Utilization of APE2 and RITE2 scores in autoimmune encephalitis patients with seizures.

PURPOSE: Immune-mediated seizures are rare but are increasingly recognized as an etiology of seizures resistant to anti-seizure medications (ASMs). Antibody Prevalence in Epilepsy 2 (APE2) and Response to Immunotherapy in Epilepsy 2 (RITE2) scores were developed recently to identify patients who may be seropositive for serum central nervous system (CNS) specific antibodies (Ab) and may benefit from immunotherapy (Dubey et al. 2018). The goal of this study was to apply APE2 and RITE2 scores to an independent cohort of patients with seizures secondary to autoimmune encephalitis (AE) and to further verify the sensitivity and specificity of the scores. PRINCIPAL RESULTS: We conducted a retrospective study at Stanford University Hospital between 2008 and 2021 and included patients who had acute seizures and AE using diagnostic criteria from Graus (n = 34 definite AE, 10 probable AE, and 12 possible AE) (Graus et al. 2016). Patients were excluded if they did not have a serum Ab panel investigated or had alternate diagnoses (n = 55). APE2 and RITE2 scores were calculated based on clinical and diagnostic data (n = 56). Serum Ab were positive in 73 % of patients, in which 63 % cases carried CNS specific Ab. An APE2 score ≥ 4 had a sensitivity of 97 % and specificity of 14 % to predict a positive serum CNS specific Ab. A RITE2 score ≥ 7 had a sensitivity of 93 % and specificity of 60 % to predict seizure responsiveness to immunotherapy. CONCLUSION: APE2 and RITE2 scores had high sensitivities but low specificities to predict seropositivity and seizure responsiveness to immunotherapy in patients with autoimmune encephalitis with seizures.

Increased cytokines/chemokines and hyponatremia as a possible cause of clinically mild encephalitis/encephalopathy with a reversible splenial lesion associated with acute focal bacterial nephritis.

OBJECTIVE: Clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), the second most common encephalopathy syndrome in Japan, is most often associated with viral infection. Bacterial MERS has been rarely reported but is mostly associated with acute focal bacterial nephritis (AFBN) for an unknown reason. We examined cytokines and chemokines in four MERS patients with AFBN to determine if they play an important role in the pathogenesis. METHODS: We examined the clinical charts and MRI results in four MERS patients with AFBN, and measured 10 cytokines and chemokines in serum and cerebrospinal fluid in the acute phase. These were analyzed using the Mann-Whitney U test, compared with the control group (cases with a non-inflammatory neurological disease). Longitudinal changes in the serum cytokine and chemokine levels were evaluated in two patients. RESULTS: Hyponatremia was observed in all four patients with MERS associated with AFBN (128-134 mEq/L). CSF analysis revealed increased cytokines/chemokines associated with Th1 (CXCL10, TNF-α, IFN-γ), T reg (IL-10), Th17 (IL-6), and neutrophil (IL-8 and CXCL1). In serum, upregulation was observed in those associated with Th1 (CXCL10, TNF-α, IFN-γ), Th17 (IL-6), and inflammasome (IL-1ß). The increased serum cytokines/chemokines in the acute stage normalized within 2 weeks in patients 1 and 2, so examined, in accordance with their clinical improvement. CONCLUSION: Increased cytokines/chemokines and hyponatremia may be factors that explain why AFBN is likely to cause MERS.

The changing spectrum of antibody-mediated encephalitis in China.

In the past 5 years, the positivity rate of autoimmune encephalitis antibody panels has significantly decreased in patients with clinically suspected encephalitis in an encephalitis center in China. Furthermore, the spectrum of patients with autoantibodies related to autoimmune encephalitis has changed significantly, exhibiting a decreased percentage of patients with anti-N-methyl-d-aspartate receptor antibodies and an increased percentage of patients with infrequently observed autoantibodies. Meanwhile, a small but non-negligible proportion of patients with autoantibodies against cell surface and synaptic proteins exhibited positivity for more than one autoantibody.

Seasonal variation in autoimmune encephalitis: A multi-center retrospective study.

