A case of inflammatory demyelinating polyradiculoneuropathy associated with T-cell lymphoma

Malignant lymphoma may present prominent peripheral nervous system disorders with variable etiologies. We describe a patient who presented with chronic relapsing polyradiculoneuropathy accompanied by right facial nerve palsy. Gadolinium enhancement of the right facial nerve and cervical spinal roots was noted on magnetic resonance imaging (MRI). Sural nerve biopsy specimens showed mononuclear cell infiltration around the vessels in the epineurium. Histopathological and immunohistochemical investigations of sural nerve specimens revealed perivascular infiltration of lymphocytes with T-cell dominancy. No apparent direct invasion of lymphoma cells was seen. The results of nerve conduction studies, sural nerve biopsy and cerebrospinal fluid examination were suggestive of immune-mediated inflammatory demyelinating neuropathy. The chronic and relapsing fashion and unique radiological findings in our patient expand on the previously reported features of peripheral neuropathy associated with peripheral T-cell lymphoma.     

Evidence favoring the involvement of CC chemokine receptor (CCR) 5 in T-lymphocyte accumulation in optic neuritis

OBJECTIVE: To define the relationships between levels of chemokine receptor (CCR)5+ T-cells in blood and cerebrospinal fluid (CSF) of optic neuritis (ON) and control patients (CON). MATERIALS AND METHODS: Expression of CCR5 and related receptors CCR1 and CCR3 on CD4- and CD8-positive T-cells in peripheral blood mononuclear cells (PBMC) and CSF was determined by flow cytometry in 20 patients with ON, 16 control patients with lumbar spondylosis, 20 healthy controls (HC) and 16 patients with rheumatoid arthritis (RA). RESULTS: CCR5+CD4+ and CD8+ T-cells were enriched in CSF, compared with PBMC, in both ON and CON patients (all P < 0.001), and the percentages of CD4+/CCR5+ (r = 0.917) and CD8+/CCR5+ (r = 0.828) cells in PBMC and CSF were strongly and directly correlated. CCR5+ T-cells produce high amounts of tumor necrosis factor-alpha (TNF-alpha) and very low amounts of interleukin-5 (IL-5). Closely related receptors (CCR1, CCR3) were not altered. CONCLUSIONS: Our data suggest an involvement of CCR5 in T-cell accumulation in the inflamed central nervous system.     

Physiology of conduction block in multifocal motor neuropathy and other demyelinating neuropathies

Conduction block is an important functional consequence of demyelination whereby nervous transmission is abolished. Its mechanism has been discussed with respect to the loss of insulation due to disruption of myelin. Recent development of threshold tracking techniques, which enabled noninvasive assessment of axonal membrane potentials and ion channels, has provided evidence that axonal excitability changes significantly and contributes to conduction failure. This view, based upon axo-glial interaction, clarifies the mechanism of muscle fatigue and fasciculation associated with peripheral demyelination and possibly explains selective motor involvement in multifocal motor neuropathy.     

Reaction of mouse brain oligodendrocytes and their precursors, astrocytes and microglia, to proinflammatory mediators circulating in the cerebrospinal fluid

The response of glial cells to the acute intracerebroventricular administration of interferon-gamma, and of this cytokine combined with the endotoxin lipopolysaccharide or with tumor necrosis factor-alpha, was investigated in the brain of adult mice over a time course of 1 week. Oligodendrocytes were identified by immunocytochemistry, using O4 to label their precursors and 2',3'-cyclic nucleotide 3'-phosphohydrolase as marker of mature cells. Astrocytes were labeled by glial fibrillary acidic protein immunoreactivity and microglial cells by tomato lectin histochemistry. Compared with ovalbumin-injected control cases, all cytokine treatments caused a marked decrease of immunostained mature oligodendrocytes in the brain since 1 day postinjection. O4+ oligodendrocyte precursors increased instead progressively from 2 to 7 days. Astrocytes, markedly activated by cytokine treatments, also exhibited a progressive quantitative increase from 2 days onward. Activation and proliferation of microglial cells were instead most evident at 24 h postinjection. Such glial responses to interferon-gamma injections were especially marked in the periventricular brain parenchyma and were enhanced by coadministration of lipopolysaccharide or tumor necrosis factor-alpha. The findings show that a pulse of proinflammatory mediators in the cerebrospinal fluid affects mature oligodendrocytes, concomitantly with the early appearance of activated microglia, and that such reactions are rapidly followed by an increase of oligodendrocyte precursors paralleled by astrocytic activation. The data, which allowed dissecting the events elicited in glial cell populations by inflammatory mediators via the cerebrospinal fluid, indicate that these molecules elicit in vivo a toxic effect on mature oligodendrocytes and a stimulation of their precursors in the adult brain.     

