Contactin-1 links autoimmune neuropathy and membranous glomerulonephritis.

Membranous glomerulonephritis (MGN) is a common cause of nephrotic syndrome in adults, mediated by glomerular antibody deposition to an increasing number of newly recognised antigens. Previous case reports have suggested an association between patients with anti-contactin-1 (CNTN1)-mediated neuropathies and MGN. In an observational study we investigated the pathobiology and extent of this potential cause of MGN by examining the association of antibodies against CNTN1 with the clinical features of a cohort of 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 256 controls. Neuronal and glomerular binding of patient IgG, serum CNTN1 antibody and protein levels, as well as immune-complex deposition were determined. We identified 15 patients with immune-mediated neuropathy and concurrent nephrotic syndrome (biopsy proven MGN in 12/12), and 4 patients with isolated MGN from an idiopathic MGN cohort, all seropositive for IgG4 CNTN1 antibodies. CNTN1-containing immune complexes were found in the renal glomeruli of patients with CNTN1 antibodies, but not in control kidneys. CNTN1 peptides were identified in glomeruli by mass spectroscopy. CNTN1 seropositive patients were largely resistant to first-line neuropathy treatments but achieved a good outcome with escalation therapies. Neurological and renal function improved in parallel with suppressed antibody titres. The reason for isolated MGN without clinical neuropathy is unclear. We show that CNTN1, found in peripheral nerves and kidney glomeruli, is a common target for autoantibody-mediated pathology and may account for between 1 and 2% of idiopathic MGN cases. Greater awareness of this cross-system syndrome should facilitate earlier diagnosis and more timely use of effective treatment.

Antineurofascin IgG2-associated paediatric autoimmune nodopathy.

In this case series of four paediatric patients, we present the first described cases of immunotherapy-responsive autoimmune nodopathy with IgG2 antineurofascin antibodies. In three cases, the antineurofascin antibodies were predominantly of the IgG2 subclass, a novel finding in comparison to previously described adult cases where IgG4 and/or IgG1/3 have typically been described. One patient had low signal for IgG2 with predominant IgG1 and IgG4 antibodies, a pattern commonly seen in adult patients. Two patients had antibodies targeting all three neurofascin isoforms (155, 186, and 140), whereas antibodies in the sera from the third targeted only the nodal isoforms 186 and 140, and the fourth patient only neurofascin 155. The three patients with IgG2 predominant antibodies appear to be responsive to intravenous immunoglobulin (IVIG) to varying degrees thus far, whereas the patient with IgG1/4 antibodies had poor response to IVIG but good response to steroids. Although the full clinical significance of IgG2 predominant antineurofascin antibodies in the context of childhood polyneuropathy remains unclear, emerging evidence of serological-phenotypic correlation may inform prognostication and therapeutic decision-making, warranting further study into this area. WHAT THIS PAPER ADDS: Paediatric immunotherapy-responsive nodopathies were associated with antineurofascin antibodies predominantly of the IgG2 subclass in 3 out of 4 patients. Identification of antibodies and understanding their phenotypic relevance could predict response to treatment and guide therapeutic decision-making in children.

Treatment of CIDP.

Chronic inflammatory demyelinating polyneuropathy is a disabling but treatable disorder. However, misdiagnosis is common, and it can be difficult to optimise its treatment. Various agents are used both for first and second line. First-line options are intravenous immunoglobulin, corticosteroids and plasma exchange. Second-line therapies may be introduced as steroid-sparing agents or as more potent escalation therapy. It is also important to consider symptomatic treatment of neuropathic pain and non-pharmacological interventions. We discuss the evidence for the various treatments and explain the practicalities of the different approaches. We also outline strategies for monitoring response and assessing the ongoing need for therapy.

An International Perspective on Preceding Infections in Guillain-Barré Syndrome: The IGOS-1000 Cohort.

