Susanne Renaud

Rituximab in the treatment of polyneuropathy associated with anti-MAG antibodies.

No causative or curative therapy exists for the polyneuropathy associated with antibodies to myelin‐associated glycoprotein (anti‐MAG). Rituximab is a mouse‐human chimeric antibody that specifically eliminates B‐cells and B‐cell precursors. Preliminary results suggest a beneficial effect on antibody‐dependent autoimmune diseases. Nine patients with an anti‐MAG–associated IgM polyneuropathy received rituximab once weekly for 4 weeks. In all patients, the number of B‐cells in the peripheral blood declined below levels of detection, and the IgM levels decreased between 35% and 82% (median, 58%). In eight patients, lowering of the anti‐MAG antibody titers of more than 52% was observed. Clinical status improved in six patients, remained stable in two, and worsened in one. The motor nerve conduction velocity improved by at least 10% in one ulnar nerve in seven patients and worsened in two. Rituximab was well tolerated and is a promising new drug in the treatment of patients with anti‐MAG–associated polyneuropathy. Muscle Nerve 27:611–615, 2003

TNF-alpha expression in painful and nonpainful neuropathies

Objective: To determine whether the cytokine tumor necrosis factor α (TNF-α) acts as a pain mediator in neuropathic pain in humans. Background: In animal models, inflammatory cytokines such as TNF-α have been shown to facilitate neuropathic pain. Methods: The expression of TNF-α was analyzed immunohistochemically in 20 human nerve biopsy specimens of patients with painful (n = 10) and nonpainful (n = 10) neuropathies. Additionally, serum soluble TNF-α receptor I (sTNF-RI) levels were determined in 24 patients with neuropathies, 16 of which were painful and 8 that were painless. Results: Colocalization studies by confocal fluorescence microscopy for S-100 and TNF-α showed expression of TNF-α in human Schwann cells. Patients with painful neuropathies showed a stronger TNF-α immunoreactivity in myelinating Schwann cells relative to the epineurial background staining compared with patients with nonpainful neuropathy (0.949 ± 0.047 vs 1.010 ± 0.053, p < 0.05). Although there was no difference in sTNF-RI levels between painful (n = 16) and nonpainful (n = 8) neuropathies (sTNF-RI: 1412 ± 545 pg/mL vs 1,318 ± 175 pg/mL), patients with a mechanical allodynia (n = 9) had elevated serum sTNF-RI (1627 ± 645 pg/mL vs 1233 ± 192 pg/mL, p < 0.05) compared with patients without allodynia (n = 15). Conclusions: TNF-α expression of human Schwann cells may be up-regulated in painful neuropathies. The elevation of sTNF-RI in patients with centrally mediated mechanical allodynia suggests that systemic sTNF-RI levels may influence central pain processing mechanisms.

Pathologic gambling in patients with Parkinson's disease.

Patients with Parkinsons disease frequently have depression, anxiety, and obsessive-compulsive disorder. We observed two patients who had episodes of pathologic gambling. At the same time, their Parkinsons disease deteriorated and they initiated self-medication with dopaminergic drugs. In both patients, signs were present of an addiction to dopaminergic medication. Pathologic gambling ceased in these patients after a few months. The significance of an insufficient dopaminergic reward system in patients with stereotypical addictive-like behavior (e.g., pathologic gambling) is discussed in this report. The most likely explanation for this newly recognized behavioral disorder in patients with Parkinsons disease is enhanced novelty seeking as a consequence of overstimulation of mesolimbic dopamine receptors resulting from addiction to dopaminergic drugs.

High-dose rituximab and anti-MAG-associated polyneuropathy

Rituximab has been administered successfully in patients with polyneuropathy associated with antibodies to myelin-associated glycoprotein (anti-MAG). The authors present a follow-up study with high-dose rituximab. Increase of rituximab from 375 mg/m2 to a dose of 750 mg/m2 was well tolerated and led to clinical improvement in four of eight patients, along with improvement of nerve conduction velocities and a reduction of anti-MAG antibody titers.

Anti-myelin-associated glycoprotein neuropathy.

Purpose of reviewThe anti-myelin-associated glycoprotein (MAG) neuropathy is an antibody-mediated demyelinating neuropathy. The clinical picture is characterized by a distal and symmetric, mostly sensory neuropathy. Monoclonal immunoglobulin M anti-MAG antibodies are uniquely found in this condition and are believed to be pathogenic. This review focuses on recent progress in understanding the mechanisms of this neuropathy and discusses new therapeutic advances. Recent findingsDifferent electrophysiological parameters have been demonstrated to distinguish the anti-MAG-associated polyneuropathy from chronic inflammatory demyelinating polyneuropathy. The electrophysiological findings generally indicate a predominantly demyelinating neuropathy with a distal accentuation of conduction slowing. Analyses of pathology in nerve tissue from anti-MAG patients using classical nerve biopsy or skin biopsy tissue demonstrated immunoglobulin M deposits at the site of MAG localization, demyelination and axonal degeneration. MAG is a Schwann cell-based glycoprotein and has been implicated as a mediator of an outside-in signaling cascade influencing the cytoskeletal integrity of axons. SummaryTherapy in patients with anti-MAG neuropathy is directed at reducing the antibody concentration, blocking the effector mechanisms and depleting the monoclonal B cells. The recent availability of rituximab, a monoclonal antibody suppressing B-cell clones, which is not myelosuppressive and does not cause secondary malignancies, allows for early targeted intervention.

