Autoimmune nodo-paranodopathies 10 years later: Clinical features,pathophysiology and treatment

Background and Aims

Autoimmune neuropathies are classified, on the basis of pathophysiology, as demyelinating or axonal. The term nodo-paranodopathy, introduced in 2013 to better categorize the neuropathies with antiganglioside antibodies and later expanded to include neuropathies with antibodies to nodal and paranodal axoglial complexes, characterizes disorders in which the nodal region is critical in the pathogenesis. These neuropathies, although presenting electrophysiologic demyelinating features do not show pathologic evidence of segmental demyelination, or, although being classified as axonal, can show reversible nerve conduction failure and rapid recovery contrary with the communal concept of an axonal neuropathy.

Methods

In this personal view is reported, with a splitting approach, an update on autoimmune nodo-paranodopathies, classified according to the domains of peripheral nerve fiber, the target antigens and the antibody class and subclass involved. The clinical features, the electrophysiologic findings, the results of the immunopathological and ultrastructural studies, the pathophysiology and treatment are also described.

Results and Interpretation

The nodo-paranodopathy category integrates the clinical classification of autoimmune neuropathies and expands the traditional dichotomous demyelinating and axonal classification. It helps to a better systematization pointing to the domain and target antigens of the autoimmune process, it resolves conflicting pathologic and electrophysiologic findings, reconciles the contradiction that axonal neuropathies may be rapidly reversible, avoids taxonomical confusion and possible misdiagnoses. Finally this categorization, through the identification of the specific antibody and its prevalent class and subclass, clarifies the pathophysiological mechanisms and addresses to a more targeted therapeutic approach.     

Caspr1 antibodies autoimmune paranodopathy with severe tetraparesis: Potential relevance of antibody titers in monitoring treatment response

Aim

Nodopathies and paranodopathies are autoimmune neuropathies associated with antibodies to nodal–paranodal antigens (neurofascin 140/186 and 155, contactin-1, contactin-associated protein 1 [Caspr1]) characterized by peculiar clinical features, poor response to standard immunotherapies (e.g., intravenous immunoglobulins, IVIg). Improvement after anti-CD20 monoclonal antibody therapy has been reported. Data on Caspr1 antibodies pathogenicity are still preliminary, and longitudinal titers have been poorly described.

Methods

We report on a young woman who developed a disabling neuropathy with antibodies to the Caspr1/contactin-1 complex showing a dramatic improvement after rituximab therapy, mirrored by the decrease of antibody titers.

Results

A 26-year-old woman presented with ataxic-stepping gait, severe motor weakness at four limbs, and low frequency postural tremor. For neurophysiological evidence of demyelinating neuropathy, she was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy and treated with IVIg without benefit. MRI showed symmetrical hypertrophy and marked signal hyperintensity of brachial and lumbosacral plexi. Cerebrospinal fluid showed 710 mg/dL protein. Despite intravenous methylprednisolone, the patient progressively worsened, and became wheelchair-bound. Antibodies to nodal–paranodal antigens were searched for by ELISA and cell-based assay. Anticontactin/Caspr1 IgG4 antibodies resulted positive. The patient underwent rituximab therapy with slow progressive improvement that mirrored the antibodies titer, measured throughout the disease course.

Conclusions

Our patient had a severe progressive course with early disability and axonal damage, and slow recovery starting only a few months after antibody-depleting therapy. The close correlation between titer, disability, and treatment, supports the pathogenicity of Caspr1 antibodies, and suggest that their longitudinal evaluation might provide a potential biomarker to evaluate treatment response.     

The electrophysiology of axonal neuropathies: More than just evidence of axonal loss

It is common belief that axonal neuropathies are characterized by simple axonal degeneration and loss and that the electrophysiological correlates are just reduced compound muscle action potential and sensory nerve action potential amplitudes with normal or slightly slow conduction velocity. However, axonal autoimmune neuropathies with involvement of the nodal region and axonal neuropathies due to energy restriction such as occurring in nerve ischemia, thiamine deficiency, critical illness, and mitochondrial disorders present conduction failure that can be either reversible with prompt recovery or progress to axonal degeneration with poor outcome. Moreover autoimmune axonal neuropathies due to nodal voltage gated sodium channels dysfunction/disruption may show slowing of conduction velocity, even in the demyelinating range, possibly due to prolongation of the depolarization time required to reach the threshold for action potential regeneration at subsequent nodes. These observations widen the spectrum of the electrophysiological features in some axonal neuropathies, should be taken into account to avoid misdiagnoses and for correct prognostication, and should stimulate the quest of timely targeted treatments that can eventually halt the progression from conduction failure to axonal degeneration.     

