Analytical evaluation of a GAD65 antibodies chemiluminescence immunoassay for CSF in neurological syndromes.

OBJECTIVES: Antibodies against glutamic acid decarboxylase isoform 65 (GAD-Ab) have been found in different severe neurological conditions associated with altered synthesis of γ-aminobutyric acid (GABA). Serum GAD-Ab can be found in up to 90 % of patients with type 1 diabetes mellitus (T1DM), mostly at relatively low concentrations, while high concentrations of GAD-ab are thought to be more frequently associate to a neurological condition, with levels 100-folds higher than those found in T1DM. Although CSF testing is recommended when suspecting a GAD-associated neurological syndrome, no commercial immunoassay is validated for this use and no cut-off is internationally recognized to support the diagnosis. METHODS: In this study we validated CSF testing of GAD-Ab on an automated chemiluminescence (CLIA) immunoassay that had previously shown good agreement with ELISA on serum. RESULTS: We tested 43 CSF from patients with typical GAD-associated neurological disorders and patients with other neurological conditions, identifying a clinical cut-off of 18 kIU/L that discriminated GAD-disease with an area under the curve (AUC) of 0.921. CLIA showed good analytical performances on repeatability and recovery tests in CSF and confirmed an excellent agreement with ELISA. CONCLUSIONS: GAD-Ab associated neurological disorders are rare but CSF testing for GAD-Ab is a common request for neurologists when suspecting an insidious autoimmune central nervous system disease. CLIA platforms are expected to be increasingly adopted in clinical laboratories due to their flexibility and reliability, therefore studies on decisional levels should be implemented for improving the interpretation and utilization of laboratory data.

Epileptic phenotypes in autoimmune encephalitis: from acute symptomatic seizures to autoimmune-associated epilepsy.

OBJECTIVE: To describe the clinical and paraclinical findings, treatment options and long-term outcomes in autoimmune encephalitis (AE), with a close look to epilepsy. METHODS: In this retrospective observational cohort study, we enrolled patients with new-onset seizures in the context of AE. We compared clinical and paraclinical findings in patients with and without evidence of antibodies. RESULTS: Overall, 263 patients (138 females; median age 55 years, range 4-86) were followed up for a median time of 30 months (range 12-120). Antineuronal antibodies were detected in 63.50%.Antibody-positive patients had multiple seizure types (p=0.01) and prevalent involvement of temporal regions (p=0.02). A higher prevalence of episodes of SE was found in the antibody-negative group (p<0.001).Immunotherapy was prescribed in 88.60%, and effective in 61.80%. Independent predictors of favourable outcome of the AE were early immunotherapy (p<0.001) and the detection of antineuronal surface antibodies (p=0.01).Autoimmune-associated epilepsy was the long-term sequela in 43.73%, associated with cognitive and psychiatric disturbances in 81.73%. Independent predictors of developing epilepsy were difficult to treat seizures at onset (p=0.04), a high number of antiseizure medications (p<0.001), persisting interictal epileptiform discharges at follow-up (p<0.001) and poor response to immunotherapy during the acute phase (p<0.001). CONCLUSIONS: The recognition of seizures secondary to AE represents a rare chance for aetiology-driven seizures management. Early recognition and treatment at the pathogenic level may reduce the risk of long-term irreversible sequelae. However, the severity of seizures at onset is the major risk factor for the development of chronic epilepsy.This study provides class IV evidence for management recommendations.

Conventional brain MRI features distinguishing limbic encephalitis from mesial temporal glioma.

