Antibody-associated Syndromes Research Articles

Autoimmune Encephalitis and Paraneoplastic Neurologic Syndromes: A Nationwide Study on Epidemiology and Antibody Testing Performance.

Autoimmune encephalitis (AIE) and paraneoplastic neurologic syndromes (PNSs) encompass a heterogeneous group of antibody-associated disorders. Both the number of syndromes and commercially available antibody tests have increased considerably over the past decade. High-quality population-based data on epidemiology of these disorders and real-world performance of antibody tests are needed. In this nationwide retrospective cohort study, we identified all serum and CSF samples tested for antibodies against intracellular antigens (IAs: Hu [ANNA1], Yo [PCA1], CV2 [CRMP5], Ri [ANNA2], Ma1, Ma2 [Ta], amphiphysin, GAD65, GFAP, KLHL11, CARP VIII) or extracellular antigens (EAs: NMDAR, LGI1, Caspr2, GABA-B-R, GABA-A-R, AMPAR, DPPX, GlyR, mGluR1, VGCC, IgLON5, Tr [DNER]) between January 2016 and December 2021 in the Netherlands. Nationwide coverage was guaranteed for all antibodies except anti-GAD65 and anti-VGCC. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV); obtained clinical information about patients who tested positive; assigned diagnosis of AIE/PNS according to diagnostic criteria; and calculated incidence rates for IA, EA, and individual antibody-associated syndromes. In the study period, 2,877 (9.5%) of 30,246 samples, belonging to 1,228 patients, tested positive. Sensitivity and specificity were high (>95%) to very high (>99%) for most tests in both serum and CSF. PPVs for several tests were moderate to poor, especially for serum testing of IA antibodies (25%-80%). Clinical data were available for 940 (76.5%) of 1,228 patients. A total of 578 AIE/PNS diagnoses were made. The incidence rate for AIE/PNS (per million person-years) increased from 4.70 (95% CI 3.72-5.85) in 2016 to 5.76 (4.69-7.00) in 2021. Overall, the incidence rate was 5.57 (5.13-6.05), 2.96 (2.64-3.31) for the EA and 2.61 (2.31-2.94) for the IA subgroup. The 4 most common AIE/PNS types were anti-NMDAR, anti-LGI1, anti-Hu, and anti-GAD65, together comprising almost two-thirds of all diagnoses (364/578, 63.0%). Most commercial antibody tests perform well overall, but important pitfalls remain. Although almost all tests had high specificity, PPV was only modest in the setting of these rare diseases and mass testing. We observe trends toward increasing incidence of antibody-associated AIE/PNS.

Autoimmune Movement Disorders.

This article reviews the clinical and antibody spectrum of autoimmune cerebellar ataxia and other autoimmune movement disorders. It highlights characteristic phenotypes and red flags to the diagnosis and how these rare, but treatable, disorders are integrated into a differential diagnosis. An increasing number of neuronal antibodies have been identified in patients with cerebellar ataxia, for example, against Kelch-like protein 11 (KLHL11), seizure-related 6 homolog-like 2, septin-3 and septin-5, or tripartite motif containing protein 9 (TRIM9), TRIM46, and TRIM67. Ig-like cell adhesion molecule 5 (IgLON5) antibody-associated syndromes have emerged as an important alternative diagnostic consideration to various neurodegenerative diseases such as Huntington disease or atypical parkinsonism. Opsoclonus-myoclonus syndrome emerged as the most relevant parainfectious movement disorder related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Autoimmune cerebellar ataxia and other autoimmune movement disorders encompass a broad spectrum of different clinical syndromes, antibodies, and immunopathophysiologic mechanisms. Clinical acumen is key to identifying the cases that should undergo testing for neuronal antibodies. Given the overlap between phenotypes and antibodies, panel testing in serum and CSF is recommended.

Anti-CASPR2 Antibody-Associated Syndrome Presenting With Episodic Ataxia

Anti-CASPR2 Antibody-Associated Syndrome Presenting With Episodic Ataxia

Anti-CASPR2 antibody-associated syndrome presenting with episodic ataxia

Anti-CASPR2 antibody-associated syndrome presenting with episodic ataxia

A Mild Phenotype of Overlapping Syndrome With Myelin-Oligodendrocyte Glycoprotein and Glial Fibrillary Acidic Protein Immunoglobulin G: Mimicking Viral Meningitis in a Patient.

