Rituximab improves not only back stiffness but also "stiff eyes" in stiff person syndrome: Implications for immune-mediated treatment.

OBJECTIVE: Stiff person syndrome (SPS) is usually characterized by truncal muscle rigidity and episodic painful spasms, but it sometimes appears with ocular symptoms called "stiff eyes". We recorded saccade movements in an SPS patient manifesting with "stiff eyes" conditions with slow saccade velocity and evaluated the effect of immunotherapy including rituximab on saccade parameters. METHODS: We repeatedly conducted saccade eye recordings using video-based eye tracking system on a 42-year-old male SPS patient with slow saccade. The velocity and onset latency of visual guided saccades (VGS) were measured at each recording. Because VGS velocity is affected by saccade amplitude, estimated peak velocity (Vmax) was also calculated by taking the relationship between the velocity and the amplitude of saccade into account. RESULTS: The mean VGS velocity improved significantly after two courses of rituximab administration compared with its lowest value. The estimated Vmax decreased as the clinical manifestations worsened, but it increased after rituximab administration. Other neurological symptoms in this patient such as muscle rigidity and gait instability also improved after the treatment. CONCLUSION: Slow saccade in a "stiff eyes" patient improved after rituximab administration. Our study also indicated that the saccade eye recording is useful for evaluating the clinical condition of SPS when it is complicated with ocular symptoms.

Comparative neuropharmacology of N-(2-methoxybenzyl)-2,5-dimethoxyphenethylamine (NBOMe) hallucinogens and their 2C counterparts in male rats.

2,5-Dimethoxyphenethylamines (2C compounds) are 5-HT2A/2C receptor agonists that induce hallucinogenic effects. N-methoxybenzylation of 2C compounds markedly increases their affinity for 5-HT2A receptors, and two such analogs, 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25C-NBOMe) and 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe), have emerged in recreational drug markets. Here, we investigated the neuropharmacology of 25C-NBOMe and 25I-NBOMe in rats, as compared to their 2C analogs and the prototypical 5-HT2A/2C agonist 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine (DOI). Compounds were tested in vitro using 5-HT2A receptor binding and calcium mobilization assays. For in vivo experiments, 25C-NBOMe (0.01-0.3 mg/kg), 25I-NBOMe (0.01-0.3 mg/kg), 2-(4-chloro-2,5-dimethoxyphenyl)ethanamine (2C-C) (0.1-3.0 mg/kg), 2-(4-iodo-2,5-dimethoxyphenyl)ethanamine (2C-I) (0.1-3.0 mg/kg) and DOI (0.03-1.0 mg/kg) were administered subcutaneously (sc) to male rats, and 5-HT2A-mediated behaviors were assessed. NBOMes displayed higher affinity for 5-HT2A receptors than their 2C counterparts but were substantially weaker in functional assays. 25C-NBOMe and 25I-NBOMe were much more potent at inducing wet dog shakes (WDS) and back muscle contractions (BMC) when compared to 2C-C and 2C-I. Pretreatment with the selective 5-HT2A antagonist (R)-(2,3-dimethoxyphenyl){1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl}methanol (M100907) reversed behaviors produced by all agonists. Interestingly, binding affinities at the 5-HT2A receptor were significantly correlated with potencies to induce BMC but not WDS. Our findings show that NBOMes are highly potent 5-HT2A agonists in rats, similar to effects in mice, and consistent with the reported hallucinogenic effects in human users. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

Interfascial Plane Blocks: Back to Basics.

Ultrasound-guided interfascial plane blocks are a recent development in modern regional anesthesia research and practice and represent a new route of transmission for local anesthetic to various anatomic locations, but much more research is warranted. Before becoming overtaken with enthusiasm for these new techniques, a deeper understanding of fascial tissue anatomy and structure, as well as precise targets for needle placement, is required. Many factors may influence the ultimate spread and quality of resulting interfascial plane blocks, and these must be understood in order to best integrate these techniques into contemporary perioperative pain management protocols.

Spread of Quadratus Lumborum Block to the Paravertebral Space Via Intramuscular Injection: A Volunteer Study.