Immunoglobulin M Deposition in Cutaneous Nerves of Anti-Myelin-Associated Glycoprotein Polyneuropathy Patients Correlates With Axonal Degeneration

Anti-myelin-associated glycoprotein (MAG) neuropathy is an antibody-mediated polyneuropathy. We correlated clinical features, immunoglobulin (Ig) M blood levels, IgM deposition and axonal degeneration in skin biopsies of anti-MAG neuropathy patients. By confocal microscopy, IgM deposits were found exclusively within perineurium-enclosed nerves; they were not found on single, non-perineurium-ensheathed myelinated axons. There was a linear correlation between IgM accumulation in nerve fascicles with IgM blood levels but not with anti-MAG antibody titer or disease duration. Axons with specific IgM deposits had signs of axonal damage, including neurofilament disintegration. Nodal structures were intact even at sites where the axons showed pathologic changes. Ultrastructural analysis revealed degeneration of myelinating Schwann cells. Taken together, these findings suggest that inanti-MAG neuropathy patients, IgM deposits are entrapped within cutaneous perineurium-ensheathed nerve bundles where they accumulate in the endoneurial space. High local IgM levels in the endoneurium may be required for IgM deposition on myelin and subsequent axonal injury and degeneration. This study underlines theimportance of early, effective anti-B-cell treatments for preventing progression of this neuropathy.

Distal motor latency and residual latency as sensitive markers of anti-MAG polyneuropathy.

Abstract. There is debate whether the terminal latency index (TLI) is a sensitive marker for polyneuropathy with anti-myelinassociated-glycoprotein antibodies (anti-MAGP). We examined 6 patients with an anti-MAGP and 6 patients with a chronic inflammatory demyelinating polyneuropathy (CIDP). The electroneurographic features studied were: distal compound motor action potential (CMAP), distal motor latency (DML), motor conduction velocity (MCV) elbow to wrist (distal MCV), MCV axilla to elbow (proximal MCV), MCV distal/proximal, terminal latency index (TLI), residual latency (RL), F-wave, and modified F ratio.We found significant differences between anti-MAGP and CIDP for DML and for RL.No significant differences were found for TLI and the other measures. The TLI values were not significant probably because our patients had a longer duration of disease,which supports the hypothesis of a distal to proximal progression of conduction slowing over time. We propose that a residual latency >4.0 and a distal motor latency >7.0 are strongly suggestive for an anti- MAGP.

Matrix metalloproteinases in neuromuscular disease

Matrix metalloproteinases (MMPs), a family of zinc‐dependent endoproteinases, are effector molecules in the breakdown of the blood–brain and blood–nerve barrier, and promote neural tissue invasion by leukocytes in inflammatory diseases of the central and peripheral nervous systems. Moreover, MMPs play an important role in synaptic remodeling, neuronal regeneration, and remyelination. Recent work concerning MMPs in patients with neuropathy, myopathy, spinal cord injury, and amyotrophic lateral sclerosis (ALS), and in corresponding animal models, is discussed in this review. Muscle Nerve, 2007

Matrix metalloproteinases-9 and -2 in secondary vasculitic neuropathies

Abstract. Matrix metalloproteinases (MMPs) are a family of zinc-dependent endoproteinases that play an important role in inflammation and tissue degradation. MMP-9 and MMP-2 are gelatinases that have been implicated in the degradation of the blood-brain or blood-nerve barrier. We present an immunohistochemical study on 11 nerve biopsy samples of inflammatory and non-inflammatory polyneuropathies. Perineurium and endothelium were positive for MMP-2 in all tissue sections. In addition, there was a specific up-regulation of MMP-2 in stromal cells of chronic inflammatory demyelinating polyneuropathy (CIDP) and even more in vasculitic neuropathies. MMP-9-positive cells were detected in vessel walls, infiltrates, epineurium and endoneurium of vasculitic neuropathies. In CIDP, MMP-9-positive cells were prominent in vessel walls. Only a few MMP-9-positive cells were detected in noninflammatory controls in blood vessels and adhering to vessel walls. Double staining indicated that the infiltrating cells were T cells and macrophages. Our findings suggest that MMP-9 plays an important role in inflammatory peripheral neuropathy probably as means for inflammatory cell invasion.

Allograft inflammatory factor-1: A pathogenetic factor for vasculitic neuropathy

Allograft inflammatory factor‐1 (AIF‐1) is a cytokine that plays a major role in the immune response and proliferative vasculopathy that occur during chronic allograft rejection. The purpose of this study was to characterize the cellular expression pattern and pathogenetic role of AIF‐1 in nerve biopsies from patients with vasculitic neuropathy. We performed immunohistochemistry in human nerve biopsies of 10 patients with vasculitic neuropathies (VASs), 6 with chronic inflammatory demyelinating polyneuropathies (CIDPs), 5 with noninflammatory axonal neuropathies (NIANs), and 3 control nerves (CNs). In the CIDP and VAS nerves, AIF‐1 expression was higher than in CN and NIAN nerves (P < 0.05). AIF‐1 was increased in the arterial walls of VAS compared with CIDP nerves (P < 0.05). Vascular smooth muscle cells in vasculitic nerve express AIF‐1 at a higher level compared with CIDP and NIAN. AIF‐1 plays a role in inflammatory nerve disease and vascular smooth muscle cell proliferation and may be a new molecular target for treatment. Muscle Nerve 38: 1272–1279, 2008