Nodes of Ranvier in health and disease

Action potential propagation along myelinated axons depends on the geometry of the myelin unit and the division of the underlying axon to specialized domains. The latter include the nodes of Ranvier (NOR), the paranodal junction (PNJ) flanking the nodes, and the adjacent juxtaparanodal region that is located below the compact myelin of the internode. Each of these domains contains a unique composition of axoglial adhesion molecules (CAMs) and cytoskeletal scaffolding proteins, which together direct the placement of specific ion channels at the nodal and juxtaparanodal axolemma. In the last decade it has become increasingly clear that antibodies to some of these axoglial CAMs cause immune-mediated neuropathies. In the current review we detail the molecular composition of the NOR and adjacent membrane domains, describe the function of different CAM complexes that mediate axon-glia interactions along the myelin unit, and discuss their involvement and the underlying mechanisms taking place in peripheral nerve pathologies. This growing group of pathologies represent a new type of neuropathies termed “nodopathies” or “paranodopathies” that are characterized by unique clinical and molecular features which together reflect the mechanisms underlying the molecular assembly and maintenance of this specialized membrane domain.     

Dysfunction of nodes of Ranvier: a mechanism for anti-ganglioside antibody-mediated neuropathies

Autoantibodies against gangliosides GM1 or GD1a are associated with acute motor axonal neuropathy (AMAN) and acute motor-sensory axonal neuropathy (AMSAN), whereas antibodies to GD1b ganglioside are detected in acute sensory ataxic neuropathy (ASAN). These neuropathies have been proposed to be closely related and comprise a continuous spectrum, although the underlying mechanisms, especially for sensory nerve involvement, are still unclear. Antibodies to GM1 and GD1a have been proposed to disrupt the nodes of Ranvier in motor nerves via complement pathway. We hypothesized that the disruption of nodes of Ranvier is a common mechanism whereby various anti-ganglioside antibodies found in these neuropathies lead to nervous system dysfunction. Here, we show that the IgG monoclonal anti-GD1a/GT1b antibody injected into rat sciatic nerves caused deposition of IgG and complement products on the nodal axolemma and disrupted clusters of nodal and paranodal molecules predominantly in motor nerves, and induced early reversible motor nerve conduction block. Injection of IgG monoclonal anti-GD1b antibody induced nodal disruption predominantly in sensory nerves. In an ASAN rabbit model associated with IgG anti-GD1b antibodies, complement-mediated nodal disruption was observed predominantly in sensory nerves. In an AMAN rabbit model associated with IgG anti-GM1 antibodies, complement attack of nodes was found primarily in motor nerves, but occasionally in sensory nerves as well. Periaxonal macrophages and axonal degeneration were observed in dorsal roots from ASAN rabbits and AMAN rabbits. Thus, nodal disruption may be a common mechanism in immune-mediated neuropathies associated with autoantibodies to gangliosides GM1, GD1a, or GD1b, providing an explanation for the continuous spectrum of AMAN, AMSAN, and ASAN.     

Autoimmune neuropathies--current aspects of immunopathologic diagnostics and therapy

The group of autoimmune neuropathies includes the Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuritis, multifocal motor neuropathy, neuropathies associated with monoclonal gammopathies, and vasculitic neuropathies. This educational review first addresses diagnostic pathways that facilitate more rational diagnostic decisions. Many therapies are effective for treating immune neuropathies. Unfortunately, none of the available therapies are specific. In the acute phase, glucocorticosteroids, plasmapheresis, and intravenous immunoglobulins play key roles. The list of long-term therapies includes azathioprine, cyclosporine, cyclophosphamide, and immunoglobulins. The therapeutic mechanisms involved are not clear for most of these compounds. Modern immunotherapy has to consider medical aspects, available therapeutic evidence, and long-term economic burden.     

