients with AN need a different treatment approach. Improvement and relapses were associated with changes in antibody titres, supporting the pathogenicity of these antibodies.

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). 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.

Pompe disease in adulthood: effects of antibody formation on enzyme replacement therapy.

PURPOSE: To determine the effect of antibodies against recombinant human acid α-glucosidase (rhGAA) on treatment efficacy and safety, and to test whether the GAA genotype is involved in antibody formation. METHODS: We used enzyme-linked immunosorbent assay (ELISA) to determine anti-rhGAA antibody titers at baseline and at 6, 12, and 36 months of rhGAA treatment. We measured the capacity of antibodies to neutralize rhGAA enzymatic activity or cellular uptake and the effects on infusion-associated reactions (IARs), muscle strength, and pulmonary function. RESULTS: Of 73 patients, 45 developed antibodies. Maximal titers were high (≥1:31,250) in 22% of patients, intermediate (1:1,250-1:31,250) in 40%, and none or low (0-1:1,250) in 38%. The common IVS1/delex18 GAA genotype was absent only in the high-titer group. The height of the titer positively correlated with the occurrence and number of IARs (P ≤ 0.001). On the group level, antibody titers did not correlate with treatment efficacy. Eight patients (11%) developed very high maximal titers (≥156,250), but only one patient showed high sustained neutralizing antibodies that probably interfered with treatment efficacy. CONCLUSIONS: In adults with Pompe disease, antibody formation does not interfere with rhGAA efficacy in the majority of patients, is associated with IARs, and may be attenuated by the IVS1/delex18 GAA genotype.Genet Med 19 1, 90-97.

Clinical Outcome Assessments in Encephalitis: A Systematic Review

BACKGROUND AND OBJECTIVES: Most patients with encephalitis experience persisting neurocognitive and neuropsychiatric sequelae in the years following this acute illness. Reported outcomes are often based on generic clinical outcome assessments that rarely capture the patient perspective. This may result in an underestimation of disease-specific sequelae. Disease-specific clinical outcome assessments can improve clinical relevance of reported outcomes and increase the power of research and trials. There are no patient-reported outcome measures (PROMs) developed or validated specifically for patients with encephalitis. The primary objective of this systematic literature review was to identify PROMs that have been developed for or validated in patients with encephalitis. METHODS: We performed a systematic review of the literature published from inception until May 2023 in 3 large international databases (MEDLINE, EMBASE and Cochrane libraries). Eligible studies should have developed or validated a PROM in patients with encephalitis or encephalopathy. Methodologic quality was evaluated using the Consensus-based Standards for the selection of health status Measurement Instruments study design checklist for PROMs. RESULTS: We identified no disease-specific PROMs developed or validated for patients with encephalitis. We identified one study on the development and validation of a disease-specific PROM for hepatic encephalopathy, although this disease course is substantially different to that of patients with encephalitis. The methodologic quality of the included study was generally rated as "doubtful." We identified 30 PROMs that have been applied in 46 studies on encephalitis or encephalopathy, although not validated in these populations. The most commonly applied PROMs for measuring Health-Related Quality of Life were the Medical Outcomes Study Short Form-36 and the Sickness Impact Profile. Emotional well-being was often assessed with the Beck Depression Inventory (BDI-II). Sporadically, PROMs were applied to address other aspects of outcome including daily functioning and sleep quality. DISCUSSION: This systematic review confirms a critical gap in clinical outcome assessments in patients with encephalitis, failing to identify a validated measuring tool for detecting neurocognitive, functional, and health status. It is therefore essential to develop and/or validate disease-specific PROMs for the population with encephalitis to capture relevant information for patient management and clinical trials about the effects of disease that are at risk of being overlooked.

Risk of Seizure Recurrence Due to Autoimmune Encephalitis With NMDAR, LGI1, CASPR2, and GABABR Antibodies: Implications for Return to Driving.

