Jan Tode

Effect of local and intravenous lidocaine on ongoing activity in injured afferent nerve fibers

&NA; Lidocaine applied systemically or locally attenuates neuropathic pain in patients. Here we tested the hypothesis that ectopic activity in injured afferent A‐ or C‐fibers is suppressed by lidocaine. In rats the sural nerve (skin nerve) or lateral gastrocnemius‐soleus nerve (muscle nerve) was crushed. Four to 11 days after crush lesion afferent fibers were isolated from the lesioned nerves in bundles rostral to the injury site. Ongoing ectopic activity was recorded from 75 A‐fibers (muscle N = 43, skin N = 32) and 69 C‐fibers (muscle N = 30, skin N = 39). Most afferent fibers were functionally characterized by their responses to mechanical and thermal (mostly heat) stimuli applied at or distal to the nerve injury site. Low‐threshold cold‐sensitive cutaneous C‐fibers were excluded from the analysis [34,35]. Lidocaine was either applied to the nerve at or distal to the injury site in concentrations of 1 to 1000 μg/mL or injected i.v. in doses of 0.09 to 9 mg/kg (skin) or 0.047 to 4.7 mg/kg (muscle). Local application of lidocaine depressed ectopic activity in A‐ and C‐fibers dose‐dependently. Depression was weaker in C‐ than in A‐fibers. Intravenous application of lidocaine depressed ongoing ectopic activity in A‐ and C‐fibers dose‐dependently. Responses to heat or mechanical stimulation of the injured nerve were not suppressed at the highest concentrations of lidocaine. The results support the hypothesis that decrease of neuropathic pain following local or systemic application of a local anesthetic is related to decrease of ectopic ongoing activity in injured afferent nerve fibers. Lidocaine may attenuate neuropathic pain in patients. Intravenous or local lidocaine suppressed the ectopic activity in injured afferent A‐ or C‐fibers in a rat model of pain.

Mechano- and thermosensitivity of injured muscle afferents

Injury of limb nerves leading to neuropathic pain mostly affects deep somatic nerves including muscle nerves. Here, we investigated the functional properties of injured afferent fibers innervating the lateral gastrocnemius-soleus muscle 4-13 h [time period (TP) I] and 4-7 days (TP II) after nerve crush in anesthetized rats using neurophysiological recordings from either the sciatic nerve (165 A-, 137 C-fibers) or the dorsal root L(5) (43 A-, 28 C-fibers). Ongoing activity and responses to mechanical or thermal stimulation of the injury site of the nerve were studied quantitatively. Of the electrically identified A- and C-fibers, 5 and 38% exhibited ectopic activity, respectively, in TP I and 51 and 61%, respectively, in TP II. Thus all afferent fibers in an injured muscle nerve developed ectopic activity since ∼ 50% of the fibers in a muscle nerve are somatomotor or sympathetic postganglionic. Ongoing activity was present in 50% of the afferent A-fibers (TP II) and in 53-56% of the afferent C-fibers (TP I and II). In TP II, mechanical, cold, and heat sensitivity were present in 91, 63, and 52% of the afferent A-fibers and in 50, 40, and 66% of the afferent C-fibers. The cold and heat activation thresholds were 5-27 and 35-48°C, respectively, covering the noxious and innocuous range. Most afferent fibers showed combinations of these sensitivities. Mechano- and cold sensitivity had a significantly higher representation in A- than in C-fibers, but heat sensitivity had a significantly higher representation in C- than in A-fibers. These functional differences between A- and C-fibers applied to large- as well as small-diameter A-fibers. Comparing the functional properties of injured muscle A- and C-afferents with those of injured cutaneous A- and C-afferents shows that both populations of injured afferent neurons behave differently in several aspects.

Long-term, therapy-related visual outcome of 49 cases with retinal arterial macroaneurysm: a case series and literature review

Purpose Retinal arterial macroaneurysms (RAMAs) are acquired dilations of branches of the central retinal artery. Treatment depends on vision-limiting complications. We compare the long-term visual acuity (VA) in three groups according to treatment. Methods 49 charts of patients with RAMA were reviewed. 16 remained untreated, 15 received photocoagulation and 18 vitrectomy. Patients underwent full ophthalmological examinations and up-to-date imaging. We evaluated chosen therapy, complications and final VA at the last visit. Results 65% of the cohort was female, aged 75±11 years (mean±SD). Follow-up was 34±23 months. These parameters did not differ significantly between the three groups. In the observed group, initial VA was 0.48 (mean log MAR) vs 0.35 at the final visit, in the photocoagulation group 0.55 vs 0.59, and in the vitrectomy group 1.8 vs 0.77. VA was significantly worse at enrolment in the vitrectomy group, while all other VA differences were not significant. Conclusions The overall visual prognosis of RAMA was good, even after macular complications. VA remained unchanged in the observed and the laser groups and was comparable in all groups after 3 years. Based on an individual treatment decision, all therapies were effective and efficient. If subfoveal haemorrhage caused a macular hole, the VA outcome was limited.

