HLA dependency and possible clinical relevance of intrathecally synthesized anti-IgLON5 IgG4 in anti-IgLON5 disease.

Background: Anti-IgLON5 disease is a rare chronic autoimmune disorder characterized by IgLON5 autoantibodies predominantly of the IgG4 subclass. Distinct pathogenic effects were described for anti-IgLON5 IgG1 and IgG4, however, with uncertain clinical relevance. Methods: IgLON5-specific IgG1-4 levels were measured in 46 sera and 20 cerebrospinal fluid (CSF) samples from 13 HLA-subtyped anti-IgLON5 disease patients (six females, seven males) using flow cytometry. Intervals between two consecutive serum or CSF samplings (31 and 10 intervals, respectively) were categorized with regard to the immunomodulatory treatment active at the end of the interval, changes of anti-IgLON5 IgG1 and IgG4 levels, and disease severity. Intrathecal anti-IgLON5 IgG4 synthesis (IS) was assessed using a quantitative method. Results: The median age at onset was 66 years (range: 54-75), disease duration 10 years (range: 15-156 months), and follow-up 25 months (range: 0-83). IgLON5-specific IgG4 predominance was observed in 38 of 46 (83%) serum and 11 of 20 (55%) CSF samples. Anti-IgLON5 IgG4 levels prior clinical improvement in CSF but not serum were significantly lower than in those prior stable/progressive disease. Compared to IgLON5 IgG4 levels in serum, CSF levels in HLA-DRB1*10:01 carriers were significantly higher than in non-carriers. Indeed, IgLON5-specific IgG4 IS was demonstrated not only in four of five HLA-DRB1*10:01 carriers but also in one non-carrier. Immunotherapy was associated with decreased anti-IgGLON5 IgG serum levels. In CSF, lower anti-IgLON5 IgG was associated with immunosuppressive treatments used in combination, that is, corticosteroids and/or azathioprine plus intravenous immunoglobulins or rituximab. Conclusion: Our findings might indicate that CSF IgLON5-specific IgG4 is frequently produced intrathecally, especially in HLA-DRB1*10:01 carriers. Intrathecally produced IgG4 may be clinically relevant. While many immunotherapies reduce serum IgLON5 IgG levels, more intense immunotherapies induce clinical improvement and may be able to target intrathecally produced anti-IgLON5 IgG. Further studies need to confirm whether anti-IgLON5 IgG4 IS is a suitable prognostic and predictive biomarker in anti-IgLON5 disease.

H-intensity scale score to estimate CSF GluN1 antibody titers with one-time immunostaining using a commercial assay.

Introduction: Anti-NMDA receptor encephalitis is an autoimmune disorder caused by autoantibodies (abs) against the conformational epitope on GluN1 subunits. GluN1-abs have been determined with cell-based assay (CBA) co-expressing GluN1/GluN2 subunits. However, commercial fixed CBA expressing only GluN1 subunit has increasingly been used in clinical practice. The ab titers can be determined with serial dilutions, but its clinical significance remains unclear. We aimed to develop an H-intensity scale (HIS) score to estimate GluN1-ab titers in cerebrospinal fluid (CSF) with one-time immunostaining using both commercial CBA and immunohistochemistry and report its usefulness. "H" is the initial of a patient with high CSF GluN1-ab titers (1:2,048). Methods: We first determined the reliability of CBA in 370 patients with suspected autoimmune encephalitis by comparing the results between commercial CBA and established assay in Dalmau's Lab. Then, we made positive control panels using the patient H's CSF diluted in a fourfold serial dilution method (1:2, 1:8, 1:32, 1:128, 1:512, and 1:2,048). Based on the panels, we scored the intensity of ab reactivity of 79 GluN1-ab-positive patients' CSF (diluted at 1:2) on a scale from 0 to 6 (with ≥1 considered positive). To assess inter-assay reliability, we performed immunostaining twice in 21 patients' CSF. We investigated an association between the score of CSF obtained at diagnosis and the clinical/paraclinical features. Results: The sensitivity and specificity of CBA were 93.7% (95% CI: 86.0-97.3) and 98.6% (95% CI: 96.5-99.5), respectively. Linear regression analysis showed a good agreement between the scores of the first and second assays. Patients with a typical spectrum, need for mechanical ventilation support, autonomic symptoms/central hypoventilation, dyskinesias, speech dysfunction, decreased level of consciousness, preceding headache, ovarian teratoma, and CSF leukocyte count >20 cells/µL had a higher median HIS score than those without, but HIS score was not associated with sex, age at onset, or seizure. HIS score at diagnosis had a significant effect on 1-year functional status. Discussion: The severity of disease and four of the six core symptoms were associated with higher GluN1-ab titers in CSF at diagnosis, which may play a role in poor 1-year functional status. An incomplete phenotype can be attributed to low CSF GluN1-ab titers.