Both dorsal and ventral spinal cord pathways contribute to overground locomotion in the adult rat

Identification of long tracts responsible for spontaneous locomotion is critical for spinal cord injury (SCI) repair strategies. We recently demonstrated that extensive demyelination of adult rat thoracic ventral columns, ventromedial, and ventrolateral white matter produces persistent, significant open-field hindlimb locomotor deficits. Locomotor movements resulting from stimulation of the pontomedullary locomotor region are inhibited by dorsolateral funiculus (DLF) lesions suggesting that important pathways for locomotion may also exist in the dorsal white matter. However, dorsal hemisections that interrupt dorsal columns/dorsal corticospinal tract (DC/CST) and DLF pathways do not produce persistent, severe locomotor deficits in the adult rat. We studied the contributions of myelinated tracts in the DLF and DC/CST to overground locomotion following complete conduction blockade of axons in the ventrolateral funiculus (VLF), a region important for locomotor movements and for transcranial magnetic motor-evoked potentials (tcMMEP). Animals received ethidium bromide plus photon irradiation to produce discrete demyelinating lesions sufficient to stop axonal conduction in the VLF, combined VLF + DLF, or combined VLF + DC/CST. Open-field BBB scores and tcMMEPs were studied at 1, 2, 3, and 4 weeks postlesion. VLF lesions resulted in mean BBB scores of 17 at 4 weeks. VLF + DC/CST and VLF + DLF lesions resulted in mean BBB scores of 15.9 and 11.1, respectively. TcMMEPs were absent in all lesion types confirming VLF conduction blockade throughout the study. Our data indicate that significant contributions to locomotion from myelinated pathways within the rat DLF can be revealed when combined with simultaneous compromise of the VLF.     

Demyelination associated with HSV-1-induced facial paralysis

In 1995, we developed an animal model of transient homolateral facial nerve paralysis by inoculating Herpes simplex virus type 1 (HSV-1) into the auricle of mice. This study examined the mechanism of facial nerve paralysis in this model histopathologically. Using the immunofluorescence technique with anti-HSV-1 antibody, the time course of viral spread and the site of viral replication were investigated over the entire course of the facial nerve. Furthermore, viral replication and nerve degeneration at the site of viral replication were observed by electron microscopy. On the 7th day after inoculation, facial paralysis was observed in more than 60% of mice. Immunofluorescence study revealed HSV-1 in the geniculate ganglion, the descending root, and the facial nucleus at this stage. On the 9th day, the descending root in the sections stained with osmium looked pale, because prominent demyelination had occurred in this region; electron micrographs showed many degenerated oligodendrocytes and large naked axons. In contrast, the facial nucleus neurons showed no remarkable degeneration, despite HSV-1 particles in their cytoplasm. From these findings, we concluded that facial nerve paralysis in this model is caused mainly by facial nerve demyelination in the descending root.     

Abnormalities of axonal excitability are not generalized in early multifocal motor neuropathy

The clinical and neurophysiological features of multifocal motor neuropathy (MMN) indicate selective involvement of motor axons, but pathological abnormalities in sensory axons suggest a more widespread disease process. The present study was undertaken to determine whether the focal abnormalities are associated with widespread subclinical abnormalities in motor axons. Threshold tracking was used to measure excitability properties (stimulus-response curves, strength-duration properties, recovery cycle, and threshold electrotonus) of the median nerve in five patients with MMN with lesions proximal to the site of testing. Patients were compared with 25 healthy controls. The changes in excitability indices were similar to those in controls, and in one patient there was no alteration after treatment with intravenous gammaglobulin. In this patient, indices of axonal excitability were also measured before, during, and after ischemia of the arm for 10 min. Again no differences were detected. This study provides no evidence for a generalized subclinical abnormality in MMN, at least when disease duration is less than 6 years.     

Dietary copper enhances the peripheral myelinopathy produced by oral pyrrolidine dithiocarbamate.

The neurotoxic hazard of a dithiocarbamate is influenced by route of exposure and acid stability of the dithiocarbamate. As an example, oral administration of the acid labile dithiocarbamate N,N-diethyldithiocarbamate (DEDC) causes a central-peripheral axonopathy thought to result from acid-promoted decomposition to CS2 in the stomach. In contrast, parenteral administration of DEDC, which bypasses the acidic environment of the stomach, causes a primary demyelination that is thought to be mediated through the intact parent dithiocarbamate. The relative acid stability of pyrrolidine dithiocarbamate (PDTC) suggests that a significant portion of a dose can be absorbed intact following oral exposure with the potential to produce a primary myelin injury. The present study was performed to characterize the neurotoxicity of PDTC and evaluate the possible role of copper in dithiocarbamate-mediated demyelination. Male Sprague Dawley rats were administered PDTC in drinking water and given either a normal- or high-copper diet for 18, 47, or 58 weeks. Examination of peripheral nerve by light microscopy and electron microscopy at the end of exposures revealed primary myelin lesions and axonal degeneration in the PDTC groups, with a significant increase in the severity of several lesions observed for the PDTC, high-copper group relative to the PDTC normal-copper diet. ICP-AES metal analysis determined that the PDTC groups had significantly increased brain copper, and at 58 weeks a significant increase in copper was seen in the sciatic nerve of PDTC high-copper animals relative to PDTC normal-copper diet animals. Although RP-HPLC analysis could not detect globin alkylaminocarbonyl cysteine modifications analogous to those seen with parenteral DEDC, LC/MS/MS identified (pyrrolidin-1-yl carbonyl)cysteine adducts on PDTC-exposed rat globin. These findings are consistent with previous studies supporting the ability of acid-stable dithiocarbamates to mediate myelin injury following oral exposure. The greater severity of lesions associated with dietary copper supplementation and elevated copper levels in nerve also suggests that perturbation of copper homeostasis may contribute to the development of myelin lesions.