Interim Results of a Multicenter Trial with the New Electronic Subretinal Implant Alpha AMS in 15 Patients Blind from Inherited Retinal Degenerations

Purpose: We assessed the safety and efficacy of a technically advanced subretinal electronic implant, RETINA IMPLANT Alpha AMS, in end stage retinal degeneration in an interim analysis of two ongoing prospective clinical trials. The purpose of this article is to describe the interim functional results (efficacy). Methods: The subretinal visual prosthesis RETINA IMPLANT Alpha AMS (Retina Implant AG, Reutlingen, Germany) was implanted in 15 blind patients with hereditary retinal degenerations at four study sites with a follow-up period of 12 months (www.clinicaltrials.gov NCT01024803 and NCT02720640). Functional outcome measures included (1) screen-based standardized 2- or 4-alternative forced-choice (AFC) tests of light perception, light localization, grating detection (basic grating acuity (BaGA) test), and Landolt C-rings; (2) gray level discrimination; (3) performance during activities of daily living (ADL-table tasks). Results: Implant-mediated light perception was observed in 13/15 patients. During the observation period implant mediated localization of visual targets was possible in 13/15 patients. Correct grating detection was achieved for spatial frequencies of 0.1 cpd (cycles per degree) in 4/15; 0.33 cpd in 3/15; 0.66 cpd in 2/15; 1.0 cpd in 2/15 and 3.3 cpd in 1/15 patients. In two patients visual acuity (VA) assessed with Landolt C- rings was 20/546 and 20/1111. Of 6 possible gray levels on average 4.6 ± 0.8 (mean ± SD, n = 10) were discerned. Improvements (power ON vs. OFF) of ADL table tasks were measured in 13/15 patients. Overall, results were stable during the observation period. Serious adverse events (SAEs) were reported in 4 patients: 2 movements of the implant, readjusted in a second surgery; 4 conjunctival erosion/dehiscence, successfully treated; 1 pain event around the coil, successfully treated; 1 partial reduction of silicone oil tamponade leading to distorted vision (silicon oil successfully refilled). The majority of adverse events (AEs) were transient and mostly of mild to moderate intensity. Conclusions: Psychophysical and subjective data show that RETINA IMPLANT Alpha AMS is reliable, well tolerated and can restore limited visual functions in blind patients with degenerations of the outer retina. Compared with the previous implant Alpha IMS, longevity of the new implant Alpha AMS has been considerably improved. Alpha AMS has meanwhile been certified as a commercially available medical device, reimbursed in Germany by the public health system.

Tocilizumab and steroid boli for treatment-resistant anterior necrotizing scleritis

(95% CI, 1.314–31.834) in PEX and PEX glaucoma, respectively. But Bonferroni-corrected p value was 0.192 and 0.216, respectively. Other SNPs were not associated with PEX syndrome (p > 0.05). The rs2151532 SNP which is closer to CTGF than rs928501 (linkage disequilibrium r = 0.046) was also associated with disease in total patients, especially associated with PEX glaucoma (p = 0.002, Bonferroni-corrected p = 0.024). Additional haplotype analyses were performed using significant SNPs and neighbouring SNPs (rs9399005-rs2151532-rs928501rs7768619). Haplotype ‘G-C-C-C’ was more frequent in cases (7.5%) than in controls (2.6%) (p = 0.040). Another haplotype ‘A-T-C-T’ also showed similar pattern (3.0% in cases and 0.5% in controls) (p = 0.069). The result showed no significant association after Bonferroni’s correction. There is limitation of small sample size in this study. Nevertheless, functional data of the ENCODE project provide diverse biochemical evidence that near the region of rs928501 are enriched protein binding, DNase I hypersensitivity and histone modification sites (http://www.regulomedb.org). Further expression quantitative loci analysis is essential to prove that the SNPs associated with PEX have an effect on the gene expression level of CTFG. Our findings might support the differentially expressed CTGF in PEX samples in previous studies and suggest the genetic basis of CTGF for the pathogenesis of PEX.