Glial fibrillary acidic protein (GFAP) astrocytopathy, an autoimmune central nervous system disorder characterized by the development of immunoglobulin G reactive with GFAP, has received growing attention in recent years. It is documented that GFAP-immunoglobulin G and other autoantibodies can be both detected in some patients. However, the coexistence of anti-myelin-oligodendrocyte glycoprotein (MOG) and GFAP antibodies is rarely reported. A 45-year-old man presented with headache, fever, backache, dysuria, tremble of hands, numbness of lower limbs, without diplopia, decreased vision, or other manifestations of optic neuritis. He was initially diagnosed with viral meningitis. After antiviral therapy, his headache, fever, and dysuria were improved, but the tremble of his upper limbs and numbness of his lower limbs still existed. A lumbar puncture was further performed and found both anti-GFAP and anti-MOG antibodies in the cerebrospinal fluid. No evidence of other immune disorders or infectious diseases was revealed. Meanwhile, a magnetic resonance scan showed enhancement of spinal pia mater in cervical, thoracic, and lumbar segments. He was then treated with immunoglobulin (intravenous immunoglobulin) therapy (25 g for 5 d), and steroid pulse therapy (methylprednisolone, 1 g for 5 d), followed by a gradual tapering of oral prednisolone. We reported a case of overlapping anti-GFAP and anti-MOG antibody-associated syndrome. This case enriches our understanding of the clinical manifestations of overlapping syndrome and expands the spectrum of this disorder.

Neuro-Ophthalmic Features of Autoimmune Encephalitides.

Over the past decade, there has been a remarkable advancement in the understanding of autoimmune etiologies of encephalitis. The first identified generation of paraneoplastic encephalitis tends to occur in older populations, responds poorly to immunotherapy, and is mediated by T-cell damage with antibodies directed toward intracellular antigens. A new generation of autoimmune encephalitides has been described, which are mediated by antibodies to cell-surface proteins, tend to occur in younger individuals, are less frequently associated with malignancy, and often respond better to treatment compared to their intracellular antigen-related paraneoplastic counterparts. This review will focus on several specific antibody-mediated autoimmune encephalitides with neuro-ophthalmic pertinence. Literature review and personal clinical experience. Several of the antibody-mediated encephalitides, specifically N-methyl-D-aspartate receptor, dipeptidyl-peptidase-like protein 6, glial fibrillary acidic protein, metabotropic glutamate receptor 1 (mGluR1), gamma-aminobutyric acid receptor, glutamic acid decarboxylase 65 (GAD65), collapsing response mediator protein 5 (CRMP5), and kelch-like protein 11 (KLHL11), contain features of neuro-ophthalmic interest. The novel cell-surface protein-directed autoimmune encephalitis group can present with a wide range of afferent and efferent neuro-ophthalmic manifestations. Neuro-ophthalmologists should be familiar with these antibody-associated syndromes, which are treatable and often require a high index of suspicion for diagnosis.

Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.

