Upper gastrointestinal motility changes following spinal cord injury.

Spinal cord injury (SCI) is associated with severe autonomic dysfunction in both the acute and chronic phases. Upper gastrointestinal (GI) motor dysfunction has been previously reported in humans and rats. Gastric emptying (GE) of a solid meal--as measured by the [(13)C]-octanoic acid breath test--is delayed in the first 3 weeks after either spinal cord transection (SCT) or contusion (SCC) in rats. This is one of the main findings of a new paper by Qualls-Creekmore et al. in the current issue of this journal. Previous studies in rats only reported impairment of GE, intestinal and GI transit of liquid after SCI, but the authors observed that the delay of the GE of solid was more prominent after SCT than SCC. Recovery of the delay of GE of solid occurred at 6 weeks after SCC, but not after SCT. However, gastric motility changes persisted despite the functional normalization of the GE in rats with SCC. Bowel dysfunction is a major physical and psychological burden for SCI patients. Collaborative efforts, like the development of international standards to evaluate autonomic function after SCI will likely clarify the mechanisms of dysfunction and lead to the development of new therapeutic strategies.

Fou rire prodromique and history of pathological laughter in the XIXth and XXth centuries.

Fou rire prodromique (prodrome of crazy laughter) is a rarely described nosological entity. In 1903, Charles Féré, a French neurologist, introduced the term fou rire prodromique to describe pathological laughter heralding an apoplectic event. He was also among the first to describe gelastic epilepsy. His description was influenced by Edouard Brissaud, who supported the existence of a thalamic center for laughter regulation and suggested that spasmodic laughter and crying were due to lesions of the faisceau psychique (anterior internal capsule) or to irritation of the faisceau géniculé (corticobulbar tract). One hundred Years later, we review the evolution of the theories about pathological laughter and crying from Charles Bell in the early XIXth Century, up to the seminal works of Kinnier Wilson and James Papez and the era of modern neuroscience.

Episodic hyperlibidinism in multiple sclerosis.

BACKGROUND: Changes in sexual function are commonly associated with MS and occur in many forms. Hypersexual thoughts or behavior are rare, but can present on the background of persistent cognitive impairment or psychiatric conditions such as mania, whereas isolated hypersexuality is still rarer. CASE REPORT: We describe the clinical, neuropsychological, electrodiagnostic, neuroimaging and endocrine findings in a MS patient with episodes of greatly increased libido. Imaging and neuropsychologicol studies indicated frontal lobe dysfunction; hormone studies showed no significant changes. CONCLUSION: Episodic hypersexuality can be a recurrent transient manifestation of MS.

Antibodies to GM1 and Gal(beta 1-3)GalNAc at the nodes of Ranvier in human and experimental autoimmune neuropathy.

Autoantibodies to Gal(beta 1-3)GalNAc epitopes on glycolipids and glycoproteins are associated with motor neuron disease and motor or sensorimotor neuropathy. These epitopes are ubiquitously distributed on cell surfaces. In the nervous system they are present on axons and myelin, specifically also at the nodes of Ranvier. Binding of GM1 antibodies to the nodal area may contribute to disease development in some of these conditions.

Expression of human immunodeficiency virus type 1 in the nervous system of transgenic mice leads to neurological disease.

Patients infected with the human immunodeficiency virus type 1 (HIV-1) frequently develop central and peripheral nervous system complications, some of which may reflect the effect of the virus itself. In order to elucidate the pathogenic mechanisms of HIV in neurological disease in a small animal model, we generated transgenic mice expressing the entire HIV genome under control of the promoter for the human neurofilament NF-L gene. The transgene was predominantly expressed in anterior thalamic and spinal motor neurons. Animals developed a neurological syndrome characterized by hypoactivity and weakness and by axonal degeneration in peripheral nerves. These results provide evidence for a role of HIV in affecting both the central and peripheral nervous systems. This animal model may also facilitate the development of therapeutic agents against the human disease.