BACKGROUND AND OBJECTIVES: Patients with ongoing seizures are usually not allowed to drive. The prognosis for seizure freedom is favorable in patients with autoimmune encephalitis (AIE) with antibodies against NMDA receptor (NMDAR), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and the gamma-aminobutyric-acid B receptor (GABABR). We hypothesized that after a seizure-free period of 3 months, patients with AIE have a seizure recurrence risk of <20% during the subsequent 12 months. This would render them eligible for noncommercial driving according to driving regulations in several countries. METHODS: This retrospective multicenter cohort study analyzed follow-up data from patients aged 15 years or older with seizures resulting from NMDAR-, LGI1-, CASPR2-, or GABABR-AIE, who had been seizure-free for ≥3 months. We used Kaplan-Meier (KM) estimates for the seizure recurrence risk at 12 months for each antibody group and tested for the effects of potential covariates with regression models. RESULTS: We included 383 patients with NMDAR-, 440 with LGI1-, 114 with CASPR2-, and 44 with GABABR-AIE from 14 international centers. After being seizure-free for 3 months after an initial seizure period, we calculated the probability of remaining seizure-free for another 12 months (KM estimate) as 0.89 (95% confidence interval [CI] 0.85-0.92) for NMDAR, 0.84 (CI 0.80-0.88) for LGI1, 0.82 (CI 0.75-0.90) for CASPR2, and 0.76 (CI 0.62-0.93) for GABABR. DISCUSSION: Taking a <20% recurrence risk within 12 months as sufficient, patients with NMDAR-AIE and LGI1-AIE could be considered eligible for noncommercial driving after having been seizure-free for 3 months.

Comparative Study of Paraneoplastic and Nonparaneoplastic Autoimmune Encephalitis With GABABR Antibodies.

BACKGROUND AND OBJECTIVES: While patients with paraneoplastic autoimmune encephalitis (AE) with gamma-aminobutyric-acid B receptor antibodies (GABABR-AE) have poor functional outcomes and high mortality, the prognosis of nonparaneoplastic cases has not been well studied. METHODS: Patients with GABABR-AE from the French and the Dutch Paraneoplastic Neurologic Syndromes Reference Centers databases were retrospectively included and their data collected; the neurologic outcomes of paraneoplastic and nonparaneoplastic cases were compared. Immunoglobulin G (IgG) isotyping and human leukocyte antigen (HLA) genotyping were performed in patients with available samples. RESULTS: A total of 111 patients (44/111 [40%] women) were enrolled, including 84 of 111 (76%) paraneoplastic and 18 of 111 (16%) nonparaneoplastic cases (cancer status was undetermined for 9 patients). Patients presented with seizures (88/111 [79%]), cognitive impairment (54/111 [49%]), and/or behavioral disorders (34/111 [31%]), and 54 of 111 (50%) were admitted in intensive care unit (ICU). Nonparaneoplastic patients were significantly younger (median age 54 years [range 19-88] vs 67 years [range 50-85] for paraneoplastic cases, p < 0.001) and showed a different demographic distribution. Nonparaneoplastic patients more often had CSF pleocytosis (17/17 [100%] vs 58/78 [74%], p = 0.02), were almost never associated with KTCD16-abs (1/16 [6%] vs 61/70 [87%], p < 0.001), and were more frequently treated with second-line immunotherapy (11/18 [61%] vs 18/82 [22%], p = 0.003). However, no difference of IgG subclass or HLA association was observed, although sample size was small (10 and 26 patients, respectively). After treatment, neurologic outcome was favorable (mRS ≤2) for 13 of 16 (81%) nonparaneoplastic and 37 of 84 (48%) paraneoplastic cases (p = 0.03), while 3 of 18 (17%) and 42 of 83 (51%) patients had died at last follow-up (p = 0.008), respectively. Neurologic outcome no longer differed after adjustment for confounding factors but seemed to be negatively associated with increased age and ICU admission. A better survival was associated with nonparaneoplastic cases, a younger age, and the use of immunosuppressive drugs. DISCUSSION: Nonparaneoplastic GABABR-AE involved younger patients without associated KCTD16-abs and carried better neurologic and vital prognoses than paraneoplastic GABABR-AE, which might be due to a more intensive treatment strategy. A better understanding of immunologic mechanisms underlying both forms is needed.

HLA and KIR genetic association and NK cells in anti-NMDAR encephalitis.