BACKGROUND AND OBJECTIVES: Infections play a key role in the development of Guillain-Barré syndrome (GBS) and have been associated with specific clinical features and disease severity. The clinical variation of GBS across geographical regions has been suggested to be related to differences in the distribution of preceding infections, but this has not been studied on a large scale. METHODS: We analyzed the first 1,000 patients included in the International GBS Outcome Study with available biosamples (n = 768) for the presence of a recent infection with Campylobacter jejuni, hepatitis E virus, Mycoplasma pneumoniae, cytomegalovirus, and Epstein-Barr virus. RESULTS: Serologic evidence of a recent infection with C. jejuni was found in 228 (30%), M. pneumoniae in 77 (10%), hepatitis E virus in 23 (3%), cytomegalovirus in 30 (4%), and Epstein-Barr virus in 7 (1%) patients. Evidence of more than 1 recent infection was found in 49 (6%) of these patients. Symptoms of antecedent infections were reported in 556 patients (72%), and this proportion did not significantly differ between those testing positive or negative for a recent infection. The proportions of infections were similar across continents. The sensorimotor variant and the demyelinating electrophysiologic subtype were most frequent across all infection groups, although proportions were significantly higher in patients with a cytomegalovirus and significantly lower in those with a C. jejuni infection. C. jejuni-positive patients were more severely affected, indicated by a lower Medical Research Council sum score at nadir (p = 0.004) and a longer time to regain the ability to walk independently (p = 0.005). The pure motor variant and axonal electrophysiologic subtype were more frequent in Asian compared with American or European C. jejuni-positive patients (p < 0.001, resp. p = 0.001). Time to nadir was longer in the cytomegalovirus-positive patients (p = 0.004). DISCUSSION: Across geographical regions, the distribution of infections was similar, but the association between infection and clinical phenotype differed. A mismatch between symptom reporting and serologic results and the high frequency of coinfections demonstrate the importance of broad serologic testing in identifying the most likely infectious trigger. The association between infections and outcome indicates their value for future prognostic models.

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.

IgG1 pan-neurofascin antibodies identify a severe yet treatable neuropathy with a high mortality.

OBJECTIVES: We aimed to define the clinical and serological characteristics of pan-neurofascin antibody-positive patients. METHODS: We tested serum from patients with suspected immune-mediated neuropathies for antibodies directed against nodal/paranodal protein antigens using a live cell-based assay and solid-phase platform. The clinical and serological characteristics of antibody-positive and seronegative patients were then compared. Sera positive for pan-neurofascin were also tested against live myelinated human stem cell-derived sensory neurons for antibody binding. RESULTS: Eight patients with IgG1-subclass antibodies directed against both isoforms of the nodal/paranodal cell adhesion molecule neurofascin were identified. All developed rapidly progressive tetraplegia. Cranial nerve deficits (100% vs 26%), autonomic dysfunction (75% vs 13%) and respiratory involvement (88% vs 14%) were more common than in seronegative patients. Four patients died despite treatment with one or more modalities of standard immunotherapy (intravenous immunoglobulin, steroids and/or plasmapheresis), whereas the four patients who later went on to receive the B cell-depleting therapy rituximab then began to show progressive functional improvements within weeks, became seronegative and ultimately became functionally independent. CONCLUSIONS: IgG1 pan-neurofascin antibodies define a very severe autoimmune neuropathy. We urgently recommend trials of targeted immunotherapy for this serologically classified patient group.

Serum Contactin-1 in CIDP: A Cross-Sectional Study.

OBJECTIVE: To investigate whether serum levels of contactin-1, a paranodal protein, correlate with paranodal injury as seen in patients with CIDP with antibodies targeting the paranodal region. METHODS: Serum contactin-1 levels were measured in 187 patients with CIDP and 222 healthy controls. Paranodal antibodies were investigated in all patients. RESULTS: Serum contactin-1 levels were lower in patients (N = 41) with paranodal antibodies compared with patients (N = 146) without paranodal antibodies (p < 0.01) and showed good discrimination between these groups (area under the curve 0.84; 95% CI: 0.76-0.93). CONCLUSIONS: These findings suggest that serum contactin-1 levels have the potential to serve as a possible diagnostic biomarker of paranodal injury in CIDP. CLASSIFICATION OF EVIDENCE: This study provides class II evidence that serum contactin-1 levels can discriminate between patients with CIDP with or without paranodal antibodies with a sensitivity of 71% (95% CI: 56%-85%) and a specificity of 97% (95% CI: 83%-100%).