Management of Autoimmune Encephalitis in a 7-Year-Old Child With CTLA-4 Haploinsufficiency and AMPA Receptor Antibodies: A Case Report.

OBJECTIVES: We report on the therapeutic management of early-onset severe neurologic symptoms in cytotoxic T lymphocyte antigen-4 haploinsufficiency (CTLA-4h) and the presence of antibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) as an important finding. METHODS: This is a case report from a Dutch academic hospital. Repeated clinical examinations, repeated brain MRI and extended diagnostics on serum and CSF were performed. We used the CARE checklist. RESULTS: A 7-year-old boy was diagnosed with CTLA-4h based on family screening. On diagnosis, he had mild chronic diarrhea and autism spectrum disorder, but no abnormalities in extensive laboratory screening. Six months later, he presented with sudden-onset autoimmune encephalitis. Repeated brain MRI revealed no abnormalities, but immunohistochemistry analysis on serum and CSF showed the presence of AMPAR antibodies. Treatment was initially focused on immunomodulation and targeted CTLA-4 replacement therapy. Because of the persistent fluctuating cerebellar and neuropsychiatric symptoms and the potential clinical significance of the AMPAR antibodies, treatment was intensified with repetition of first-line immunomodulation and rituximab. This combined therapy resulted in sustained clinical improvement and served as a bridge to curative hematopoietic stem cell transplantation. DISCUSSION: This case illustrates the rare early onset of autoimmune encephalitis and presence of AMPAR antibodies in CTLA-4h. Targeted CTLA-4 replacement therapy resulted in a partial response. However, awaiting its optimal therapeutic effect, refractory CNS symptoms required intensification of immunomodulation. The identification of AMPAR antibodies guided our treatment decisions. CLASSIFICATION OF EVIDENCE: This provides Class IV evidence. It is a single observational study without controls.

Case report: Isolated brainstem-cerebellar symptoms in a patient with anti-NMDA receptor encephalitis.

Cerebellar ataxia is an uncommon and atypical manifestation of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, often accompanied by seizures, psychiatric symptoms, and cognitive deficits. Previous cases of isolated brainstem-cerebellar symptoms in patients with anti-NMDAR encephalitis have not been documented. This report presents a case of anti-NMDAR encephalitis in which the patient exhibited cerebellar ataxia, nystagmus, diplopia, positive bilateral pathological signs, and hemiparesthesia with no other accompanying symptoms or signs. The presence of positive CSF anti-NMDAR antibodies further supports the diagnosis. Other autoantibodies were excluded through the use of cell-based assays. Immunotherapy was subsequently administered, leading to a gradual recovery of the patient.

Serum NfL and EGFR/NfL ratio mRNAs as biomarkers for phenotype and disease severity of myelin oligodendrocyte glycoprotein IgG-associated disease.

