Clinical, prognostic and pathophysiological implications of MOG-IgG detection in the CSF: the importance of intrathecal MOG-IgG synthesis.

BACKGROUND: Cerebrospinal fluid myelin oligodendrocyte glycoprotein IgG (CSF MOG-IgG) are found in a proportion of patients with MOG antibody-associated disorder (MOGAD) and have been associated with severe disease presentations. However, most studies did not systematically investigate the role of MOG-IgG intrathecal synthesis (ITS). METHODS: We retrospectively studied 960 consecutive patients with paired serum and CSF samples screened for MOG-IgG using a live cell-based assays. MOG-IgG-specific antibody index (AIMOG) was systematically calculated using serum and CSF titres to assess MOG-IgG ITS, and clinical features were compared between MOG-IgG CSF+/CSF- and ITS+/ITS- patients. RESULTS: MOG-IgG were found in 55/960 patients (5.7%; serum+/CSF-: 58.2%, serum+/CSF+: 34.5%; serum-/CSF+: 7.3%). Serum/CSF MOG-IgG titres showed a moderate correlation in patients without ITS (ρ=0.47 (CI 0.18 to 0.68), p<0.001), but not in those with ITS (ρ=0.14 (CI -0.46 to -0.65), p=0.65). There were no clinical-paraclinical differences between MOG-IgG CSF+ vs CSF- patients. Conversely, patients with MOG-IgG ITS showed pyramidal symptoms (73% vs 32%, p=0.03), spinal cord involvement (82% vs 39%, p=0.02) and severe outcome at follow-up (36% vs 5%, p=0.02) more frequently than those without MOG-IgG ITS. A multivariate logistic regression model indicated that MOG-IgG ITS was an independent predictor of a poor outcome (OR: 14.93 (CI 1.40 to 19.1); p=0.03). AIMOG correlated with Expanded Disability Status Scale (EDSS) scores at disease nadir and at last follow-up (p=0.02 and p=0.01). CONCLUSIONS: Consistently with physiopathology, MOG-IgG ITS is a promising prognostic factor in MOGAD, and its calculation could enhance the clinical relevance of CSF MOG-IgG testing, making a case for its introduction in clinical practice.

Diagnostic accuracy of voluntary and stimulated neuromuscular jitter studies in ocular myasthenia gravis.

INTRODUCTION/AIMS: There is a lack of studies comparing the accuracy of neuromuscular jitter analysis during voluntary activation (v-jitter study) versus axonal stimulation (s-jitter study). The study aimed to compare these two techniques in the same population of patients with suspected ocular myasthenia gravis (OMG). METHODS: Fourteen control subjects (mean age: 55.5 ± 15.2 years) and 34 patients with suspected OMG (mean age: 59 ± 13.9 years) were prospectively evaluated. Twenty spike pairs and 30 individual spikes were analyzed during v-jitter and s-jitter study, respectively. Two different criteria for abnormal individual jitter values were evaluated: ≥ or > than 10% values exceeding the upper normal limit. RESULTS: OMG was diagnosed in 19 patients based on clinical and laboratory findings, without considering jitter measurements. In most patients, v-jitter and s-jitter analyses provided comparable results. The maximum sensitivity (89%) was achieved with s-jitter study using the ≥10% criterion, while the maximum specificity (93%) was found with v-jitter study using the >10% criterion. DISCUSSION: Both v-jitter and s-jitter studies showed good to very good accuracy for the diagnosis of OMG, in the absence of any statistically significant difference. Therefore, the patient's cooperation level and examiner's experience should guide the choice of performing v-jitter or s-jitter analysis in patients with suspected OMG.

Overcoming therapeutic challenges: Successful management of a supposedly triple seronegative, refractory generalized myasthenia gravis patient with efgartigimod.

BACKGROUND AND PURPOSE: This study was undertaken to highlight neonatal Fc receptor inhibition (efgartigimod) as a valuable therapeutic option for patients with refractory seronegative myasthenia gravis (MG) and to emphasize the concept that seronegative MG is greatly constrained by the limitations of currently available diagnostic methods and therapeutic measures. METHODS: We describe the first refractory, generalized MG (gMG) patient successfully treated with efgartigimod after testing negative on standard autoantibody detection tests. RESULTS: Our patient presented with severe fluctuating bulbar and generalized weakness, resulting in multiple myasthenic crises requiring intubation. After a 28-year medical history of multiple failed lines of treatment, our patient was started on efgartigimod. Over five treatment cycles, a definite improvement in her clinical condition was observed (Myasthenia Gravis Foundation of America class: IIIb to IIb; MG-Activities of Daily Living score: 11 to 0; MG-Quality of Life 15 score: 30 to 0; Quantitative MG score: 28 to 6). Standard autoantibody detection tests failed to detect known pathogenic autoantibodies, but cell-based assay (CBA) identified autoantibodies against clustered adult acetylcholine receptor (AChR). CONCLUSIONS: In light of recent approvals of efgartigimod by the European Medicines Agency and US Food and Drug Administration exclusively for AChR-positive gMG forms, our case highlights evidence suggesting that such an approach might be shortsighted and could limit therapeutic options for patients with refractory seronegative gMG. Additionally, introducing more sensitive analytical techniques, exemplified by CBA, may help bridge the gap between seronegative and seropositive patients. This represents an urgent unmet need for gMG patients, as the antibody profile dramatically influences the therapeutic approach.

