The Discovery of Autoimmune Nodopathies and the Impact of IgG4 Antibodies in Autoimmune Neurology.

In the past decade, significant progress has been made on the understanding of IgG4-mediated autoimmune diseases, of both the central and the peripheral CNS. In addition to the description of diverse antigenic targets, the description of IgG subclasses associated with specific pathogenic autoantibodies has provided useful insights into the pathophysiology and, more importantly, into the therapeutic implications of the autoantibody subclasses. This understanding has affected how myasthenia gravis, autoimmune encephalitis, and autoimmune neuropathies are treated.

Stiff-person syndrome and related disorders - diagnosis, mechanisms and therapies.

Stiff-person syndrome (SPS) is the prototypical and most common autoimmune neuronal hyperexcitability disorder. It presents with stiffness in the limbs and axial muscles, stiff gait with uncontrolled falls, and episodic painful muscle spasms triggered by anxiety, task-specific phobias and startle responses, collectively leading to disability. Increased awareness of SPS among patients and physicians has created concerns about diagnosis, misdiagnosis and treatment.

Stiff Person Syndrome and GAD Antibody-Spectrum Disorders.

Objective: Antibodies against glutamic acid decarboxylase (GAD), originally associated with stiff person syndrome (SPS), define the GAD antibody-spectrum disorders that also include cerebellar ataxia, autoimmune epilepsy, limbic encephalitis, progressive encephalomyelitis with rigidity and myoclonus (PERM), and eye movement disorders, all of which are characterized by autoimmune neuronal excitability. This article elaborates on the diagnostic criteria for SPS and SPS spectrum disorders, highlights disease mimics and misdiagnoses, describes the electrophysiologic mechanisms and underlying autoimmunity of stiffness and spasms, and provides a step-by-step therapeutic scheme.

Latest Developments: Very-high serum GAD antibody titers are diagnostic for GAD antibody-spectrum disorders and also predict the presence of GAD antibodies in the CSF, increased intrathecal synthesis, and reduced CSF γ-aminobutyric acid (GABA) levels.

The impact of HLA-DRB1 alleles in a Hellenic, Pediatric-Onset Multiple Sclerosis cohort: Implications on clinical and neuroimaging profile.

Background: Pediatric-Onset Multiple Sclerosis (POMS) is considered a complex disease entity and several genetic, hormonal, and environmental factors have been associated with disease pathogenesis. Linkage studies in Caucasians have consistently suggested the human leukocyte antigen (HLA) polymorphisms, as the genetic locus most strongly linked to MS, with the HLA-DRB1*15:01 allele, being associated with both adult and pediatric MS patients. Here we aim to investigate the prevalence of the HLA-DRB1 alleles among a Hellenic POMS cohort and any possible associations with clinical and imaging disease features.

Late-onset stiff-person syndrome: challenges in diagnosis and management.

Background: Stiff person syndrome (SPS) is a rare slowly progressive autoimmune neuronal hyperexcitability disease with very-high GAD-65 antibody titers that most commonly presents above the age of 20, with muscle stiffness, painful muscle spasms, slow gait, and falls leading to disability. In other autoimmune disorders, late-onset disease has different symptom-spectrum and outcomes, but there is no information regarding late-onset SPS (LOSPS).

Objective: Highlight delayed diagnosis and poor tolerance or incomplete response to therapies of patients with LOSPS and outline how best to increase disease awareness early at onset.

Severe Stiff-Person Syndrome After COVID: The First Video-Documented COVID Exacerbation and Viral Implications.

Objectives: To describe a patient with mild GAD-positive stiff-leg syndrome (SLS) who developed severely disabling stiff-person syndrome (SPS) 1 week after mild COVID-19 and discuss the impact of viral implications.

Methods: Video-documented serial clinical observations at baseline, after acute COVID-19, and after IVIG treatments.

Results: A 39-year-old man with left-SLS was stable during a 2-year follow-up with low-dose antispasmodics, working fully and functioning normally, even able to run.

Objectivity, practicality, and significance of practice guidelines for the practicing neurologists: What we learnt from consensus criteria in CIDP, Myasthenia Gravis and Inflammatory Myopathies.

The value of practice guidelines in the three most common autoimmune neuromuscular disorders, namely Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Myasthenia Gravis (MG) and Autoimmune Inflammatory Myopathies (AIM), has been extensively debated regarding their usefulness in clinical practice, objectivity and universal value considering that guidelines are also established regionally in certain countries. This commentary highlights common concerns on how guidelines are presently generated, pointing out: (a) non-sufficient diversity among Task-Force members to identify and address not only routine clinical and electrophysiology issues but also immunology, imaging, pathology, biomarkers, epidemiology or treatment economics; (b) Task-Force being often comprised by the same or seemingly like-minded members conveying the erroneous impression that experts with opposing views might have been excluded, even if this is clearly not the case; and (c) relying on web-based registries or retrospective data collections from heterogeneous sources. As a result, the existing practice guidelines in CIDP, MG and AIM remain an unfinished business but an excellent base for further enhancement.

Autoimmune inflammatory myopathies.

