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Numerous clinical forms of CIDP have been described, but pain is generally considered a rare or secondary sign. We describe here the clinical, electrophysiological and neuropathological characteristics of five patients with CIDP and pain as the main presenting symptom, and their course with treatment. Between January 2003 and December 2004, we selected five patients with prominent or isolated pain among 27 patients diagnosed with CIDP. All patients were subjected to clinical and electrophysiological examinations, and had a complete laboratory work up to exclude other causes of neuropathy. In view of the atypical clinical presentation, all five patients underwent nerve biopsy. There were two men and three women. The mean age at onset of neuropathy was 70+/-7.39 years. All patients initially presented with pain in the lower limbs associated with modest motor impairment (1 case), distal paresthesia (4 cases), cramps (1 case) and fatigue (2 cases). CSF was normal in three cases. On electrophysiological examination, three patients had nerve conduction abnormalities with subtle or clear signs of demyelination: three (case 1, 2 and 4) fulfilled the criteria of Rotta et al. and two (case 2 and 4) the criteria of both Nicolas et al and the INCAT group. Patients were all given symptomatic treatment and four patients received an immunomodulatory treatment, which was constantly effective. Pain may be a major and disabling symptom in patients with CIDP, so this diagnosis has to be considered in patients referred for a painful polyneuropathy. Moreover, immunomodulatory treatment has to be considered in such patients as symptomatic therapy may be ineffective.

Leprosy, also known as Hansen's disease, is a chronic, infectious disease caused by Mycobacterium leprae. Bacilli localize preferentially in the skin and peripheral nerves and have a propensity to cause nerve damage. The resulting disability has caused great suffering for victims in many countries. Despite recent advances in the immunopathogenesis, epidemiology and prognostic factors of leprosy nerve damage, many aspects of the disease have remained enigmatic. The spectrum of clinical and pathological manifestations of the disease ranges from lepromatous to tuberculoid, depending on the host's T-cell-mediated immune response. Diagnosis is based on three criteria: characteristic skin lesions in association with thickened nerves, demonstration of acid fast bacilli in slit skin smears, and histopathology of skin biopsies. Nerve biopsy is necessary to establish the diagnosis of pure "neural leprosy". In developed countries, the diagnosis is suspected when a patient who has stayed in an endemic area suffers from a peripheral neuropathy of unknown etiology. To facilitate determination of the appropriate antibiotic regimen, patients are classified as either paucibacillary or multibacillary. Some patients may have multibacillary leprosy in nerves and paucibacillary leprosy in skin, which emphasizes the usefulness of nerve biopsy. The course of the disease is often complicated by immune mediated "reactions", which can rapidly lead to further nerve damage, namely reversal reaction and erythema nodosum leprosy. However, nerves are often functionally impaired before developing obvious symptoms such as skin reactions or nevralgia (silent neuropathy). Early recognition and prompt treatment with corticosteroids of leprous reactions and "silent neuropathies" is very important to prevent disability with all its attendant problems. Research progress from clinical trials may improve current methods of prevention and treatment of nerve damage in leprosy.

Protein Zero (P0), the major structural protein in the peripheral nervous system (PNS) myelin, acts as a homotypic adhesion molecule and is thought to mediate compaction of adjacent wraps of myelin membrane. E-Cadherin, a calcium-dependent adhesion molecule, is also expressed in myelinating Schwann cells in the PNS and is involved in forming adherens junctions between adjacent loops of membrane at the paranode. To determine the relationship, if any, between P0-mediated and cadherin-mediated adhesion during myelination, we investigated the expression of E-cadherin and its binding partner, beta-catenin, in sciatic nerve of mice lacking P0 (P0(-/-)). We find that in P0(-/-) peripheral myelin neither E-cadherin nor beta-catenin are localized to paranodes, but are instead found in small puncta throughout the Schwann cell. In addition, only occasional, often rudimentary, adherens junctions are formed. Analysis of E-cadherin and beta-catenin expression during nerve development demonstrates that E-cadherin and beta-catenin are localized to the paranodal region after the onset of myelin compaction. Interestingly, axoglial junction formation is normal in P0(-/-) nerve. Taken together, these data demonstrate that P0 is necessary for the formation of adherens junctions but not axoglial junctions in myelinating Schwann cells.