OBJECTIVE: The aim of this study was to examine the seasonal distribution in clinical onset of autoimmune encephalitis (AE) in a multi-center cohort in China. METHODS: This retrospective study consecutively recruited patients with new-onset definite neuronal surface antibody-associated AE between January 2015 and December 2020 from 3 tertiary hospitals. Demographic and clinical characteristics of the participants were comprehensively collected. Statistical analyses were performed using R. RESULTS: Of the 184 patients of AE in our database, 149 (81.0%) were included in the final analysis. The median age of onset was 40.0 years, and 66 (44.3%) patients were female. AE predominantly started in autumn (47, 31.5%) and summer (43, 28.9%) months. Summer-autumn predominance of the clinical onsets was also present in the anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis group (54, 60.0%) and anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis group (20, 76.9%). No obvious seasonal variations were observed among gender, onset age, disease duration, prodromal symptoms, clinical type of initial symptoms, and disease severity by the time of admission. CONCLUSION: This study suggested summer-autumn predominance of the clinical onsets in patients with AE, especially anti-NMDAR and anti-LGI1 encephalitis. Therefore, clinicians should have a high index of suspicion for AE in encephalopathy patients in summer and autumn period.

Limitations of a Commercial Assay as Diagnostic Test of Autoimmune Encephalitis.

Detection of neuronal surface antibodies (NSAb) is important for the diagnosis of autoimmune encephalitis (AE). Although most clinical laboratories use a commercial diagnostic kit (Euroimmun, Lübeck, Germany) based on indirect immunofluorescence on transfected cells (IIFA), clinical experience suggests diagnostic limitations. Here, we assessed the performance of the commercial IIFA in serum and CSF samples of patients with suspected AE previously examined by rat brain immunohistochemistry (Cohort A). Of 6213 samples, 404 (6.5%) showed brain immunostaining suggestive of NSAb: 163 (40%) were positive by commercial IIFA and 241 (60%) were negative. When these 241 samples were re-assessed with in-house IIFA, 42 (18%) were positive: 21 (9%) had NSAb against antigens not included in the commercial IIFA and the other 21 (9%) had NSAb against antigens included in the commercial kit (false negative results). False negative results occurred more frequently with CSF (29% vs 10% in serum) and predominantly affected GABABR (39%), LGI1 (17%) and AMPAR (11%) antibodies. Results were reproduced in a separate cohort (B) of 54 AE patients with LGI1, GABABR or AMPAR antibodies in CSF which were missed in 30% by commercial IIFA. Patients with discordant GABABR antibody results (positive in-house but negative commercial IIFA) were less likely to develop full-blown clinical syndrome; no significant clinical differences were noted for the other antibodies. Overall, NSAb testing by commercial IIFA led to false negative results in a substantial number of patients, mainly those affected by anti-LG1, GABABR or AMPAR encephalitis. If these disorders are suspected and commercial IIFA is negative, more comprehensive antibody studies are recommended.

Thymoma-associated autoimmune encephalitis with positive Titin antibodies: A case report.

We report a case of thymoma-associated autoimmune encephalitis with positive Titin antibodies. The patient had cognitive dysfunction, psychiatric symptoms and symptomatic epilepsy. PET-CT indicated space-occupied lesion at the thoracic entrance. The patient was diagnosed with paraneoplastic autoimmune encephalitis. After immunotherapy, his condition improved and underwent thymectomy. Pathology revealed type A thymoma. The patient recurred 10 days after the operation. Thymoma is associated with AE. And Titin antibodies may be involved in the extensive immune response to antigens which the patient's thymoma ectopically expressed. This case reflects the complexity of the immune relationship among autoimmune encephalitis, Titin antibodises and thymoma. Titin antibody may have a certain guiding significance for the treatment and prognosis of autoimmune encephalitis.

Autoimmune Encephalitis in Tunisia: Report of a Pediatric Cohort.