Nodal and paranodal antibody-associated neuropathies.

Within the last decade, antibodies targeting the node and paranode of myelinated peripheral nerves have been increasingly identified in patients with acquired immune-mediated neuropathies, commonly termed 'nodo-paranodopathies'. Crucially, these patients often present with additional clinical features not usually seen with the most common immune-mediated neuropathies, Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy, and respond poorly to conventionally used immunomodulatory therapies. Emerging evidence that these are pathologically distinct diseases has further prompted the use of more targeted treatment, such as the B cell depleting monoclonal antibody rituximab, which has been reported to significantly improve functional outcomes in this subset of patients. We provide an overview of the emerging clinical and serological phenotypes in patients with specific nodal/paranodal antibodies, the practicalities of antibody testing and current evidence supporting the use of non-standard therapies.

Antibodies to the Caspr1/contactin-1 complex in chronic inflammatory demyelinating polyradiculoneuropathy.

Previous studies have described the clinical, serological and pathological features of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and antibodies directed against the paranodal proteins neurofascin-155, contactin-1 (CNTN1), contactin-associated protein-1 (Caspr1), or nodal forms of neurofascin. Such antibodies are useful for diagnosis and potentially treatment selection. However, antibodies targeting Caspr1 only or the Caspr1/CNTN1 complex have been reported in few patients with CIDP. Moreover, it is unclear if these patients belong to the same pathophysiological subgroup. Using cell-based assays in routine clinical testing, we identified sera from patients with CIDP showing strong membrane reactivity when both CNTN1 and Caspr1 were co-transfected (but not when CNTN1 was transfected alone). Fifteen patients (10 male; aged between 40 and 75) with antibodies targeting Caspr1/CNTN1 co-transfected cells were enrolled for characterization. The prevalence of anti-Caspr1/CNTN1 antibodies was 1.9% (1/52) in the Sant Pau CIDP cohort, and 4.3% (1/23) in a German cohort of acute-onset CIDP. All patients fulfilled European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite diagnostic criteria for CIDP. Seven (47%) were initially diagnosed with Guillain-Barré syndrome due to an acute-subacute onset. Six (40%) patients had cranial nerve involvement, eight (53%) reported neuropathic pain and 12 (80%) ataxia. Axonal involvement and acute denervation were frequent in electrophysiological studies. Complete response to intravenous immunoglobulin was not observed, while most (90%) responded well to rituximab. Enzyme-linked immunosorbent assay (ELISA) and teased nerve fibre immunohistochemistry confirmed reactivity against the paranodal Caspr1/CNTN1 complex. Weaker reactivity against Caspr1 transfected alone was also detected in 10/15 (67%). Sera from 13 of these patients were available for testing by ELISA. All 13 samples reacted against Caspr1 by ELISA and this reactivity was enhanced when CNTN1 was added to the Caspr1 ELISA. IgG subclasses were also investigated by ELISA. IgG4 was the predominant subclass in 10 patients, while IgG3 was predominant in other three patients. In conclusion, patients with antibodies to the Caspr1/CNTN1 complex display similar serological and clinical features and constitute a single subgroup within the CIDP syndrome. These antibodies likely target Caspr1 primarily and are detected with Caspr1-only ELISA, but reactivity is optimal when CNTN1 is added to Caspr1 in cell-based assays and ELISA.

Overlapping central and peripheral nervous system syndromes in MOG antibody-associated disorders.

