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Abstract
Inflammatory neuropathies are uncommon but important to diagnose because they are treatable. This review summarizes the immunological role in the pathogenesis , and different modalities in the diagnosis and treatment of Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), Diabetic neuropathies and related neuropathies which are thought to be caused by direct autoimmune attack on peripheral nerves.
Inflammatory neuropathies cause severe paralysis and loss of sensation. Antibodies were found within patients with inflammatory neuropathies and shown that they bind to nerve fibres at the nodes of Ranvier where nerve impulses are generated. Some antibodies affect the activity of ion channels and hence cause a block in the nerve conduction. Other antibodies bind to components of the Schwann cells that form the insulating compact myelin around nerve fibres thereby slowing nerve conduction. Features that suggest that a neuropathy is likely to be inflammatory include loss of reflexes without muscle wasting, elevated cerebrospinal fluid (CSF) protein, positive sensory symptoms such as pain or tingling, asymmetry, and proximal weakness. Nerve conduction studies show features of demyelination, especially motor nerve conduction block and temporal dispersion. Inflammatory neuropathy has been arbitrarily classified according to the time from symptom onset until maximal severity, where “acute” is less than four weeks and “chronic” is more than eight weeks, with a rare intermediate “subacute” group.
By using treatment which removes or neutralises such antibodies we are able to restore nerve function so that patients formerly confined to bed or wheelchair can return to normal lives. Intravenous immunoglobulin (IVIg) is the major treatment for inflammatory neuropathy.
Guillain-Barre syndrome is the most common cause of acute generalized weakness. Of the identified antecedent pathogens, Campylobacter jejuni is most common. Cytomegalovirus, Epstein-Barr virus, and Mycoplasma pneumoniae are other commonly identified antecedent pathogens. The underlying pathogenesis of all subtypes of Guillain-Barre syndrome remains incompletely understood. It is considered an autoimmune disease with both cell mediated and humeral immune system involvement. Recent research highlights the role of molecular mimicry with antibodies to a foreign antigen believed to crossreact against various gangliosides. The lipopolysaccharide from C. jejuni, the most commonly associated antecedent pathogen, contains a tetrasaccharide identical to that of ganglioside GM1, and serum samples from patients with GBS following infection with C. jejuni have demonstrated high titres of antibodies against a number of gangliosides, including GM1, GM1b, and GD1a. Many trials have demonstrated the efficacy of plasma exchange and intravenous immunoglobulin (IVIg) in the treatment of GBS. Both treatments are equally effective in hastening recovery. The risk of adverse events, however, appears somewhat higher with plasma exchange as compared with IVIg. For this reason, we advocate the use of IVIg unless unavailable or contraindicated.
Despite their apparent similarities, CIDP is a different disease from GBS. Unlike GBS, however, there is no consistent evidence of association with antecedent infection. The diagnosis rests primarily on clinical criteria, with electrophysiologic and laboratory data used to support the clinical diagnosis. Chronic inflammatory demyelinating polyneuropathy may be associated with concurrent systemic illness, including HIV, systemic lupus erythematosus, hepatitis B or C, lymphoma, monoclonal gammopathy of uncertain significance, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes), Castleman disease, diabetes, and inflammatory bowel disease. There is also an association with organ or bone marrow transplantation.
The pathogenic basis of CIDP is presumably autoimmune. Both humoral and cell-mediated mechanisms appear to contribute to the pathogenesis; however, the exact mechanism is unknown. Endoneurial inflammatory changes with T-cell infiltrates are seen in the acute phase. Myelin degradation appears to be initiated by macrophages, as no consistent changes have been identified in fibers that are not in contact with these cells. Although some evidence for molecular mimicry has been identified in GBS, no such correlation has yet been demonstrated in CIDP.
Randomized controlled trials have demonstrated the efficacy of corticosteroids, plasma exchange, and IVIg. In general, either IVIg or prednisone is used as initial therapy. Although plasma exchange could be used as a first-line treatment, it is generally reserved for patients who do not respond adequately to either prednisone and/or IVIg. Plasma exchange is used in combination with highdose prednisone for acute treatment of severely disabled patients (ie, those unable to walk at the time of presentation).
Other immunomodulating therapies (ie, azathioprine, mycophenolate mofetil, cyclosporine, and cylcophosphamide) can be used in patients who do not adequately respond to prednisone, IVIg, or plasma exchange. However, the long-term effect of these therapies on the neuropathy remains unclear so far. Moreover, serious side effects or even toxicity may be associated with this therapy. It remains still open whether, until safer and more effective therapy become available, current immune therapies should be reserved for severely impaired patients only. More recent data support the use of a new promising drug: Rituximab, a monoclonal antibody directed against the B cell surface membrane marker CD 20,which has been shown to be able to improve strength and reduce the level of serum IgM antibodies.
Regarding diabetic neuropathies, the pathophysiologic basis leading to the development of peripheral neuropathy in diabetes is not understood completely. Multiple hypotheses have been advanced. It is generally accepted as a multifactorial process.The most accepted theories are ; the metabolic theory, the vascular theory, laminin theory, altered neurotrophic support theory and autoimmune theory. Diabetic Amyotrophy has been lately associated with an inflammatory angitis. based on this , IVIg is used in the treatment of it.