BACKGROUND: Autoimmune encephalitis (AE) is a rapidly progressive encephalopathy caused by antibodies targeting neurons in the central nervous system generating specific immune responses. It is increasingly recognized in children. OBJECTIVE: To describe clinical, neuroimaging, and laboratory features, treatment, and outcome in a cohort of Tunisian children with AE. METHODS: We conducted a retrospective review of the medical records of all children attending the Department of Child and Adolescent Neurology (Tunis) with autoimmune encephalitis between 2004 and 2020. Clinical, neuroimaging, laboratory features, therapeutic data, and outcome were analyzed. RESULTS: Nineteen children were included in the study (12 girls and 7 boys). The median age at diagnosis was 7.68 years (range: 10 months-13 years). The most frequent manifestations were seizures and behavioral disorders. Eleven cases were diagnosed with anti-NMDA receptor encephalitis, 4 cases with anti-Ma2 encephalitis, 3 cases with anti-GAD encephalitis, and 1 case with anti-SOX1 encephalitis. Brain MRI showed increased T2 and fluid-attenuated inversion recovery (FLAIR) signal of the temporal lobe in 5 patients. Eighteen patients showed improvement following first-line immunotherapy (high-dose corticosteroids, intravenous immunoglobulin). One patient with anti-GAD encephalitis died despite escalating immunotherapy. CONCLUSION: Diagnosis of autoimmune encephalitis is challenging in children, because of misleading presentations. An early and accurate diagnosis is important to enable proper therapeutic interventions.

Encephalitis with Autoantibodies against the Glutamate Kainate Receptors GluK2.

OBJECTIVE: The objective of this study was to report the identification of antibodies against the glutamate kainate receptor subunit 2 (GluK2-abs) in patients with autoimmune encephalitis, and describe the clinical-immunological features and antibody effects. METHODS: Two sera from 8 patients with similar rat brain immunostaining were used to precipitate the antigen from neuronal cultures. A cell-based assay (CBA) with GluK2-expressing HEK293 cells was used to assess 596 patients with different neurological disorders, and 23 healthy controls. GluK2-ab effects were determined by confocal microscopy in cultured neurons and electrophysiology in GluK2-expressing HEK293 cells. RESULTS: Patients' antibodies precipitated GluK2. GluK2 antibody-specificity was confirmed by CBA, immunoprecipitation, GluK2-immunoabsorption, and GluK2 knockout brain immunohistochemistry. In 2 of 8 samples, antibodies reacted with additional GluK2 epitopes present in GluK1 or GluK3; in both, the reactivity was abrogated after GluK2 immuno-absorption. Six of 8 patients developed acute encephalitis and clinical or magnetic resonance imaging (MRI) features of predominant cerebellar involvement (4 presenting as cerebellitis, which in 2 patients caused obstructive hydrocephalus), and 2 patients had other syndromes (1 with cerebellar symptoms). One of the samples showed mild reactivity with non-kainate receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors [AMPAR] and N-methyl-D-aspartate receptors [NMDAR]) leading to identify 6 additional cases with GluK2-abs among patients with anti-AMPAR (5/71) or anti-NMDAR encephalitis (1/73). GluK2-abs internalized GluK2 in HEK293 cells and neurons; these antibody-effects were reversible in neurons. A significant reduction of GluK2-mediated currents was observed in cells treated with patients' GluK2 serum following the time frame of antibody-mediated GluK2 internalization. INTERPRETATION: GluK2-abs associate with an encephalitis with prominent clinicoradiological cerebellar involvement. The antibody effects are predominantly mediated by internalization of GluK2. ANN NEUROL 2021;90:107-123.

Assessing the role of a tissue-based assay in the diagnostic algorithm of autoimmune encephalitis.

Tissue-based assay (TBA) is a widely-used method to detect neural autoantibodies, but the diagnostic accuracy for autoimmune encephalitis (AE) has not yet been adequately measured. We retrospectively evaluated the sensitivity and specificity of an indirect immunofluorescence TBA (IIF-TBA) in 159 patients with suspected AE. Serum and cerebrospinal fluid (CSF) specimens were collected and tested from December 2012 to September 2020. In the paired sample analysis, serum testing showed higher sensitivity than CSF, while the latter had higher specificity. Based on these results, we clarify the advantages of using a TBA as the principal screening method for patients with suspected AE.