OBJECTIVE: Antibodies to myelin oligodendrocyte glycoprotein (MOG) are associated with CNS demyelination inclusive of optic neuritis (ON) and transverse myelitis (TM). To examine whether peripheral nervous system (PNS) involvement is associated with MOG antibody-associated disorders (MOGAD), we performed detailed characterization of an Australasian MOGAD cohort. METHODS: Using a live cell-based assay, we diagnosed 271 adults with MOGAD (2013-2018) and performed detailed clinical and immunologic characterization on those with likely PNS involvement. RESULTS: We identified 19 adults with MOGAD and PNS involvement without prior TM. All patients had CNS involvement including ON (bilateral [n = 3], unilateral [n = 3], and recurrent [n = 7]), a cortical lesion (n = 1), meningoencephalitis (n = 1), and subsequent TM (n = 4). Clinical phenotyping and neurophysiology were consistent with acute inflammatory demyelinating polyneuropathy (n = 1), myeloradiculitis (n = 3), multifocal motor neuropathy (n = 1), brachial neuritis (n = 2), migrant sensory neuritis (n = 3), and paresthesia and/or radicular limb pain (n = 10). Onset MRI spine was consistent with myeloradiculitis with nerve root enhancement in 3/19 and normal in 16/19. Immunotherapy resulted in partial/complete PNS symptom resolution in 12/15 (80%) (steroids and/or IV immunoglobulin n = 9, rituximab n = 2, and plasmapheresis n = 1). We identified serum antibodies targeting neurofascin 155, contactin-associated protein 2, or GM1 in 4/16 patients with MOGAD PNS compared with 0/30 controls (p = 0.01). There was no binding to novel cell surface antigens using an in vitro myelinating sensory neuronal coculture model. CONCLUSIONS: Myeloradiculitis, combined central and peripheral demyelination syndromes, and inflammatory neuropathies may be associated with MOGAD and may be immunotherapy responsive. We identified a subgroup who may have pathology mediated by coexistent autoantibodies.

Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome.

Reports of Guillain-Barré syndrome (GBS) have emerged during the Coronavirus disease 2019 (COVID-19) pandemic. This epidemiological and cohort study sought to investigate any causative association between COVID-19 infection and GBS. The epidemiology of GBS cases reported to the UK National Immunoglobulin Database was studied from 2016 to 2019 and compared to cases reported during the COVID-19 pandemic. Data were stratified by hospital trust and region, with numbers of reported cases per month. UK population data for COVID-19 infection were collated from UK public health bodies. In parallel, but separately, members of the British Peripheral Nerve Society prospectively reported incident cases of GBS during the pandemic at their hospitals to a central register. The clinical features, investigation findings and outcomes of COVID-19 (definite or probable) and non-COVID-19 associated GBS cases in this cohort were compared. The incidence of GBS treated in UK hospitals from 2016 to 2019 was 1.65-1.88 per 100 000 individuals per year. GBS incidence fell between March and May 2020 compared to the same months of 2016-19. GBS and COVID-19 incidences during the pandemic also varied between regions and did not correlate with one another (r = 0.06, 95% confidence interval: -0.56 to 0.63, P = 0.86). In the independent cohort study, 47 GBS cases were reported (COVID-19 status: 13 definite, 12 probable, 22 non-COVID-19). There were no significant differences in the pattern of weakness, time to nadir, neurophysiology, CSF findings or outcome between these groups. Intubation was more frequent in the COVID-19 affected cohort (7/13, 54% versus 5/22, 23% in COVID-19-negative) attributed to COVID-19 pulmonary involvement. Although it is not possible to entirely rule out the possibility of a link, this study finds no epidemiological or phenotypic clues of SARS-CoV-2 being causative of GBS. GBS incidence has fallen during the pandemic, which may be the influence of lockdown measures reducing transmission of GBS inducing pathogens such as Campylobacter jejuni and respiratory viruses.

Clinical characteristics, risk factors, and outcomes of POEMS syndrome: A longitudinal cohort study.