Background and purpose: Myelin oligodendrocyte glycoprotein (MOG) IgG is frequently elevated in pediatric patients with acquired demyelinating syndrome (ADS). However, no specific biomarkers exist for phenotype classification, symptom severity, prognosis, and treatment guidance of MOG-IgG-associated disease (MOGAD). This study evaluated neurofilament light chain (NfL) and endothelial growth factor receptor (EGFR) mRNA expression levels in serum and cerebrospinal fluid (CSF) as potential biomarkers for MOGAD in Chinese children. Methods: This was a cross-sectional and single-center study. We enrolled 22 consecutive pediatric patients hospitalized with MOGAD and 20 control pediatric patients hospitalized for noninflammatory neurological diseases in Hebei Children's Hospital. Serum and CSF were collected from MOGAD patients within 3 days before immunotherapy. The mRNA levels of NfL and EGFR in serum and CSF were measured by real-time polymerase chain reaction (qPCR), and the EGFR/NfL ratio mRNA was calculated. These measurement values were then compared between disease groups and among MOGAD phenotypes. In addition, the correlations between the mRNAs of three markers (NfL, EGFR, EGFR/NfL ratio), extended disability status scale (EDSS) scores, and clinical phenotypes were analyzed. Results: Serum and CSF NfL mRNA levels were significantly higher of acute-stage MOGAD patients than those of control patients (p< 0.05 and p< 0.01, respectively), while the mRNA levels of serum EGFR and EGFR/NfL ratio were significantly lower of MOGAD patients than those of controls (p < 0.05, p < 0.0001). Serum NfL mRNA was significantly correlated with mRNA of serum EGFR (r =0.480, p < 0.05). Serum and CSF NfL mRNA levels in MOGAD patients with the ADEM-like phenotype were also significantly higher than those in control patients (p < 0.01, p < 0.01) and optic neuritis (ON) phenotype (p < 0.05, p < 0.05). Both mRNAs of NfL in CSF and EGFR/NfL ratio in serum were correlated with EDSS scores (p < 0.05, r = 0.424; p < 0.05, r= -0.521). Conclusion: The mRNA levels of elevated NfL in serum and CSF as well as lower EGFR and EGFR/NfL ratio in serum could help distinguish acute-phase MOGAD. Higher mRNA levels of NfL in serum and CSF of MOGAD patients help distinguish ADEM-like phenotype. In addition, serum EGFR/NfL mRNA ratio is indicative of disease severity in pediatric patients with MOGAD. Further investigations are warranted to elucidate the pathological mechanisms underlying these associations.

Autoimmune encephalitis in glial fibrillary acidic protein astrocytopathy.

Autoimmune encephalitis due to glial fibrillar acidic protein (GFAP) astrocytopathy is a rare cause of subacute neuropsychiatric changes. In this case, a young patient presented with a viral prodrome and meningismus, followed by progressive encephalopathy and movement disorders over the span of 2 weeks. Due to his clinical trajectory, inflammatory cerebrospinal fluid (CSF) analysis, initial normal brain imaging and negative serum autoimmune encephalopathy panel, his initial diagnosis was presumed viral meningoencephalitis. The recurrence and progression of neuropsychiatric symptoms and myoclonus despite antiviral treatment prompted further investigation, inclusive of testing for CSF autoimmune encephalopathy autoantibodies, yielding a clinically meaningful, positive GFAP autoantibody. This case highlights the importance of appropriately testing both serum and CSF autoantibodies when an autoimmune encephalitic process is considered. Through this case, we review the clinical and radiographic manifestations of GFAP astrocytopathy, alongside notable pearls pertaining to this autoantibody syndrome and its management.

Antibody-positive autoimmune encephalitis and paraneoplastic neurological syndrome: A Swedish case series.

