Sudomotor dysfunction in autoimmune autonomic ganglionopathy.

BACKGROUND: Autoimmune autonomic ganglionopathy is characterized by impairment of multiple autonomic domains of which sudomotor function is among the most common. Many patients with this disorder have difficulties with thermoregulation and anhidrosis. Our objective was to characterize the distribution and severity of sudomotor dysfunction in this disorder. METHODS: Sudomotor function was analyzed in a cohort of 21 patients with ganglionic alpha3 nicotinic acetylcholine receptor (nAChR) antibody positive autoimmune autonomic ganglionopathy. Standard measurements of sudomotor function were used including the Thermoregulatory Sweat Test and Quantitative Sudomotor Axon Reflex Test. RESULTS: The clinical presentation in all patients was characterized by widespread sudomotor dysfunction. Sudomotor impairment was predominantly postganglionic in 17 of the 21 patients studied. Higher ganglionic alpha3 nAChR antibody levels resulted in progressive postganglionic predominant dysfunction (postganglionic, r = 0.637, p = 0.002; mixed ganglionic, r = 0.709, p < 0.001). The pattern of anhidrosis on Thermoregulatory Sweat Testing was consistent with a ganglionopathy in the majority of patients (14 of 21) and a distal pattern in a minority of patients (8 of 21). These patterns of anhidrosis coupled with increasing postganglionic dysfunction in a proximal to distal pattern (foot > distal leg > proximal leg > forearm) indicate lesions at both the ganglia and distal axon of the postganglionic sudomotor sympathetic neuron. CONCLUSIONS: Our data characterize the unique sudomotor dysfunction in autoimmune autonomic ganglionopathy as widespread, predominantly postganglionic, and a result of lesions at both the ganglia and distal axon. This study provides important support to the hypothesis that this disorder represents a ganglionic neuropathy.

Efficacy of immunotherapy in seropositive and seronegative putative autoimmune autonomic ganglionopathy.

OBJECTIVE: To evaluate the efficacy of immunotherapy in the treatment of patients with seropositive and seronegative putative autoimmune autonomic ganglionopathy (AAG) using validated autonomic function tests and instruments. BACKGROUND: AAG is an immune-mediated disorder characterized by prominent and selective involvement of autonomic nerve fibers or ganglia. Treatment with i.v. immunoglobulin (IVIg) or plasma exchange (PE) has been reported to be effective in single case reports. METHODS: We studied six patients, four with seropositive and two with seronegative putative AAG, who underwent autonomic function tests and completed two validated questionnaires, to assess autonomic symptoms before and after immunomodulatory treatment. Patients were treated with standard doses of IVIg, PE, or immunosuppressants in a specific sequential therapy protocol depending on clinical response. RESULTS: Of the six patients (all women, mean ages 49.3 +/- 10.6 years), four patients were ganglionic (alpha3) AChR autoantibody positive and two were autoantibody negative. All patients showed clinical improvement after treatment. Sudomotor function assessed by quantitative sudomotor axon reflex test and thermoregulatory sweat test improved in four patients after treatment. CONCLUSIONS: Immunomodulatory treatment can be effective in both seropositive and seronegative putative autoimmune autonomic ganglionopathy. Plasma exchange or combined therapy with immunosuppressive agents should be considered in patients who do not benefit from i.v. immunoglobulin alone.

Neurite growth promotion by nerve growth factor and insulin-like growth factor-1 in cultured adult sensory neurons: role of phosphoinositide 3-kinase and mitogen activated protein kinase.

Although neurons of the PNS no longer require neurotrophins such as Nerve Growth Factor (NGF) for their survival, such factors are involved in regulating axonal sprouting and regeneration after injury. In addition to the neurotrophin receptors, sensory neurons are reported to express IGF-1, EGF and FGF receptors. To investigate the influence of growth factors in addition to NGF, we examined the effects of IGF-1 EGF and FGF on neurite growth from adult rat dorsal root ganglion sensory neurons in both dissociated cultures and in compartmented cultures. As expected, NGF elicited robust neuritic growth in both the dissociated and compartmented cultures. The growth response to IGF-1 was similar, although there was minimal neurite growth in response to EGF or FGF. In addition, IGF-1 (but neither FGF nor EGF), when applied to cell bodies in compartmented cultures, potentiated the distal neurite growth into NGF-containing side compartments. This potentiation was not seen when these factors were provided along with NGF in the side compartments of compartmented cultures, or in the dissociated cultures. To determine the contribution of signaling intermediates downstream of receptor activation, we used inhibitors of the potential effectors and Western blotting. The PI 3-kinase inhibitor, LY294002 attenuated neurite growth evoked by NGF, IGF and EGF in dissociated cultures, although the MAP kinase kinase (MEK) inhibitor PD098059 diminished the growth in only IGF. Immunoprecipitation and Western blotting results demonstrated differential activation of MAPK, PI 3-kinase, PLCgamma1 and SNT by the different factors. Activation of PI 3-kinase and SNT by both NGF and IGF-1 correlated with their effects on neurite growth. These results support the hypothesis that the PI 3-kinase pathway plays an important role in neuritogenesis.