OBJECTIVE: POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin lesions) is a paraneoplastic disorder resulting in severe neurologic disability. Understanding the clinical, laboratory, neurophysiologic, and histopathologic features as well as treatment responses of POEMS will assist in more accurate and timely diagnosis, risk stratification, and effective management. METHODS: This was a retrospective longitudinal cohort study from 1998 to March 2019, with 7,184 person-months of follow-up time. Hospital databases were used to collate presenting features, investigations, therapies, and response. RESULTS: One hundred patients were included with a median follow-up time of 59 months (range, 1-252). Mean symptom onset to diagnosis was 15 months (range, 1-77), with 54% of patients initially misdiagnosed with chronic inflammatory demyelinating polyneuropathy. Median number of multisystem features at diagnosis was 7. Ninety-six (96%) presented with neuropathy, which was length-dependent in 93 (93%) and painful in 75 (75%). At diagnosis, 35% of patients were wheelchair or bedbound, with median Overall Neuropathy Limitation Score of 6, improving to 3 following treatment (p < 0.05). Five-year survival was 90% and 82% at 10 years, with 5- and 10-year progression-free survival of 65% and 53%. Nontreatment with autologous stem cell transplantation, nonhematologic response, and non-vascular endothelial growth factor response are significant risk factors in multivariate analysis to predict progression or death. Risk factors are incorporated to develop a risk score enabling stratification of high- and low-risk cases. CONCLUSIONS: POEMS syndrome is a rare multisystem condition with delayed diagnosis and poor neurologic function at presentation. Therapy has favorable outcomes. Patients at high risk of death or progression can be identified, which may allow for more active monitoring and influence management.

Immunoadsorption and Plasma Exchange in Seropositive and Seronegative Immune-Mediated Neuropathies.

The inflammatory neuropathies are disabling conditions with diverse immunological mechanisms. In some, a pathogenic role for immunoglobulin G (IgG)-class autoantibodies is increasingly appreciated, and immunoadsorption (IA) may therefore be a useful therapeutic option. We reviewed the use of and response to IA or plasma exchange (PLEx) in a cohort of 41 patients with nodal/paranodal antibodies identified from a total of 573 individuals with suspected inflammatory neuropathies during the course of routine diagnostic testing (PNAb cohort). 20 patients had been treated with PLEx and 4 with IA. Following a global but subjective evaluation by their treating clinicians, none of these patients were judged to have had a good response to either of these treatment modalities. Sequential serology of one PNAb+ case suggests prolonged suppression of antibody levels with frequent apheresis cycles or adjuvant therapies, may be required for effective treatment. We further retrospectively evaluated the serological status of 40 patients with either Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP), and a control group of 20 patients with clinically-isolated syndrome/multiple sclerosis (CIS/MS), who had all been treated with IgG-depleting IA (IA cohort). 32 of these patients (8/20 with CIDP, 13/20 with GBS, 11/20 with MS) were judged responsive to apheresis despite none of the serum samples from this cohort testing positive for IgG antibodies against glycolipids or nodal/paranodal cell-adhesion molecules. Although negative on antigen specific assays, three patients' pre-treatment sera and eluates were reactive against different components of myelinating co-cultures. In summary, preliminary evidence suggests that GBS/CIDP patients without detectable IgG antibodies on routine diagnostic tests may nevertheless benefit from IA, and that an unbiased screening approach using myelinating co-cultures may assist in the detection of further autoantibodies which remain to be identified in such patients.

A rare case of Miller Fisher variant of Guillain-Barré Syndrome (GBS) induced by a checkpoint inhibitor.