CIDP - the relevance of recent advances in Schwann cell/axonal neurobiology

Early pathological studies in patients with acute and chronic inflammatory demyelinating neuropathies, and the animal model experimental autoimmune neuritis (EAN) showed similarities in the process of demyelination. These studies focused on compact myelin proteins and peptides as targets of immune attack in Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and EAN. However, serological studies in patients with subsets of GBS highlighted the importance of gangliosides - glycolipids enriched in non-compact Schwann cell regions and the node, paranodal, and internodal axolemma. In the acute motor axonal neuropathy (AMAN) rabbit model, antibodies to the ganglioside GM1 bind in the nodal region, impair Na channel clustering and disturb Schwann cell/axon organisation. Schwann cell neurobiological studies now highlight the importance of adhesion molecules, including neurofascins, gliomedin, contactins, and NrCAM to Schwann cell/axon integrity. Changes to nodal fine structure by immune responses against such molecules may provide a mechanism for reversible conduction failure or block. Recovery of patients with CIDP or multifocal motor neuropathy (MMN) following treatment may sometimes be better explained by reversal of conduction failure than remyelination or regeneration. This review considers the importance of the intricate molecular arrangements at the nodal and paranodal regions in inflammatory neuropathies such as CIDP. Early images of compact myelin stripping and phagocytosis, may have diverted the research focus away from these vital non-compact myelin Schwann cell areas.     

Immune mechanisms in spontaneously occurring CIDP in NOD mice

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease affecting the peripheral nervous system (PNS) and is thought to involve both cellular and humoral immunity. Although its etiology remains to be fully elucidated, the use of animal models has provided some important information regarding its pathogenetic mechanisms. The development of a spontaneous autoimmune polyneuropathy (SAP) in B7-2 knockout non-obese diabetic (NOD) mice underscores the importance of co-stimulatory pathways such as B7-1/B7-2:CD28/CTLA-4 molecules in inflammatory neuropathies. These co-stimulatory molecules regulate the balance between pathogenic and regulatory T cells (Tregs). In SAP, pathogenic T cells are directed against myelin protein zero (P0), the most prominent PNS myelin protein that is a member of immunoglobulin gene superfamily.     

Disruption of nodal architecture in skin biopsies of patients with demyelinating neuropathies

Cutaneous nerves represent the most distal part of the sensory nervous system. We took advantage of the good discernibility of longitudinal myelinated fibers in skin biopsies to analyze the distribution of nodal and paranodal proteins in neuropathies and to assess nodal disorganization as a diagnostic marker of demyelinating neuropathy (NP). We analyzed myelinated nerve fibers in skin biopsies from the finger and the proximal leg of 52 prospectively recruited patients with different peripheral neuropathies and 17 controls. We performed immunohistochemical double labeling with anti‐MBP, anti‐PGP9.5, anti‐caspr, anti‐pan‐neurofascin, and anti‐pan‐sodium‐channel. Three potential features of demyelinating NP could be established: elongated nodes of Ranvier and dispersion of contactin‐associated protein (caspr) staining were found more often in demyelinating than in axonal neuropathies (p < 0.05) and were not detectable in normal controls. Broadening of neurofascin staining was detectable more often in demyelinating neuropathies compared with normal controls (p < 0.05). Our data suggest that pathological changes of nodal architecture can be visualized in skin biopsies and that the detection of elongated nodes of Ranvier and alterations in the distribution of paranodal proteins may be useful in the diagnostic assessment of peripheral NP.     

Intravenous immunoglobulin treatment in peripheral nerve disorders--indications, mechanisms of action and side-effects

This review summarizes observations of clinical use of high dose intravenous immunoglobulin G (IVIg) in regards to administration, kinetics, known or postulated mechanisms of action, and adverse reactions. Indications and value of IVIg for the treatment of various neuropathies with presumed autoimmune aetiology are examined. New knowledge that advances the understanding of the pathogenesis of the neuropathies and of the mechanisms of action of IVIg is discussed.     

自身免疫性脑炎与睡眠障碍

自身免疫性脑炎与睡眠障碍关系密切。抗Ma2抗体介导的神经系统副肿瘤综合征可以导致发作性睡病和快速眼动睡眠期行为障碍。边缘性脑炎和Morvan综合征可以导致严重失眠及其他睡眠障碍,常伴抗电压门控性钾离子通道抗体(包括抗富亮氨酸胶质瘤失活基因1抗体和抗接触蛋白相关蛋白-2抗体)阳性。中枢性低通气常见于抗N-甲基-D-天冬氨酸受体脑炎患者。阻塞性睡眠呼吸暂停、喘鸣和异态睡眠是抗IgLON家族蛋白5抗体相关脑病的常见表现。由此可见,睡眠障碍是自身免疫性脑炎的重要表现,免疫治疗有可能改善临床症状和预后。     

Therapeutic Monoclonal Antibody Therapies in Chronic Autoimmune Demyelinating Neuropathies