PURPOSE: Radiological hallmark of autoimmune limbic encephalitis (LE) is a hyperintense signal in MRI T2-weighted images of mesial temporal structures. We aimed to identify conventional magnetic resonance imaging (MRI) features that can help distinguish LE from temporal glioma. METHODS: Brain MRIs of 25 patients affected by antibody-positive autoimmune LE, 24 patients affected by temporal glioma (tumor group), and 5 negative controls were retrospectively blindly evaluated in random order. RESULTS: Ten brain MRIs from the LE group were correctly recognized; one additional patient with mesial temporal hyperintensity with anti-AK5 abs LE was wrongly diagnosed as having a tumor. The brain MRIs of the remaining 14 of the 25 patients with LE were judged negative or, in three cases, showed features not typical for LE. In the tumor group, all MRIs showed pathological alterations diagnosed as tumors in 22/24 cases and as LE in two (2/22, 9%). Unilateral lesions were more common in tumors than in neuroradiologically abnormal LE (96% vs. 18%, p < 0.001). T2/FLAIR hyperintensity of the parahippocampal gyrus was associated more with tumor than with LE (71% vs. 18%) (p = 0,009), as T2/FLAIR hyperintensity of extralimbic structures (p = 0.015), edema (p = 0.041), and mass effect (p = 0.015). Maintenance of gray/white matter distinction was strongly associated with LE (91% vs. 17%, p < 0.001). CONCLUSION: Conventional brain MRI is a fundamental tool in the differential diagnosis between LE and glioma. Bilateral involvement and maintenance of gray/white matter distinction at the cortical/subcortical interface are highly suggestive of LE.

Management of antibody-mediated autoimmune encephalitis in adults and children: literature review and consensus-based practical recommendations.

Autoimmune encephalitis associated with antibodies against neuronal surface targets (NSAE) are rare but still underrecognized conditions that affect adult and pediatric patients. Clinical guidelines have recently been published with the aim of providing diagnostic clues regardless of antibody status. These syndromes are potentially treatable but the choice of treatment and its timing, as well as differential diagnoses, long-term management, and clinical and paraclinical follow-up, remain major challenges. In the absence of evidence-based guidelines, management of these conditions is commonly based on single-center expertise.Taking into account different published expert recommendations in addition to the multicenter experience of the Italian Working Group on Autoimmune Encephalitis, both widely accepted and critical aspects of diagnosis, management and particularly of immunotherapy for NSAE have been reviewed and are discussed.Finally, we provide consensus-based practical advice for managing hospitalization and follow-up of patients with NSAE.

Diagnostics of paraneoplastic neurological syndromes.

This document presents the guidelines for onconeural antibody testing that have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on paraneoplastic neurological syndromes, indications and limits of onconeural antibody testing, instructions for result interpretation, and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.

Diagnostics of autoimmune encephalitis associated with antibodies against neuronal surface antigens.

This document presents the guidelines for testing antibodies against neuronal surface antigens that have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on autoimmune encephalitis associated with antibodies against neuronal surface antigens, indications and limits of testing for such antibodies, instructions for result interpretation, and an agreed laboratory protocol (Appendix A) are reported for the communicative community of neurologists and clinical pathologists.

Diagnostics of the neuromyelitis optica spectrum disorders (NMOSD).

This document presents the guidelines for anti-aquaporin-4 (AQP4) antibody testing that has been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on neuromyelitis optica spectrum disorders, indications and limits of anti-AQP4 antibody testing, instructions for result interpretation, and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.

Voltage-Gated Potassium Channel Antibodies in Slow-Progression Motor Neuron Disease.

BACKGROUND: The spectrum of autoimmune neurological diseases associated with voltage-gated potassium channel (VGKC)-complex antibodies (Abs) ranges from peripheral nerve disorders to limbic encephalitis. Recently, low titers of VGKC-complex Abs have also been reported in neurodegenerative disorders, but their clinical relevance is unknown. OBJECTIVE: The aim of the study was to explore the prevalence of VGKC-complex Abs in slow-progression motor neuron disease (MND). METHODS: We compared 11 patients affected by slow-progression MND with 9 patients presenting typical progression illness. Sera were tested for VGKC-complex Abs by radioimmunoassay. The distribution of VGKC-complex Abs was analyzed with the Mann-Whitney U test. RESULTS: The statistical analysis showed a significant difference between the mean values in the study and control groups. A case with long-survival MND harboring VGKC-complex Abs and treated with intravenous immunoglobulins is described. CONCLUSION: Although VGKC-complex Abs are not likely to be pathogenic, these results could reflect the coexistence of an immunological activation in patients with slow disease progression.

