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Lower-extremity Dynamometry as a Novel Outcome Measure in a Double-blind, Placebo-controlled, Feasibility Trial of Intravenous Immunoglobulin (IVIG) for HIV-associated Myelopathy.

ABSTRACT: Objective: Open-label data suggest that intravenous immunoglobulin (IVIG) might improve lower-extremity strength in human immunodeficiency virus (HIV)-associated myelopathy (HIVM), a rare but debilitating neurologic complication of HIV. We sought to determine the feasibility of testing the efficacy of IVIG for HIVM more rigorously. Design: We conducted a randomized, double-blind, placebo-controlled feasibility trial of IVIG for HIVM, using dynamometry as an outcome measure (Clinical Trial No. NCT01561755). Setting: The study took place in an academic medical center in New York, New York Participants: Only 12 participants were enrolled in four years; critical impediments to the study were the rarity of patients with new HIVM diagnoses and prior exposure to IVIG in patients with an established diagnosis. Measurements: Dynamometry of hip flexion, knee flexion, and ankle dorsiflexion were measured; the HIV Dementia Motor Score (HDMS); and the two-minute timed walk test were utilized. Results: Recruitment was the major feasibility issue. Dynamometry was generally well-tolerated, had good test-retest reliability (r=0.71-0.86, p<0.02 for all muscle groups), and good inter-item reliability as judged by the correlations between the muscle groups (r=0.76-0.81, p=0.001-0.005). Dynamometry was valid and clinically meaningful based on its correlations with the HDMS and the two-minute timed walk test. Conclusion: We conclude that an adequately powered clinical trial of IVIG for HIVM would likely require a prolonged recruitment period and multiple participating sites. Lower limb dynamometry is a useful outcome measure for HIVM, which might also be useful in other HIV-related gait disorders.

SUBMITTER: Robinson-Papp J

PROVIDER: S-EPMC5819718 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIschemic stroke causes a high rate of deaths and permanent neurological damage in survivors. Ischemic stroke triggers the release of damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB1), which activate toll-like receptors (TLRs) and receptor for advanced glycation endproducts (RAGE) in the affected area, leading to an exaggerated inflammatory response and cell death. Both TLRs and RAGE are transmembrane pattern recognition receptors (PRRs) that have been shown to contribute to ischemic stroke-induced brain injury. Intravenous immunoglobulin (IVIg) preparations obtained by fractionating human blood plasma are increasingly being used as an effective therapeutic agent in the treatment of several inflammatory diseases. Its use as a potential therapeutic agent for treatment of stroke has been proposed, but little is known about the direct neuroprotective mechanisms of IVIg. We therefore investigate whether IVIg exerts its beneficial effects on the outcome of neuronal injury by modulating HMGB1-induced TLR and RAGE expressions and activations.MethodsPrimary cortical neurons were subjected to glucose deprivation or oxygen and glucose deprivation conditions and treated with IVIg and recombinant HMGB1. C57/BL6J mice were subjected to middle cerebral artery occlusion, followed by reperfusion, and IVIg was administered intravenously 3 h after the start of reperfusion. Expression of TLRs, RAGE and downstream signalling proteins in neurons and brain tissues were evaluated by immunoblot.ResultsTreatment of cultured neurons with IVIg reduced simulated ischemia-induced TLR2, TLR4, TLR8 and RAGE expressions, pro-apoptotic caspase-3 cleavage and phosphorylation of the cell death-associated kinases such as c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK) as well as the p65 subunit of nuclear factor kappa B (NF-κB). These results were recapitulated in an in vivo model of stroke. IVIg treatment also upregulated the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) in cortical neurons under ischemic conditions. Finally, IVIg protected neurons against HMGB1-induced neuronal cell death by modulating TLR and RAGE expressions and signalling pathways.ConclusionsTaken together, these results provide a rationale for the potential use of IVIg to target inappropriately activated components of the innate immune system following ischemic stroke.

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Lower-extremity Dynamometry as a Novel Outcome Measure in a Double-blind, Placebo-controlled, Feasibility Trial of Intravenous Immunoglobulin (IVIG) for HIV-associated Myelopathy.

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