Primary and Acquired Immunodeficiencies Associated With Severe Varicella-Zoster Virus Infections.

BACKGROUND: Although most cases of varicella or zoster are self-limited, patients with certain immune deficiencies may develop severe or life-threatening disease. METHODS: We studied a patient with varicella-zoster virus (VZV) central nervous system (CNS) vasculopathy and as part of the evaluation, tested his plasma for antibodies to cytokines. We reviewed the literature for cases of varicella or zoster associated with primary and acquired immunodeficiencies. RESULTS: We found that a patient with VZV CNS vasculopathy had antibody that neutralized interferon (IFN)-α but not IFN-γ. The patient's plasma blocked phosphorylation in response to stimulation with IFN-α in healthy control peripheral blood mononuclear cells. In addition to acquired immunodeficiencies like human immunodeficiency virus (HIV) or autoantibodies to IFN, variants in specific genes have been associated with severe varicella and/or zoster. Although these genes encode proteins with very different activities, many affect IFN signaling pathways, either those that sense double-stranded RNA or cytoplasmic DNA that trigger IFN production, or those involved in activation of IFN stimulated genes in response to binding of IFN with its receptor. CONCLUSIONS: Immune deficiencies highlight the critical role of IFN in control of VZV infections and suggest new approaches for treatment of VZV infection in patients with certain immune deficiencies.

Chronic nerve health following implantation of femoral nerve cuff electrodes.

BACKGROUND: Peripheral nerve stimulation with implanted nerve cuff electrodes can restore standing, stepping and other functions to individuals with spinal cord injury (SCI). We performed the first study to evaluate the clinical electrodiagnostic changes due to electrode implantation acutely, chronic presence on the nerve peri- and post-operatively, and long-term delivery of electrical stimulation. METHODS: A man with bilateral lower extremity paralysis secondary to cervical SCI sustained 5 years prior to enrollment received an implanted standing neuroprosthesis including composite flat interface nerve electrodes (C-FINEs) electrodes implanted around the proximal femoral nerves near the inguinal ligaments. Electromyography quantified neurophysiology preoperatively, intraoperatively, and through 1 year postoperatively. Stimulation charge thresholds, evoked knee extension moments, and weight distribution during standing quantified neuroprosthesis function over the same interval. RESULTS: Femoral compound motor unit action potentials increased 31% in amplitude and 34% in area while evoked knee extension moments increased significantly (p < 0.01) by 79% over 1 year of rehabilitation with standing and quadriceps exercises. Charge thresholds were low and stable, averaging 19.7 nC ± 6.2 (SEM). Changes in saphenous nerve action potentials and needle electromyography suggested minor nerve irritation perioperatively. CONCLUSIONS: This is the first human trial reporting acute and chronic neurophysiologic changes due to application of and stimulation through nerve cuff electrodes. Electrodiagnostics indicated preserved nerve health with strengthened responses following stimulated exercise. Temporary electrodiagnostic changes suggest minor nerve irritation only intra- and peri-operatively, not continuing chronically nor impacting function. These outcomes follow implantation of a neuroprosthesis enabling standing and demonstrate the ability to safely implant electrodes on the proximal femoral nerve close to the inguinal ligament. We demonstrate the electrodiagnostic findings that can be expected from implanting nerve cuff electrodes and their time-course for resolution, potentially applicable to prostheses modulating other peripheral nerves and functions. TRIAL REGISTRATION: ClinicalTrials.gov NCT01923662 , retrospectively registered August 15, 2013.

Implanted High Density Cuff Electrodes Functionally Activate Human Tibial and Peroneal Motor Units Without Chronic Detriment to Peripheral Nerve Health.

OBJECTIVE: Peripheral nerve stimulation via multi-contact nerve cuff electrodes (NCEs) has proved effective in restoring function to individuals with lower-extremity paralysis. This study investigates clinical measures of nerve health over one year post-implantation of a composite flat-interface nerve electrode (C-FINE) on the tibial and peroneal nerves above the knee in a human volunteer. This represents the first deployment of a novel NCE on new neural targets in a uniquely challenging location prone to prolonged externally applied forces, making acute and chronic postoperative observation critical. MATERIALS AND METHODS: A 27-year-old man with an incomplete spinal cord injury (AIS C) at the C3 to C4 level received eight-contact C-FINEs bilaterally on the tibial and peroneal nerves, proximal to the knee. Access to four contacts per cuff exhibiting the most desirable responses was externalized via temporary percutaneous leads. Percutaneous leads were later removed, with contacts generating the best dorsiflexion (two of four) and plantar flexion (one of four) reconnected to a permanently implanted pulse generator. For 13 months post-implantation, nerve health and cuff performance were assessed through motor nerve conduction velocity (MNCV) studies, clinical needle electromyography, compound motor action potential (CMAP), sensory nerve action potential (SNAP), stimulation-evoked tetanic moment collection, and lower-limb circumference measurements. RESULTS: Tibial and peroneal MNCVs remained stable bilaterally above 40 m/sec, with CMAPs increased or stable after six months. SNAPs remained stable across all measurements. CMAP initial charge thresholds remained below 50 nC, with minimal changes to muscle recruitment order in three of four externalized contacts per cuff. Peak tetanic moments remained stable, with bilateral increases in thigh and calf circumferences of 5% and 14% over one year. CONCLUSIONS: Above-knee tibial and peroneal NCEs can restore stimulated ankle-joint function without chronic nerve health detriments. Alongside previous femoral nerve data, this study demonstrates the ability of NCEs to enhance lower-extremity function with limited neuromuscular impact.

Intraoperative Responses May Predict Chronic Performance of Composite Flat Interface Nerve Electrodes on Human Femoral Nerves.

Peripheral nerve cuff electrodes (NCEs) in motor system neuroprostheses can generate strong muscle contractions and enhance surgical efficiency by accessing multiple muscles from a single proximal location. Predicting chronic performance of high contact density NCEs based on intraoperative observations would facilitate implantation at locations that maximize selective recruitment, immediate connection of optimal contacts to implanted pulse generators (IPGs) with limited output channels, and initiation of postoperative rehabilitation as soon as possible after surgery. However, the stability of NCE intraoperative recruitment to predict chronic performance has not been documented. Here we report the first-in-human application of a specific NCE, the composite flat interface nerve electrode (C-FINE), at a new and anatomically challenging location on the femoral nerve close to the inguinal ligaments. EMG and moment recruitment curves were recorded for each of the 8 contacts in 2 C-FINE intraoperatively, perioperatively, and chronically for 6 months. Intraoperative measurements predicted chronic outcomes for 87.5% of contacts with 14/16 recruiting the same muscles at 6 months as intraoperatively. In both 8-contact C-FINEs, 3 contacts elicited hip flexion and 5 selectively generated knee extension, 3 of which activated independent motor unit populations each sufficient to support standing. Recruitment order stabilized in less than 3 weeks and did not change thereafter. While confirmation of these results will be required with future studies and implant locations, this suggests that remobilization and stimulated exercise may be initiated 3 weeks after surgery with little risk of altering performance.