Multicentre comparison of a diagnostic assay: aquaporin-4 antibodies in neuromyelitis optica.

OBJECTIVE: Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD). METHODS: Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1). RESULTS: Results of tests on 92 controls identified 12assays as highly specific (0-1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5-100%) of all 21 assays. The specificities (85.8-100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples. CONCLUSIONS: The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology.

Paraneoplastic encephalitis.

The first reports of encephalitis associated with cancer date to the 1960s and were characterized by clinical and pathologic involvement of limbic areas. This specific association was called limbic encephalitis (LE). The subsequent discovery of several "onconeural" antibodies (Abs), i.e., Abs targeting an antigen shared by neurons and tumor cells, supported the hypothesis of an autoimmune paraneoplastic etiology of LE and other forms of rapidly progressive encephalopathy. Over the past 20 years, similar clinical pictures with different clinical courses have been described in association with novel Abs-binding neuronal membrane proteins and proved to be pathogenic. The most well-known encephalitis in this group was described in 2007 as an association of a complex neuro-psychiatric syndrome, N-methyl-d-aspartate (NMDA) receptor-Abs, and ovarian teratoma in young women. Later on, nonparaneoplastic cases of NMDA receptor encephalitis were also described. Since then, the historical concept of LE and Ab associated encephalitis has changed. Some of these occur in fact more commonly in the absence of a malignancy (e.g., anti-LG1 Abs). Lastly, seronegative cases were also described. The term paraneoplastic encephalitis nowadays encompasses different syndromes that may be triggered by occult tumors.

Central nervous system immune-related disorders after SARS-CoV-2 vaccination: a multicenter study.

Background: COVID-19 vaccines have been approved due to their excellent safety and efficacy data and their use has also permitted to reduce neurological complications of SARS-CoV-2. However, clinical trials were underpowered to detect rare adverse events. Herein, the aim was to characterize the clinical spectrum and immunological features of central nervous system (CNS) immune-related events following SARS-CoV-2 vaccination. Methods: Multicenter, retrospective, cohort study (December 1, 2020-April 30, 2022). Inclusion criteria were (1) de novo CNS disorders developing after SARS-CoV-2 vaccination (probable causal relationship as per 2021 Butler criteria) (2); evidence for an immune-mediated etiology, as per (i) 2016 Graus criteria for autoimmune encephalitis (AE); (ii) 2015 Wingerchuk criteria for neuromyelitis optica spectrum disorders; (iii) criteria for myelitis. Results: Nineteen patients were included from 7 tertiary referral hospitals across Italy and France (one of them being a national referral center for AE), over almost 1 year and half of vaccination campaign. Vaccines administered were mRNA-based (63%) and adenovirus-vectored (37%). The median time between vaccination and symptoms onset was 14 days (range: 2-41 days). CSF was inflammatory in 74%; autoantibodies were detected in 5%. CSF cytokine analysis (n=3) revealed increased CXCL-10 (IP-10), suggesting robust T-cell activation. The patients had AE (58%), myelitis (21%), acute disseminated encephalomyelitis (ADEM) (16%), and brainstem encephalitis (5%). All patients but 2 received immunomodulatory treatment. At last follow-up (median 130 days; range: 32-540), only one patient (5%) had a mRS>2. Conclusion: CNS adverse events of COVID-19 vaccination appear to be very rare even at reference centers and consist mostly of antibody-negative AE, myelitis, and ADEM developing approximately 2 weeks after vaccination. Most patients improve following immunomodulatory treatment.

Morvan syndrome: clinical and serological observations in 29 cases.