BACKGROUND AND OBJECTIVES: Several types of quadratus lumborum block (QLB) are used for postoperative analgesia and are believed to be effective against both somatic and visceral pain via a local anesthetic (LA) effect in the paravertebral space (PVS). However, it remains unclear whether all QLB techniques result in LA spread into the PVS. We hypothesized that LA administered via intramuscular QLB would spread into the paravertebral space and investigated the spread and sensory block area of LA in intramuscular QLB. METHODS: This volunteer study included 5 healthy men and 1 woman, with no previous medical history. Intramuscular QLB and lateral transversus abdominis plane block were performed under real-time ultrasound guidance for comparison of sensory deprivation range. Two days later, the same procedure was performed on the contralateral side of the body. The spread of LA via intramuscular QLB spread to the PVS was assessed 1 hour after the first injections using magnetic resonance imaging. Sensory perception was also evaluated by the pinprick test at 90 minutes after injection. RESULTS: In total, we performed 11 intramuscular QLBs and 11 lateral transversus abdominis plane blocks. Magnetic resonance imaging showed that LA did not spread into the PVS after ultrasound-guided intramuscular QLB. The analgesic area corresponded to the side of the body that was ipsilateral to the block. CONCLUSIONS: Ultrasound-guided intramuscular QLBs are not clinically useful for procedures requiring LA spread into the PVS but do result in an ipsilateral analgesic effect in healthy volunteers. CLINICAL TRIAL REGISTRATION: This study was registered at University Hospital Medical Information Network Clinical Trials Registry, UMIN 000019149.

Prolotherapy for the Thoracolumbar Myofascial System.

Prolotherapy has focused on entheses as a key source of chronic low back pain, even without clear diagnosis of enthesopathy. Treatment has traditionally been guided by anatomic knowledge and careful palpation. This article integrates ultrasonographic diagnosis of fascial injury with examination findings taught in traditional prolotherapy technique. Thoracolumbar fascial anatomy and biotensegrity theory are used to explain patient presentation and response to treatment at these pathologic findings. Detailed case reports provide proof of concept for the 60-year history of prolotherapy in the treatment of chronic low back pain.

Sympathetic regulation and anterior cingulate cortex volume are altered in a rat model of chronic back pain.

Chronic pain is associated with autonomic disturbance. However, specific effects of chronic back pain on sympathetic regulation remain unknown. Chronic pain is also associated with structural changes in the anterior cingulate cortex (ACC), which may be linked to sympathetic dysregulation. The aim of this study was to determine whether sympathetic regulation and ACC surface and volume are affected in a rat model of chronic back pain, in which complete Freund Adjuvant (CFA) is injected in back muscles. Sympathetic regulation was assessed with renal blood flow (RBF) changes induced by electrical stimulation of a hind paw, while ACC structure was examined by measuring cortical surface and volume. RBF changes and ACC volume were compared between control rats and rats injected with CFA in back muscles segmental (T10) to renal sympathetic innervation or not (T2). In rats with CFA, chronic inflammation was observed in the affected muscles in addition to increased nuclear factor-kappa B (NF-kB) protein expression in corresponding spinal cord segments (p=0.01) as well as decreased ACC volume (p<0.05). In addition, intensity-dependent decreases in RBF during hind paw stimulation were attenuated by chronic pain at T2 (p's<0.05) and T10 (p's<0.05), but less so at T10 compared with T2 (p's<0.05). These results indicate that chronic back pain alters sympathetic functions through non-segmental mechanisms, possibly by altering descending regulatory pathways from ACC. Yet, segmental somato-sympathetic reflexes may compete with non-segmental processes depending on the back region affected by pain and according to the segmental organization of the sympathetic nervous system.

Lumbar Muscle Cross-Sectional Areas Do Not Predict Clinical Outcomes in Adults With Spinal Stenosis: A Longitudinal Study.