Investigations of myelin oligodendrocyte glycoprotein (MOG) antibodies are usually focused on demyelinating syndromes, but the entire spectrum of MOG antibody-associated syndromes in children is unknown. In this study, we aimed to determine the frequency and distribution of paediatric demyelinating and encephalitic syndromes with MOG antibodies, their response to treatment, and the phenotypes associated with poor prognosis. In this prospective observational study, children with demyelinating syndromes and with encephalitis other than acute disseminated encephalomyelitis (ADEM) recruited from 40 secondary and tertiary centres in Spain were investigated for MOG antibodies. All MOG antibody-positive cases were included in our study, which assessed syndromes, treatment and response to treatment (ie, number of relapses), outcomes (measured with the modified Rankin scale [mRS]), and phenotypes associated with poor prognosis. We used Fisher's exact and Wilcoxon rank sum tests to analyse clinical features, and survival Cox regression to analyse time to antibody negativity. Between June 1, 2013, and Dec 31, 2018, 239 children with demyelinating syndromes (cohort A) and 296 with encephalitis other than ADEM (cohort B) were recruited. 116 patients had MOG antibodies, including 94 (39%) from cohort A and 22 (7%) from cohort B; 57 (49%) were female, with a median age of 6·2 years (IQR 3·7-10·0). Presenting syndromes in these 116 patients included ADEM (46 [68%]), encephalitis other than ADEM (22 [19%]), optic neuritis (20 [17%]), myelitis (13 [11%]), neuromyelitis optica spectrum disorders (six [5%]), and other disorders (nine [8%]). Among the patients with autoimmune encephalitis in cohort B (n=64), MOG antibodies were more common than all neuronal antibodies combined (22 [34%] vs 21 [33%]). After a median follow-up of 42 months (IQR 22-67), 33 (28%) of the 116 patients had relapses, including 17 (17%) of 100 diagnosed at first episode. Steroids, intravenous immunoglobulin, or plasma exchange were used in 100 (86%) patients at diagnosis, and 32 (97%) of 33 at relapses. Rituximab was mainly used at relapses (11 [33%]). 99 (85%) of 116 patients had substantial recovery (mRS <2) and 17 (15%) moderate to severe deficits (mRS >2; one died). Phenotypes of poor prognosis included ADEM-like relapses progressing to leukodystrophy-like features, and extensive cortical encephalitis evolving to atrophy. Time to antibody negativity was longer in patients with relapses (HR 0·18, 95% CI 0·05-0·59). The spectrum of paediatric MOG antibody-associated syndromes is wider than previously reported and includes demyelinating syndromes and encephalitis. Recognition of these disorders has important clinical and prognostic implications. Mutua Madrileña Foundation; ISCIII-Subdirección General de Evaluación y Fomento de la Investigación Sanitaria; Fondo Europeo de Desarrollo Regional; Pediatrics Spanish Society; Departament de Salut, Generalitat de Catalunya; Marato TV3 Foundation; Red Española de Esclerosis Múltiple; La Caixa Foundation; and Fundació CELLEX.

Anti-GAD Antibody-associated Syndrome Presenting with Limb Myoclonus.

BackgroundThe clinical spectrum of anti-glutamic acid decarboxylase (GAD) antibody-associated neurologic syndromes is expanding, with focal, generalized, and atypical forms.Case ReportWe describe a 59-year-old female showing continuous right lower limb myoclonus and mild encephalopathy. These symptoms started 2 weeks prior to evaluation. The patient had great improvement with intravenous steroids. An autoantibody panel was positive for anti-GAD.DiscussionVarious clinical manifestations, including myoclonus, may relate to anti-GAD antibodies. The treatment options available include symptomatic drugs, intravenous immunoglobulin, steroids, and other immunosuppressant agents.

Anti-GAD Antibody-associated Syndrome Presenting with Limb Myoclonus

<strong>Background:</strong> The clinical spectrum of anti-glutamic acid decarboxylase (GAD) antibody-associated neurologic syndromes is expanding, with focal, generalized, and atypical forms. <strong>Case Report:</strong> We describe a 59-year-old female showing continuous right lower limb myoclonus and mild encephalopathy. These symptoms started 2 weeks prior to evaluation. The patient had great improvement with intravenous steroids. An autoantibody panel was positive for anti-GAD. <strong>Discussion:</strong> Various clinical manifestations, including myoclonus, may relate to anti-GAD antibodies. The treatment options available include symptomatic drugs, intravenous immunoglobulin, steroids, and other immunosuppressant agents.

Clinical spectrum and IgG subclass analysis of anti-myelin oligodendrocyte glycoprotein antibody-associated syndromes: a multicenter study

Anti-myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) recently emerged as a potential biomarker in patients with inflammatory demyelinating diseases of the central nervous system. We here compare the clinical and laboratory findings observed in a cohort of MOG-Ab seropositive and seronegative cases and describe IgG subclass analysis results. Consecutive serum samples referred to Verona University Neuropathology Laboratory for aquaporin-4 (AQP4)-Ab and/or MOG-Ab testing were analysed between March 2014 and May 2017. The presence of AQP4-Ab was determined using a cell-based assay. A live cell immunofluorescence assay was used for the detection of MOG-IgG and IgG subclass analysis. Among 454 analysed samples, 29 were excluded due to AQP4-Ab positivity or to the final demonstration of a disorder not compatible with MOG-Ab. We obtained clinical data in 154 out of 425 cases. Of these, 22 subjects resulted MOG-Ab positive. MOG-Ab positive patients were mainly characterised by the involvement of the optic nerve and/or spinal cord. Half of the cases presented relapses and the recovery was usually partial. Brain MRI was heterogeneous while short lesions were the prevalent observation on spinal cord MRI. MOG-Ab titre usually decreased in non-relapsing cases. In all MOG-IgG positive cases, we observed IgG1 antibodies, which were predominant in most subjects. IgG2 (5/22), IgG3 (9/22) and IgG4 (3/22) antibodies were also detectable. We confirm that MOG-Ab-related syndromes have distinct features in the spectrum of demyelinating conditions, and we describe the possible role of the different IgG subclasses in this condition.

