CIDP is a rare disease: its prevalence is 0.5–1/100,000 in childhood and 1–2/100,000 in adult populations. CIDP responds well to corticosteroid and immunosuppressive treatments (Gorson et al. 1997; Laughlin et al. 2009; Hughes and Mehndiratta 2012; Mahdi-Rogers et al. 2013; Stübgen 2013).

A core criterion for the diagnosis is the subacute onset progressing for at least 8 weeks; in about 16 % of patients, the onset may be acute, but the progression extends over 8 weeks, or at least 3 relapses occur (Barohn et al. 1989; Joint Task Force of the EFNS and the PNS 2010c). Motor symptoms are usually symmetric and prominent, affect the lower extremities more than the upper extremities, and are present both distally and proximally. The rare pure motor and sensory variants are defined as atypical CIDP by the EFNS guidelines (Joint Task Force of the EFNS and the PNS 2010c).

The diagnosis of definite CIDP requires electrophysiological examination, which indicates primary demyelination of at least two peripheral nerves (Joint Task Force of the EFNS and the PNS 2010c). In case of axonal degeneration or demyelinating electrophysiological feature only in one nerve, supportive criteria are required. Such supportive data can be obtained by the examination of the CSF, MRI examination of the plexus and roots, or pathological examination of peripheral nerves (Bosboom et al. 2001; Joint Task Force of the EFNS and the PNS 2010c).

Elevated CSF albumin levels in CIDP are likely caused by damage of the blood-CSF barrier permitting serum proteins to enter the CSF. One study looked at changes in protein levels and CSF index of proteins other than albumin using an ELISA approach (Table 19.1). They found higher levels of fibrinogen in CSF but not in plasma (low CSF index), as well as high levels of haptoglobin and normal CSF prealbumin index when comparing CIDP to controls (Zhang et al. 2012). Similarly, a proteome analysis of CSF from CIDP compared to controls also found upregulation of two haptoglobin isoforms as well as 8 other proteins (two transferrin isoforms, alpha-1 acid glycoprotein 1 precursor, apolipoprotein A IV, transthyretin, retinol binding protein, and two isoforms of proapolipoprotein). In this study, one protein (integrin beta 8) was downregulated (Tumani et al. 2009). Another study that focused only on transthyretin using ELISA, however, found no difference between CIDP and controls (Chiang et al. 2009).

Several studies investigated immune cells, cytokine, and chemokine profiles of CSF obtained from CIDP patients (Table 19.1). One pioneering study found an increase in the chemokine receptor CXCR3 on infiltrating T cells in sural biopsies from inflammatory neuropathy (Kieseier et al. 2002). In accordance, they also found high expression of the CXCR3 ligand IP10 (now named CXCL10) in CSF from CIDP patients when compared to controls. There was however no significant increase in the expression of another main CXCR3 ligand Mig (now named CXCL9).

The increase in CXCL10 was later confirmed in other studies (Mahad et al. 2002; Press et al. 2003). These studies also found increased concentrations of other important chemoattractants such as MIP1-α (now named CCL3) (Mahad et al. 2002) and MIP-3β (now named CCL19) (Press et al. 2003). In contrast to the initial study, Mahad and colleagues also found increased expression of the CXCL10 ligand CXCL9 in CSF from CIDP patients compared to controls.

By using an ELISA-based approach, no detectable levels of interleukin (IL)-1α, IL-1β, IL-2, IL-6, IL-10, interferon (IFN)-γ, tumor necrosis factor (TNF), and macrophage colony-stimulating factor (M-CSF) were found in the CSF (Sivieri et al. 1997). Others detected increased IL-6, IL-8, and IL-17 and decreased IL-4, IL-5, and IL-7 levels in CSF using a more sensitive bead assay. IL-17 and IL-8 correlated strongly with CSF protein levels, and this type 1 cytokine upregulation and type 2 downregulation coincided with an increase in IFN-γ-producing CD4⁺ T cells, suggesting a T helper 1 (Th1) shift in CIDP (Mei et al. 2005). Accordingly, another study found increased Th1 cells in the CSF of active and remitting CIDP patients, whereas Th17 cell number was increased only in active patients (Chi et al. 2010). A recent multiplex bead-based ELISA assay investigating 32 inflammatory mediators also found an increased level of CXCL10 besides CCL2, CCL7, CCL27, CXCL9, CXCL12, ICAM-1, and VCAM-1 VEGF, when compared to control samples. No differences were found in the concentration of IL-6, IL-9, IL-15, IL-18, CCL4, CXCL1, LIF, MIF, PDGFbb, IFN-γ, IL-2ra, IL-12(p40), IL-16, SCGF-β, TRAIL, FGF, G-CSF, GM-CSF, and M-CSF. IL-17, IL-4, and IL-5 were not investigated (Sainaghi et al. 2010).