Autoimmune diseases of the peripheral nervous system have so far been treated mainly with exogenous high-dose intravenous immunoglobulins (IVIg), that act through several mechanisms, including neutralization of pathogenic autoantibodies, modulation of lymphocyte activity, interference with antigen presentation, and interaction with Fc receptors, cytokines, and the complement system. Other therapeutic strategies have recently been developed, in part to address the increasing shortage of IVIg, prime among which is the use of B cell depleting monoclonal antibodies, or small molecule inhibitors targeting the B-cell specific kinases. Rituximab, a chimeric monoclonal antibody against CD20 + B lymphocytes, is currently the most used, especially in anti-MAG antibody neuropathy and autoimmune neuropathies with antibodies to nodal/paranodal antigens that are unresponsive to IVIg. After several reports of its efficacy in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), rituximab is currently under investigation in three Phase 2 trials in CIDP. In addition, the possible role of complement activation in the pathogenesis of chronic autoimmune neuropathies has brought into consideration drugs that can block the complement cascade, such as eculizumab, a monoclonal antibody already assessed in acute polyradiculoneuropathies, and approved for myasthenia gravis. Preliminary data on eculizumab in multifocal motor neuropathy have been published, but randomized controlled studies are pending. Moreover, the neonatal Fc receptor, that recycles IgGs by preventing their lysosome degradation, is an important and attractive pharmacological target. Antibodies against FcRn, which reduce circulating IgG (both pathogenic and non-pathogenic) have been developed. The FcRn blocker efgartigimod, a humanized IgG1-derived Fc fragment, which competitively inhibits the FcRn, has recently been approved for the treatment of myasthenia gravis and is currently under investigation in CIDP. In addition, the anti-human FcRn monoclonal antibody rozanolixizumab is currently being assessed in phase 2 trials in CIDP. However, none of the abovementioned monoclonal antibodies is currently approved for treatment of any immune-mediated neuropathies. While more specific and individualized therapies are being developed, the possibility of combined treatments targeting different pathogenic mechanisms deserves consideration as well.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-022-01222-x.     

What is autoimmune encephalitis-associated epilepsy? Proposal of a practical definition

Seizures resulting from cerebral autoimmunity are either acutely symptomatic in the context of autoimmune encephalitis (AIE) with neural surface antibodies, or they are indicative of an enduring predisposition to seizures, that is, epilepsy. Here, we propose a practical definition for autoimmune encephalitis-associated epilepsy (AEAE): Seizures associated with antibodies against glutamic acid decarboxylase, paraneoplastic syndromes, or Rasmussen encephalitis are classified as AEAE. AEAE secondary to AIE with antibodies against the N-methyl-D-aspartate receptor, leucine-rich glioma inactivated protein 1, contactin-associated protein-2, or γ-aminobutyric acid-B receptor can be diagnosed if the following criteria are met: seizures persist for at least 2 years after immunotherapy initiation; no signs of encephalitis on magnetic resonance imaging and no fluorodeoxyglucose positron emission tomography hypermetabolism; normal cerebrospinal fluid cell count; and a substantial decrease in antibody titers. This classification corresponds to different disease mechanisms. While AIE results from the pathogenic effects of neural antibodies, AEAE is probably the consequence of encephalitis-related tissue damage and thereby mainly structurally mediated. The distinction between AIE and AEAE also has practical consequences: In AIE, immunotherapy is usually highly beneficial, whereas anti-seizure medication has little effect. In AEAE, immunotherapy is less promising and the usual anti-seizure interventions are preferable. In addition, the diagnosis of AEAE has social consequences in terms of driving and professional limitations.     

Nodo-paranodopathy: Beyond the demyelinating and axonal classification in anti-ganglioside antibody-mediated neuropathies

In some anti-ganglioside antibody-mediated neuropathies, human and experimental data suggest a common pathogenic mechanism of dysfunction/disruption at the node of Ranvier resulting in a pathophysiologic continuum from transitory nerve conduction failure to axonal degeneration. The traditional classification of polyneuropathies into demyelinating or axonal may generate some confusion in the electrophysiological diagnosis of Guillain–Barré syndrome subtypes associated with anti-ganglioside antibodies. The axonal forms show, besides axonal degeneration, promptly reversible nerve conduction failure. This may be interpreted, by a single electrophysiological study, as demyelinating conduction block or distal axonal degeneration leading to errors in classification and in establishing prognosis. Moreover the term axonal may be misleading as it is commonly associated to axonal degeneration and not to a transitory, promptly reversible, dysfunction of the excitable axolemma. To focus on the site of nerve injury and overcome the classification difficulties, we propose the new category of nodo-paranodopathy which seems appropriate to various acute and chronic neuropathies associated with anti-ganglioside antibodies and we think better systematizes the neuropathies characterized by an autoimmune attack targeting the nodal region.     