Mutations in the connexin 32 gene (Cx 32) are associated with the x-linked form of Charcot-Marie-Tooth disease (CMTX) and segregate with a CMT 1 phenotype. The gap junction protein Cx 32 is expressed in myelinating Schwann cells and has been localized to regions of non-compacted cytoplasm in paranodes and in Schmidt-Lanterman incisures. Mutant Cx 32 myelin proteins are predicted to impair Schwann cell functions. We have studied the resulting pathology in motor and sensory nerves from the probands of 13 CMTX kindreds with precisely defined genotype. This report provides a detailed descriptive and morphometric analysis of 14 CMTX nerve biopsy samples, taken at various stages in the development of the neuropathy and studied by light and electron microscopic examination. Findings indicated unusually prominent changes in paranodal myelin with resulting widened nodes of Ranvier, but with segmental demyelination being less common. In parallel early axonal cytoskeletal abnormalities were noted, which were followed later by axonal atrophy, degeneration and loss of myelinated nerve fibers, occurring in a length-dependent fashion. Regenerative sprouting was also unusually prominent. Ultrastructural abnormalities included a frequent dilatation of the adaxonal spaces, prominence of the adaxonal Schwann cell cytoplasm and widening of the Schmidt-Lanterman incisures. We conclude that mutations in Cx 32 gap junction protein lead to a compromise of Schwann cell functions and to impaired Schwann cell-axon interactions with subsequent pathology in both myelin and axons.

Pelizaeus-Merzbacher disease (PMD) is a dysmyelinating disorder of the central nervous system typically caused by duplications or missense mutations of the proteolipid protein (PLP) gene. Most investigators have found that peripheral nerve function and structure is normal in PMD patients. We have found that null mutations of the PLP gene cause demyelinating peripheral neuropathy, whereas duplications and a proline 14 to leucine mutation do not affect nerve function. A family with a nonsense mutation at position 144, which affects only PLP but not the alternatively spliced gene product DM20, has a very mild syndrome, including normal peripheral nerve function. Our findings suggest that DM20 alone is sufficient to maintain normal nerve function and that there may be domains of PLP/DM20 that have a relatively more active role in the peripheral nervous system compared with that in the central nervous system.

The association between a peripheral neuropathy (PN) and a monoclonal dysglobulinemia has often been reported. A causative link is however not always easy to establish. Therefore, to demonstrate with certainty that the dysglobulinemia is actually responsible for the PN, various clinical, electrophysiological and immunological criteria are employed. As a result of our personal experience, we wish to emphasize the benefit of the histological and immunopathological findings revealed by the nerve biopsy of these patients. The nerve biopsy results have, in addition, been combined and compared with the results of an indirect immunofluorescence study of the sera of these patients on normal human nerve. The results of these studies have permitted us, in about 70% of cases, to ascertain the mechanisms in question: the role of an eventual chemotherapy, the dysimmune process, the presence of abnormal immunoglobulins in the nerve, amyloidosis deposits, infiltrations of nerve parenchyma by abnormal cells, a combination of one or several of these mechanisms, etc... We were able to divide our 70 patients into 4 groups: group 1: "direct link" (55-60% of the cases), group 2: "indirect link" (10-15%), group 3: "no link" (10%), and group 4: "undetermined link" (about 20%). Analysis of group 1 revealed a statistically significant association between PN and type IgM Kappa MGUS.

For many years, nerve biopsy has been very useful for clarifying the mechanism and aetiology of human peripheral neuropathies. Recently, this morphological examination has greatly benefited from the contribution of new immunocytochemical, ultrastructural and molecular biological techniques, which can often be used together in studies on inflammatory, paraproteinaemic and genetic neuropathies.

The authors have reported four cases where the study of peripheral nerve biopsy revealed the presence of abnormal cells in the endoneurial space. Their bulky nuclei contain in fact numerous deposits more or less tubular reminiscent of the intranuclear structures observed in the multiple sclerosis brains, and other very rare diseases. Exceptionally it seems have these images been described in peripheral nerves. It must be stressed that only one patient had an inflammatory type disease. The meaning of these images is discussed, though no definite conclusion could be reached.

Recent reports have shown that intraneural injections of sera from patients with Guillain-Barré syndrome have demyelinating effects on rat peripheral nerve. Some authors have proposed that this could merely result from immune phenomena due to species differences. In this study we injected normal human sera and sera from normal Lewis rats into nerves of Lewis rats. We consider that the small lesions observed were due more to the injection procedure itself than to effects of the sera.

A case of Creutzfeldt-Jakob disease (CJD) in a 52-year-old man is described. At post mortem, extensive involvement of white matter was seen. A few similar cases have been reported mainly by Japanese authors. Our patients belonged to a French family in which 14 cases of CJD over three generations have been recorded. One of the patient's first cousins also had extensive white matter involvement. This is an unusual panencephalopathic form of CJD. The causes of the involvement of white matter are unknown. There was no clinical evidence of neuropathy but an electron-microscopic study of biopsied superficial peroneal nerve showed it to be present. Study of peripheral nerves is suggested for all patients with CJD.

The authors describe two typical cases of Portuguese amyloid neuropathy in immigrants. One of the patients had been ill for only a short time while the other's condition had been developing over more than ten years. The first patient's neuropathy was characterized by a perforating ulcer of the foot and loss of sensation. The neurological disorder as well as the effect on general health were much more serious in the second patient. Neuro-muscular biopsy was carried out on each of these patients and revealed excessive endoneural amyloid and very severe lesions of nerve parenchyma mainly secondary to Wallerian degeneration. The results were compared with the few existing ultrastructural studies on the peripheral nerve in amyloid neuropathies.