Search

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.

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.

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.

Background and Aims Recently a number of antigens have been identified as pathogenic antibody targets in cases of primary membranous glomerulonephritis(MGN), including phospholipase A2 receptor (PLA2R), thrombospondin type 1 domain containing 7A(THSD7A), and NELL-1, while exostosin is found in secondary (lupus associated) MGN. However, other as yet undiscovered antigens are thought to exist. Although rare, there is a recognised association between chronic inflammatory demyelinating polyneuriopathy (CIDP) and nephrotic syndrome. Method We investigated the link between CICP and MGN and the associations with Contactin-1(CNTN1), a node of Ranvier neuronal protein, as a potential common autoantigen, by immunohistochemistry, RT-PCR and proteomic analysis of isolated glomeruli. We tested sera from 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 210 disease controls, for CNTN1 antibodies. Results We describe a series of 16 patients, all presenting with CIDP, nephrotic syndrome due to MGN, and with circulating and deposited anti-contactin-1 (CNTN1) antibodies (IgG4 predominant in those tested) in the kidney. The onset and resolution of both disorders had a close temporal relationship, and the majority of cases were resistant to first-line therapies typically employed for inflammatory neuropathies, but achieved a good outcome with non-standard treatment. Importantly, four (1.4%) further patients with isolated MGN identified from a serum bank of 295 idiopathic MGN patients with no CIDP were also positive for anti-CNTN1 antibodies. CNTN1 protein was detected by mass spectroscopy within glomeruli from patients with CNTN1 antibodies, but not in healthy kidney or anti-PLA2R associated MGN. CNTN1 mRNA was found in renal cortical tissue. Conclusion These data provide evidence that CNTN1 antibodies precipitate both autoimmune neuropathy and MGN. The temporal correlation of these disorders, as well as the presence of CNTN1 protein and antibodies in both peripheral nerve and diseased glomeruli, supports a common antibody-mediated pathological process, and defines a new antigenic target in MGN. CNTN1 antibodies have diagnostic and therapeutic relevance, and may additionally serve as a means of monitoring disease activity in both conditions. Other factors may explain presentation with isolated neurological disease or MGN.

ObjectivesWe aimed to define the clinical and serological characteristics of pan-neurofascin antibody-positive patients.MethodsWe 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.ResultsEight 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.ConclusionsIgG1 pan-neurofascin antibodies define a very severe autoimmune neuropathy. We urgently recommend trials of targeted immunotherapy for this serologically classified patient group.

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.

ObjectivePOEMS 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.MethodsThis 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.ResultsOne 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.ConclusionsPOEMS 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.

BackgroundReports 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.MethodsThe epidemiology of GBS cases reported via the UK National Immunoglobulin Database were studied from 2016-2019 and compared to cases reported during the COVID-19 pandemic. For the cohort study, members of the British Peripheral Nerve Society reported all cases of GBS during the pandemic. The clinical features, investigation findings and outcomes of COVID-19 (definite or probable) and non-COVID-19 associated GBS cases were compared.ResultsThe UK GBS incidence from 2016-2019 was 1.65-1.88 per 100,000 people per year. GBS and COVID-19 incidence varied between regions and did not correlate (r = 0.06, 95% CI −0.56 to 0.63, p=0.86). GBS incidence fell between March and May 2020 compared to the same months of 2016-2019. Forty-seven GBS cases were included in the cohort study (13 definite, 12 probable COVID-19 and 22 non-COVID-19). There were no significant differences in the pattern of weakness, time to nadir, neurophysiology, CSF findings or outcome. Intubation was more frequent in the COVID-19+ve cohort (7/13, 54% vs 5/22, 23% in COVID negative) thought to be related directly to COVID-19 pulmonary involvement.ConclusionsThis 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.

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-Barr&eacute, 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&rsquo, 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.

Background: There is an established association between acquired inflammatory demyelinating neuropathies and nephrotic syndrome, but a common immunopathological mechanism has yet to be determined. Antibodies to known glomerular podocyte antigens occur in up to 90% of patients with nephrotic syndrome due to idiopathic membranous glomerulonephritis (MGN), the majority targeting the phospholipase A2 receptor (PLA2R). In patients with immune-mediated neuropathies, antibodies targeting molecules of the node of Ranvier, such as contactin-1 (CNTN1), are increasingly recognised. Methods: In this study, sera from 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 210 disease controls, were tested for CNTN1 antibodies. Topographical binding patterns were determined using teased nerve fibres and live myelinated nerve co-cultures. CNTN1 expression in human kidney was characterised by immunohistochemistry, western blotting and PCR. Findings: A total of 16 patients with an immune-mediated neuropathy and MGN were seropositive for IgG4 anti-CNTN1 antibodies. The onset and resolution of both disorders had a close temporal relationship. The majority of cases were resistant to first-line therapies typically employed for inflammatory neuropathies, but achieved a good outcome with non-standard treatment. Four further patients with isolated MGN were also positive for the same antibodies at lower titres. CNTN1 protein was detected within glomerular deposits in biopsies from patients with CNTN1 antibodies, but not in healthy kidney or anti-PLA2R associated MGN. Interpretation: These data provide evidence that CNTN1 antibodies precipitate both autoimmune neuropathy and MGN. The temporal correlation of these disorders, as well as the presence of CNTN1 protein and antibodies in both peripheral nerve and diseased glomeruli, supports a common antibody-mediated pathological process, and defines a new antigenic target in MGN. CNTN1 antibodies have diagnostic and therapeutic relevance, and may additionally serve as a means of monitoring disease activity in both conditions. Funding Statement: Medical Research Council (MRC), GBS/CIDP Foundation International, MRC and Kidney Research UK. Declaration of Interests: SR runs a not-for-profit diagnostic testing service for nodal/paranodal antibodies. He has received a speaker’s honorarium and/or travel expenses from Fresenius Medical Care, Excemed, Alnylam and argenx. AR has received honoraria from Sarepta, Roche and Sanofi Aventis, is a member of MND Association Clinical Advisory Board, and was a member of NICE MND Guideline Development Group. ASC receives funding from NIHR University College London Hospitals Biomedical research centre. AM is a clinical fellow with grant reference number MR/P001777/1. SPi is was funded by a grant from the Karolinska Institutet during the course of the study. All other authors have nothing to declare. Ethics Approval Statement: Research Ethics Committee approval number 14/SC/0280