Plasma exchange and intravenous immunoglobulins: mechanism of action in immune-mediated neuropathies

Immune-mediated neuropathies are a heterogeneous group of peripheral nerve disorders, which are classified by time course, clinical pattern, affected nerves and pathological features. Plasma exchange (PE) and intravenous immunoglobulins (IVIg) are mainstays in the treatment of immune-mediated neuropathies. Of all treatments currently used, IVIg has probably the widest application range in immune-mediated neuropathies and efficacy has been well documented in several randomized controlled trials for Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP). Beneficial effects of IVIg have also been proven for multifocal motor neuropathy (MMN). Likewise, PE is an established treatment for GBS and CIDP, whereas it is considered to be ineffective in MMN. Different mechanisms of action are sought to be responsible for the immunemodulatory effect of PE and IVIg in autoimmune disorders. Some of those might be important for immune-mediated neuropathies, while others are probably negligible. The aim of this review is to summarize the recent advances in elucidating disease-specific mechanisms of actions of PE and IVIg in the treatment of immune-mediated neuropathies.     

副蛋白血症性神经病

副蛋白血症与数种周围神经病（PN）有关，在PN患者中识别单克隆球蛋白（M蛋白）的存在很重要，M蛋白持续增高可能与未定性的单克隆球蛋白病（MGUS）和PN同时存在。因此，MGUS多发性PN被认为是M蛋白所介导的自身免疫疾病，本文就PN患者体内M蛋白的存在进行阐述，同时简要分析了其作用机制。     

Structure and function of the contactin-associated protein family in myelinated axons and their relationship with nerve diseases

The contactin-associated protein(Caspr) family participates in nerve excitation and conduction, and neurotransmitter release in myelinated axons. We analyzed the structures and functions of the Caspr family–CNTNAP1(Caspr1), CNTNAP2(Caspr2), CNTNAP3(Caspr3), CNTNAP4(Caspr4) and CNTNAP5(Caspr5), Caspr1–5 is not only involved in the formation of myelinated axons, but also participates in maintaining the stability of adjacent connections. Caspr1 participates in the formation, differentiation, and proliferation of neurons and astrocytes, and in motor control and cognitive function. We also analyzed the relationship between the Caspr family and neurodegenerative diseases, multiple sclerosis, and autoimmune encephalitis. However, the effects of Caspr on disease course and prognosis remain poorly understood. The effects of Caspr on disease diagnosis and treatment need further investigation.     

Immunotherapy in Peripheral Neuropathies

Immunotherapy has been investigated in a small subset of peripheral neuropathies, including an acute one, Guillain-Barré syndrome, and 3 chronic forms: chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, and neuropathy associated with IgM anti-myelin-associated glycoprotein. Several experimental studies and clinical data are strongly suggestive of an immune-mediated pathogenesis. Either cell-mediated mechanisms or antibody responses to Schwann cell, compact myelin, or nodal antigens are considered to act together in an aberrant immune response to cause damage to peripheral nerves. Immunomodulatory treatments used in these neuropathies aim to act at various steps of this pathogenic process. However, there are many phenotypic variants and, consequently, there is a significant difference in the response to immunotherapy between these neuropathies, as well as a need to improve our knowledge and long-term management of chronic forms.     

The expanding spectrum of clinically-distinctive, immunotherapy-responsive autoimmune encephalopathies

The autoimmune encephalopathies are a group of conditions that are associated with autoantibodies against surface neuronal proteins, which are likely to mediate the disease. They are established as a frequent cause of encephalitis. Characteristic clinical features in individual patients often allow the specificity of the underlying antibody to be confidently predicted. Antibodies against the VGKC-complex, mainly LGI1(leucine-rich glioma-inactivated 1), CASPR2 (contactin-associated protein 2), and contactin-2, and NMDA (N-methyl, D-aspartate) -receptor are the most frequently established serological associations. In the minority of cases, an underlying tumour can be responsible. Early administration of immunotherapies, and tumour removal, where it is relevant, offer the greatest chance of improvement. Prolonged courses of immunotherapies may be required, and clinical improvements often correlate well with the antibody levels. In the present article, we have summarised recent developments in the clinical and laboratory findings within this rapidly expanding field.     

Antibodies against the node of Ranvier: a real-life evaluation of incidence,clinical features and response to treatment based on a prospective analysis of 1500 sera

Journal of Neurology - IgG4 antibodies against neurofascin (Nfasc155 and Nfasc140/186), contactin (CNTN1) and contactin-associated protein (Caspr1) are described in specific subtypes of chronic...