The anti-p75 antibody, MC192, and brain-derived neurotrophic factor inhibit nerve growth factor-dependent neurite growth from adult sensory neurons.

We have investigated nerve growth factor-dependent neurite growth from adult sensory neurons using the compartmented culture system. The requirement of both TrkA and the p75 neurotrophin receptors in neurite growth was examined using several experimental interventions. Inhibition of TrkA activation using K252a resulted in a total block of distal neurite extension into nerve growth factor-containing compartments. Brain-derived neurotrophic factor and the anti-p75 monoclonal antibody MC192 have been shown to interfere with the binding of nerve growth factor to p75. Brain-derived neurotrophic factor, which binds p75 but not TrkA, competes with nerve growth factorforp75, while the anti-p75 antibody MC192 has been shown to decrease the interaction of nerve growth factor with TrkA. The addition of brain-derived neurotophic factor to nerve growth factor-containing distal compartments inhibited, but did not totally block, distal neurite extension. MC192, on the other hand, totally inhibited nerve growth factor-dependent neurite growth. To test whether MC192 and brain-derived neurotrophic factor might be influencing Trk activation, TrkA phosphorylation was examined biochemically. Both compounds were found to attenuate nerve growth factor-induced Trk phosphorylation, although neither inhibited the activation completely. The possibility that MC192 or brain-derived neurotrophic factor might activate p75 signaling directly (and potentially antagonize TrkA signaling) was also investigated. This was assessed by quantitating the activation and nuclear translocation of the transcription factor NFkB using immunocytochemistry. Only treatment with the anti-p75 antibody MC192 resulted in prolonged and significant increase in the number of neurons displaying nuclear staining for NFkB. Our results demonstrate that both TrkA and p75 play a role in neurite growth response to nerve growth factor, and further suggest that any alteration in optimal TrkA-p75 interactions, or direct activation of p75 at the expense of TrkA, results in an inhibition of nerve growth factor-dependent neurite growth in adult sensory neurons.

Effects of the neurotrophins nerve growth factor, neurotrophin-3, and brain-derived neurotrophic factor (BDNF) on neurite growth from adult sensory neurons in compartmented cultures.

We used compartmented cultures to study the regulation of adult sensory neurite growth by neurotrophins. We examined the effects of the neurotrophins nerve growth factor (NGF), neurotrophin-3 (NT3), and BDNF on distal neurite elongation from adult rat dorsal root ganglion (DRG) neurons. Neurons were plated in the center compartments of three-chambered dishes in the absence of neurotrophin, and neurite extension into the distal (side) compartments containing NGF, BDNF, or NT3 was quantitated. Initial proximal neurite growth did not require any of the neurotrophins, while subsequent elongation into distal compartments required NGF. After neurites had extended into NGF-containing distal compartments, removal of NGF by treatment with anti-NGF resulted in the cessation of growth with minimal neurite retraction. In contrast to the effects of NGF, no distal neurite elongation was observed into compartments with BDNF or NT3. To examine possible additive influences, neurite extension into compartments containing BDNF plus NGF or NT3 plus NGF was quantitated. There was no increased neurite extension into NGF plus NT3 compartments, while the combination of BDNF plus NGF resulted in an inhibition of neurite extension compared with NGF alone. We then investigated whether the regrowth of neurites that had originally grown into NGF subsequent to in vitro axotomy still required NGF. The results demonstrated that unlike adult sensory nerve regeneration in vivo, the in vitro regrowth did require NGF, and neither BDNF nor NT3 was able to substitute for NGF. Since the initial growth from neurons after dissociation (which is also a regenerative response) did not require NGF, it would appear that neuritic growth and regrowth of adult DRG neurons in vitro includes both NGF-independent and NGF-dependent components. The compartmented culture system provides a unique model to further study aspects of this differential regulation of neurite growth.