OBJECTIVE: This study aimed to explore the clinical characteristics and temporal disease course of patients with autoimmune encephalitis (AE) and paraneoplastic neurological syndrome (PNS) in Sweden. METHODS: Thirty-seven antibody-positive AE and PNS cases were identified in the Healthcare region Mid Sweden between 2015 and 2019. Clinical data were collected through a retrospective review of electronic health records. Patients were divided into three subgroups based on antibody type: neuronal surface antibodies (NSAbs), onconeural antibodies, and anti-GAD65 antibodies. RESULTS: Nineteen patients had NSAbs, 11 onconeural antibodies, and seven anti-GAD65 antibodies. Anti-LGI1 and anti-NMDAR were the most frequently detected NSAbs, with anti-NMDAR cases having an older-than-expected age distribution (median age 40, range 17-72). Only 11 of 32 (30%) of patients had findings suggesting encephalitis on initial MRI, but 28 of 31 (90%) had pathological findings on initial cerebrospinal fluid analysis. All patients but one had abnormal EEG findings. Median time to immunotherapy was comparable among the three subgroups, whereas patients with anti-LGI1, anti-CASPR2, and anti-IgLON5 had an eightfold longer time to immunotherapy than anti-NMDAR and anti-GABA-B (p = .0016). There was a seasonal variation in onset for patients with non-tumor-related NSAbs and anti-GAD65 antibodies, with most patients (72%) falling ill in spring or summer. CONCLUSION: Swedish patients with AE and PNS had similar clinical characteristics as previously described cohorts from other geographical regions except for anti-NMDAR encephalitis, with older onset than expected. The onset of non-tumor-related AE occurred predominantly in the warm seasons, and AE with a more insidious onset was associated with delayed treatment initiation.

MOG Antibody-Associated Disease in the Setting of Metastatic Melanoma Complicated by Immune Checkpoint Inhibitor Use.

OBJECTIVES: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an autoimmune demyelinating disease rarely associated with malignancy. We report the clinical, MRI, immunopathology, and treatment response in a person with MOGAD and melanoma. METHODS: This is a case report of a person with a multidisciplinary evaluation at a tertiary referral center. RESULTS: A 52-year-old man presented with progressive encephalomyelitis that led to identification of metastatic melanoma. Investigations revealed positive MOG-IgG at high titers in serum (1:1,000; normal, <1:20) and CSF (1:4,096; normal, <1:2). MRI demonstrated multifocal T2 lesions with enhancement in the brain and spine. Brain biopsy showed demyelination and inflammation. MOG immunostaining was not present in the tumor tissue. He initially improved with methylprednisolone, plasmapheresis, prolonged oral steroid taper, and cancer-directed treatment with BRAF and MEK 1/2 inhibitors, but then developed bilateral optic neuritis. IV immunoglobulin (IVIG) was initiated. Five months later, he developed metastases and immune checkpoint inhibitor (ICI) treatment was started, which precipitated optic neuritis and myelitis despite IVIG and prednisone. Tocilizumab, an interleukin-6 receptor blocker, was started with excellent and sustained clinical and radiologic response. DISCUSSION: This case revealed a presentation of MOGAD concurrent with melanoma without tumor MOG immunostaining. We highlight tocilizumab as a dual-purpose treatment of MOGAD and the neurologic immune-related adverse effect of ICI.

Antiganglioside antibody frequency in routine clinical care settings.

BACKGROUND AND PURPOSE: Antiganglioside antibodies (AGAs) might be involved in the etiopathogenesis of many neurological diseases, such as Miller-Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS). Available comprehensive reference data regarding AGA positivity rates and cross-responsiveness among AGAs (where one line immunoblot is positive for ≥1 AGA) during routine clinical care are scant. METHODS: In this 10-year monocentric retrospective study, 3560 immunoglobulin (Ig) G and IgM line blots (GA Generic Assays' Anti-Ganglioside Dot kit) obtained using cerebrospinal fluid (CSF) and serum samples from 1342 patients were analyzed for AGA positivity in terms of 14 diagnosis categories and AGA cross-responsiveness. RESULTS: Of all 3560 line blots 158 (4.4%) and of all CSF samples 0.4% (4/924) CSF line blots were AGA positive. For serum IgG, blots with positivity rates higher than the standard deviation of 15.6% were associated with MFS (GD3, GD1a, GT1a and GQ1b) and acute motor axonal neuropathy (AMAN) (GM1, GD1a and GT1a). For serum IgM, blots with positivity rates higher than the standard deviation of 8.1% were associated with AMAN (GM2, GT1a and GQ1b), MFS (GM1, GT1a and GQ1b), multifocal motor neuropathy (MMN) (GM1, GM2 and GQ1b) and chronic inflammatory demyelinating polyneuropathy (CIDP) (GM1). Cross-responsiveness was observed in 39.6% of all positive serum AGA. CONCLUSIONS: Testing for AGAs during routine clinical care rarely led to positive findings, both in serum and even less in CSF, except for the diagnoses AMAN, MFS, MMN and CIDP. Nonspecific findings found as cross-responsiveness between different AGA samples occur frequently, impacting the positivity of most AGA subtypes.