Preoperative aqueous humour flare values do not predict proliferative vitreoretinopathy in patients with rhegmatogenous retinal detachment

Background/aims Patients with rhegmatogenous retinal detachment (RRD) who develop postoperative proliferative vitreoretinopathy (PVR) have been found to have higher preoperative laser flare values than patients with RRD who do not develop this complication. Measurement of laser flare has therefore been proposed as an objective, rapid and non-invasive method for identifying high-risk patients. The purpose of our study was to validate the use of preoperative flare values as a predictor of PVR risk in two additional patient cohorts, and to confirm the sensitivity and specificity of this method for identifying high-risk patients. Methods We combined data from two independent prospective studies: centre 1 (120 patients) and centre 2 (194 patients). Preoperative aqueous humour flare was measured with a Kowa FM-500 Laser Flare Meter. PVR was defined as redetachment due to the formation of traction membranes that required reoperation within 6 months of initial surgery. Logistic regression and receiver operating characteristic analysis determined whether higher preoperative flare values were associated with an increased risk of postoperative PVR. Results PVR redetachment developed in 21/314 patients (6.7%). Median flare values differed significantly between centres, therefore analyses were done separately. Logistic regression showed a small but statistically significant increase in odds with increasing flare only for centre 2 (OR 1.014; p=0.005). Areas under the receiver operating characteristic showed low sensitivity and specificity: centre 1, 0.634 (95% CI 0.440 to 0.829) and centre 2, 0.731 (95% CI 0.598 to 0.865). Conclusions Preoperative laser flare measurements are inaccurate in discriminating between those patients with RRD at high and low risk of developing PVR.

Thinning of Inner Retinal Layers after Vitrectomy with Silicone Oil versus Gas Endotamponade in Eyes with Macula-Off Retinal Detachment

Purpose: To evaluate retinal layer thickness with optical coherence tomography (OCT) in eyes with macula-off retinal detachment after silicone oil (SiO) or gas endotamponade. Procedures: Cross-sectional study of 40 eyes with macula-off rhegmatogenous retinal detachment that underwent vitrectomy. 20 eyes received SiO tamponade and 20 matched eyes received gas. 33 healthy fellow eyes served as controls. Macular spectral domain OCT was performed with automated layer detection in the 5 inner subfields of the Early Treatment Diabetic Retinopathy Study (ETDRS) map. Results: Comparing the SiO group with the gas group, the ganglion cell layer showed a significant thinning in all fields of the inner ring of the ETDRS map, the inner plexiform layer in the nasal, superior and temporal quadrants, and the outer plexiform layer in the nasal quadrant. Conclusions: Inner retinal layers in the fovea/parafovea were significantly thinner in the SiO group. Prospective studies are warranted to further elucidate possible retinal adverse effects of SiO tamponade.

Intravitreal injection of anti-Interleukin (IL)-6 antibody attenuates experimental autoimmune uveitis in mice

Purpose To evaluate the effect of an intravitreally applied anti‐IL‐6 antibody for the treatment of experimental autoimmune uveitis (EAU). Methods EAU was induced in female B10.RIII mice by Inter‐Photoreceptor‐Binding‐Protein (IRBP) in complete Freund’s adjuvant, boosted by Pertussis toxin. Single blinded intravitreal injections of anti‐IL‐6 antibody were applied 5–7 days as well as 8–10 days (3 day interval) after EAU induction into the randomized treatment eye and phosphate buffered saline (PBS) into the fellow control eye. Clinical and fluorescein angiography scoring (6 EAU grades) was done at each injection day and at enucleation day 14. Enucleated eyes were either scored histologically (6 EAU grades) or examined by ELISA for levels of IL‐6, IL‐17 and IL‐6 soluble Receptor (sIL‐6R). Results Uveitis developed in all 12 mice. Clinical uveitis score was significantly reduced (p = 0.035) in treated eyes (median 2.0, range 0–4.0, n = 12) compared to the fellow control eyes (median 3.0, range 1.0–4.0, n = 12). Angiography scores were reduced in 9/12 treated eyes and histological scores in 3/4 treated eyes compared to the fellow control eyes. Cytokine levels were determined in 8 mice, of which 4 responded to anti‐IL‐6 treatment and 4 did not respond. All mice responding to treatment had a significant reduction of IL‐6 (p < 0.01) and IL‐17 (p = 0.01) levels in treated eyes compared to the fellow control eyes. This difference was not seen in non‐responding mice. Conclusions Intravitreal anti‐IL‐6 treatment significantly attenuates experimental autoimmune uveitis in mice. EAU activity correlates with ocular IL‐6 and IL‐17 levels. HighlightsNew treatment possibility for Experimental Autoimmune Uveitis (EAU).Intravitreal anti‐IL‐6 injections attenuate EAU.EAU activity is correlated with ocular IL‐6 and IL‐17 levels.

