The paranodopathies as a new entity among the immune neuropathies.

Paranodopathies are a new special form of inflammatory polyneuropathies, mediated by autoantibody-induced damage at Ranvier’s lacing ring. What are characteristics of this disease and how can it be treated?

Polyneuropathies are a heterogeneous group of disorders that result from damage to the axon or myelin sheath of peripheral nerves. Although the cause remains unclear in about 25% of all polyneuropathies, etiologic differentiation is essential in clinical practice [1,2]. In this way, treatable causes can be identified and specific therapies offered, especially in the immune neuropathies. Basic diagnostics in addition to history, examination and laboratory diagnostics include electroneurography, which can distinguish between an axonal and demyelinating pattern, and nerve ultrasound. In recent years, the new entity of paranodopathies has been described, which cannot be assigned to the classical concept of “axonal” and “demyelinating” [3–5]: Here, Ranvier’s  lacing ring represents the starting point of the disease. Paranodal autoantibodies are valuable biomarkers in immune neuropathies because paranodopathies differ from other immune neuropathies in terms of response to therapy.

Inflammatory neuropathies

Inflammatory neuropathies include infectious neuropathies, which are rare in Central Europe, and autoimmune-mediated neuropathies, which, with a prevalence of about 10%, are the third most common cause of all polyneuropathies after diabetic and ethyltoxic polyneuropathies [2,6]. The prominent representatives of demyelinating forms are acute-onset Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and multifocal motor neuropathy (MMN). In these diseases, the myelin sheath is damaged by humoral and cellular immune processes, and axonal loss may occur secondarily. In vasculitic neuropathy, on the other hand, ischemic axonal damage results from mostly isolated involvement of the vasa nervorum. For the differential diagnosis of immune neuropathies, the course, distribution pattern, laboratory diagnostics, and especially electrophysiology and nerve biopsy are crucial. The exact differentiation is particularly important with regard to the different therapy options (Tab. 1).

The paranodium as the starting point of rare immune neuropathies

The Ranvier’s cord ring of peripheral myelinated nerves is subdivided into three sections (Fig. 1). At the nodium, the voltage-gated sodium channels, which are responsible for saltatory excitation conduction, are bundled by neurofascin-186 [7]. The region is flanked by the paranodium, where the terminal myelin loops lie loosely around the axon. Here, the protein complex of glial neurofascin-155 and axonal contactin-1 and caspr-1 connects myelin and axon and is crucial for maintaining nodal architecture and normal nerve conduction velocities [8,9]. Lateral to this, voltage-gated potassium channels are concentrated at the juxtaparanodium by a protein complex of contactin-2 and caspr-2 [10].

Several histopathological studies describe an alteration of the lacing ring architecture in various polyneuropathies [11–13]. In recent years, IgG autoantibodies and more recently IgM autoantibodies against the paranodal proteins neurofascin-155, contactin-1, and caspr-1 have been described in patients with immune neuropathies [14–20]. In most cases, these are autoantibodies of the complement-independent IgG subclass 4, but IgG3 autoantibodies that can bind and activate complement in vitro have also been described in patients with acute disease [16,21]. Electrophysiologically, these autoantibody-mediated immune neuropathies may meet criteria for CIDP or GBS, but not histopathologically. Here, there is no macrophage-dependent de- and remyelination, but (secondary) axonal damage and detachment of terminal myelin loops from the paranodal axon, as well as elongation of the nodes and dispersion of paranodal proteins and ion channels [14,16,22,23]. This architectural disruption of Ranvier’s lacing ring is thought to be responsible for conduction blocks and prolonged nerve conduction velocities in the paranodopathies [5,24]. Passive-transfer models confirm paranodal destruction and conduction blocks in vivo after injection of anti-contactin-1 IgG4 and anti-neurofascin-155 IgG autoantibodies [25,26]. Thus, the starting point of the disease is not the myelin sheath but the cord ring, which is why no assignment to the classical categories “axonal” or “demyelinating” is possible. Therefore, the term “paranodopathy,” which originally referred to anti-ganglioside autoantibody-associated immune neuropathies, has now been established to refer specifically to immune neuropathies with paranodal autoantibodies [3,4,22,27].

Clinical features, diagnostics and therapy

Paranodal autoantibodies have been identified almost exclusively in patients with the clinical presentation of CIDP and GBS. Here, the prevalences are mostly <10% [28–30]. Affected patients show acute or subacute onset of disease and develop severe motor involvement. In addition, a pronounced tremor and sensory ataxia can aggravate the clinical course [31,32]. IgG4 antibodies to neurofascin-155 have the highest prevalence [33]. In these seropositive patients, central demyelination foci, tremor, and cerebellar ataxia have also been described as possible signs of central autoantibody-mediated damage. The pathomechanism and prevalence of anti-neurofascin-155 IgG autoantibodies in patients with clinically combined central and peripheral involvement have not been adequately studied and are controversial in the literature [30,33–36]. Autoantibodies to Caspr-1 have rarely been detected, with IgG4 autoantibodies described in patients with a chronic course and IgG3 autoantibodies in a patient with GBS [16,37]. Neuropathic pain has been proposed as a common characteristic with histopathological correlate, namely binding of autoantibodies to nociceptive spinal ganglion neurons. However, larger clinical and experimental studies to confirm this are lacking [16]. Table 2 gives an overview of the autoantibody-specific characteristics of the paranodopathies.

The autoantibodies can be detected in serum by ELISA as well as binding assays on mouse or rat pluck nerves and transfected cells (Fig. 2) [33]. No validated commercial test is available yet, but testing is possible in specialized research laboratories. Screening is only useful in patients with the typical clinical phenotype. In the case of mild, chronic, distal sensory-motor neuropathies, on the other hand, clarification of the common causes is useful.

Because of the low number of cases of patients with paranodopathies, there are no controlled therapy studies so far. Case series indicate that, in contrast to classical CIDP, patients with IgG4-mediated paranodopathy respond poorly, whereas patients with IgG3-mediated paranodopathy respond quite well to IVIG [14,21,30].

Patients with IgG4 autoantibodies respond very well to rituximab in the case series, with a significant reduction in antibody titers found as a surrogate parameter (Table 3) [14,16,20,38]. It is possible that early initiation of therapy may prevent chronic axonal injury. Therefore, the current guideline also recommends an individual therapy trial with rituximab in case of detection of paranodal IgG4 autoantibodies, which should be performed under close follow-up at specialized centers [39]. Furthermore, follow-up of patients with paranodopathies is essential for a better understanding of the disease of this new entity.

Take-Home Messages

• The etiology of inflammatory polyneuropathies is heterogeneous and differs between axonal and demyelinating polyneuropathies.
• The paranodopathies are a new special form of inflammatory polyneuropathies, mediated by autoantibody-induced damage at Ranvier’s lacing ring.
• Clinical features of paranodopathies include: subacute onset, severe motor involvement, poor response to standard therapies, tremor, and young age of onset for autoantibodies to neurofascin-155, plus ataxia for autoantibodies to contactin-1 and pain for antibodies to caspr-1.
• Identification of patients with paranodal autoantibodies is important for a better understanding of the disease and for treatment decisions.

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