Cholesterol-added antigens can enhance antiglycolipid antibody activity: Application to antibody testing.

We analysed the effect of adding cholesterol to glycolipid antigens on antibody activity with enzyme-linked immunosorbent assay in 123 subjects consisting of 96 patients with Guillain-Barré syndrome, 25 Miller Fisher syndrome, and two Bickerstaff brainstem encephalitis. The use of cholesterol-added GM1 antigens increased anti-GM1 activity in 11 out of 23 anti-GM1-positive patients and resulted in six out of 100 anti-GM1-negative patients becoming anti-GM1-positive. Enhancement of anti-GM1 activity by cholesterol addition was significantly associated with antecedent gastrointestinal infection. The use of cholesterol-added glycolipid antigens can increase the detection rate of anti-glycolipid antibodies and accurately evaluate the anti-glycolipid antibody activity in vivo.

Unilateral cerebral cortical encephalitis (CCE) with positive anti-MOG antibodies: A case report.

RATIONALE: Nowadays, myelin oligodendrocyte glycoprotein (MOG)-antibody-associated disease (MOGAD) is regarded as an independent inflammatory demyelinating disease. Here, we report a rare case of unilateral cerebral cortical encephalitis (CCE) with positive anti-MOG antibodies. PATIENT CONCERNS: A 19-year-old woman was admitted to our hospital owing to acute onset fever and headache. Four days later, she experienced a focal seizure that progressed to generalized tonic-clonic seizures. DIAGNOSIS: Brain magnetic resonance imaging (MRI) demonstrated cortical lesions in the left cerebral hemisphere on T2-weighted fluid-attenuated inversion recovery imaging. The patient was positive for anti-MOG antibodies in serum and diagnosed with anti-MOG antibody-associated unilateral CCE. INTERVENTIONS: She was administrated with intravenous methylprednisolone followed by oral corticosteroids. OUTCOMES: On day 14 after admission, a repeat MRI revealed partial resolution of the initial abnormalities. The patient received a quick recovery without residual symptoms. CONCLUSIONS: Unilateral CCE with positive anti-MOG antibodies has emerged as a special clinical phenotype of MOGAD. It should be emphasized that the characteristic neuroradiological features of CCE would be an important clue to the correct diagnosis of MOGAD.

Autoimmune encephalitis in a South Asian population.

BACKGROUND: Autoimmune encephalitis (AE) is now considered a main, potentially curable cause of encephalitis, but remains conspicuously underreported from South Asia. We studied the clinical characteristics in relation to their antibody status and outcomes of patients presenting with AE in Sri Lanka. METHODS: Patients admitting to government hospitals who were clinically suspected of AE by an on-site neurologist were prospectively recruited over a period of 12 months. Sera and cerebrospinal fluid were tested for NMDAR, AMPAR1, AMPAR2, LGI1, CASPR2, GABARB1/B2 antibodies (Ab) using commercial cell-based assays. Demographic, clinical and laboratory data were compiled into an investigator-administered proforma. Patients were reviewed at 1 year follow up either in person or via telephone. RESULTS: One-hundred and forty-two patients from 21 of 25 districts in Sri Lanka (median age = 20.5 years; range 1-86 years; females = 61.3%) were recruited. Of them, 65 (45.8%; median age = 19 years; range 1-86 years; females = 64.6%) fulfilled diagnostic criteria for probable NMDAR-antibody encephalitis (NMDARE) and 6 (4.2%; median age = 44 years; range 28-71 years; females = 83.3%) limbic encephalitis (LE). Abnormal behaviour (95.3%), seizures (81.5%) and movement disorders (69.2%) were the most frequent clinical manifestations of probable NMDARE. NMDAR-antibodies were detectable in 29 (44.6%) and not detectable in 36 in CSF of probable-NMDARE patients. Abnormal EEG was more frequent (p = 0.003) while a worse outcome (OR = 2.78; 95% CI = 0.88-9.09) and deaths (OR = 2.38; 95% CI = 0.67-8.33) were more likely in antibody-negative than antibody-positive probable-NMDARE. Most patients with LE had amnesia (50%) and/or confusion (100%) with agitation (83.3%) and seizures (100%) but none had detectable antibodies to any of the antigens tested. CONCLUSIONS: NMDARE is the commonest type of AE among South Asians as is the case worldwide. Clinical presentations of NMDARAb-positive and NMDARAb-negative AE patients do not significantly differ but EEG may be a useful marker of an autoimmune basis for psychiatric symptoms.

