Walking and talking: an investigation of cognitive-motor dual tasking in multiple sclerosis.

BACKGROUND: Deficits in motor functioning, including walking, and in cognitive functions, including attention, are known to be prevalent in multiple sclerosis (MS), though little attention has been paid to how impairments in these areas of functioning interact. OBJECTIVES: This study investigated the effects of performing a concurrent cognitive task when walking in people with MS. Level of task demand was manipulated to investigate whether this affected level of dual-task decrement. METHOD: Eighteen participants with MS and 18 healthy controls took part. Participants completed walking and cognitive tasks under single- and dual-task conditions. RESULTS: Compared to healthy controls, MS participants showed greater decrements in performance under dual-task conditions in cognitive task performance, walking speed and swing time variability. In the MS group, the degree of decrement under dual-task conditions was related to levels of fatigue, a measure of general cognitive functioning and self-reported everyday cognitive errors, but not to measures of disease severity or duration. CONCLUSIONS: Difficulty with walking and talking in MS may be a result of a divided attention deficit or of overloading of the working memory system, and further investigation is needed. We suggest that difficulty with walking and talking in MS may lead to practical problems in everyday life, including potentially increasing the risk of falls. Clinical tools to assess cognitive-motor dual-tasking ability are needed.

Guillain-Barre syndrome occurring after adjuvant chemo-radiotherapy for endometrial cancer.

BACKGROUND: The association between Guillain-Barre syndrome (GBS) and malignancy is uncommon and has not been previously reported in gynecological cancers. CASE: Our case documents this syndrome occurring in a patient shortly after completion of adjuvant chemo-radiotherapy for endometrial carcinoma. We review the current literature and discuss potential pathogenic mechanisms of this likely paraneoplastic association. CONCLUSION: GBS in cancer patients is a potentially life-threatening condition and should be differentiated from simple chemotherapy toxicity, particularly as effective treatment is available.

The clinical and laboratory features of chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies.

The clinical and laboratory phenotype of a paraproteinaemic neuropathy syndrome termed chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies is described in a series of 18 cases. Previous single case reports have outlined some features of this syndrome. All 18 cases were defined by the presence of serum IgM antibodies which react principally with NeuAc (alpha2-8)NeuAc(alpha2-3)Gal-configured disialosyl epitopes common to many gangliosides including GDlb, GD3, GTlb and GQlb. In 17 out of 18 cases, the serum contained benign IgM paraproteins, and in four of these cases at least two IgM paraproteins were present. The IgM antibodies were also cold agglutinins in 50% of cases. The clinical picture comprised a chronic neuropathy with marked sensory ataxia and areflexia, and with relatively preserved motor function in the limbs. In addition, 16 out of 18 cases had motor weakness affecting oculomotor and bulbar muscles as fixed or as relapsing-remitting features. When present in their entirety, these clinical features have been described previously under the acronym CANOMAD: chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins and disialosyl antibodies. This distribution of clinical features is reminiscent of Miller Fisher syndrome, in which acute-phase anti-disialylated ganglioside IgG antibodies are found. Clinical electrophysiology and nerve biopsy show both demyelinating and axonal features. A partial response to intravenous immunoglobulin and other treatments is reported in some cases.

Spinal AVM, epidermal nevus, and rhabdomyosarcoma: A rare neurocutaneous syndrome?

A 26-year-old man with a history of an embryonal rhabdomyosarcoma arising from the urachus and a large, right-sided, epidermal nevus presented with a rapidly evolving tetraparesis. Investigations confirmed an intramedullary hemorrhage of the cervical spinal cord and an extensive arteriovenous malformation (AVM). An association between his nevus, rhabdomyosarcoma, and spinal AVM is hypothesized.

The role of antiglycolipid antibodies in peripheral neuropathies.

The role of antiglycolipid antibodies in peripheral neuropathy continues to be defined in terms of clinical-serological associations and innovative experimental work establishing the role of these antibodies in pathogenesis. The present review focuses on the major developments in this field over the past 12 months.

Accumulation of macrophages with dendritic cell characteristics in the pulmonary response to Listeria.

