LAUSR

The pathogenesis of chronic inflammatory demyelinating polyneuropathy (CIDP) remains highly debated among experts. In recent times, literature has divulged a riveting yet plausible association between colorectal carcinoma and CIDP as its paraneoplastic ramification. Initially, research suggested that chronic inflammatory demyelinating polyneuropathy (CIDP) was caused solely by macrophages [1]. However, recent studies have insinuated towards an alternative pathogenesis, one involving autoantibodies against paranodal junction proteins [2]. These two distinct mechanisms are the primary contenders responsible for the development of CIDP, rendering it an elusive paraneoplastic manifestation of colorectal carcinoma. Traditionally, macrophages have been purported to be responsible for the phagocytosis of the myelin surrounding peripheral neurons [1]. A recent study divulged that macrophage-induced demyelination is not only responsible for classical CIDP but also atypical CIDP such as distal acquired disseminated symmetric (DADS) CIDP, multifocal acquired demyelinating sensory and motor (MADSAM) CIDP, and pure sensory subtypes [3]. However, of note, this was not found to be true in all cases [3]. A teased-fibre preparation of a sural nerve biopsy taken from the same patients showed sections without myelin due to macrophages-induced phagocytosis [2]. Moreover, electron microscopy showed that the macrophages were found within the tubes of basement membrane, which itself is normally encompassed by myelin [2]. Yet myelin debris was detected in macrophage cytoplasm [2]. On the other hand, the cytoplasm of the Schwann cells, found in the outermost layer of the myelinated fibers, were intact and unaffected by macrophages [2]. Factors responsible for the phagocytosis of myelin are still unclear [2]. A recent study examining a sural nerve biopsy through an electron microscope showed that macrophages tend to target specific sites of the myelinated fibers [4]. In particular, the region surrounding the nodes of Ranvier and the internodes in certain patients appear to be major sites of attack; notably, this is the internal space of the basement membrane, which encompasses the myelinated fibers [4]. These findings suggest the presence of local factors that differentiate between the nodal and internodal region [4]. One possible explanation may be the deposition of undiscovered antibodies on the peripheral nerves [4]. When the macrophages detect these antibodies, they activate, triggering myelin phagocytosis [4]. In fact, antibodies to a specific peripheral nerve glycolipid, sialosylneolactotetraosylceramide (LM1), were detected in cases with macrophages-induced demyelination [5]. Moreover, complement (C9) was also found on the myelin. In patients with Guillain-Barre syndrome (GBS), macrophage-induced demyelination is morphologically identical to patients with CIDP [6]. In the peripheral nervous system, foreign epitopes from infectious agents mimic the self epitope, which leads to autoantibody production [7]. This concept, molecular mimicry, has been proven in GBS [7]. A similar mechanism may indeed be responsible for the initial steps of the immunological process in CIDP [2]. However, studies have not yet shown a direct association between macrophages and autoantibodies apart from the study mentioned earlier [5]. Another emerging theory is that of IgG4 autoantibodies [2]. Studies have shown that in patients with CIPD, specific antibodies act on components of the nodes of Ranvier and paranodes [4]. Example of these IgG4 autoantibodies include anti-contactin-1 and anti-neurofascin-155 antibodies, which target the paranodal junction between axolemma and the myelin terminal loops [8]. Patients with these antibodies have been found to have distinct clinical features including tremor and sensory ataxia, as well as being unresponsive to intravenous immunoglobulin [9]. A sural nerve biopsy that contained anti-neurofascin-155 and anti-contactin-1 autoantibodies showed endoneural edema, decreased density of myelinated fibres due to axonal degradation, and a lack of cellular infiltration due to inflammation [10]. These observations are the basis for the alternative pathogenesis theory of CIPD [2]. CIDP can be divided into a “classical/typical” subtype and into atypical subtypes, of which there are many, suggesting that it is a spectrum of disease as classified by the European Federation of Neurological Societies/Peripheral Nerve Society Guidelines on the Management of CIDP (EFN/PNS) [11,12]. There are five main subtypes of CIDP; predominantly distal (distal acquired demyelinating symmetric [DADS]), asymmetrical (multifocal acquired demyelinating sensory and motor neuropathy [MADSAM]/Lewis-Sumner syndrome), focal, pure motor or pure sensory [12]. Clinically, it is imperative to distinguish between classical and atypical phenotypes of the disease as immunosuppressive drugs that are effective in typical CIDP demonstrate varying responses in atypical phenotypes [13]. Epidemiologically, only 51% of patients exhibit the classical phenotype [14]. Patients typically present with proximal and distal sensorimotor deficits with demyelination that is defined by the EFNS/PNS Criteria [12]. Pathologically, this definition includes vertical accumulation of Schwann cell cytoplasmic process, resulting in onion-bulb formation, segmental demyelination, and mononuclear cell infiltrates [15]. More specifically, macrophage-induced demyelination followed by remyelination is evident [3]. DADS is an IgM monoclonal protein associated neuropathy [15]. Clinically, DADS presents with a distal, symmetric sensory-predominant neuropathy that may cause sensory ataxia. Electrophysiology demonstrates abnormally increased distal latencies [16]. Although the accepted pathogenesis of classical CIDP and DADS is through macrophage-induced demyelination, recent studies also suggest that patients with autoantibodies against paranodal junction proteins—specifically contactin 1and neurofascin 155-IgG4—may also present another mechanism by which immune-mediated neuropathies