MMN has been considered as a separate chronic demyelinating polyneuropathy since 1988 (Parry and Clarke 1988). It is a rare disease with an incidence of 1–3/100,000 (Muley and Parry 2012). The disease is characterized by slowly progressive multifocal muscle weakness, which starts distally (Figure 19.1). Weakness of the finger extensors is considered typical. Sensory symptoms are absent except mild vibration sense abnormalities distally. Muscle atrophy and cramps appear in about half of the patients. The characteristic electrophysiological feature is conduction block of the peripheral nerves. MRI may indicate edema, T2 hyperintense signal, and thickening of the brachial plexus. The disease is progressive in about 80 % of the cases; stepwise worsening can be observed in about one-tenth of the patients, and relapses are exceptional (Nobile-Orazio et al. 2005; van Schaik et al. 2011; Muley and Parry 2012).

The pathological picture is similar to CIDP and indicates inflammatory demyelination, but the primary pathology is unclear. Antibody-mediated complement activation at the nodal axolemma has been considered similar to acute motor axonal neuropathy (AMAN) (Vlam et al. 2013). In about 30–80 % of patients, monoclonal or polyclonal IgM can be identified in the sera, which is reactive with the ganglioside GM1 (Pestronk et al. 1990; van Schaik et al. 1995; Willison et al. 2001; Cats et al. 2010b). The pathogenicity of the anti-GM1 antibodies is unclear, but they can activate complement in vitro (Uncini et al. 1993; Parry 1994; Harvey et al. 1995; Roberts et al. 1995; Yuki et al. 2011). The presence of anti-GM1 antibody is not specific, since it can be also identified in around 20 % of cases with lower motor neuron syndromes (Nobile-Orazio et al. 1990), but the titer is approximate tenfold higher in MMN (Muley and Parry 2012). EFNS guidelines consider the presence of anti-GM1 antibodies as a supportive factor of diagnosis. It may be especially important in cases with atypical clinical picture or mononeuropathy or in the absence of conduction block by electroneurography (ENG) (Joint Task Force of the EFNS and the PNS 2010a; van Schaik et al. 2011).

Four randomized, double-blind placebo-controlled studies showed the effectiveness of intravenous immunoglobulin (IVIG) in MMN, which supports the pathogenic role of autoantibodies (Azulay et al. 1994; Van den Berg et al. 1995; Federico et al. 2000; Léger et al. 2001; van Schaik et al. 2005; Parry and Clarke 1988). Remission can be achieved and maintained in about one-fifth of the patients. Seventy percent of the patients require long-term treatment with IVIG, and half of these need combination with another immunosuppressant (Meucci et al. 1997). The prognosis of the disease is relatively good (Cats et al. 2010a; van Schaik et al. 2011; Muley and Parry 2012).

Analysis of CSF in 32 patients found elevated protein concentrations in 41 %. The median value was 0.42 g/l, but the range was abnormal (0.21–0.97 g/l). Patients with elevated protein in the CSF did not differ clinically or electrophysiologically from those with normal CSF protein levels (Taylor et al. 2000). Other studies also found slightly increased protein levels (usually up to 0.8 g/l) in the CSF in about one-third of patients (Taylor et al. 1996; van den Berg-Vos et al. 2000; Nobile-Orazio 2001). CSF is normal in about two-thirds of the patients, including absence of oligoclonal bands. Such normal findings may help in distinguishing MMN from CIDP, in which protein level in the CSF is usually markedly increased (Nobile-Orazio et al. 2005).