Introduction: Genetic predisposition to autoimmune encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDAR) is poorly understood. Given the diversity of associated environmental factors (tumors, infections), we hypothesized that human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptors (KIR), two extremely polymorphic gene complexes key to the immune system, might be relevant for the genetic predisposition to anti-NMDAR encephalitis. Notably, KIR are chiefly expressed by Natural Killer (NK) cells, recognize distinct HLA class I allotypes and play a major role in anti-tumor and anti-infection responses. Methods: We conducted a Genome Wide Association Study (GWAS) with subsequent control-matching using Principal Component Analysis (PCA) and HLA imputation, in a multi-ethnic cohort of anti-NMDAR encephalitis (n=479); KIR and HLA were further sequenced in a large subsample (n=323). PCA-controlled logistic regression was then conducted for carrier frequencies (HLA and KIR) and copy number variation (KIR). HLA-KIR interaction associations were also modeled. Additionally, single cell sequencing was conducted in peripheral blood mononuclear cells from 16 cases and 16 controls, NK cells were sorted and phenotyped. Results: Anti-NMDAR encephalitis showed a weak HLA association with DRB1*01:01~DQA1*01:01~DQB1*05:01 (OR=1.57, 1.51, 1.45; respectively), and DRB1*11:01 (OR=1.60); these effects were stronger in European descendants and in patients without an underlying ovarian teratoma. More interestingly, we found increased copy number variation of KIR2DL5B (OR=1.72), principally due to an overrepresentation of KIR2DL5B*00201. Further, we identified two allele associations in framework genes, KIR2DL4*00103 (25.4% vs. 12.5% in controls, OR=1.98) and KIR3DL3*00302 (5.3% vs. 1.3%, OR=4.44). Notably, the ligands of these KIR2DL4 and KIR3DL3, respectively, HLA-G and HHLA2, are known to act as immune checkpoint with immunosuppressive functions. However, we did not find differences in specific KIR-HLA ligand interactions or HLA-G polymorphisms between cases and controls. Similarly, gene expression of CD56dim or CD56bright NK cells did not differ between cases and controls. Discussion: Our observations for the first time suggest that the HLA-KIR axis might be involved in anti-NMDAR encephalitis. While the genetic risk conferred by the identified polymorphisms appears small, a role of this axis in the pathophysiology of this disease appears highly plausible and should be analyzed in future studies.

Enzyme replacement therapy and fatigue in adults with Pompe disease.

BACKGROUND: Pompe disease is a hereditary metabolic myopathy, for which enzyme replacement therapy (ERT) has been available since 2006. We investigated whether ERT reduces fatigue in adult patients with Pompe disease. METHODS: In this prospective international observational survey, we used the Fatigue Severity Scale (FSS) to measure fatigue. Repeated measures ANOVA was used to analyze the data over time. In a subgroup of patients, we also evaluated muscle strength using the Medical Research Council Scale, measured pulmonary function as Forced Vital Capacity, and assessed depression using the Hospital Anxiety and Depression Scale. RESULTS: We followed 163 patients for a median period of 4 years before ERT and for 3 years during ERT. Before ERT, the mean FSS score remained stable at around 5.3 score points; during ERT, scores improved significantly by 0.13 score points per year (p < 0.001). Fatigue decreased mainly in women, in older patients and in those with shorter disease duration. Patients' improvements in fatigue were moderately correlated with the effect of ERT on depression (r 0.55; CI 95% 0.07 to 0.70) but not with the effect of ERT on muscle strength or pulmonary function. CONCLUSIONS: Fatigue is a common and disabling problem in patients with early and advanced stages of Pompe disease. Our finding that ERT helps to reduce fatigue is therefore important for this patient population, irrespective of the mechanisms underlying this effect.

Brain stem encephalitis is a rare complication of COVID-19.

Here, we describe the clinical phenotype of SARS-CoV-2-related CNS disease and evaluate the SARS-CoV-2 antibody index as a tool to differentiate between a direct (viral) and indirect etiology. Out of >4000 hospitalized patients with COVID-19, we included 13 patients with neurological symptoms with suspicion of neuroinflammation. On clinical grounds, eight were classified as having a possible/probable relationship between neurological symptoms and COVID-19. A clinically distinctive phenotype of brainstem and cerebellar symptoms was seen in 6/8 patients. As we found a positive SARS-CoV-2 antibody index in 3/5 patients, indicating specific intrathecal SARS-CoV-2 IgG production, a direct link with SARS-CoV-2 is likely.