Microangiopathic antiphospholipid antibody-associated syndrome in a pregnant lady

We describe a gravid 37-year-old Chinese lady with known triple positive primary antiphospholipid syndrome with previous recurrent deep vein thrombosis and early spontaneous miscarriages. She was managed with low-molecular weight heparin, aspirin, hydroxychloroquine, prednisolone and monthly intravenous immunoglobulin. She presented with recurrent per-vaginal bleeding at 22 weeks of gestation and was found to have abruptio placentae. Anti-coagulation was held off. She subsequently delivered a stillborn at 24 weeks and anti-coagulation was restarted. Day 5 post-delivery, she developed HELLP, with hemolytic anaemia (Hb 10.1 g/dL, haptoglobin <30 g/L, LDH 2206 U/L), elevated transaminases (AST 1196 U/L, ALT 1130 U/L) and thrombocytopenia (platelet 28 × 10^9/L). There were also episodes of acute severe headache and abdominal pain assessed to be secondary to microvascular ischemia as CT did not reveal any thrombosis. Her blood pressure hovered persistently above systolic 180 mmHg, and required at least three anti-hypertensives. These were coupled with a new onset proteinuria of 2 to 3 g/day. There was no evidence of disseminated intravascular coagulation. She was assessed to have microangiopathic antiphospholipid syndrome and was started on plasmapheresis. On Day 10 post-partum, the patient complained of foul-smelling vaginal discharge and was found to have retained products of conception, which was immediately evacuated. Her course was followed by poly-microbial sepsis secondary to Enterococcus fecalis, Klebsiella Pneumoniae and Escherichia coli. The patient was further treated with imipenem and she completed eight exchanges of plasmapheresis followed by five days of intravenous immunoglobulins with good clinical and biochemical improvement.

“The more we know”

Almost half of the articles in this issue of Neurology® Neuroimmunology & Neuroinflammation (N2) are focused on disorders related to autoantibodies against well-defined antigens expressed by astrocytes (aquaporin-4 [AQP4]), oligodendrocytes (myelin oligodendrocyte glycoprotein [MOG]), or neurons, either synaptic receptors (NMDA receptor, dipeptidyl-peptidase-like protein-6 [DPPX]) or intracellular proteins (glutamic acid decarboxylase [GAD], collapsing response-mediator protein 5 [CRMP-5]). Although these disorders are already known, a common theme of the current N2 articles is that when atypical syndromes occur, additional mechanisms or the presence of concurrent autoantibodies should be carefully investigated. This is particularly relevant when the involved autoantibodies are known to be unambiguously pathogenic in cultured cells (astrocytes, oligodendrocytes, or neurons) or in animal models.1–3 Indeed, if, after hundreds of patients are reported with a specific antibody-associated syndrome, one encounters a patient with atypical manifestations, it is more reasonable to search for an additional pathogenic mechanism than to label the case as an “expansion” of the syndrome.

Determination of Antibodies to GAD67 and Other Antigens in Patients with GAD65 Antibody-Associated Syndromes (P5.033)

Determination of Antibodies to GAD67 and Other Antigens in Patients with GAD65 Antibody-Associated Syndromes (P5.033)

Caspr2 antibody limbic encephalitis is associated with Hashimoto thyroiditis and thymoma

BackgroundContactin-associated protein 2 (Caspr2) antibody is a neuronal surface antibody (NSAb) capable of causing disorders involving central and peripheral nervous systems (PNS). Thymoma can be found in patients with Caspr2 antibodies and is most frequently associated with PNS symptoms. Myasthenia gravis can be found in these patients, but Hashimoto thyroiditis (HT) has not been reported. MethodsA 76-year-old woman presented with sub-acute-onset changes in mental status. Further investigations revealed thymoma and HT. The presence of NSAb was tested by immunofluorescence on human embryonic kidney-293 cells. Treatment included corticosteroids, azathioprine, thyroxine, plasmapheresis, and thymectomy. ResultsCaspr2 antibody was positive in serum but absent in CSF. Brain magnetic resonance imaging (MRI) showed diffuse cortical atrophy, but did not change significantly after treatments. Brain positron emission tomography (PET) revealed diffuse hypometabolism over the cerebral cortex. The patient's mental status only partially improved. ConclusionsIn Caspr2 antibody-associated syndromes, thymoma can occur in patients presenting only with LE, and HT can be an accompanying disease. Brain MRI and PET may not show specific lesions in limbic area. Patients with Caspr2 antibodies and thymoma may not have good prognosis.

