Francesca Gallia

How useful are anti-neural IgM antibodies in the diagnosis of chronic immune-mediated neuropathies?

Antibodies against several neural antigens have been associated with different chronic immune-mediated neuropathies but their practical clinical relevance remains unclear. To determine the possible diagnostic usefulness of these antibodies we reviewed the clinical correlate of IgM antibodies to the myelin-associated glycoprotein (MAG), sulfatide, the gangliosides GM1, GM2, GD1a and GD1b in 539 consecutive patients examined for neuropathy or related diseases in our Neuropathy Clinics and tested for these antibodies in our laboratory since 1985. 302 patients (56%) had an established diagnosis of definite or possible chronic immune-mediated neuropathy while 237 had a neuropathy of non-immune-mediated origin or of unknown aetiology or a closely related disease. Antibodies to one or more antigen were more frequent (chi(2)=63.32; p<0.00001) in patients with chronic immune-mediated neuropathy (37.7%) than with other neuropathy or related diseases (7.2%) and their presence was associated in 87% of the patients with an immune-mediated neuropathy, incrementing by 31% the probability of having this form. Testing for MAG permitted to identify 24.8% of patients with an immune-mediated neuropathy, GM1 an additional 9.9%, while GM2, GD1b, GD1a and sulfatide altogether an additional 3% of the patients. Concerning clinical correlations, all 75 patients with anti-MAG IgM had neuropathy and IgM monoclonal gammopathy (PN+IgM) with a positive predictive value for this neuropathy of 100%. A similarly high predictive value for neuropathy (91.4%) was observed among 269 patients with IgM monoclonal gammopathy including 103 patients without neuropathy. Anti-sulfatide IgM, though rare, were also significantly and constantly associated with PN+IgM and permitted to identify few patients not bearing anti-MAG IgM. Anti-GM1 IgM were significantly associated with multifocal motor neuropathy (MMN) (29.2%) but where also found in a few patients with other immune or non-immune neuropathies or related diseases with a positive predictive value for MMN of 25.5%. Anti-GM2 IgM were also significantly associated with MMN and increased the sensitivity (36.2%) for MMN obtained with anti-GM1 IgM only, without affecting its specificity and positive predictive value. Anti-GD1a, GD1b, though not significantly more frequent in patients with immune-mediated neuropathy, were associated in 80 to 100% of patients with these neuropathies. In conclusion anti-neural IgM antibodies may help in identifying patients with a chronic immune-mediated neuropathy, even if only anti-MAG and anti-sulfatide IgM appear to be strictly associated with a definite clinical syndrome.

SERUM VEGF LEVELS IN POEMS SYNDROME AND IN IMMUNE-MEDIATED NEUROPATHIES

POEMS syndrome is a multiorgan disorder defined by the association of polyneuropathy (P), organomegaly (O), endocrinopathy (E), M-protein (M), and skin changes (S).1 Serum levels of vascular endothelial growth factor (VEGF) are often markedly elevated in patients with POEMS,2-5 but not with other monoclonal gammopathies.2,4,5 Few patients with other neuropathies have been examined,2-5,6 so that the specificity of elevated VEGF levels for POEMS among patients with neuropathy remains unclear, especially when levels are moderately increased. ### Methods. We measured serum VEGF in 161 patients with neuropathy or related syndromes consecutively recruited and tested for antinerve antibodies at our neuropathy clinic. Six patients had POEMS diagnosed in the presence of at least four of the five features of POEMS, 13 had Guillain-Barre syndrome (GBS), 33 had chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with no other feature of POEMS, 13 had multifocal motor neuropathy (MMN), 19 had neuropathy associated with IgM monoclonal gammopathy of undetermined significance (MGUS) (PN+IgM) with anti-MAG or anti-sulfatide IgM, 49 had neuropathies of other (diabetes in 8, multiple myeloma or lymphoma in 8, systemic vasculitis or other rheumatic diseases in 5, amyloidosis in 3, toxic in 2, inherited in 2, paraneoplastic and small fiber neuropathy in 1 each) or of undetermined causes (19) (other PN), and 28 had amyotrophic lateral sclerosis (ALS). We also tested 21 patients with MGUS or multiple myeloma (MM) without neuropathy (MGUS/MM), and 22 …

Frequency and time to relapse after discontinuing 6-month therapy with IVIg or pulsed methylprednisolone in CIDP

