Treatment of multifocal motor neuropathy with intravenous immunoglobulin.

Multifocal motor neuropathy (MMN) is a rare inflammatory, chronically progressive, unremitting disorder affecting the peripheral nervous system. Although the etiology of this condition is not known, high titers of IgM Ab to GM1 may serve as a biomarker for this disease. Clinical findings of motor weakness are associated with focal conduction blocks and with time, axonal destruction. Evidence supporting an immune etiology as well as the use of intravenous immunoglobulin to limit the disease progression is reviewed.

Intravenous immunoglobulin use for neurologic diseases.

Intravenous immunoglobulin (IVIG) has been used primarily for immune deficiency patients, and its greatest expansion is seen more and more in the treatment of autoimmune disorders, especially in neurology. The benefits of IVIG treatment include its availability in all treatment centers and its ease of administration in an outpatient setting. This article gives an overview of some autoimmune neurologic diseases and explores the clinical evidence supporting the use of IVIG.

JNK1 activation mediates C5b-9-induced P0 mRNA instability and P0 gene expression in Schwann cells.

The protein zero (P0) glycoprotein is an important component of compact peripheral nerve myelin produced by the glial cells of the mammalian peripheral nervous system. P0 mRNA expression is reduced following exposure of Schwann cells to sublytic C5b-9, the terminal activation complex of the complement cascade. Sublytic complement treatment decreased P0 mRNA by 81% within 6 h and required C5b-9 assembly. C5b-9 induced a threefold increase in both JNK1 activity and c-jun mRNA within 20 and 30 min, respectively, compared with cells treated with either human serum depleted of complement component C7 (C7dHS) or medium alone. Sublytic C5b-9 stimulation, in the presence of the transcription inhibitor Actinomycin D, decreased P0 mRNA expression by 52%, indicating that mRNA was selectively destabilized. This effect was prevented by pretreatment with L-JNK inhibitor 1 (L-JNKI1). To study a potential inhibition of P0 gene transcription, we transfected Schwann cells with a P0 promoter-firefly luciferase construct. Sublytic C5b-9 stimulation of the transfected cells decreased luciferase activity by 82% at 6 h, and this effect was prevented by pretreatment with L-JNKI1 inhibitor. Our results indicate that the ability of C5b-9 in vitro to affect P0 gene expression is mediated via JNK1 activation that leads to enhanced mRNA decay and transcriptional repression of P0.

Initial and long-term management of autoimmune neuropathies.

The inflammatory neuropathies (chronic inflammatory demyelinating polyradiculoneuropathy [CIDP], Guillain-Barré syndrome [GBS] and multifocal motor neuropathy [MMN]) affect only one to two individuals per 100 000 of the population, but result in major disability and impairment. Intravenous immunoglobulin (IVIg) can be used as an initial treatment for CIDP, GBS and MMN. While plasma exchange and corticosteroids can also be used initially, they are not as uniformly effective for each of these disorders as IVIg. Substituting corticosteroids, plasma exchange or immunosuppressants may be appropriate for patients not responding to initial IVIg therapy, and combination therapy may be needed in some patients. There are no data from controlled clinical trials of long-term management strategies for CIDP and MMN; however, empirical evidence suggests that a positive long-term response to IVIg can be achieved by increasing the initial dose or its frequency of administration. Corticosteroids and immunosuppressants may be appropriate in some patients with CIDP. Adverse events with IVIg are usually mild and not treatment limiting; however, patients do need to be monitored for uncommon, but serious, adverse events such as renal insufficiency, stroke and thromboembolic events. Nevertheless, the safety profile of IVIg is exceptional relative to the potential complications of other long-term treatments for CIDP and MMN, especially corticosteroids and immunosuppressants. Predictors of response have been reported for each of the neuropathies, and until controlled clinical trials provide evidence on which to base treatment strategies, effective management will require individualising therapy according to patient response.

Regulation of cytokine-induced neuron death by ovarian hormones: involvement of antiapoptotic protein expression and c-JUN N-terminal kinase-mediated proapoptotic signaling.

Mechanisms underlying the divergent effects of ovarian hormones on neuron death induced by TNFalpha were investigated in differentiated PC12 cells (dPC12). dPC12 cells were exposed to 17beta-estradiol (E, 1.0 nm), progesterone (P, 100 nm), or a combination of both hormones for 0-72 h before treatment with TNFalpha (0-150 ng) to induce cell death. Cells undergoing apoptosis were identified by a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling assay and fluorescence-activated cell sorting after 18 h. Cell death induced by TNFalpha was decreased 89% after E treatment and increased 2-fold after P treatment compared with cells treated with TNFalpha alone. Treatment with E for 24 h before TNFalpha exposure was required for maximum neuroprotection, whereas P-enhanced death was maximal after a 30-min P treatment. TNFalpha induced a 3-fold increased activity of c-JUN-N-terminal kinase (JNK) 1 in d PC12 cells within 20 min that could be increased 5- to 8-fold by P together with TNFalpha. A peptide inhibitor of JNK1 abrogated P enhancement of TNFalpha-mediated dPC12 death but had only a minimal effect on cell death by TNFalpha alone. Inhibition of caspase-8 activation reduced death induced by TNFalpha alone but was much less effective for P+TNF. P alone did not activate caspase-8. E increased estrogen receptor alpha (ERalpha) and Bcl-xL expression and all but abolished TNFalpha receptor 1 (TNFR1) expression. P decreased ERalpha and Bcl-xL expression and doubled TNFR1 expression. These data suggest that P regulates apoptosis or survival through augmentation of JNK signaling and altered TNFR1 expression, whereas E mainly affects the expression of BCL-xL, TNFR1, and ERalpha.

Therapy of CIDP and related immune-mediated neuropathies.

This study assesses the data supporting the current use of immunotherapy for management of neuropathies with a presumed autoimmune basis. Immune or inflammatory mechanisms are implicated in an increasing number of disorders that involve damage to peripheral nerves and sensory ganglia. The most prevalent of these is chronic inflammatory demyelinating polyradiculoneuritis (CIDP). CIDP is clinically distinguishable from a series of other immune- or inflammation-mediated neuropathies. These include the following: multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy associated with conduction block; brachial or lumbar plexitis; multifocal motor neuropathy, a distal demyelinating neuropathy associated with antibodies to the myelin-associated glycoprotein (MAG); and sensory neuronopathy. We reviewed the literature of the National Library of Medicine using the above terms and their variations. The results from short-term, randomized, controlled trials support the efficacy of intravenous immunoglobulin (IVIg), plasma exchange, and corticosteroids in the treatment of CIDP, and the efficacy of IVIg in the treatment of MMN. Only anecdotal experience is available for assessing the treatment of MADSAM neuropathy, lumbar and brachial plexitis, MAG neuropathy, and sensory neuronopathy. Cytotoxic and immunosuppressive drugs are frequently used to treat patients with many of these disorders when they are refractory to standard treatments, but no controlled trials have been done to support their use. This review discusses the complications and criteria for use of these therapies. Selecting the best immunotherapy for an individual patient should be based on the proven efficacy of a given regimen in modulating the pathophysiology underlying the neuropathy, the anticipated duration of disease, and the patient's age, reproductive status, and coexisting metabolic derangement.