BACKGROUND: Minimal longitudinal data exist regarding the role of lumbar musculature in predicting back pain and function. In cross-sectional study designs, there is often atrophy of the segmental multifidus muscle in subjects with low back pain compared with matched controls. However, the cross-sectional design of these studies prevents drawing conclusions regarding whether lumbar muscle characteristics predict or modify future back pain or function. OBJECTIVE: The primary objective of this study is to determine whether the cross-sectional area (CSA) of lumbar muscles predict functional status or back pain at 6- or 12-month follow-up in older adults with spinal degeneration. The secondary objective is to evaluate whether these muscle characteristics improve outcome prediction above and beyond the prognostic information conferred by demographic and psychosocial variables. DESIGN: Secondary analysis of a randomized controlled trial. PARTICIPANTS: A total of 209 adults aged 50 years and older with clinical and radiographic spinal stenosis from the Lumbar Epidural steroid injection for Spinal Stenosis (LESS) trial. METHODS: Using baseline magnetic resonance images, we calculated CSAs of the lumbar multifidus, psoas, and quadratus lumborum muscles using a standardized protocol by manually tracing the borders of each of the muscles. The relationship between lumbar muscle CSAs and baseline measures was assessed with Pearson or Spearman correlation coefficients. The relationship between lumbar muscle characteristics and 6- and 12-month Roland Morris Disability Questionnaire (RDQ) and back pain Numeric Rating Scale (NRS) responses was further evaluated with multivariate linear regression. A hierarchical approach to the regression was performed: a basic model with factors of conceptual importance including age, gender, BMI, and baseline RDQ score formed the first step. The second and third steps evaluated whether psychosocial variables or muscle measures conferred additional prognostic information to the basic model. MAIN OUTCOME MEASURES: Function as measured by the RDQ and back pain as measured by the NRS at 6- and 12-month follow-up. RESULTS: Lumbar muscle CSA was not a significant predictor of 6- or 12-month RDQ or pain score in multivariate analyses. CONCLUSIONS: Cross-sectional areas of lumbar muscles do not predict function or pain at medium- and long-term follow-up in adults with lumbar spinal stenosis. LEVEL OF EVIDENCE: III.

Evaluation of Soft Tissue Reaction to Corundum Ceramic Implants Infiltrated with Colloidal Silver.

BACKGROUND: Corundum ceramic is a biomaterial used as a bone graft substitute. Silver is a well known antiseptic substance with many practical, clinical applications. OBJECTIVES: The aim of this study was to estimate soft tissue (in vivo) reaction to a new kind of ceramic implants. In our experiment, we examined the soft tissue reaction after implantation of corundum ceramic infiltrated with colloidal silver in the back muscles of 18 Wistar rats. The use of colloidal silver as a coating for the implant was designed to protect it against colonization by bacteria and the formation of bacterial biofilm. MATERIAL AND METHODS: In our study, based on the experimental method, we performed implantation operations on 18 Wistar rats. We implanted 18 modified ceramic implants and, as a control group, 18 unmodified implants. As a follow up, we observed the animals operated upon, and did postoperative, autopsy and histopathological examinations 14, 30, 90 and 180 days after implantation. RESULTS: We didn't observe any pathological reactions and significant differences between the soft tissue reaction to the modified implants and the control group. CONCLUSIONS: Lack of pathological reaction to the modified implants in the living organism is the proof of their biocompatibility. This is, of course, the first step on the long path to introduce a new kind of biocompatible ceramic implant with antiseptic cottage. Our experiment has an only introductory character and we plan to perform other, more specific, tests of this new kind of implant.

Interaction between ultraviolet B-induced cutaneous hyperalgesia and nerve growth factor-induced muscle hyperalgesia.

BACKGROUNDS AND OBJECTIVES: Clinical observations indicate that cutaneous hyperalgesia may arise from pain located in deep structures. The objective of this study was to investigate whether combined sensitization of deep and superficial somatic tissues facilitates skin hyperalgesia. METHODS: The interaction between muscle and cutaneous hyperalgesia was investigated in 16 healthy volunteers. Skin sensitization was induced unilaterally on the same randomly selected part of the body by ultraviolet B (UVB) irradiation above the upper trapezius and low back muscles. The next day, muscle hyperalgesia was induced bilaterally in low back muscles by injections of nerve growth factor (NGF). Thus, 1 day after irradiation there was skin sensitization, whereas after 2 days both skin and muscle sensitizations were present. Cutaneous blood flow, pin-prick thresholds, pressure pain thresholds (PPTs), temporal summation to repetitive painful pressure stimulation, and stimulus-response functions of graded pressure stimulations and pain intensity were assessed within the irradiated skin area and in the surrounding area before and 1, 2 and 3 days after irradiation. RESULTS: Comparing baseline with 1 day after irradiation, UVB and UVB+NGF locations demonstrated: (1) Increased superficial blood flow inside the irradiated area (p < 0.01); (2) Reduced pin-prick (p < 0.01) and PPTs (p < 0.05) within the irradiated area and in the surrounding area; (3) Left-shifted pressure stimulus-response function within the irradiated area (p < 0.01); (4) Facilitated temporal summation inside the irradiated area (p < 0.01). CONCLUSIONS: Using skin and deep tissue pain sensitization models simultaneously, no significant synergistic effects were found within the 3-day investigation suggesting little integration between the two phenomena in this period.