Pulmonary immunity reflects a balance between proinflammatory and immunosuppressive factors in the lung. To determine the immune activities of exudate macrophages in the pulmonary immune response, Lewis rats were injected intratracheally with heat-killed Listeria (HKL), labeled ex vivo with the lipophilic dye PKH-26. At 24 h, macrophages from bronchoalveolar lavage fluid were purified on the basis of their surface membrane expression of RMA, a macrophage-specific antigen, which is brightly expressed by resident alveolar macrophages but dimly expressed by monocytes. Pulmonary macrophages were analyzed for uptake of PKH-26-HKL, and RMA(bright/dim) macrophages sorted by FACS were compared for cytokine expression, nitric oxide (NO) release, and APC activities. RMA(bright) macrophages were OX-62(-), B7(-), and factor XIIIa(-); they were the dominant mediators of phagocytosis when low doses of HKL were administered intratracheally but did not support the proliferation of T lymphocytes. RMA(dim) exudate macrophages were OX-62(+), B7(+), and factor XIIIa(+). They expressed more IL-1 and TNF, but less nitric oxide, than did RMA(bright) macrophages; they were excellent APCs for T cell responses. We conclude that a subset of RMA(dim) exudate macrophages shows phenotypic and functional evidence of dendritic cell differentiation.

Accessory cells with immunophenotypic and functional features of monocyte-derived dendritic cells are recruited to the lung during pulmonary inflammation.

Pulmonary macrophages (Mphi) increase in tissue and bronchoalveolar lavage (BAL) fluid during inflammation caused by bleomycin (BLM). This study demonstrates that increasing numbers of exudate Mphi in BLM lung injury exhibit dendritic cell (DC) features. After the intratracheal administration of BLM (0.075 U), adherent mononuclear cells from the bronchoalveolar lavage fluid (BAMC) of C57BL/6 mice were characterized for morphology, immunophenotype, and accessory cell activities. At day 7 post-BLM, 48% of CD11b+ BAMC displayed features of DC differentiation, as judged by dendritic morphology, expression of class II MHC, 33D1, Factor XIIIa, CD80, and CD86 antigens, and the ability to support a primary allogeneic lymphocyte response (MLR). After BLM treatment, CD11b+ peripheral blood monocytes also showed increased expression of 33D1, Factor XIIIa, CD86, and the ability to stimulate an MLR. We conclude that inflammatory DC with immunophenotypic features of monocyte-derived DC increase in the peripheral blood and lung after an inflammatory stimulus.

Anti-ganglioside antibodies can bind peripheral nerve nodes of Ranvier and activate the complement cascade without inducing acute conduction block in vitro.

The neurophysiological effects of nine neuropathy-associated human anti-ganglioside antisera, three monoclonal antibodies to ganglioside GM1 (GM1) and of the cholera toxin B subunit (a GM1 ligand) were studied on mouse sciatic nerve in vitro. GM1 antisera and monoclonal antibodies from patients with chronic motor neuropathies and Guillain-Barre syndrome, and GQ1b/ disialosyl antisera and monoclonal antibodies from patients with chronic ataxic neuropathies and Miller Fisher syndrome were studied. In vitro recording, for up to 6 h, of compound nerve action potentials, latencies, rise times and stimulus thresholds from isolated desheathed sciatic nerve was performed in the presence of antiganglioside antibodies and fresh human serum as an additional source of complement. No changes were observed over this time course, with 4-6 h values for all electrophysiological parameters being within 15% of the starting values for both normal and antibody containing sera and for the cholera toxin B subunit. Parallel experiments on identically prepared desheathed nerves performed with 0.5 nM saxitoxin led to complete conduction block within 10 min of application. Under identical conditions to those used for electrophysiological recordings, quantitative immunohistological evaluation revealed a significant increase in IgM (immunoglobulin M) deposition at nodes of Ranvier from 5.3+/-3.1% to 28.7+/-8.4% (mean+/-SEM) of desheathed nerves exposed to three normal and three antibody containing sera, respectively (P < 0.03). Complement activation was seen at 100% of normal and 79% of disease-associated IgM positive nodes of Ranvier. These data indicate that anti-ganglioside antibodies can diffuse into a desheathed nerve, bind to nodes of Ranvier and fix complement in vitro without resulting in any overt physiological deterioration of the nerve over 4-6 h. This suggests that the node of Ranvier is relatively resistant to acute antiganglioside antibody mediated injury over this time scale and that anti-ganglioside antibodies and the cholera toxin B subunit are unlikely to have major direct pharmacological effects on nodal function, at least in comparison with the effect of saxitoxin. This in vitro sciatic nerve model appears of limited use for analysing electrophysiologically the effects of anti-ganglioside antibodies on nerve function, possibly because its short-term viability and isolation from circulating systemic factors do not permit the evolution of an inflammatory lesion of sufficient magnitude to induce overt electrophysiological abnormalities. In vivo models may be more suitable for identifying the effects of these antibodies on nerve conduction.

Pulmonary immunity to Listeria is enhanced by elimination of alveolar macrophages.