Cardiac and Brainstem Neuroinflammatory Pathways Account for Androgenic Incitement of Cardiovascular and Autonomic Manifestations in Endotoxic Male Rats.

ABSTRACT: Inconsistent reports are available on the role of testosterone in end-organ damage caused by endotoxemia. Here, pharmacologic, surgical, and molecular studies were employed to assess the testosterone modulation of cardiovascular, autonomic, and peripheral and central inflammatory derangements caused by endotoxemia. Studies were performed in conscious male rats preinstrumented with femoral indwelling catheters for the measurement of blood pressure and subjected to castration or pharmacologic interventions that interrupt the biosynthetic cascade of testosterone. Compared with the effects of lipopolysaccharide (10 mg/kg intravenously) in sham operated rats, 2-week castration reduced the lipopolysaccharide-evoked (1) falls in blood pressure, (2) decreases in time- and frequency-domain indices of heart rate variability, (3) shifts in spectral measures of cardiac sympathovagal balance toward parasympathetic dominance, and (4) increases in protein expressions of toll-like receptor-4 and monocyte chemoattractant protein-1 in heart and medullary neurons of the nucleus tractus solitarius and rostral ventrolateral medulla. While the ameliorating actions of castration on endotoxic cardiovascular manifestations were maintained after testosterone replacement, the concomitant inflammatory signals were restored to near-sham levels. The favorable influences of castration on inflammatory and cardiovascular abnormalities of endotoxemia were replicated in intact rats pretreated with degarelix (gonadotropin-releasing hormone receptor blocker) or finasteride (5α-reductase inhibitor) but not formestane (aromatase inhibitor). The data signifies the importance of androgens and its biosynthetic enzymes in cardiovascular and autonomic insults induced by the endotoxic inflammatory response. Clinically, the interruption of testosterone biosynthesis could offer a potential strategy for endotoxemia management.

High-Fat Diet Aggravates Cerebral Infarct, Hemorrhagic Transformation and Neuroinflammation in a Mouse Stroke Model.

BACKGROUND: Stroke in context of type 2 diabetes (T2D) is associated with a poorer outcome than in non-diabetic conditions. We aimed at creating a new reproducible mouse model of stroke in impaired glucose tolerance conditions induced by high-fat diet. METHODS: Adult C57BL6 mice were fed for 2 months with either normal diet (ND) or high-fat diet (HFD). We used a model of Middle Cerebral Artery Occlusion (MCAO) for 90 min. Oral Glucose Tolerance Test (OGTT) and Insulin Tolerance Test (ITT) were used to assess pre-diabetic status. Brain infarct volume, hemorrhagic transformation (HT) as well as systemic and cerebral inflammatory markers were evaluated. RESULTS: HFD was associated with an increased body weight and glycemia following OGTT. The HFD group presented a significant increase in brain infarct volume (38.7 (IQR 30-46.7%) vs. 28.45 (IQR 21-30%); p = 0.016) and HT (HFD: 2 (IQR 1-5) vs. ND: 0 (IQR 0-1); p = 0.012) and higher levels of IL-6 and MCP-1 in infarcted hemisphere compared to the ND group. CONCLUSION: Two months of HFD in adult mice were sufficient to alter the lipid profile and the control of hyperglycemia. These metabolic perturbations were significantly associated with increased infarct volume and hemorrhagic complications.

The 'Great Imitator': A Case of COVID-19 Presenting with Encephalitis and Acute Coronary Syndrome.

Although typically patients with coronavirus disease-19 (COVID-19) have pulmonary symptoms atypical cases can occasionally present with extra-pulmonary symptoms. We report an interesting case of COVID-19 female patient presenting with combination of central nervous system disorder and acute myocardial infarct as initial manifestation. Multiorgan involvement in COVID-19 might lead to multiple atypical presentation which could be overlooked by the physician.