Tomaculous neuropathy in chromosome 1 Charcot-Marie-Tooth syndrome.

We performed morphological and immunohistochemical studies on sural nerve biopsies from two members of a Charcot-Marie-Tooth type 1B family, in which a mutation of the P0 gene on chromosome 1 had been found. Biopsies showed a tomaculous neuropathy with loss of myelinated fibers and frequent small onion bulbs. Immunofluorescence with antibodies to P0 showed this protein to be present in tomaculous and non-tomaculous areas of the myelin sheath. The severity of the myelin abnormalities suggests that in this family Charcot-Marie-Tooth disease may result from a generalized disturbance of Schwann cells as a result of an abnormal P0 protein.

Vasculitic neuropathy in a patient with cryoglobulinemia and anti-MAG IGM monoclonal gammopathy.

A patient with sensorimotor mononeuritis multiplex had a type II cryoglobulin with an IgM kappa M-protein that appeared to contain monoclonal anti-MAG antibodies of the same isotype. A sural nerve biopsy demonstrated necrotizing arteritis and features of both axonal degeneration and demyelination. IgM kappa and C3 deposits were present on the myelin sheath of some residual nerve fibers. The findings suggest that the anti-MAG antibodies contributed to the myelin damage, while cryoprecipitates may have caused the vasculitis and axonal degeneration.

Experimental conduction block induced by serum from a patient with anti-GM1 antibodies.

Increased titers of antibodies to GM1 ganglioside in humans are associated with lower motor neuron disease and predominantly motor neuropathy with or without conduction block. To investigate the possible mechanism of these antibodies, we injected the serum of a patient with anti-GM1 antibodies who had motor neuron disease and multifocal motor conduction block, into rat sciatic nerve. When injected with fresh human complement, the serum-induced conduction block with temporal dispersion and deposits of immunoglobulin were detected at the nodes of Ranvier. Electron microscopic studies revealed demyelination in 6.5% of the fibers. After preabsorption with GM1, the serum had no effect, suggesting that the anti-GM1 antibodies were responsible for the conduction abnormalities.

Identification of glycoconjugates which are targets for anti-Gal(beta 1-3)GalNAc autoantibodies in spinal motor neurons.

Human IgM anti-Gal(beta 1-3)GalNAc antibodies which bind to GM1 and GD1b, are implicated in the pathogenesis of predominantly motor neuropathy or motor neuron disease. By immunofluorescence microscopy, the human antibodies immunostain the surface of motor neurons from bovine spinal cord. The motor neurons are also immunostained by cholera toxin (CT), which is specific for GM1. Glycolipid analysis using thin-layer chromatography (TLC) and immunostaining reveals that the relative concentration of GM1 and GD1b in motor neurons is greatly reduced in comparison to whole spinal cord, and that other motor neuron gangliosides are unreactive with the anti-Gal(beta 1-3)GalNAc antibodies. By Western blot analysis, the antibodies react with several protein bands in motor neuron extracts, and many of the same proteins are also recognized by PNA. These data suggest that both glycoproteins and glycolipids might be targets for anti-Gal(beta 1-3)GalNAc antibodies in spinal motor neurons.

Human monoclonal antineurofilament antibody cross-reacts with a neuronal surface protein.

Increased titres of anti-neurofilament antibodies have been reported in neurodegenerative disorders, and it has been suggested that such antibodies might be pathogenic. We investigated the specificity of an IgA monoclonal antibody (MAb) from a patient with amyotrophic lateral sclerosis which reacted with neurofilaments and bound to the surface of neuroblastoma cells. In Western blots, the immunoaffinity-purified IgA bound to the 220-kD, high-molecular-weight neurofilament protein (NFH) and cross-reacted with several closely migrating protein bands with apparent mobility of 62-68 kD in neuroblastoma cells and extracts of normal human spinal cord. Following crosslinking to the surface of radiolabeled neuroblastoma cells, the IgA MAb immunoprecipitated a 65-kD protein, indicating that the protein was present on the cell surface and available to the antibodies for binding. Several other MAbs to NFH did not immunostain the surface of neuroblastoma cells or bind to the 65-kD protein, indicating that the protein was not a fragment of NFH. Thus, antibody binding to the 65-kD protein, possibly by cross-reacting with NFH, may have contributed to the neuronal degeneration.