To determine how resident alveolar macrophages (AM) regulate the antigen-presenting-cell (APC) activities of pulmonary dendritic cells (DC) in the response to particulate antigen, we pretreated Lewis rats intratracheally with liposomes containing clodronate (LIP-CLOD), which eliminated AM in vivo. Controls received saline encapsulated in liposomes (LIP-SAL) or saline alone intratracheally. At Day 3, rats were injected intratracheally with 1 x 10(7) heat-killed Listeria (HKL) and DC purified from lung were examined for their ability to stimulate HKL-immune T cells without added HKL. Only DC from LIP-CLOD-treated rats displayed enhanced APC activities for HKL. A second intratracheal HKL challenge at Day 14 yielded lymphocytic cuffing of the microvasculature in LIP-CLOD-treated lungs only. Intratracheal adoptive transfer of normal syngeneic AM into LIP-CLOD-treated rats suppressed APC activities of DC in vitro and the lymphocytic response in vivo. Bronchoalveolar macrophages from rats treated with LIP-CLOD and HKL showed decreased production of nitric oxide (NO), a potent suppressor of DC and T-helper 1 lymphocyte activities as compared with those of controls. We conclude that eliminating AM in vivo reduces local production of NO and promotes pulmonary cell-mediated immunity to HKL.

Mechanisms of action of anti-GM1 and anti-GQ1b ganglioside antibodies in Guillain-Barré syndrome.

Anti-GM1 and anti-GQ1b ganglioside antibodies are found in association with acute and chronic peripheral neuropathies, including Guillain-Barré syndrome. They are believed to arise as a result of molecular mimicry with immunogenic microbial polysaccharides. Although anti-ganglioside antibodies are suspected to play a causal role in neuropathy pathogenesis, the details of this have yet to be proven. The approach in this laboratory to solving this issue has been to generate anti-GM1 and anti-GQ1b monoclonal antibodies from peripheral blood lymphocytes of affected patients and to study their immunolocalization in peripheral nerve and their electrophysiologic effects in animal models in which peripheral nerve sites are exposed to anti-ganglioside antibodies. These data show that anti-ganglioside antibody-reactive epitopes are widely distributed in peripheral nerve and can cause electrophysiologic abnormalities in a variety of model systems; thus, these data support the view that anti-ganglioside antibody-reactive epitopes may directly contribute to neuropathy pathogenesis.

Autoimmune ataxic neuropathies (sensory ganglionopathies).

Autoimmune ataxic neuropathies are a subset of the sensory ataxic neuropathies which are characterized by ataxia as the dominant presenting feature. The major known causes of autoimmune ataxic neuropathies include sensory variants of the Guillain-Barré syndrome, including Miller-Fisher syndrome, subsets of immunoglobulin M paraproteinaemic neuropathy, paraneoplastic neuropathy and the neuropathy associated with Sjögren's syndrome. Identified antigens as targets for autoantibodies include gangliosides, myelin associated glycoprotein, Hu antigen and extractable nuclear antigens. Some recent studies support the pathogenic role of anti-GD1b ganglioside antibody in autoimmune ataxic neuropathies. The major site of pathology in autoimmune ataxic neuropathies is the dorsal root ganglion, but dorsal roots and peripheral nerve myelin and axons may also be affected.

Muscle hypertrophy in multifocal motor neuropathy is associated with continuous motor unit activity.

Multifocal motor neuropathy (MMN) is typically associated with distal upper limb weakness and wasting. However, proximal muscle bulk, particularly of biceps brachii, may be well preserved even in the presence of severe proximal weakness. Here we report 3 patients with MMN who had true muscle hypertrophy of severely weakened biceps muscles and positive motor symptoms including cramp and fasciculations in these muscles. Electromyographic studies demonstrated markedly impaired recruitment in the affected muscles and continuous motor unit activity comprising multiple fasciculation potentials at a frequency of up to 30 per minute. We propose that this continuous motor unit activity may have contributed to the hypertrophy in these muscles.

Acute oropharyngeal palsy is associated with antibodies to GQ1b and GT1a gangliosides.

Three patients with acute oropharyngeal palsy had high titre anti-GQ1b and anti-GT1a IgG antibodies. No patients had ophthalmoplegia or ptosis. In all patients limb ataxia or areflexia were present without notable limb weakness. These patients describe an oropharyngeal variant of Guillain-Barré syndrome in terms of anti-GQ1b antibody reactivity and show that high titre anti-GQ1b antibodies, serologically indistinguishable from those found in Miller Fisher syndrome, can occur in a clinical setting without ophthalmoplegia. The anti-GQ1b and anti-GT1a antibody assays may be helpful tests when considering the differential diagnosis of acute oropharyngeal palsy.

Two-color flow cytometry and functional analysis of lymphocytes cultured from human renal allografts: identification of a Leu-2+3+ subpopulation.