Association of rheumatological markers with neuronal antibodies, cerebrospinal fluid, electroencephalography, and magnetic resonance imaging findings in 224 patients with psychotic syndromes.

INTRODUCTION: Psychotic syndromes can have autoimmune-mediated causes in some patients. Thus, this retrospective work aims to investigate the role of rheumatological markers in the development of psychosis. PATIENTS AND METHODS: In total, 224 patients with psychotic syndromes receiving a "rheumatological laboratory screening" (including C-reactive protein [CRP], immunofixation, complement factors, rheumatoid factor [RF], antiphospholipid antibodies [APAs], antineutrophil cytoplasmic antibodies [ANCAs], and antinuclear antibodies [ANAs]) were analyzed. A further diagnostic work-up included investigations of neuronal antibodies and cerebrospinal fluid (CSF), as well as electroencephalography (EEG) and magnetic resonance imaging (MRI) of the brain. ANA testing was routinely performed in all patients using serum on human epithelioma-2 (Hep2) cells, and a subset of patients (N = 73) also underwent tissue-based assays from serum and CSF. The number of cases with autoimmune psychotic syndromes was descriptively collected, and ANA-positive and -negative patients were compared in detail. RESULTS: CRP was elevated in 9 % of patients, immunofixation identified alterations in 8 %, complement factor C3 was decreased in 14 %, RF was elevated in 1 %, APAs were elevated in 7 %, ANCAs were not clearly positive, and ANAs were positive in 19 % (extractable nuclear antigen [ENA] differentiation resulted in positive findings in 14 patients). From the 73 patient samples additionally investigated using tissue-based assays, there were 26 positive results for some kind of ANA (36 %), and overall using both methods, 54 patients (24 %) were considered positive for ANAs. A neuropsychiatric evaluation revealed a possible autoimmune psychotic syndrome in seven patients (3 %) and a probable autoimmune psychotic syndrome in two patients (1 %). ANA-positive patients were more frequently treated with antidepressants (p = 0.040) and had a higher number of somatic comorbidities (p < 0.001). In addition, (chronic) inflammatory MRI lesions (p = 0.008) and focal atrophies (p = 0.012) were found more frequently in ANA-positive than ANA-negative patients. DISCUSSION: Rheumatological screening led to suspicion of a possible or probable autoimmune psychotic syndrome in 4%. ANAs were associated with MRI pathologies. Therefore, rheumatological processes may contribute to the development of psychotic syndromes in rare cases.

FLAMES overlaying anti-N-methyl-D-aspartate receptor encephalitis: a case report and literature review.