Experimental autoimmune neuropathy with anti-GM1 antibodies and immunoglobulin deposits at the nodes of Ranvier.

Antibodies to GM1 or Gal(beta 1-3)GalNAc are associated with motor or sensorimotor neuropathy and with motor neuron disease. To investigate the role of these antibodies in the neurological disorder, rabbits were immunized with GM1 or with Gal(beta 1-3)GalNAc-BSA, and studied serologically, electrophysiologically and pathologically. Development of antibodies to the immunizing antigens was associated with a fall in the ratio of the amplitudes of the compound muscle action potential evoked by proximal versus distal stimulation of the sciatic nerve. Pathological studies revealed mild axonal degeneration and immunoglobulin deposits at the nodes of Ranvier in peripheral nerve, resembling those reported in a patient with motor neuropathy, motor conduction block and anti-GM1 antibodies. These studies provide evidence that anti-GM1 or anti-Gal(beta 1-3)GalNAc antibodies cause conduction abnormalities and indicate that the antibodies may exert their effect, in part, by binding at the nodes of Ranvier in peripheral nerve.

[Anti-Gm1 antibodies in motor system diseases and neuropathies]. / Anti-GM1 Antikörper bei motorischen Systemerkrankungen und Neuropathien.

Increased serum titers of antibodies against the ganglioside GM1 or its carbohydrate epitope Gal(B1-3)GalNAc have been associated with motor neuron disease, motor neuropathies with or without conduction block and sensorimotor neuropathies, whereas low level titers are part of the normal immune repertoire and are present in control groups and in neonatal blood. The target antigens of the antibodies are widely distributed and highly concentrated in the peripheral and central nervous system. The antibodies could damage neural tissue at several anatomic sites. Possible binding sites are the anterior horn cells in the spinal cord and the nodes of Ranvier. Reduction of serum titers with chemotherapy or plasmapheresis can lead to clinical improvement.

IgM deposits at nodes of Ranvier in a patient with amyotrophic lateral sclerosis, anti-GM1 antibodies, and multifocal motor conduction block.

We studied a patient with amyotrophic lateral sclerosis, multifocal motor conduction block, and IgM anti-GM1 antibodies. A sural nerve biopsy demonstrated deposits of IgM at nodes of Ranvier by direct immunofluorescence. The deposits were granular and located in the nodal gap between adjacent myelin internodes, and in some instances, they extended along the surface of the paranodal myelin sheath. When injected into rat sciatic nerve, the serum IgM bound to the nodes of Ranvier, and the binding activity was removed by preincubation with GM1. These observations suggest that anti-GM1 antibodies may have caused motor dysfunction by binding to the nodal and paranodal regions of peripheral nerve.

A monoclonal IgA in a patient with amyotrophic lateral sclerosis reacts with neurofilaments and surface antigen on neuroblastoma cells.

A 75-year-old woman had breast carcinoma, an IgA paraprotein and autopsy-proven amyotrophic lateral sclerosis. Autopsy tissues showed immune-reactive IgA within surviving motor neurons and deposits of IgA and C3 within renal glomeruli. By indirect immunofluorescence, the patient's serum contained high-titer IgA that bound to axons and to the perikarya of nerve cells in central and peripheral nervous system. The IgA paraprotein reacted with the 200 kDa, high molecular weight subunit of neurofilament protein (NFH) in Western blots of purified neurofilaments. It also reacted with dephosphorylated NFH and with NFH expressed as a fusion protein in E. coli, suggesting that the autoantibody recognized a peptide epitope. The IgA crossreacted with a surface antigen of cultured human neuroblastoma cells but mouse monoclonal antibodies to NFH did not. Absorption of the patient's serum with neurofilaments eliminated IgA binding to neuroblastoma cells, indicating that the same antibodies bound to both determinants. The IgA paraprotein seems to be an autoantibody with specificity for neurofilament protein and a cell surface component of neuronal cells; the antibody may have been important in the pathogenesis of neuronal degeneration.