Comparison of nerve growth factor-induced sensitization pattern in lumbar and tibial muscle and fascia.

INTRODUCTION: Nerve growth factor (NGF) induces profound hyperalgesia. In this study we explored patterns of NGF sensitization in muscle and fascia of distal and paraspinal sites. METHODS: We injected 1 µg of NGF into human (n = 8) tibialis anterior and erector spinae muscles and their fasciae. The spatial extent of pressure sensitization, pressure pain threshold, and mechanical hyperalgesia (150 kPa, 10 s) was assessed at days 0.25, 1, 3, 7, 14, and 21. Chemical sensitization was explored by acidic buffer injections (pH 4, 100 µl) at days 7 and 14. RESULTS: The mechanical hyperalgesia area was larger in tibial fascia than in muscle. Pressure pain thresholds were lower, tonic pressure pain ratings, and citrate buffer evoked pain higher in fascia than in muscle. CONCLUSIONS: Spatial mechanical sensitization differs between muscle and fascia. Thoracolumbar fasciae appear more sensitive than tibial fasciae and may be major contributors to low back pain, but the temporal sensitization profile is similar between paraspinal and distal sites. Muscle Nerve 52: 265-272, 2015.

Injection of nerve growth factor into a low back muscle induces long-lasting latent hypersensitivity in rat dorsal horn neurons.

Little is known about the central mechanisms underlying the transition from local or regional to widespread pain in low back pain patients. The aim of the study was to find out if muscle input induced by injection of nerve growth factor (NGF) can be used as an animal model for studying spinal mechanisms involved in widespread myofascial low back pain. Electrophysiological recordings from rat dorsal horn neurons were made in vivo to study alterations in their responsiveness caused by 2 injections of NGF into the multifidus muscle at an interval of 5 days. NGF is known to be closely associated with many painful muscle disorders. The results demonstrate that the 2 NGF injections-but not a single one-caused a significant hyperexcitability of spinal neurons. Five days after the first NGF injection, the neurons were not significantly sensitized but were easier to sensitize by a second injection. The state of the neurons resembles nociceptive priming. Important findings were that the proportion of neurons having multiple receptive fields (RFs) in various tissues was significantly higher after 2 NGF injections, and new RFs appeared on the distal hind limb. The new RFs were located not in the skin but in deep tissues (muscles, thoracolumbar fascia). If similar changes occur in patients, the data might explain the diffuse nature and spread of myofascial low back pain.

Population divergence in venom bioactivities of elapid snake Pseudonaja textilis: role of procoagulant proteins in rapid rodent prey incapacitation.

This study looked at how toxic proteins in venoms of adult Australian eastern Brown snakes Pseudonaja textilis from South Australian and Queensland populations interact with physiological functions of the lab SD rat Rattus norvegicus. Circulatory collapse and incoagulable blood occurred instantly after injection of venom under the dorsal skin of anaesthetised and mechanically ventilated rats in an imitation of a P. textilis bite. Intravenous injection of purified P. textilis (Mackay, QLD) venom prothrombin activator proteins caused instant failure of circulation, testifying of high toxicity of these proteins and suggesting their role in rapid incapacitation of rodent prey. The hypothesis is further supported by circulatory collapse occurring instantly despite artificial respiration in envenomed rats and the finding of extremely high venom procoagulant potency in rat plasma. LC-MS and physiology assays revealed divergent venom composition and biological activity of South Australian (Barossa locality) and Queensland (Mackay locality) populations, which may be driven by selection for different prey. The Queensland venom of P. textilis was found to be more procoagulant and to exhibit predominately presynaptic neurotoxicity, while the South Australian venom contained diverse postsynaptic type II and III α-neurotoxins in addition to the presynaptic neurotoxins and caused significantly faster onset of neuromuscular blockade in the rat phrenic nerve-diaphragm preparation. LC-MS analysis found evidence of multiple coagulation factor X-like proteins in P. textilis venoms, including a match to P. textilis coagulation factor X isoform 2, previously known to be expressed only in the liver.