With the recent development of novel, more potent cancer treatment, in particular, immune 'checkpoint inhibitors', cases of neurological immune-related adverse events are on the rise. Although rare, this includes Guillain-Barré Syndrome (GBS). We present the case of a 68-year-old male who was admitted with sudden onset of worsening neurological symptoms following immunotherapy treatment. These symptoms progressed quickly to respiratory failure requiring intubation and admission to the intensive care unit. He was thoroughly investigated and is believed to have an axonal neuropathy in the form of Miller Fisher Syndrome (MFS) variant of GBS, secondary to immunotherapy treatment. He was initially treated with intravenous immunoglobulin, and later, perhaps more effectively, with high dose steroids which significantly improved his symptoms. This case of checkpoint inhibitor-induced MFS is one of few in the literature and is an important reminder of the potential for new immunotherapeutic agents to cause significant neurotoxic effects. These should be promptly and thoroughly investigated, in particular, as the management of these patients can differ from standard treatments used in these conditions.

Nodes, paranodes and neuropathies.

This review summarises recent evidence supporting the involvement of the specialised nodal and perinodal domains (the paranode and juxtaparanode) of myelinated axons in the pathology of acquired, inflammatory, peripheral neuropathies.The identification of new target antigens in the inflammatory neuropathies heralds a revolution in diagnosis, and has already begun to inform increasingly targeted and individualised therapies. Rapid progress in our basic understanding of the highly specialised nodal regions of peripheral nerves serves to strengthen the links between their unique microstructural identities, functions and pathologies. In this context, the detection of autoantibodies directed against nodal and perinodal targets is likely to be of increasing clinical importance. Antiganglioside antibodies have long been used in clinical practice as diagnostic serum biomarkers, and associate with specific clinical variants but not to the common forms of either acute or chronic demyelinating autoimmune neuropathy. It is now apparent that antibodies directed against several region-specific cell adhesion molecules, including neurofascin, contactin and contactin-associated protein, can be linked to phenotypically distinct peripheral neuropathies. Importantly, the immunological characteristics of these antibodies facilitate the prediction of treatment responsiveness.

Tumefactive demyelination presenting during bevacizumab treatment.

We report the emergence of tumefactive demyelination during treatment with intravitreal bevacizumab (Avastin). This is of particular significance given that bevacizumab is currently being assessed as a potential treatment option for neuromyelitis optica, another demyelinating condition.

Out of hours intravenous fluid therapy: a prompt to guide prescribing.

Recent NICE guidance has highlighted the importance of appropriate and safe intravenous fluid use. We aimed to improve the quality of out of hours fluid prescription in a Bristol hospital by ensuring that indications and cautions for fluid therapy were clearly documented at the time of initiation. Time-pressured on-call doctors need quick access to information regarding patients' care. A documented "fluid plan" allows doctors to undertake a more informed assessment of the patient's fluid balance, leading to safer prescriptions. Our ideal was for 100% of out of hours intravenous fluid prescriptions to be appropriate. Our process measures included the proportion of patients on intravenous fluids who had a documented fluid plan in the medical notes or on the prescription chart on Friday, prior to the weekend on call period. This was defined as mention of indications and/or cautions to fluid therapy. The introduction of a sticker to prompt fluid plan documentation did marginally improve use of fluid plans. It was notable that 96% of these were followed where plans were documented (n=23). Initiation of IV fluid with an accompanying plan is likely to make subsequent fluid prescriptions safer. Rapid turnover of staff and stationary proved significant barriers to consistent implementation of the sticker. Despite these challenges we demonstrated a "proof of concept", suggesting system modification to include fluid plans is safe and effective.

Long-term survival of neonatal mitochondrial complex III deficiency associated with a novel BCS1L gene mutation.

Mutations of the BCS1L gene are a recognised cause of isolated respiratory chain complex III deficiency and underlie several fatal, neonatal mitochondrial diseases. Here we describe a 20-year-old Kenyan woman who initially presented as a floppy infant but whose condition progressed during childhood and adolescence with increasing muscle weakness, focal motor seizures and optic atrophy. Muscle biopsy demonstrated complex III deficiency and the pathogenicity of a novel, homozygous BCS1L mutation was confirmed by yeast complementation studies. Our data indicate that BCS1L mutations can cause a variable, neurological course which is not always fatal in childhood.