Autoimmune encephalitis: what the radiologist needs to know.

Autoimmune encephalitis is a relatively novel nosological entity characterized by an immune-mediated damage of the central nervous system. While originally described as a paraneoplastic inflammatory phenomenon affecting limbic structures, numerous instances of non-paraneoplastic pathogenesis, as well as extra-limbic involvement, have been characterized. Given the wide spectrum of insidious clinical presentations ranging from cognitive impairment to psychiatric symptoms or seizures, it is crucial to raise awareness about this disease category. In fact, an early diagnosis can be dramatically beneficial for the prognosis both to achieve an early therapeutic intervention and to detect a potential underlying malignancy. In this scenario, the radiologist can be the first to pose the hypothesis of autoimmune encephalitis and refer the patient to a comprehensive diagnostic work-up - including clinical, serological, and neurophysiological assessments.In this article, we illustrate the main radiological characteristics of autoimmune encephalitis and its subtypes, including the typical limbic presentation, the features of extra-limbic involvement, and also peculiar imaging findings. In addition, we review the most relevant alternative diagnoses that should be considered, ranging from other encephalitides to neoplasms, vascular conditions, and post-seizure alterations. Finally, we discuss the most appropriate imaging diagnostic work-up, also proposing a suggested MRI protocol.

Anti-pan-neurofascin nodopathy: cause of fulminant neuropathy.

Autoimmune nodopathies are inflammatory diseases of the peripheral nervous system with clinical and neurophysiological peculiar characteristics. In this nosological category, we find patients with autoantibodies against Neurofascin 140/186 and 155, Contactin1, and Caspr1 directed precisely towards nodal and paranodal structures. These antibodies are extremely rare and cause severe clinical symptoms. We describe the clinical case of a patient with autoimmune nodopathy caused by the coexistence of anti-neurofascin (NF) 186/140 and 155, characterized by progressive weakness in all limbs leading to tetraplegia, involving cranial nerves, and respiratory insufficiency. Response to first-line treatments was good followed by rapid dramatic clinical relapse. There are few reported cases of anti-pan NF neuropathy in the literature, and they present a clinical phenotype similar to our patient. In these cases, early recognition of clinical red flags of nodopathies and serial neurophysiological studies can facilitate the diagnosis. However, the severe clinical relapse suggests a possible early use of immunosuppressive therapies for this rare category of patients.

Patient With Rigidity and Fasciculations: Steroid-Responsive Presentation of Anti-IgLON5 Disease

An 82-year-old man presented with 2-year lasting widespread muscular fasciculations, cramps, and limb stiffness, with spontaneous movements in the right lower limb, unsteady gait (Video 1), and falls. Neurophysiologic studies disclosed signs of neuromuscular hyperexcitability. CSF analysis showed high tau protein concentration (543 pg/mL; reference values, <404) and unique-to-CSF oligoclonal bands. Serum and CSF anti-IgLON5 antibodies were positive (Figure 1). He carried the anti-IgLON5 disease-associated HLA-DRB1*10:01 allele.1 Brain MRI, thoracoabdominal CT, whole-body FDG-PET, and video-polysomnography were unremarkable. No sleep disturbances, bulbar symptoms, parkinsonism, or dementia were detected. Intravenous methylprednisolone (500 mg/d for 5 days), followed by oral benzodiazepines, prompted rapid functional recovery, with limb stiffness and gait improvement (Video 1), which persisted at 6-month follow-up. Anti-IgLON5 disease has progressive course and protean clinical presentations,2 representative, in our patient, for overlapping signs and symptoms of neuromuscular hyperexcitability and rigidity. Identification of rare phenotypes is important because prompt recognition and treatment can improve prognosis.

Prevalence of anti-myelin oligodendrocyte glycoprotein antibodies across neuroinflammatory and neurodegenerative diseases.

Inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), are characterized by humoral immune abnormalities. Anti-MOG antibodies are not specific to MOGAD, with their presence described in MS. Autoantibodies may also be present and play a role in various neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease driven by motor neuron dysfunction. While immune involvement in ALS has been recognized, the presence of antibodies targeting CNS myelin antigens has not been established. We aimed to establish a live cell-based assay for quantification of serum anti-MOG IgG1 in patients with CNS diseases, including MS and ALS. In total, 771 serum samples from the John L. Trotter MS Center and the Northeast ALS Consortium were examined using a live cell-based assay for detection of anti-MOG IgG1. Samples from three cohorts were tested in blinded fashion: healthy control (HC) subjects, patients with clinically diagnosed MOGAD, and an experimental group of ALS and MS patients. All samples from established MOGAD cases were positive for anti-MOG antibodies, while all HC samples were negative. Anti-MOG IgG1 was detected in 65 of 658 samples (9.9%) from MS subjects and 4 of 108 (3.7%) samples from ALS subjects. The presence of serum anti-MOG IgG1 in MS and ALS patients raises questions about the contribution of these antibodies to disease pathophysiology as well as accuracy of diagnostic approaches for CNS inflammatory diseases.

