Fabrizia Terenghi

How long is IVIg effective in multifocal motor neuropathy

The authors treated 10 patients with multifocal motor neuropathy (MMN) responding to an initial course of IV immunoglobulin (IVIg) with periodic infusion for 5 to 12 years (mean 8.2 years). At last follow-up, only two patients had maintained the maximal improvement achieved during therapy while eight worsened despite increasing Ig dosage. This decline started after 3 to 7 years (mean 4.8 years) of therapy and correlated with a reduction of distal compound muscle action potential amplitudes (p < 0.019). The effectiveness of IVIg in MMN often declines after several years possibly associated with the development of axonal degeneration.

Multifocal motor neuropathy: clinical and immunological features and response to IVIg in relation to the presence and degree of motor conduction block

Objective: To determine whether patients with clinically typical multifocal motor neuropathy (MMN) with or without definite or probable conduction block (CB) differ in terms of clinical presentation, immunological findings, or response to treatment with intravenous immunoglobulin (IVIg). Methods: 23 consecutive patients were studied with the typical clinical features of MMN, consisting of a progressive multineuropathic motor impairment with minimal or no sensory loss. In 14 patients, electrophysiological studies disclosed the presence of a definite or probable CB according to the criteria proposed by the American Association of Electrodiagnostic Medicine (AAEM) in at least one motor nerve. Six patients had possible CB, defined as a degree of CB 10% less than that required by the AAEM for probable CB, while no CB was detected in three patients. Results: Patients with possible CB did not differ from those with a definite or probable CB in terms of age at disease onset (mean 38.8 v 38.2 years, respectively), distribution and severity of limb weakness, clinical impairment (mean Rankin score 2.2 in both), and frequency of antiganglioside antibodies (33% v 29%). Patients with possible CB had a longer mean disease duration (9 v 5.9 years, p < 0.05) and a less frequent consistent response to IVIg (67% v 86%) than those with a definite or probable CB. Patients without a detectable CB had a similar frequency of antiganglioside antibodies (33%) but had a longer disease duration (20.3 years), greater impairment (Rankin score 2.7), and more frequent signs of axonal degeneration (41% of examined motor nerves) than patients with CB (13–15%, p < 0.005). Only one patient without detectable CB (33%) consistently improved with IVIg. Conclusions: Patients with possible CB were clinically and immunologically indistinguishable from those with definite or probable CB, albeit with a slightly less frequent response to IVIg. This finding suggests that failure to fulfil AAEM criteria for CB in patients with otherwise clinically typical MMN should not preclude this diagnosis and consequently a treatment trial with IVIg. Whether the longer duration and greater severity of the disease and more frequent axonal impairment in patients without detectable CB than in those with CB explain their lower response to IVIg remains to be established.

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 …

Guillain-Barré syndrome after combined CHOP and rituximab therapy in non-Hodgkin lymphoma.

Dear Editor, Guillain-Barré syndrome (GBS) is an acute inflammatory polyneuropathy characterised by rapidly progressive predominantly motor impairment and areflexia. The pathogenesis of GBS remains unclear even if there is strong evidence for an immune-mediated process (Hughes et al., 1999). GBS has been reported in patients with Hodgkin’s (Kelly and Karcher, 2005) and, less frequently, non-Hodgkin’s lymphoma (NHL) (Vallat et al., 1995; Magne et al., 2005) where it is thought to be caused by an immune dysfunction caused by the disease or its therapy. A 51-year-old man was diagnosed with B-cell NHL in August 2005 after biopsy of a symptomatic inguinal lymph node. Therapy was immediately initiated. After an initial course of cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, and methylprednisolone 100 mg (CHOP), he received four cycles of combined CHOP and rituximab (375 mg/m2) (R-ICHOP) at 2-week intervals ending in October 2005. After the first three courses, the patient complained of mild paresthesias at the fingertips. Three weeks after the fourth course and a 2 weeks after transient fever without additional symptoms, he reported worsening of finger paresthesias followed by rapidly progressive leg weakness extending within 2 days to the arms and bulbar muscles with difficulty in swallowing. Neurological examination 3 days after onset of weakness showed severe, symmetrical, predominantly distal, flaccid quadriparesis more pronounced in the legs (Medical Research Council [MRC] score 3/5 in the upper and 4/5 in the lower limbs), with absent deep tendon reflexes and normal sensation. Forced vital capacity was normal. Routine laboratory tests were normal apart from reduced white blood cell and lymphocyte counts (Fig. 1). Serum immunoglobulin (Ig)M antibodies to cytomegalovirus, herpes simplex virus 1 and 2, varicella-zoster virus, Ebstein-Barr virus, mycoplasma pneumoniae, IgG and IgM antibodies to Campylobacter Jejuni, and anti-GM1, -GM2, -GD1b, -GD1a and -GQ1b IgG antibodies were normal. Cerebrospinal fluid proteins were increased (72 mg/dl) while cell count was normal. Nerve conduction studies performed 4 days after onset showed conduction blocks in the right peroneal (50%, distal compound muscle action potential [CMAP] amplitude 1.6 mV), right tibialis posterior (50%, distal CMAP amplitude 1.6 mV) and left posterior tibialis nerves (55%, distal CMAP amplitude 3.1 mV), reduced motor conduction velocities (34 m/sec on the right and 33 m/sec on the left) and increased distal (14.8 and 19 msec), and F wave latencies (44 msec and absent) in the median nerves, where distal CMAP amplitudes were also reduced (0.5 and 0.6 mV, respectively). Despite three daily plasma exchanges started 5 days after disease onset, the patient continued to worsen and became bedridden. He was then treated with high-dose intravenous immunoglobulin (IVIg) therapy (0.5 g/kg/day) and IV methylprednisolone (500 mg) for four consecutive days with moderate improvement followed after 1 week by further deterioration (MRC score 2/5 in the upper and 0/5 in the lower limbs), with progressive respiratory insufficiency (forced vital capacity of 0.9 l). He was transferred to the intensive care unit and placed on non-invasive assisted ventilation. The patient was treated again with IVIg and IV methylprednisolone for 2 days. The patient gradually and steadily improved over the following 3 weeks when a slight worsening was treated again with the same 2day regimen with further progressive improvement. At the follow-up 2 months later, the patient could walk normally for several meters without support. His NHL is in remission. The clinical, electrophysiological, and laboratory features were diagnostic of GBS, possibly superimposed on an underlying neuropathy induced by chemotherapy. Several factors may have contributed to the development of GBS in this patient, including NHL itself, a possible antecedent infection suggested by the transient fever, and chemotherapy with CHOP Address correspondence to: Eduardo Nobile-Orazio, MD, PhD, Department of Neurological Sciences, Milan University, IRCCS Istituto Clinico Humanitas, Via Manzoni 56, 20089, Rozzano Milan, Italy. Tel: þ390282242209; Fax: þ390282242298; E-mail: eduardo.nobile@ unimi.it Journal of the Peripheral Nervous System 12:142–143 (2007)