BACKGROUND: In recent years, simultaneous or sequential occurrence of MOG antibody disease and anti-NMDAR encephalitis in the same patient has been reported with increasing frequency. Scholars refer to the overlapping occurrence of these two disorders as MOG antibody disease and anti-NMDAR encephalitis overlap syndrome (MNOS). Cortical T2-weighted fluid-attenuated inversion recovery (FLAIR) -hyperintense lesions in anti-MOG-associated encephalitis with seizures (FLAMES) is a rare clinical phenotype of MOGAD in which cortical FLAIR high-signal lesions are unilateral, with little spread to the cortex and meninges bilaterally. Although cases of FLAMES have been consistently reported. However, to our knowledge, such cases of FLAMES combined with NMDARE are rare. CASE PRESENTATION: Here, we describe a case of FLAMES combined with anti-NMDARE. The patient was a young male, 29 years old, admitted to our hospital with isolated seizures, whose MRI showed unilateral thalamic and bilateral frontal and parietal leptomeningeal involvement. Since we were unaware of the possibility of bilateral meningo-cortical MOGAD manifestations, the case was initially diagnosed as viral encephalitis and was given antiviral therapy. The diagnosis was not clarified until anti-NMDAR-IgG and MOG-IgG positivity was detected in the cerebrospinal fluid and serum. The patient was then treated with high-dose corticosteroids and his symptoms responded well to the steroids. Therefore, this case expands the clinical spectrum of MNOS overlap syndrome. In addition, we describe the clinical features of MNOS by summarizing the existing literature and exploring the possible mechanisms of its immune response. CONCLUSIONS: Our case serves as a reminder to clinicians that when patients present with atypical clinical manifestations such as seizures, consideration should be given to MNOS and conduct testing for various relevant autoantibodies (including MOG abs) and viruses in both serum and cerebrospinal fluid, as it is easy to misdiagnose the disease as other CNS diseases, such as viral meningoencephalitis. This syndrome exhibits a high responsiveness to steroids, highlighting the critical importance of recognizing the clinical and neuroimaging features of this overlap syndrome for prompt diagnosis and treatment. Furthermore, it enriches the disease spectrum of MNOS.

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.

Cerebrospinal fluid eosinophils in pediatric myelin oligodendrocyte glycoprotein antibody-associated disease.

BACKGROUND: Eosinophils in cerebrospinal fluid (CSF) are an uncommon finding most often associated with parasitic infections, but have also been described in some neuroinflammatory disorders. Eosinophilic infiltration is not thought to be a typical feature of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). We aim to describe the rate of CSF eosinophil positivity in a cohort of pediatric MOGAD patients. METHODS: Single-center retrospective chart review of pediatric MOGAD patients. Clinical and laboratory data was collected from the electronic medical record and analyzed. RESULTS: Of 46 pediatric patients with positive serum myelin oligodendrocyte glycoprotein antibody (MOG-IgG) identified, 38 patients fulfilling internationally proposed MOGAD diagnostic criteria were included for analysis. 6 patients with MOGAD were excluded as no CSF data was available, and 2 patients with positive MOG-IgG but diagnosis more consistent with MS were excluded. Median age was 7.3 years, and 19/38 (50 %) were female. Acute disseminated encephalomyelitis (ADEM) was the most common presenting phenotype (23/38, 61 %), and other phenotypes included optic neuritis (10/38, 26 %), transverse myelitis (3/38, 8 %), and neuromyelitis optica spectrum disorder (NMOSD) (2/38, 5 %). 12 of 36 (33 %) patients with all lumbar puncture (LP) data available had CSF eosinophils present, with eosinophil mean of 3 % and range from 1 % to 18 % of CSF while blood cells. CONCLUSION: CSF eosinophils were present in one third of pediatric MOGAD patients, which is a higher rate than previously reported in either MOGAD or aquaporin-4 antibody positive NMOSD cohorts. Understanding the CSF composition of pediatric MOGAD patients helps to facilitate more prompt diagnosis and treatment and may shed light onto underlying pathologic mechanisms of disease with the goal to inform future therapeutic targets.

Clinical Spectrum, Treatment and Outcome of Children with Autoimmune Encephalitis.