The spectrum of neurologic disease associated with anti-GM1 antibodies.

We compared anti-GM1 IgM antibody titers in patients with various neurologic diseases and in normal subjects. We found increased titers in patients with lower motor neuron disease, sensorimotor neuropathy, or motor neuropathy with or without multifocal conduction block. In patients with other diseases, titers are similar to those in normal individuals, suggesting that anti-GM1 antibody levels are not increased nonspecifically after neural injury or inflammatory diseases. Anti-GM1 antibodies in many of the patients occur as monoclonal gammopathies, predominantly of lambda light-chain type, but the antibodies are sometimes polyclonal with normal or increased serum IgM concentrations. Most of the anti-GM1 antibodies appear to react with the Gal(beta 1-3)GalNAc epitope which is shared with asialo-GM1 and GD1b, but in some patients the antibodies are more specific for GM1 and associated with motor neuropathy. Patients with motor or sensorimotor peripheral neuropathy or lower motor neuron disease should be tested for anti-GM1 antibodies or anti-Gal(beta 1-3)GalNAc antibodies, as therapeutic reduction in antibody concentrations was reported to result in clinical improvement in some patients.

Human monoclonal IgM anti-Gal(beta 1-3)GalNAc autoantibodies bind to the surface of bovine spinal motoneurons.

An IgM monoclonal autoantibody (M-protein) with anti-Gal(beta 1-3)GalNAc activity from a patient with lower motor neuron disease bound to the surface of motoneurons isolated from bovine spinal cord. The Gal(beta 1-3)GalNAc epitope is shared by the gangliosides GM1 and GD1b and by several glycoproteins in the nervous system, and binding was abolished by preabsorbing the patient's serum with GM1. Antibodies specific for GM1, however, which do not bind to GaL(beta 1-3)GalNAc, did not bind to the motoneurons. This suggests that Gal(beta 1-3)GalNAc bearing glycoproteins or glycolipids other than GM1 are expressed on the surface of motoneurons, while GM1 may be absent or shielded, and that antibody binding to the cell surface might contribute to the development of the motor neuron disease.

Characterization of HNK-1 bearing glycoproteins in human peripheral nerve myelin.

The HNK-1 carbohydrate epitope, which is shared by several members of the immunoglobulin gene super-family, is also the target epitope for IgM anti-MAG autoantibodies in patients with demyelinating neuropathy. By Western blot analysis, there are 7 HNK-1 immunoreactive glycoproteins in human peripheral nerve myelin, two of which have previously been identified as the myelin associated glycoprotein (MAG) and the P0 glycoprotein. In this study, the remaining HNK-1 bearing glycoprotein bands were characterized by immunoblot and NH2-terminal sequence analysis, and were all identified as degradation products or aggregates of the Po glycoprotein. MAG and P0 are therefore the only HNK-1 bearing glycoproteins in human peripheral nerve myelin.

B cell small lymphocytic lymphoma and chronic lymphocytic leukemia with peripheral neuropathy: two cases with neuropathological findings and lymphocyte marker analysis.

Two patients with lymphoproliferative disorders developed peripheral neuropathy and neoplastic lymphocytic nerve infiltrates. One of these patients, with B cell small lymphocytic lymphoma, presented with a chronic axonal neuropathy. CD22+, CD5- cells were identified in the epineurium. The other patient with chronic lymphocytic leukemia of 3 years duration developed a mixed axonal and demyelinating neuropathy. CD22+ and CD5+ cells were observed in the endoneurium. While the cause of the neuropathy in these two cases is unknown, intraneural or systemic autoantibody production may have led to the development of disease.