Background We reported that 6-month therapy with intravenous immunoglobulin (IVIg) was more frequently effective or tolerated than intravenous methylprednisolone (IVMP) in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We now retrospectively compared the proportion of patients who eventually worsened after discontinuing therapy and the median time to clinical worsening. Methods By March 2013, data were available from 41 of the 45 patients completing the trial with a median follow-up after therapy discontinuation of 42 months (range 1–60). Three patients withdrew during the original study and one failed to respond to either of the therapies. No patient received a diagnosis alternative to CIDP during the follow-up. Results Twenty-eight of the 32 patients treated with IVIg (as primary or secondary therapy after failing to respond to IVMP) improved after therapy (87.5%) as compared with 13 of the 24 patients treated with IVMP as primary or secondary therapy (54.2%). After a median follow-up of 42 months (range 1–57), 24 out of 28 patients responsive to IVIg (85.7%) worsened after therapy discontinuation. The same occurred in 10 out of 13 patients (76.9%) responsive to IVMP (p=0.659) after a median follow-up of 43 months (range 7–60). Worsening occurred 1–24 months (median 4.5) after IVIg discontinuation and 1–31 months (median 14) after IVMP discontinuation (p=0.0126). Conclusions A similarly high proportion of patients treated with IVIg or IVMP eventually relapse after therapy discontinuation but the median time to relapse was significantly longer after IVMP than IVIg. This difference may help to balance the more frequent response to IVIg than to IVMP in patients with CIDP.

Multifocal motor neuropathy: current therapies and novel strategies.

Multifocal motor neuropathy (MMN) is a purely motor mononeuritis multiplex characterized by the presence of conduction block on motor but not on sensory nerves and by the presence of high titers of anti-GM1 antibodies. Several data point to a pathogenetic role of the immune system in this neuropathy, although this has not yet been proved. Several uncontrolled studies and randomized controlled trials have demonstrated the efficacy of therapy with high-dose intravenous immunoglobulin (IVIg) in MMN. However, this therapy has a short-lasting effect that needs to be maintained with periodic infusions. This can be partly overcome by the use of subcutaneous immunoglobulin (SCIg) at the same dose. The high cost and need for repeated infusions have led to the search for other immune therapies, the efficacy of which have not yet been confirmed in randomized trials. In addition, some therapies, including corticosteroids and plasma exchange, are not only ineffective but have been associated with clinical worsening. More recently, a number of novel therapies have been investigated in MMN, including interferon-β1a, the anti-CD20 monoclonal antibody rituximab and the complement inhibitor eculizumab. Preliminary data from open-label uncontrolled studies show that some patients improve after these therapies; however, randomized controlled trials are needed to confirm efficacy. Until then, IVIg (and SCIg) remains the mainstay of treatment in MMN, and the use of other immune therapies should only be considered for patients not responding to, or becoming resistant to, IVIg.

Chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy: treatment update.

PURPOSE OF REVIEW Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy usually respond to immune therapies including steroids and plasma exchange for CIDP and high-dose intravenous immunoglobulins (IVIgs) for both diseases. Other immune therapies have been used to reduce the costs or the side-effects of these therapies, but their efficacy was only recently assessed in randomized controlled trials (RCTs). RECENT FINDINGS The prolonged efficacy of IVIg in CIDP has been confirmed in a 48-week RCT. Two other RCTs showed that oral methotrexate or intramuscular interferon beta were not more effective than placebo in improving the efficacy or reducing the dose of IVIg or steroids. In multifocal motor neuropathy, a RCT showed that oral mycophenolate mofetil was not more effective than placebo in increasing the efficacy or reducing the dose of IVIg. Other immune therapies were assessed in open trials in both diseases, but their efficacy remains unclear, even if in some patients a possible efficacy of rituximab was reported. Some preliminary studies suggest that subcutaneous immunoglobulin may be as effective as IVIg in the maintenance therapy of CIDP and multifocal motor neuropathy. SUMMARY After several years of anecdotal reports, a number of RCT have now appeared in CIDP and multifocal motor neuropathy, but their results are still insufficient to support the use of new therapies in these diseases.

Lower motor neuron disease with respiratory failure caused by a novel MAPT mutation.

Objective: To investigate the molecular defect underlying a large Italian kindred with progressive adult-onset respiratory failure, proximal weakness of the upper limbs, and evidence of lower motor neuron degeneration. Methods: We describe the clinical features of 5 patients presenting with prominent respiratory insufficiency, proximal weakness of the upper limbs, and no signs of frontotemporal lobar degeneration or semantic dementia. Molecular analysis was performed combining linkage and exome sequencing analyses. Further investigations included transcript analysis and immunocytochemical and protein studies on established cell models. Results: Genome-wide linkage analysis showed an association with chromosome 17q21. Exome analysis disclosed a missense change in MAPT segregating dominantly with the disease and resulting in D348G-mutated tau protein. Motor neuron cell lines overexpressing mutated D348G tau isoforms displayed a consistent reduction in neurite length and arborization. The mutation does not seem to modify tau interactions with microtubules. Neuropathologic studies were performed in one affected subject, which exhibited α-motoneuron loss and atrophy of the spinal anterior horns with accumulation of phosphorylated tau within the surviving motor neurons. Staining for 3R- and 4R-tau revealed pathology similar to that observed in familial cases harboring MAPT mutations. Conclusion: Our study broadens the phenotype of tauopathies to include lower motor neuron disease and implicate tau degradation pathway defects in motor neuron degeneration.