Thermal Stimulation of the Retina Reduces Bruch's Membrane Thickness in Age Related Macular Degeneration Mouse Models

Purpose To investigate the effect of thermal stimulation of the retina (TS-R) on Bruchs membrane (BrM) thickness in age-related macular degeneration (AMD) mouse models as a novel concept for the prophylaxis and treatment of dry AMD. Methods Two knockout AMD mouse models, B6.129P2-Apoetm1Unc/J (ApoE−/−) and B6.129X1-Nfe2I2tm1Ywk/J (NRF2−/−), were chosen. One randomized eye of each mouse in four different groups (two of different age, two of different genotype) of five mice was treated by TS-R (532 nm, 10-ms duration, 50-μm spot size), the fellow eye served as control. Laser power was titrated to barely visible laser burns, then reduced by 70% to guarantee for thermal elevation without damage to the neuroretina, then applied uniformly to the murine retina. Fundus, optical coherence tomography (OCT), and fluorescein angiography (FLA) images were obtained at the day of treatment and 1 month after treatment. Eyes were enucleated thereafter to analyze BrM thickness by transmission electron microscopy (TEM) in a standardized blinded manner. Results Fundus images revealed that all ApoE−/− and NRF2−/− mice had AMD associated retinal alterations. BrM thickness was increased in untreated controls of both mouse models. Subvisible TS-R laser spots were not detectable by fundus imaging, OCT, or FLA 2 hours or 1 month after laser treatment. TEM revealed a significant reduction of BrM thickness in laser-treated eyes of all four groups compared to their fellow control eyes. Conclusions TS-R reduces BrM thickness in AMD mouse models ApoE−/− and NRF2−/− without damage to the neuroretina. It may become a prophylactic or even therapeutic treatment option for dry AMD. Translational Relevance TS-R may become a prophylactic or even therapeutic treatment option for dry AMD.

Mechano- and thermosensitivity of injured muscle afferents 20 to 80 days after nerve injury

Chronic injury of limb nerves leading to neuropathic pain affects deep somatic nerves. Here the functional properties of injured afferent fibers in the lateral gastrocnemius-soleus nerve were investigated 20 and 80 days after suturing the central stump of this muscle nerve to the distal stump of the sural nerve in anesthetized rats. Neurophysiological recordings were made from afferent axons identified in either the sciatic nerve (87 A-, 63 C-fibers) or the dorsal root L4/L5 (52 A-, 26 C-fibers) by electrical stimulation of the injured nerve. About 70% of the functionally identified A-fibers had regenerated into skin by 80 days after nerve suture; the remaining A-fibers could be activated only from the injured nerve. In contrast, 93% of the functionally identified C-fibers could only be activated from the injured sural nerve after 80 days. Nearly half of the injured A- (45%) and C-fibers (44%) exhibited ongoing and/or mechanically or thermally evoked activity. Because ~50% of the A- and C-fibers are somatomotor or sympathetic postganglionic axons, respectively, probably all injured muscle afferent A- and C-fibers developed ectopic activity. Ongoing activity was present in 17% of the A- and 46% of the C-fibers. Mechanosensitivity was present in most injured A- (99%) and C-fibers (85%), whereas thermosensitivity was more common in C-fibers (cold 46%, heat 47%) than in A-fibers (cold 18%, heat 12%). Practically all thermosensitive A-fibers and C-fibers were also mechanosensitive. Thus, unlike cutaneous axons, almost all A- and C-fibers afferents in injured muscle nerves demonstrate ectopic activity, even chronically after nerve injury. NEW & NOTEWORTHY After chronic injury of a muscle nerve, allowing the nerve fibers to regenerate to the target tissue, 1) most afferent A-fibers are mechanosensitive and regenerate to the target tissue; 2) ectopic ongoing activity, cold sensitivity, and heat sensitivity significantly decrease with time after injury in A-afferents; 3) most afferent C-fibers do not regenerate to the target tissue; and 4) injured C-afferents maintain the patterns of ectopic discharge properties they already show soon after nerve injury.