OBJECTIVE: A study was undertaken to describe the clinical spectrum, voltage-gated potassium channel (VGKC) complex antibody specificities, and central nervous system localization of antibody binding in 29 patients diagnosed with Morvan syndrome (MoS). METHODS: Clinical data were collected using questionnaires. Radioimmunoassay, cell-based assays, and mouse brain immunohistochemistry were used to characterize the serum antibodies. RESULTS: Neuromyotonia (100%), neuropsychiatric features (insomnia 89.7%, confusion 65.5%, amnesia 55.6%, hallucinations 51.9%), dysautonomia (hyperhidrosis 86.2%, cardiovascular 48.3%), and neuropathic pain (62.1%) were the most common manifestations. A total of 93.1% of MoS patients were male. VGKC-complex antibodies were present in 23 of 29 (79%) MoS patients at referral; 24 of 27 available sera had CASPR2, LGI1, or both CASPR2 and LGI1 antibodies (3 also with contactin-2 antibodies). CASPR2 antibodies were generally higher titer than LGI1 antibodies. Tumors (41.4%), mainly thymomas, were associated with CASPR2 antibodies and a poor prognosis, whereas LGI1 antibodies were associated with serum hyponatremia. In brain tissue regions including the hypothalamus, raphe, and locus coeruleus, commercial antibodies to LGI1 bound to neuronal cell bodies including the antidiuretic hormone-secreting and orexin-secreting hypothalamic neurons, whereas CASPR2 commercial antibodies bound more often to the neuropil. MoS antibodies bound similarly, but there was evidence of additional antibodies in some sera that were not adsorbed by LGI1- or CASPR2-expressing cells and bound to mouse Caspr2(-/-) tissue. INTERPRETATION: MoS is clinically distinct from other VGKC-complex antibody-associated conditions, and usually is associated with high-titer CASPR2 antibodies, often accompanied by lower-titer LGI1 antibodies. CASPR2 and LGI1 antibodies bind to multiple brain regions, which helps to explain the multifocal clinical features of this disease, but other antibodies are likely to play a role in some patients and need to be characterized in future studies.

CACNA1H antibodies associated with headache with neurological deficits and cerebrospinal fluid lymphocytosis (HaNDL).

BACKGROUND: Patients with the syndrome of headache with neurological deficits and lymphocytosis (HaNDL) typically present with recurrent and temporary attacks of neurological symptoms and cerebrospinal fluid lymphocytosis. AIM AND METHODS: To identify potential HaNDL-associated antibodies directed against neuronal surface and/or synapse antigens, sera of four HaNDL patients and controls were screened with indirect immunohistochemistry, immunofluorescence, cell-based assay, radioimmunoassay, protein macroarray and enzyme-linked immunosorbent assay (ELISA). RESULTS: Although HaNDL sera did not yield antibodies to any of the well-characterized neuronal surface or synapse antigens, protein macroarray and ELISA studies showed high-titer antibodies to a subunit of the T-type voltage-gated calcium channel (VGCC), CACNA1H, in sera of two HaNDL patients. CONCLUSION: Our results support the notion that ion channel autoimmunity might at least partially contribute to HaNDL pathogenesis and occurrence of neurological symptoms.

Anti-LGI1 encephalitis: A family affair.

Here we describe the second ever-reported case of familial anti-leucine-rich glioma-inactivated protein 1 (LGI1) limbic encephalitis (LE). Two elderly Caucasian sisters presented with psychiatric symptoms and cognitive impairment, followed by faciobrachial dystonic seizures. Anti-LGI1 antibodies were detected in their serum. Considering they had been living in distant regions for decades, environmental factors could be ruled out. Human leukocyte antigen (HLA) genotyping revealed that both carried HLA-DRB1*07, found in 90% of anti-LGI1 encephalitis patients, HLA-DQA1*02:01 and HLA-DQB1*03:03, commonly associated with DRB1*07:01. Considering the exceptional nature of familial cases, as-yet-unknown genetic contributors other than HLA might play a role in our siblings.

Early Immunotherapy and Longer Corticosteroid Treatment Are Associated With Lower Risk of Relapsing Disease Course in Pediatric MOGAD.