Anti-sulfatide IgM antibodies in peripheral neuropathy: to test or not to test?

Anti‐sulfatide immunoglobulin M (IgM) antibodies have been associated with different forms of neuropathies but their diagnostic role in neuropathy remains unclear.

Oral methotrexate as adjunctive therapy in patients with multifocal motor neuropathy on chronic IVIg therapy

Dear Editor, Placebo-controlled studies confirm that intravenous human immunoglobulin therapy (IVIg) improves muscle strength in almost 80% of patients with multifocal motor neuropathy (MMN) (Nobile-Orazio et al., 2005; van Schaik et al., 2005). The effect of IVIg is usually transient and needs to be maintained with periodic IVIg infusions (Terenghi et al., 2004; Leger et al., 2008). Other immune therapies have been used in MMN, although there is no clinical trial evidence that any of them affects the disease (Umapathi et al., 2009). Experts have agreed on the need for randomized controlled trials (RCTs) with immunosuppressive drugs in MMN (Umapathi et al., 2009). Methotrexate (MTX) was considered a possible option (Hughes et al., 2005) because it is usually well tolerated, effective, and low cost (Willkens et al., 1984; Weinblatt et al., 1985). Eight patients with definite or probable MMN (Joint Task Force of the EFNS and the PNS, 2006) who had responded to IVIg and were clinically stable on chronic maintenance IVIg therapy signed an informed consent to receive an off-label add-on therapy with MTX to either improve their strength or reduce IVIg dosage. In all, an attempt at reducing their IVIg dose in the previous 6 months was associated with clinical worsening. In all, IVIg therapy had not been modified during the last three previous IVIg courses. The study was approved by the Institutional Review Boards. Oral MTX was begun at 7.5 mg weekly, then increased to 10 mg after 4 weeks, and to 15 mg after another 4 weeks. Oral folic acid 10 mg weekly was also given. MTX was planned to be given for at least 12 months. After 4 months of combined IVIg and MTX therapy, patients who were stable or improving had their IVIg doses reduced by approximately 10–15%

Update on the treatment of chronic inflammatory demyelinating polyradiculoneuropathy.

PURPOSE OF REVIEW Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic and often disabling neuropathy, which often responds to immune therapies including corticosteroids, plasma exchange, and high-dose intravenous immunoglobulin (IVIg). The reasons for choosing one of these therapies and the factors that may predict response to these therapies remain, however, unclear. It is also unclear whether other immune therapies may be useful in CIDP. We will here review the studies addressing these points in CIDP. RECENT FINDINGS Recent studies have shown that IVIg are initially more frequently effective than steroids in CIDP even if steroids, when effective, have a more prolonged efficacy. Some clinical and immunological features including the presence of antibodies against proteins at the nodes of Ranvier were associated with specific response to therapy even if the data need to be confirmed in large series of patients. A few anecdotal studies also reported the efficacy in some patients of new immune therapies whose efficacy needs to be confirmed in controlled trials. SUMMARY IVIg are initially more frequently effective than steroids in CIDP, but the latter have a more prolonged efficacy. Some clinical presentations and their association with specific antibodies reactions may help in predicting the response to specific treatment. The possible benefit of new immune therapies await confirmation from randomized studies.

Chronic motor axonal neuropathy

The identification of a distinct subgroup of patients within the spectrum of lower motor neuron syndromes (LMNS) is crucial as some are potentially treatable. We describe the clinical and neuropathological characteristics of a patient presenting with a rapidly progressive LMNS associated with high titers of anti‐GM1 antibodies, leading to respiratory failure within 10 months. Histopathological study of a biopsy of a obturator nerve motor branch demonstrated a predominantly axonal motor neuropathy, while electron microscopy analysis localized macrophages located within the periaxonal space. Immunohistochemistry demonstrated deposits of complement activation products (C3i) and immunoglobulins (IgM) on nerve fibers. The patients clinical, immunological and pathological findings are consistent with a diagnosis of a chronic motor axonal neuropathy (CMAN), likely of immune‐mediated origin.