Tofacitinib treatment for refractory autoimmune encephalitis.

To treat intractable cases of autoimmune encephalitis, the need for novel immunotherapy that penetrates the blood-brain barrier (BBB) is increasing. Tofacitinib is a Janus kinase (JAK) inhibitor used to treat refractory immune-mediated diseases that effectively penetrates the BBB. Accordingly, tofacitinib could be a new option for patients with refractory autoimmune encephalitis. Patients treated with tofacitinib were selected from Seoul National University Hospital cohort for autoimmune encephalitis from April 2019 until July 2020. We retrospectively analyzed the efficacy of tofacitinib in patients with autoimmune encephalitis who showed insufficient responses to multimodal conventional immunotherapies. Tofacitinib was administered orally at a dose of 5 mg twice daily. A total of eight patients were treated with tofacitinib; two had good responses (clinical global impression-improvement score [CGI-I] = 1 or 2), three had partial responses (CGI-I = 3), and three showed no significant improvements (CGI-I = 4) in response to tofacitinib. The two good responders showed the improvement of chronic autoimmune meningoencephalitis and the cessation of the new-onset refractory status epilepticus in anti-myelin oligodendrocyte glycoprotein (MOG)-associated disorder, which was previously intractable to anesthetics and the other immunotherapies. No patients had serious side effects. Our findings suggest the potential of tofacitinib as a therapeutic option for central nervous system autoimmune diseases.

Association between EBV serological patterns and lymphocytic profile of SjS patients support a virally triggered autoimmune epithelitis.

Sjögren's syndrome (SjS) is characterized by lymphocytic infiltration of exocrine glands, i.e. autoimmune epithelitis. Lymphocytes are central in SjS pathogenesis, with B-cell hyperactivity mediated by T-cells. B-cells are main targets of Epstein-Barr virus (EBV) infection, a frequently-suggested trigger for SjS. We aimed to evaluate how the EBV infection modulates B and T-cell subsets in SjS, including as controls Rheumatoid arthritis patients (RA) and healthy participants (HC). SjS patients presented decreased CXCR5+T-cells, although IL21-secreting Tfh and Tfc cells were increased. Tfc were positively correlated with ESSDAI scores, suggesting their relevant role in SjS pathogenesis. As previously described, SjS patients showed expanded circulating naïve B-cell compartments. SjS patients had a higher incidence of EBV-EA-D-IgG+ antibodies, characteristic of recent EBV-infection/reactivation. SjS patients with past infection or recent infection/reactivation showed increased CXCR3+Th1 and CXCR3+Tfh1 cells compared to those without active infection. SjS patients with a recent infection/reactivation profile presented increased transitional B-cells compared to patients with past infection and increased plasmablasts, compared to those without infection. Our results suggest EBV-infection contributes to B and T-cell differentiation towards the effector phenotypes typical of SjS. Local lymphocyte activation at ectopic germinal centres, mediated by Tfh and Tfc, can be EBV-driven, perpetuating autoimmune epithelitis, which leads to gland destruction in SjS.

Association of Epileptic and Nonepileptic Seizures and Changes in Circulating Plasma Proteins Linked to Neuroinflammation.

