Validation of the 2023 International Diagnostic Criteria for MOGAD in a Selected Cohort of Adults and Children.

BACKGROUND AND OBJECTIVES: To test the performance of the 2023 myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) criteria in adults and children with inflammatory demyelinating conditions who were tested for MOG antibodies (Abs). METHODS: This was a retrospective study of patients tested for MOG-Abs from 2018 to 2022 in 2 specialist hospitals. The inclusion criteria comprised ≥1 attendance in an adult or pediatric demyelinating disease clinic and complete clinical and MRI records. The final clinical diagnosis of MOGAD, made by the treating neurologist, was taken as the benchmark against which the new criteria were tested. The international MOGAD diagnostic criteria were applied retrospectively; they stipulate at least 1 clinical or MRI supporting feature for MOGAD diagnosis in positive fixed MOG cell-based assay without a titer. The performance MOG-Ab testing alone for MOGAD diagnosis was also assessed and compared with that of MOGAD criteria using the McNemar test. RESULTS: Of the 1,879 patients tested for MOG-Abs, 539 (135 pediatric and 404 adults) met the inclusion criteria. A clinical diagnosis of MOGAD was made in 86/539 (16%) patients (37 adults, 49 children), with a median follow-up of 3.6 years. The MOGAD diagnostic criteria had sensitivity of 96.5% (adults 91.9%, children 100%), specificity of 98.9% (adults 98.8%, children 98.9%), positive predictive value of 94.3% (adults 89.4%, children 98%), negative predictive value of 99.3% (adults 99.2%, children 100%), and accuracy of 98.5% (adults 98.3%, children 99.2%). When compared with MOG-Ab testing alone, a difference was seen only in adults: a significantly higher specificity (98.9% vs 95.6%, p = 0.0005) and nonstatistically significant lower sensitivity (91.9% vs 100%, p = 0.08). DISCUSSION: The international MOGAD diagnostic criteria exhibit high performance in selected patients with inflammatory demyelinating diseases (who had a high pretest probability of having MOGAD) compared with best clinical judgment; their performance was better in children than in adults. In adults, the MOGAD criteria led to an improvement in specificity and positive predictive value when compared with MOG-Ab testing alone, suggesting that the requirement of at least 1 clinical or MRI supporting feature is important. Future work should address the generalizability of the diagnostic criteria to cohorts of greater clinical diversity seen within neurologic settings.

Autoimmune encephalitis: recent clinical and biological advances.

In 2015, we wrote a review in The Journal of Neurology summarizing the field of autoantibody-associated neurological diseases. Now, in 2023, we present an update of the subject which reflects the rapid expansion and refinement of associated clinical phenotypes, further autoantibody discoveries, and a more detailed understanding of immunological and neurobiological pathophysiological pathways which mediate these diseases. Increasing awareness around distinctive aspects of their clinical phenotypes has been a key driver in providing clinicians with a better understanding as to how these diseases are best recognized. In clinical practice, this recognition supports the administration of often effective immunotherapies, making these diseases 'not to miss' conditions. In parallel, there is a need to accurately assess patient responses to these drugs, another area of growing interest. Feeding into clinical care are the basic biological underpinnings of the diseases, which offer clear pathways to improved therapies toward enhanced patient outcomes. In this update, we aim to integrate the clinical diagnostic pathway with advances in patient management and biology to provide a cohesive view on how to care for these patients in 2023, and the future.

Leucine-Rich Glioma-Inactivated 1 versus Contactin-Associated Protein-like 2 Antibody Neuropathic Pain: Clinical and Biological Comparisons.

Pain is a under-recognized association of leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies. Of 147 patients with these autoantibodies, pain was experienced by 17 of 33 (52%) with CASPR2- versus 20 of 108 (19%) with LGI1 antibodies (p = 0.0005), and identified as neuropathic in 89% versus 58% of these, respectively. Typically, in both cohorts, normal nerve conduction studies and reduced intraepidermal nerve fiber densities were observed in the sampled patient subsets. In LGI1 antibody patients, pain responded to immunotherapy (p = 0.008), often rapidly, with greater residual patient-rated impairment observed in CASPR2 antibody patients (p = 0.019). Serum CASPR2 antibodies, but not LGI1 antibodies, bound in vitro to unmyelinated human sensory neurons and rodent dorsal root ganglia, suggesting pathophysiological differences that may underlie our clinical observations. ANN NEUROL 2021;90:683-690.

Absence of Neuronal Autoantibodies in Neuropsychiatric Systemic Lupus Erythematosus.

This study aimed to characterise both neuronal autoantibodies and levels of interferon α, two proposed causative agents in neuropsychiatric systemic lupus erythematosus (NPSLE). Cerebrospinal fluid (CSF) and plasma from 35 patients with systemic lupus erythematosus (SLE; 15 with NPSLE) showed no antibodies against natively expressed N-methyl-D-aspartate receptors (NMDARs), or the surface of live hippocampal neurons. By comparison to controls (n = 104), patients with SLE had antibodies that bound to a peptide representing the extracellular domain of NMDARs (p < 0.0001), however, binding was retained against both rearranged peptides and no peptide (r = 0.85 and r = 0.79, respectively, p < 0.0001). In summary, neuronal-surface reactive antibodies were not detected in NPSLE. Further, while interferon α levels were higher in SLE (p < 0.0001), they lacked specificity for NPSLE. Our findings mandate a search for novel biomarkers in this condition. ANN NEUROL 2020;88:1244-1250.

Innate and adaptive immunity in human epilepsies.

Inflammatory mechanisms have been increasingly implicated in the origin of seizures and epilepsy. These mechanisms are involved in the genesis of encephalitides in which seizures are a common complaint. Experimental and clinical evidence suggests different inflammatory responses in the brains of patients with epilepsy depending on the etiology. In general, activation of both innate and adaptive immunity plays a role in refractory forms of epilepsy. Epilepsies in which seizures develop after infiltration of cells of the adaptive immune system in the central nervous system (CNS) include a broad range of epileptic disorders with different (known or unknown) etiologies. Infiltration of lymphocytes is observed in autoimmune epilepsies, especially the classical paraneoplastic encephalitides with antibodies against intracellular tumor antigens. The presence of lymphocytes in the CNS also has been found in focal cerebral dysplasia type 2 and in cortical tubers. Various autoantibodies have been shown to be associated with temporal lobe epilepsy (TLE) and hippocampal sclerosis of unknown etiology, which may be due to the presence of viral DNA. During the last decade, an increasing number of antineuronal autoantibodies directed against membranous epitopes have been discovered and are associated with various neurologic syndromes, including limbic encephalitis. A major challenge in epilepsy is to define biomarkers, which would allow the recognition of patient populations who might benefit from immune-modulatory therapies. Some peripheral inflammatory markers appear to be differentially expressed in patients with medically controlled and medically refractory and, as such, could be used for diagnostic, prognostic, or therapeutic purposes. Establishing an autoimmune basis in patients with drug-resistant epilepsy allows for efficacious and targeted immunotherapy. Although current immunotherapies can give great benefit to the correctly identified patient, there are limitations to their efficacy and they may have considerable side effects. Thus the identification of new immunomodulatory compounds remains of utmost importance.