The phenotype of T lymphocyte subsets present in renal biopsies showing acute cellular allograft rejection in six patients on cyclosporine have been characterized in situ by immunoperoxidase staining, and after expansion in vitro in interleukin 2 (IL-2) by two-color flow cytometry, sorting, and functional analysis. After 8 to 42 days in organ culture, both Leu-3+ (CD4) and Leu-2+ (CD8) subsets were found in each culture, in a ratio that varied from 0.2 to 5.0, which was not significantly different than the results of in situ immunoperoxidase staining of the uncultured biopsy. The cultured cells were almost all Leu-4+ (CD3) T cells (89% +/- 4), which expressed the activation markers DR (82% +/- 6) and the IL 2 (CD25) receptor (15% +/- 4). The Leu-3+ cells were largely Leu-8- (90% +/- 6), whereas a minority of the Leu-2+ cells were Leu-15+ (CD11) (26% +/- 4). Only a small fraction of the Leu-2+ cells stained for Leu-7 (8% +/- 6). Functional analysis of FACS-purified Leu-2-3+ and Leu-2+3- populations indicated that both subsets proliferated in response to graft donor antigens in a mixed lymphocyte reaction (MLR) and produced IL 2. Only the Leu-2+3- population demonstrated donor-specific cytotoxic activity. A minor subpopulation in each culture were both Leu-3+ and Leu-2+ (2.0%). Leu-2+3+ cells from one biopsy were purified to homogeneity (99.8%), and were found to express the T cell antigen receptor complex Ti/CD3 (WT-31+, Leu-4+), but not the common thymocyte antigen CD1 (OKT6). The Leu-2+3+ cells neither responded in the MLR, nor showed any cytotoxic capacity. The Leu-2+3+ cells were capable of IL 2 but not interferon-gamma production. None of the purified cultures demonstrated NK activity. A subset of the purified Leu-2+3+ cells lost Leu-2+ during 1 to 3 wk in culture, and became Leu-2-3+. These studies provide evidence that the cells that infiltrate renal allografts during rejection include alloproliferative, lymphokine-producing cells of both Leu-2+ and Leu-3+ subsets. The Leu-2+3- cells are also highly cytotoxic against donor lymphocytes, indicating the presence of helper independent cytotoxic T cells. A minor population of Leu-2+3+ T cells that do not express donor specific function was also identified.

T-cell subsets in human lymphocytes maintained in IL-2 medium after PHA or mixed lymphocyte reaction activation.

The culture of human T lymphocytes in interleukin-2 (IL-2) containing growth factor medium results in a significant shift in the T-lymphocytes subsets isolated from such cultures at weekly intervals. If normal peripheral blood mononuclear cells are stimulated with phytohemagglutinin (PHA) or in a mixed lymphocyte reaction (MLR), the resulting T lymphoblasts can be propagated in growth factor medium. Staining of the cultured cells with monoclonal antibodies was evaluated by indirect immunofluorescence on a laser-activated flow cytometer (Ortho Spectrum III). The antibodies used were: OKT3 (mature T lymphocytes), OKT4 (helper/inducer T lymphocytes), OKT8 (cytotoxic/suppressor T lymphocytes, OKT10 (immature and "activated" lymphocytes), OKT11a (cells which rosette with sheep erythrocytes), and OKIa-I (HLA-DR constant region). Both PHA and MLR activation resulted in initial preservation of the OKT4+ subset predominance over OKT8+ T lymphocytes noted on normal circulating blood lymphocytes. However, during culture in T-cell growth factor medium, there was a progressive increase in the percentage of OKT8+ cells, and a concomitant decrease in OKT4+ lymphoblasts. The increase in OKT8+ cells in the MLR-stimulated cultures was paralleled by an increase in specific cell-mediated cytotoxicity against the stimulating lymphocyte population. In addition to the shift in T-lymphocyte subset, there was virtual 100% staining with OKT3 and OKT11a, indicating the T-cell nature of the proliferating cells. OKT10 which was present on a small subset of fresh blood lymphocytes appeared rapidly in stimulated cultures, and was retained on virtually all lymphoblasts of either OKT4+ or OKT8+ subset. OKIa-1 cells increased slowly in PHA-stimulated cultures. HLA-DR+ T cells were detected earlier in MLR cultures. The activation of T lymphocytes results in a significant increase in the number of molecules of OKT11a bound per cell, in concert with the increased avidity of T lymphoblasts for sheep erythrocytes. The significant change in the phenotype and function of lymphoblasts isolated from long-term cultures demonstrates the importance of monitoring cultures, and the potential hazards in equating a cultured cell population with a freshly isolated one.