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.

ObjectiveAntibodies 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.MethodsUsing 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.ResultsWe 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.ConclusionsMyeloradiculitis, 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.

A 72-year-old man with type 2 diabetes mellitus was admitted under nephrology with malaise. He was diagnosed with acute kidney injury secondary to urinary retention and hydronephrosis. Over 10 days during this admission he developed progressive symmetrical limb paraesthesia and weakness with areflexia.Neurophysiological studies demonstrated a severe demyelinating polyneuropathy with widespread motor slowing and prolonged distal motor latencies. CSF was acellular with a protein of 5.9 g/L. He was treated with IV immunoglobulins and stabilised for 2 weeks. He then deteriorated over the next four weeks despite IV methylprednisolone, oral corticosteroids and 5 cycles of plasma exchange. He had profound limb weakness (0/5) and required ventilation. He had hypoalbuminaemia, with 1.5 g proteinuria consistent with a nephrotic syndrome.We phoned a friend.IgG4 anti–contactin-1 (CNTN1) antibodies were identified in serum with a CNTN1 at 1:1600.He received 4 cycles of Rituximab. After 6 weeks he was off ventilation with grade 4 power in both arms.Recently autoantibodies against node of Ranvier proteins have emerged in a subset of patients with CIDP. These patients have a homogenous clinical phenotype with an aggressive polyneuropathy, proteinuria and poor response to conventional therapy, but seem to respond to other agents, including Rituximab and Cyclophosphamide.

A 51-year-old right-handed man developed a sensory neuropathy with the sensation of walking on pebbles, and tight cramping pains in the calves requiring amitriptyline. Two months later, he became unsteady with difficulty walking downstairs necessitating a stick, with associated fatigue and weight loss of half a stone. He had a history of haemophilia type A and liver cirrhosis from hepatitis C, contracted through the transfusion of blood products in the 1980s. On examination, there was evidence of a distal symmetrical sensorimotor polyneuropathy with Medical Research Council (MRC) power grade 4+/5 in the intrinsic hand muscles and 0/5 in ankle plantar and dorsiflexion. Supinator, knee and ankle deep tendon reflexes were all absent, with mute plantar responses. He had a loss of pinprick sensation to the knees, vibration loss to the costal margins and temperature perception was altered to the mid-thighs. There was dusky pigmentation of the skin and peripheral oedema in the lower limbs. His history and examination findings are typical of a distal symmetrical neuropathy (see box 1 for the differential diagnosis of a painful large fibre neuropathy). Serological workup for a neuropathy should include full blood count, B12, folate, erythrocyte sedimentation rate (ESR), glucose, thyroid function, a serum protein electrophoresis and immunofixation, and possibly an antinuclear antibody. Note that it is typical for hospital laboratories only to perform serum immunofixation if the serum protein electrophoresis is abnormal. The greater sensitivity of immunofixation may find low-level paraproteins that would be otherwise undetectable, and which may be highly relevant in the context of neuropathy. He also has a history of hepatitis C which is associated with cryoglobulinaemia and cryoglobulinaemic peripheral nerve vasculitis, and therefore an important differential. Constitutional symptoms, including weight loss, are uncommon in isolated peripheral neuropathy, and therefore systemic causes should be considered, including vasculitis, malignancies, metabolic (diabetes), …

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.

An MRI spine may be requested for the investigation of an acutely weak leg, but it is not just the cord and exiting nerve roots that one should look at. We report an unusual case of a 41 year old gentleman with a spontaneous iliacus haematoma causing a compressive femoral neuropathy, as a first presentation of Haemophilia B (Factor IX deficiency). He presented with acute right groin pain followed closely by right lower limb weakness and sensory disturbance. He had a history of sciatica and a lumbar microdiscectomy 13 years earlier but no personal or family history of abnormal bleeding. Examination revealed sensorimotor disturbance in the right leg consistent with a femoral mono-neuropathy, with exacerbation of pain in hip extension. Initial lumbosacral MRI, performed for nerve root entrapment, did not reveal a cause for the patient9s symptoms. It was only on further review of the surrounding pelvic structures on the MRI that a haematoma was detected. Abnormal coagulation studies led to a diagnosis of factor IX deficiency. He was managed conservatively with replacement of his clotting factors and physiotherapy. This case nicely illustrates the wide differential diagnosis in an acute mononeuropathy.

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.