Rotigotine for Apathy in Limbic Autoimmune Encephalitis

Rotigotine for Apathy in Limbic Autoimmune Encephalitis

Synthetic disialylgalactose immunoadsorbents deplete anti-GQ1b antibodies from autoimmune neuropathy sera.

Acute and chronic autoimmune neuropathies, including Guillain-Barré syndromes (GBS) are often characterized by the presence of autoantibodies that react with neural gangliosides. Evidence from human and animal studies indicates that anti-ganglioside antibodies play a primary neuropathogenic role, and their rapid elimination from the circulation through specific immunoadsorption therapy thus has the potential to ameliorate the course of the disease. Here we have tested this therapeutic principle in the Miller Fisher variant of GBS that is associated serologically with acute phase anti-GQ1b ganglioside immunoglobulin G (IgG) antibodies, and in chronic ataxic neuropathies associated with persistently elevated immunoglobulin M (IgM) antibodies that react with GQ1b, GD3 and other disialylated gangliosides. Human and mouse anti-GQ1b IgG and IgM antibodies may also react with GD3, suggesting the shared terminal disialoside epitope could be involved in antibody binding. We thus synthesized the terminal trisaccharide, NeuAc(alpha2-8)NeuAc(alpha2-3)Gal common to GQ1b and GD3, and conjugated it to bovine serum albumin (BSA). This disialylgalactose glycoconjugate (DSG-BSA) binds anti-GQ1b antibodies in 32/58 (55%) human sera containing IgG or IgM anti-GQ1b antibodies at titres up to 1/130 000; it also binds a wide range of mouse monoclonal anti-GQ1b and -GD3 antibodies. When conjugated to Sepharose as mock therapeutic immmunoaffinity columns, the immobilized trisaccharide (DSG-Sepharose) eliminates anti-GQ1b antibodies from positive sera in proportion to their level of binding to DSG-BSA. Oligosaccharide-specific immunoadsorption therapy thus provides a new therapeutic approach to anti-GQ1b antibody-associated syndromes that could be applied to clinical practice. Furthermore, modification of the immobilized oligosaccharide epitopes to incorporate other glycan structures may allow this approach to be adapted to other forms of autoimmune neuropathy associated with uniform anti-glycolipid antibody profiles.

The effect of comorbid conditions on hemodialysis access patency.

Vascular access complications are a continuing source of hospitalization and morbidity in chronic dialysis patients. Several factors have been identified that are associated with complications in patients with native vein and prosthetic bridge arteriovenous graft fistulas. Early failure of native vein arteriovenous fistulas most consistently are related to small blood vessels. It remains unclear whether other comorbid factors play a role in complications of this fistula type. Prosthetic bridge fistulas are frequently placed in the United States and are associated with frequent complications. Factors most consistently associated with higher complication rates are diabetes mellitus, older age, and black race. Antiphospholipid antibody-associated syndromes and erythropoietin therapy have also been suggested as contributing factors. In addition, elevated lipoprotein(a) and hypoalbuminemia have been found to be associated with an increase of prosthetic graft thrombosis in white and Hispanic dialysis patients. This information strongly suggests that fistula complications are multifactorial. An improved understanding of the mechanisms of these associations may aid in the delineation of the pathogenesis and an improvement in the outcome of this important problem.

Immunologic renal injury.

This review summarizes recent progress in the immunologic aspects of parenchymal renal disease. Progress in understanding basic immune mechanisms of glomerular injury is outlined, including the roles of chemoattractants, adhesion molecules, metalloproteinases, and cytokines. Current basic and clinical studies of focal segmental glomerulosclerosis, membranous nephropathy, membranoproliferative glomerulonephritis, minimal-change nephropathy, and IgA nephropathy are summarized. Finally, research in glomerular involvement in systemic disorders, such as lupus nephritis, antineutrophil cytoplasmic antibody-associated syndromes, and human immunodeficiency virus-associated nephropathy, is reviewed.