The disease was described in 1982 (Lewis et al. 1982). Similarly to MMN and in contrast to CIDP and DADS, MADSAM is an asymmetric neuropathy, which usually starts in the upper extremity (Fig. 19.1) (Saperstein et al. 1999; Verschueren et al. 2005). However, there are definite sensory symptoms, and ENG also proves the conduction abnormalities of sensory fibers. The EFNS guidelines describe MADSAM as atypical, asymmetric CIDP (Joint Task Force of the EFNS and the PNS 2010c). Corticosteroids may be effective in 65 % of patients according to a recent report reviewing 26 patients (Verschueren et al. 2005), but deterioration has been also described similar to MMN (Van den Berg-Vos et al. 2000; Rajabally and Chavada 2009). Efficacy of IVIG varies between 50 and 100 % (Saperstein et al. 1999; Van den Berg-Vos et al. 2000; Verschueren et al. 2005). Steroids appeared less effective than IVIG in other series (25 % vs 80 %) (Rajabally and Chavada 2009).

The common feature of these diseases is the presence of an M protein (monoclonal gammopathy) in the serum (Fig. 19.1).

Monoclonal gammopathy is more common in the elderly: above 70 years of age, it is present in about 3 % of the population and rising to 10 % above 80 years of age (Crawford et al. 1987). In the majority of cases, the presence of a paraprotein is not associated with hematological diseases and is called MGUS (monoclonal gammopathy of unknown significance). Up to one-third of patients with MGUS have neuropathy, which is significantly more frequent in cases of IgM compared to IgG or IgA paraprotein (Osby et al. 1982; Nobile-Orazio et al. 1992; Vrethem et al. 1993). One study found that 10 % of polyneuropathy cases with undetermined etiology were associated with an M protein, and the frequency was equal to that of CIDP, alcoholic neuropathies, and other toxic neuropathies (Kelly et al. 1981). Moreover, others have found M protein in 8 of 29 patients diagnosed with CIDP or DADS (Mygland and Monstad 2001). The frequency of neuropathy in hematological malignancies with paraproteinemia varies: 85–100 % in osteosclerotic multiple myeloma, 3–4 % in multiple myeloma, 2–8 % in lymphoma, and 5–50 % in Waldenström macroglobulinemia (Miralles et al. 1992; Nobile-Orazio et al. 1992; Latov 1995). Neuropathy associated with M protein is present in 17 % of cases with systemic amyloidosis (Kyle and Gertz 1995).

In cases of plasmacytoma (multiple myeloma) and POEMS (Crow-Fukase syndrome), the M protein is usually of the IgG or IgA classes; in Waldenström macroglobulinemia, chronic lymphocytic leukemia (CLL), and lymphoma, it is mainly an IgM antibody. The M protein belongs to the IgM class only in about 10–20 % of the cases; its prevalence in the population above 50 years of age is about 20/100,000. However, the proportion of paraprotein in patients with neuropathy is the highest for the IgM class (50 %) and less for IgG (35 %) and IgA (15 %); indeed, the proportion of IgM paraprotein without neuropathy is only 15 %, while it is 75 % for IgG paraprotein (Ramchandren and Lewis 2012). In neuropathies associated with IgM paraprotein, the M protein targets MAG in about 50–60 % of the cases (Nobile-Orazio 2013), and a characteristic symmetrical distal neuropathy (DADS, see below) may be present. The anti-MAG IgM paraprotein is associated with MGUS in about 80 % of the cases, but with malignant hematological disease (mainly Waldenström macroglobulinemia) only in 20 % of cases (Ramchandren and Lewis 2012; Nobile-Orazio 2013, 2014). In about 2 % of patients with neuropathy and IgM paraprotein, the M protein targets gangliosides containing disialosyl groups, and the characteristic clinical picture with prominent ataxia and recurrent ophthalmoplegia is present (CANOMAD) (Willison et al. 1996; Nobile-Orazio et al. 2008).

Neuropathies associated with M proteins have two major clinical significances: First, they should be considered in the differential diagnosis of CIDP. Second, the only clinical signs of MGUS might be the peripheral neuropathy, so the necessity of treatment is driven not by hematological but by neurological symptoms (Joint Task Force of the EFNS and the PNS 2010b).