OBJECTIVE: To assess the clinical spectrum, treatment, and outcome of children with autoimmune encephalitis (AE). STUDY DESIGN: Descriptive study. Place and Duration of the Study: Department of Paediatrics, The Aga Khan University Hospital, Karachi, Pakistan, from January 2017 to December 2021. METHODOLOGY: Medical records of children with a diagnosis of AE were reviewed for clinical features, treatment details, and outcomes. Outcome was defined as good (0-2) or poor (3-6) based on a modified Rankin Scale (mRS) score at 3-month follow-up. Descriptive statistics were reported and logistic regression was used to assess the prognostic factors associated with outcome. RESULTS: Thirty-three patients were identified with AE. Thirteen (39.3%) were antibody positive. Anti-N-methyl-D-aspartate receptor (NMDAR) antibody was seen in 92% of positive cases. Behavioural abnormalities (87.8%), seizures (81.8%), movement disorders (66.6%), psychiatric symptoms (63.6%), and mutism (33.3%) were the prominent symptoms. Thirty (91%) patients received first-line immunotherapy. Good outcome was seen in 14 (48.2%) patients. Univariable analysis showed that the odds of having poor outcome were 2.5 (95% confidence interval [CI] 0.37-16.88, p=0.34) in patients with chorea. In addition, an elevated cerebrospinal fluid (CSF) protein had an odds ratio (OR) of 8.6 (CI 0.88-84.83, p=0.064) and positive CSF antibodies had an OR of 3.7 (CI 0.79-17.72, p=0.095) for a poor outcome. Mortality was seen in 4 (12.1%) patients. CONCLUSION: A very low threshold is needed for the diagnosis of AE in children presenting with behavioural symptoms and chorea. Although the odds for poor prognosis were higher in patients with chorea, elevated CSF protein and positive CSF antibodies, the p-value did not come out significant. KEY WORDS: Autoimmune encephalitis, Antibodies, NMDAR, Immunotherapies, mRS score, Outcome.

Patterns and utility of myelin oligodendrocyte glycoprotein (MOG) antibody testing in cerebrospinal fluid.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an idiopathic central nervous system (CNS) demyelinating disease gaining recognition with wider availability of cell-based assay (CBA) testing and recently published diagnostic criteria. However, uncertainty remains regarding the interpretation of antibody titers, particularly cerebrospinal fluid (CSF) MOG antibody titers. METHODS: All MOG IgG CBA results performed by the provincial MitogenDx laboratory in Alberta from July 2017 to July 2023 were retrieved. Chart review was performed in patients with both serum and CSF testing and ≥ 1 positive MOG antibody result. Demographics, antibody titers, clinical and imaging features, treatment, and diagnosis were analyzed based on serum/CSF status. RESULTS: Among 4494 MOG CBA assays, there were 413 CSF samples in 402 patients, and 268 patients had at least one associated serum sample. Mean time between CSF and serum testing was 20.9 days (range 0-870 days), most with testing within 30 days. Five of the 268 patients had serum positive/CSF positive MOG antibodies, 4 with acute disseminated encephalomyelitis and 1 with longitudinally extensive transverse myelitis. Twenty-three patients had serum positive/CSF negative MOG and 13/23 with optic neuritis. CSF MOG antibody positive patients were younger, and more likely to remain MOG seropositive versus CSF negative patients. No seronegative patient had MOG antibodies in CSF. CONCLUSIONS: In province-wide testing, CSF MOG antibodies were rare, only in MOG seropositive patients and none with optic neuritis. Our study does not support a clear role for CSF MOG antibody testing in the majority of patients, although further study is required.

[Clinical features and pathogenesis of Glial fibrillary acidic protein (GFAP) antibody-associated disorders].

Glial fibrillary acidic protein (GFAP) antibody-associated disorders (AD) were recently proposed to be immune-mediated neurological disorders. The pathogenesis of GFAP antibody-AD is poorly understood. Pathologically, there is a marked infiltration of large numbers of lymphocytes, including CD8+ and CD4+ T cells, into the meningeal and brain parenchyma, especially around the perivascular areas. GFAP-specific cytotoxic T cells are considered to be the effector cells of GFAP antibody-AD. The common phenotype of GFAP antibody-AD includes meningoencephalitis with or without myelitis. During the clinical disease course, patients present with consciousness disturbances, urinary dysfunction, movement disorders, meningeal irritation, and cognitive dysfunction. The detection of GFAP antibodies in the cerebrospinal fluid (CSF) by cell-based assay is essential for a diagnosis of GFAP antibody-AD. The CSF can be examined for lymphocyte-predominant pleocytosis and elevated protein levels. Brain linear perivascular radial enhancement patterns are observed in about half of GFAP antibody-AD patients. Spinal cord magnetic resonance imaging is used to detect longitudinal extensive spinal cord lesions. Although corticosteroid therapy is generally effective, some patients have a poor prognosis and relapse.