Multifocal motor neuropathy and Campylobacter jejuni reactivity

Abstract—In some patients, Campylobacter jejuni infection has been associated with the development of multifocal motor neuropathy (MMN) and high titers of antiganglioside antibodies. The authors measured anti–C. jejuni antibodies by ELISA and immunoblot in 20 patients with MMN, and correlated their presence with antiganglioside reactivity and a history of recent diarrhea. Only one patient had high titers of anti–C. jejuni antibodies, indicating that C. jejuni is unlikely to be involved in the pathogenesis of MMN in most patients.

Circulating levels of cytokines and their modulation by intravenous immunoglobulin in multifocal motor neuropathy.

Abstract  We found comparable levels of tumor necrosis factor (TNF)‐α, interferon‐γ, interleukin (IL)‐2, IL‐4, IL‐10, and IL‐12 in the sera of 22 patients with multifocal motor neuropathy (MMN), 12 with amyotrophic lateral sclerosis (ALS), 12 multiple sclerosis, seven chronic inflammatory demyelinating polyneuropathy, five myasthenia gravis, and 13 healthy controls (NS). TNF‐α levels, however, were higher in 15 (68%) MMN patients than in any NS. In all but one MMN patient tested, TNF‐α levels repeatedly, albeit slightly, increased after each intravenous immunoglobulin infusion in parallel with clinical improvement and decreased 3–4 weeks after therapy, while in both ALS patients tested, they decreased or remained unchanged. The possible pathogenetic relevance of serum TNF‐α modification in MMN remains to be clarified.

IVIg in idiopathic autoimmune neuropathies: Analysis in the light of the latest results

High-dose intravenous immunoglobulin (IVIg) is effective in the treatment of idiopathic autoimmune neuropathies including Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating neuropathy (CIDP) and multifocal motor neuropathy (MMN), representing a useful option or, as in MMN, the gold standard for their treatment. In GBS, two randomised, controlled trials (RCT) showed that IVIg is at least as effective as plasma exchange (PE). IVIg may however be preferred due to its low number of contraindications and complications and the fact that it can be administered at any time, in any department, including patients with contraindications to PE, or in intensive care units. In CIDP, at least four RCTs have demonstrated the efficacy of IVIg in over 60% of CIDP patients, while two additional RCTs have shown a comparable effect to steroids and PE as initial treatment. As with PE, the effects of IVIg usually last a few weeks meaning that the majority of patients require periodic maintenance infusions. The lower cost and easier administration of oral steroids compared to IVIg may be partly compensated by the safer long-term profile of IVIg over steroids. In MMN, almost 80% of patients improve with IVIg, the efficacy of which has been confirmed by four RCTs, making of IVIg the first-choice therapy in MMN, for which steroids and PE are ineffective or even detrimental. Also in these patients, IVIg induces a rapid improvement that usually lasts only a few weeks and has to be maintained with periodic IVIg infusions for long periods of time, if not indefinitely.

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.

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%