OBJECTIVE: To develop a diagnostic test that stratifies epileptic seizures (ES) from psychogenic nonepileptic seizures (PNES) by developing a multimodal algorithm that integrates plasma concentrations of selected immune response-associated proteins and patient clinical risk factors for seizure. METHODS: Daily blood samples were collected from patients evaluated in the epilepsy monitoring unit within 24 hours after EEG confirmed ES or PNES and plasma was isolated. Levels of 51 candidate plasma proteins were quantified using an automated, multiplexed, sandwich ELISA and then integrated and analyzed using our diagnostic algorithm. RESULTS: A 51-protein multiplexed ELISA panel was used to determine the plasma concentrations of patients with ES, patients with PNES, and healthy controls. A combination of protein concentrations, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), intercellular adhesion molecule 1 (ICAM-1), monocyte chemoattractant protein-2 (MCP-2), and tumor necrosis factor-receptor 1 (TNF-R1) indicated a probability that a patient recently experienced a seizure, with TRAIL and ICAM-1 levels higher in PNES than ES and MCP-2 and TNF-R1 levels higher in ES than PNES. The diagnostic algorithm yielded an area under the receiver operating characteristic curve (AUC) of 0.94 ± 0.07, sensitivity of 82.6% (95% confidence interval [CI] 62.9-93.0), and specificity of 91.6% (95% CI 74.2-97.7). Expanding the diagnostic algorithm to include previously identified PNES risk factors enhanced diagnostic performance, with AUC of 0.97 ± 0.05, sensitivity of 91.3% (95% CI 73.2-97.6), and specificity of 95.8% (95% CI 79.8-99.3). CONCLUSIONS: These 4 plasma proteins could provide a rapid, cost-effective, and accurate blood-based diagnostic test to confirm recent ES or PNES. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that variable levels of 4 plasma proteins, when analyzed by a diagnostic algorithm, can distinguish PNES from ES with sensitivity of 82.6% and specificity of 91.6%.

Thyroid crisis mimicking clinically mild encephalitis/encephalopathy with a reversible splenial lesion: A pediatric case report.

BACKGROUND: Reversible lesions in the splenium of the corpus callosum (SCC) with viral infections are associated mainly with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). We report a pediatric patient in thyroid crisis with reversible SCC lesions. CASE DESCRIPTION: We diagnosed a 9-year-old girl with thyroid crisis. She had presented with fever, tachycardia, and impaired consciousness. Magnetic resonance imaging revealed hyperintense signals in the splenium and genu of the corpus callosum and a white matter lesion of the left hemisphere in diffusion-weighted imaging. The initial, tentative diagnosis was clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). We initiated intravenous methylprednisolone pulse therapy; thereafter, her level of consciousness rapidly improved. On admission, thyroid function studies revealed elevation of free thyroxine and a low level of thyroid stimulating hormone with thyroid-related autoantibodies. She was begun on thiamazole and was discharged without neurological sequelae. CONCLUSION: Thyroid crisis is similar to acute encephalitis or encephalopathy associated with viral infection, especially with MERS, because the clinical and radiological features resemble those of thyroid crisis; therefore, thyroid diseases should be considered as a possible cause of reversible lesions in the splenium of the corpus callosum.

Clinical features which predict neuronal surface autoantibodies in new-onset focal epilepsy: implications for immunotherapies.

OBJECTIVE: To generate a score which clinically identifies surface-directed autoantibodies in adults with new-onset focal epilepsy, and evaluate the value of immunotherapy in this clinical setting. METHODS: Prospective clinical and autoantibody evaluations in a cohort of 219 consecutive patients with new-onset focal epilepsy. RESULTS: 10.5% (23/219) of people with new-onset focal epilepsy had detectable serum autoantibodies to known or novel cell surface antigenic targets. 9/23 with autoantibodies were diagnosed with encephalitis, by contrast to 0/196 without autoantibodies (p<0.0001). Multivariate analysis identified six features which predicted autoantibody positivity (area under the curve=0.83): age ≥54 years, ictal piloerection, lowered self-reported mood, reduced attention, MRI limbic system changes and the absence of conventional epilepsy risk factors. 11/14 (79%) patients with detectable autoantibodies, but without encephalitis, showed excellent long-term outcomes (modified Rankin Score=0) despite no immunotherapy. These outcomes were superior to those of immunotherapy-treated patients with confirmed autoantibody-mediated encephalitis (p<0.05). CONCLUSIONS: Seizure semiology, cognitive and mood phenotypes, alongside inflammatory investigation findings, aid the identification of surface autoantibodies among unselected people with new-onset focal epilepsy. The excellent immunotherapy-independent outcomes of autoantibody-positive patients without encephalitis suggests immunotherapy administration should be guided by clinical features of encephalitis, rather than autoantibody positivity. Our findings suggest that, in this cohort, immunotherapy-responsive seizure syndromes with autoantibodies largely fall under the umbrella of autoimmune encephalitis.