The autoimmune inflammatory myopathies constitute a heterogeneous group of acquired myopathies that have in common the presence of endomysial inflammation and moderate to severe muscle weakness. Based on currently evolved distinct clinical, histologic, immunopathologic, and autoantibody features, these disorders can be best classified as dermatomyositis, necrotizing autoimmune myositis, antisynthetase syndrome-overlap myositis, and inclusion body myositis. Although polymyositis is no longer considered a distinct subset but rather an extinct entity, it is herein described because its clinicopathologic information has provided over many years fundamental information on T-cell-mediated myocytotoxicity, especially in reference to inclusion body myositis.

Spatial and Ecological Factors Modulate the Incidence of Anti-NMDAR Encephalitis-A Systematic Review.

Anti-NMDAR encephalitis has been associated with multiple antigenic triggers (i.e., ovarian teratomas, prodromal viral infections) but whether geographic, climatic, and environmental factors might influence disease risk has not been explored yet.

Stiff person spectrum disorder diagnosis, misdiagnosis, and suggested diagnostic criteria.

Background: Stiff person spectrum disorder (SPSD) is heterogeneous, and accurate diagnosis can be challenging.

Methods: Patients referred for diagnosis/suspicion of SPSD at the Mayo Autoimmune Neurology Clinic from July 01, 2016, to June 30, 2021, were retrospectively identified. SPSD diagnosis was defined as clinical SPSD manifestations confirmed by an autoimmune neurologist and seropositivity for high-titer GAD65-IgG (>20.

Therapies in Stiff-Person Syndrome: Advances and Future Prospects Based on Disease Pathophysiology.

Among the glutamic acid decarboxylase (GAD)-antibody-spectrum disorders, the most common phenotypic subset is the stiff-person syndrome (SPS), caused by impaired GABAergic inhibitory neurotransmission and autoimmunity characterized by very high titers of GAD antibodies and increased GAD-IgG intrathecal synthesis. If not properly treated or untreated because of delayed diagnosis, SPS progresses leading to disability; it is therefore fundamental to apply the best therapeutic schemes from the outset. This article is focused on the rationale of specific therapeutic strategies based on the SPS pathophysiology targeting both the impaired reciprocal GABAergic inhibition to symptomatically improve the main clinical manifestations of stiffness in the truncal and proximal limb muscles, gait dysfunction, and episodic painful muscle spasms and the autoimmunity to enhance improvement and slow down disease progression.

Intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): mechanisms of action and clinical and genetic considerations.

Introduction: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune peripheral nerve disorder that is characterized by subacute onset, progressive or relapsing weakness, and sensory deficits. Proven treatments include intravenous immunoglobulin (IVIg), corticosteroids, and plasma exchange. This review focuses on the mechanisms of action, pharmacodynamics, genetic variations, and disease characteristics that can affect the efficacy of IVIg.

Repurposing MS immunotherapies for CIDP and other autoimmune neuropathies: unfulfilled promise or efficient strategy?

Despite advances in the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and other common autoimmune neuropathies (AN), still-many patients with these diseases do not respond satisfactorily to the available treatments. Repurposing of disease-modifying therapies (DMTs) from other autoimmune conditions, particularly multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD), is a promising strategy that may accelerate the establishment of novel treatment choices for AN. This approach appears attractive due to homologies in the pathogenesis of these diseases and the extensive post-marketing experience that has been gathered from treating MS and NMOSD patients.

First-line disease modifying treatments in pediatric-onset multiple sclerosis in Greece: therapy initiation at more advanced age is the main cause of treatment failure, in a retrospective observational study, with a cohort from a single Multiple Sclerosis Center.

Objectives: Long-term immunomodulatory therapy of pediatric onset-multiple sclerosis (POMS) is based mainly on published case series and internationally agreed guidelines. Relevant studies in the Greek population are absent from the literature. The purpose of this study is to present data on the efficacy and safety of the 1st line immunomodulatory drugs in the treatment of POMS patients.

The role of complement and complement therapeutics in neuromyelitis optica spectrum disorders.

Introduction: Neuromyelitis optica spectrum disorders (NMOSD) are characterized in the majority of cases by the presence of IgG1 autoantibodies against aquaporin 4 (AQP4) and myelin-oligodendrocyte glycoprotein (MOG), both capable of activating complement.

Areas Covered: We review evidence of complement involvement in NMOSD pathophysiology from pathological, in vitro, in vivo, human studies, and clinical trials.

Expert Opinion: In AQP4 NMOSD, complement deposition is a prominent pathological feature, while in vitro and in vivo studies have demonstrated complement-dependent pathogenicity of AQP4 antibodies.

Long-term Effectiveness of IVIg Maintenance Therapy in 36 Patients With GAD Antibody-Positive Stiff-Person Syndrome.

Background And Objectives: IVIg has been the preferred immunotherapy in stiff-person syndrome (SPS) based on a 3-month controlled trial, but whether it is also effective in inducing long-term benefits or arresting disease progression is unknown. The information is needed because SPS is a progressively disabling disease and IVIg is liberally used as chronic therapy without efficacy data. The present study explores the long-term effects of IVIg in the largest cohort of well-characterized patients with SPS followed by the same clinicians over 10 years.