Anti-GM-CSF autoantibodies predict outcome of cryptococcal meningitis in patients not infected with HIV: A cohort study.

OBJECTIVES: To explore the seroprevalence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies in non-HIV cryptococcal meningitis (CM) and assess its predictive value for survival. METHODS: This is a retrospective study of 12 years of non-HIV CM. We detected serum anti-GM-CSF autoantibodies, and evaluated the clinical features and outcomes, together with the exploration of prognostic factors for 2-week and 1-year survival. RESULTS: A total of 584 non-HIV CM cases were included. 301 of 584 patients (51.5%) were phenotypically healthy. 264 Cryptococcus isolates were obtained from cerebrospinal fluid (CSF) culture, of which 251 were identified as C. neoformans species complex and 13 as C. gattii species complex. Thirty-seven of 455 patients (8.1%) tested positive for serum anti-GM-CSF autoantibodies. Patients with anti-GM-CSF autoantibodies were more susceptible to C. gattii species complex infection (66.7% vs. 6.3%; p < 0.001) and more likely to develop pulmonary mass lesions with a diameter >3 centimetres (42.9% vs. 6.5%; p 0.001). Of 584 patients 16 (2.7%) died within 2 weeks, 77 of 563 patients (13.7%) died at 1 year, and 93 of 486 patients (19.1%) lived with disabilities at 1 year. Univariant Cox regression analysis found that anti-GM-CSF autoantibodies were associated with lower 1-year survival (HR, 2.66; 95% CI, 1.34-5.27; p 0.005). Multivariable Cox proportional hazards modelling revealed that CSF cryptococcal antigen titres ≥1:1280 were associated with both, reduced 2-week and 1-year survival rates (HR, 5.44; 95% CI, 1.23-24.10; p 0.026 and HR, 5.09; 95% CI, 1.95-13.26; p 0.001). DISCUSSION: Presence of serum anti-GM-CSF autoantibodies is predictive of poor outcomes, regardless of host immune status and the causative Cryptococcus species complex.

Autoimmune Cerebellar Ataxia Associated with Anti-Glutamate Receptor δ2 Antibodies: a Rare but Treatable Entity.

We report two novel cases of autoimmune cerebellar ataxia (ACA) associated with anti-glutamate receptor δ2 antibodies (Gluδ2-Abs). The first case was confirmed by indirect immunofluorescence and cell-based assays: a 29-year-old woman presented after 5 days of headache and vomiting, a pancerebellar syndrome, downbeat nystagmus, decreased visual acuity linked to bilateral retrobulbar optic neuritis (RON), and lymphocytic pleocytosis in the cerebrospinal fluid (CSF) without any abnormality detected using cerebral magnetic resonance imaging (MRI). Second-line immunotherapy allowed progressive clinical improvement, with full recovery achieved after a 4-year follow-up. Thereafter, we retrospectively tested Gluδ2-Abs in 350 patients with a suspicion of autoimmune encephalitis without characterized autoantibody. We identified a second case, a 12-year-old boy who developed 10 days after a respiratory infection, a static cerebellar syndrome with lymphocytosis in the CSF, and right cerebellum hyperintensity in MRI. Five days of corticosteroid treatment allowed a quick clinical improvement. No tumor was identified in both cases, whereas laboratory analyses revealed autoimmune stigma. The present cases suggested that ACA associated with Gluδ2-Abs is an extremely rare but treatable disease. Therefore, testing for Gluδ2-Abs might be considered in the setting of suspected ACA and no initial antibody identification. The visual deficits and ocular motility abnormalities observed in the first reported case might be part of the clinical spectrum of Gluδ2-Abs ACA. Young age, infectious prodromes, lymphocytic pleocytosis, and autoimmune background usually appear together with this syndrome and should lead to discuss the initiation of immunotherapy (after ruling out differential diagnosis, especially infectious causes).