BACKGROUND AND OBJECTIVES: We sought to identify early factors associated with relapse and outcome in paediatric-onset myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD). METHODS: In a multicenter retrospective cohort of pediatric MOGAD (≤18 years), onset features and treatment were compared in patients with monophasic vs relapsing disease (including cases with follow-up ≥12 months after onset or relapse at any time) and in patients with final Expanded Disability Status Scale (EDSS) 0 vs ≥1 at last follow-up (including cases with follow-up >3 months after last event or EDSS0 at any time). Multivariable logistic regression models were used to evaluate factors associated with relapsing disease course and EDSS ≥ 1 at final follow-up. RESULTS: Seventy-five children were included (median onset age 7 years; median 30 months of follow-up). Presentation with acute disseminated encephalomyelitis was more frequent in children aged 8 years or younger (66.7%, 28/42) than in older patients (30.3%, 10/33) (p = 0.002), whereas presentation with optic neuritis was more common in children older than 8 years (57.6%, 19/33) than in younger patients (21.4%, 9/42) (p = 0.001). 40.0% (26/65) of patients relapsed. Time to first relapse was longer in children aged 8 years or younger than in older patients (median 18 vs 4 months) (p = 0.013). Factors at first event independently associated with lower risk of relapsing disease course were immunotherapy <7 days from onset (6.7-fold reduced odds of relapsing course, OR 0.15, 95% CI 0.03-0.61, p = 0.009), corticosteroid treatment for ≥5 weeks (6.7-fold reduced odds of relapse, OR 0.15, 95% CI 0.03-0.80, p = 0.026), and abnormal optic nerves on onset MRI (12.5-fold reduced odds of relapse, OR 0.08, 95% CI 0.01-0.50, p = 0.007). 21.1% (15/71) had EDSS ≥ 1 at final follow-up. Patients with a relapsing course had a higher proportion of final EDSS ≥ 1 (37.5%, 9/24) than children with monophasic disease (12.8%, 5/39) (p = 0.022, univariate analysis). Each 1-point increment in worst EDSS at onset was independently associated with 6.7-fold increased odds of final EDSS ≥ 1 (OR 6.65, 95% CI 1.33-33.26, p = 0.021). DISCUSSION: At first attack of pediatric MOGAD, early immunotherapy, longer duration of corticosteroid treatment, and abnormal optic nerves on MRI seem associated with lower risk of relapse, whereas higher disease severity is associated with greater risk of final disability (EDSS ≥ 1).

Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition.

The concept of antibody mediated CNS disorders is relatively recent. The classical CNS paraneoplastic neurological syndromes are thought to be T cell mediated, and the onconeural antibodies merely biomarkers for the presence of the tumour. Thus it was thought that antibodies rarely, if ever, cause CNS disease. Over the past 10 years, identification of autoimmune forms of encephalitis with antibodies against neuronal surface antigens, particularly the voltage gated potassium channel complex proteins or the glutamate N-methyl-D-aspartate receptor, have shown that CNS disorders, often without associated tumours, can be antibody mediated and benefit from immunomodulatory therapies. The clinical spectrum of these diseases is not yet fully explored, there may be others yet to be discovered and some types of more common disorders (eg, epilepsy or psychosis) may prove to have an autoimmune basis. Here, the known conditions associated with neuronal surface antibodies are briefly reviewed, some general aspects of these syndromes are considered and guidelines that could help in the recognition of further disorders are suggested.

Contactin-associated protein-2 antibodies in non-paraneoplastic cerebellar ataxia.