Moving towards a new era for the treatment of neuromyelitis optica spectrum disorders.

Neuromyelitis optica spectrum disorders (NMOSD) include a rare group of autoimmune conditions that primarily affect the central nervous system. They are characterized by inflammation and damage to the optic nerves, brain and spinal cord, leading to severe vision impairment, locomotor disability and sphynteric disturbances. In the majority of cases, NMOSD arises due to specific serum immunoglobulin G (IgG) autoantibodies targeting aquaporin 4 (AQP4-IgG), which is the most prevalent water-channel protein of the central nervous system. Early diagnosis and treatment are crucial to manage symptoms and prevent long-term disability in NMOSD patients. NMOSD were previously associated with a poor prognosis. However, recently, a number of randomized controlled trials have demonstrated that biological therapies acting on key elements of NMOSD pathogenesis, such as B cells, interleukin-6 (IL-6) pathway, and complement, have impressive efficacy in preventing the occurrence of clinical relapses. The approval of the initial drugs marks a revolutionary advancement in the treatment of NMOSD patients, significantly transforming therapeutic options and positively impacting their prognosis. In this review, we will provide an updated overview of the key immunopathological, clinical, laboratory, and neuroimaging aspects of NMOSD. Additionally, we will critically examine the latest advancements in NMOSD treatment approaches. Lastly, we will discuss key aspects regarding optimization of treatment strategies and their monitoring.

MOG-IgG testing strategies in accordance with the 2023 MOGAD criteria: a clinical-laboratory assessment.

BACKGROUND: Live cell-based assay (LCBA) is the gold standard for MOG-IgG detection, and fixed CBA (FCBA) is a widely used commercial alternative. Recent criteria attributed a diagnostic value to MOG-IgG titration with both LCBA and FCBA, with low-titre samples requiring additional supporting features for MOGAD diagnosis. However, FCBA titration is not validated. We aimed to assess the impact of the criteria-based MOG-IgG testing in MOGAD diagnosis. METHODS: Thirty-eight serum samples of LCBA MOG-IgG1-positive MOGAD patients were titred on MOG-IgG LCBA and FCBA, and the presence of supporting features for MOGAD assessed. MOGAD criteria were evaluated in four testing scenarios: (a) FCBA without titration; (b) FCBA with titration; c) LCBA without titration; (d) LCBA with titration. RESULTS: FCBA without titration failed to reach MOGAD diagnosis in 11/38 patients (28.9%, negative results in 5, lack of supporting features in 6). Patients with unconfirmed diagnosis had optic neuritis (ON, n = 8), or transverse myelitis (TM, n = 3). FCBA with titration allowed MOGAD diagnosis in 4 additional patients. Correlation between LCBA and FCBA titres was moderate (Spearman's rho 0.6, p < 0.001). CONCLUSIONS: FCBA yields high rate of misdiagnosis mainly due a lower analytical sensitivity. FCBA titration provides a moderate diagnostic advantage in FCBA positive patients.

Kappa index in the diagnostic work-up of autoimmune encephalitis.

BACKGROUND: The presence of inflammatory changes in the cerebrospinal fluid (CSF), including immunoglobulin intrathecal synthesis (IS), can support the diagnosis of autoimmune encephalitis (AE) and allow prompt treatment. The main aim of our study was to calculate the Kappa index as a marker of IS, in patients with AE. METHODS: Charts of patients undergoing a diagnostic work-up for suspected AE between 2009 and 2023 were reviewed and the Graus criteria applied. CSF and serum kappa free light chains were determined using the Freelite assay (The Binding Site Group) and the turbidimetric Optilite analyzer. RESULTS: We identified 34 patients with "definite" AE (9 anti-NMDAR AE and 25 limbic AE) and nine patients with "possible" AE. Five patients (15%) with definite AE had pleocytosis and twelve (34%) showed CSF-restricted oligoclonal bands (OCB) at isoelectric focusing. The Kappa index was >6 in 29.4% and > 3 in 50% of the definite AE patients. It was elevated (>3) in 36.4% of patients with definite AE who resulted negative to OCB testing and was the only altered parameter suggestive of an ongoing inflammatory process in the CNS in three definite AE patients with otherwise normal CSF findings (i.e. normal cell count and protein levels, no OCBs). In the possible AE group, one patient had a Kappa index >3 in the absence of OCB. CONCLUSIONS: The Kappa index could be useful, as a more sensitive marker of IS and as a supportive marker of neuroinflammation, in the diagnostic work-up of suspected AE.

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.