BACKGROUND: Relatively few studies have searched for potentially pathogenic antibodies in non-paraneoplastic patients with cerebellar ataxia. METHODS AND RESULTS: We first screened sera from 52 idiopathic ataxia patients for binding of serum IgG antibodies to cerebellar neurons. One strong-binding serum was selected for immunoprecipitation and mass spectrometry, which resulted in the identification of contactin-associated protein 2 (CASPR2) as a major antigen. CASPR2 antibodies were then found by a cell-based assay in 9/88 (10%) ataxia patients, compared to 3/144 (2%) multiple sclerosis or dementia controls (p=0.011). CASPR2 is strongly expressed in the cerebellum, only partly in association with voltage-gated potassium channels. CONCLUSIONS: Prospective studies are now needed to see whether identification of CASPR2 antibodies has relevance for the diagnosis and treatment of idiopathic cerebellar ataxia.

Safety profile of SARS-CoV-2 vaccination in patients with antibody-mediated CNS disorders.

OBJECTIVES: In this retrospective multicenter study, we evaluated the safety of SARS-CoV-2 vaccination in patients harboring autoantibodies targeting neuronal surface and/or synaptic antigens. METHODS: From eight Italian Neurology Units, we included patients with: a) serum and/or CSF positivity for specific neuronal autoantibodies; b) a compatible neurological syndrome; and c) available follow-up ≥6 weeks after vaccination with any of the approved SARS-CoV-2 vaccines. Demographics, clinical data, and information regarding previous SARS-CoV-2 infection and vaccination were collected. Disease relapses were considered "post-infectious" or "post-vaccination" when occurring within 6 weeks from infection/vaccination. RESULTS: We included 66 patients; 7/66 (11%) had a previous history of SARS-CoV-2 infection and 1/7 (14%) had post-infection relapses. BNT162b2-Pfizer-BioNTec was administered in 55 cases (83.3%) and mRNA-1273-Moderna in 11 (16.7%). The median number of doses administered per patient was 2 (1-3) and >50% of patients did not experience side effects. Five patients (8%) had post-vaccination relapses (seizure 3/5); 4/5 improved after immunotherapy, while one did not receive immunotherapy and worsened. Patients with post-vaccination relapses had higher disability scores at vaccination (p = 0.025), a trend favoring Leucine-rich glioma-inactivated protein 1 LGI1 glutamic acid decarboxylase 65 (GAD65) antibodies (p =  0.054) and shorter time from last relapse (p = 0.057). DISCUSSION: Our data support the safety of SARS-CoV-2 vaccines in patients with neurological disorders associated with antibodies to neuronal and synaptic antigens.

Olfactory impairment in autoimmune encephalitis: another piece of the puzzle.

BACKGROUND: Despite being long neglected, olfaction has recently become a focus of intense research in neuroscience, as smell impairment has been consistently documented in both neurodegenerative and neuroinflammatory diseases. Considering the close anatomo-functional correlations between the limbic system and the central olfactory structures, we investigated olfaction in a population of patients with autoimmune encephalitis (AE). METHODS: Nineteen adult subjects (14 males, median age 64 years) diagnosed with definite (14/19) or possible (5/19) AE and followed for ≥ 6 months were enrolled. The Brief Smell Identification Test (B-SIT), a 12-item, forced-choice, scratch-and-sniff measure, was used to assess the patients' olfactory function in comparison with a group of sex- and age-matched healthy controls (HC). According to the B-SIT score, subjects were classified as anosmic (< 6), hyposmic (6-8) and normal (≥ 9). Electro-clinical, laboratory and neuroimaging findings were reviewed. RESULTS: Smell impairment was revealed in 15/19 patients (9 hyposmic, 6 anosmic), compared with 5/19 HC (p = 0.0029). Age, gender and smoking habits did not affect the participants' performance at B-SIT. Olfactory dysfunction appeared more common among patients with definite AE (p = 0.0374), regardless of autoantibody status. Subjects with higher modified Rankin Scale (mRS) scores at AE onset more likely presented hyposmia/anosmia (p = 0.033), and so did those with bilateral ictal/interictal EEG abnormalities (p = 0.006). CONCLUSIONS: We found olfaction to be impaired in a significantly large proportion of AE cases. Smell deficits appeared more common in subjects with severe AE (as indicated by both definite diagnosis and higher mRS score), and might represent an additional feature of immune-mediated encephalitis.