Ultrasound-guided blocks for the treatment of chronic pain

Ultrasound (US) is an emerging imaging technique in interventional pain management. The main advantages are the identification of soft tissues, vessels, and nerves, without exposing patients and personnel to radiation, the possibility to perform continuous imaging, and the visualization of the fluid injected in a real-time fashion. Possible applications are nerve blocks of the cervical and lumbar zygapophysial joints, stellate ganglion block, intercostal nerve blocks, occipital nerve blocks, blocks of the inguinal nerves, peripheral nerve blocks of the extremities, blocks of painful stump neuromas, caudal epidural injections, and injections of tender points. US may also be used for destructive procedures, such as cryoanalgesia, radiofrequency lesions, or chemical neurolysis. The increasing published data available suggest that US has a potential usefulness in interventional pain management, but also limitations. There is still a need for clinical trials investigating efficacy and safety of US-guided pain procedures. Until these studies are made, fluoroscopy or computed tomography remain the gold standard for most interventional pain procedures.

Clinical presentation of a traumatic cervical spine disc rupture in alpine sports: a case report

ABSTRACT: Isolated non-skeletal injuries of the cervical spine are rare and frequently missed. Different evaluation algorithms for C-spine injuries, such as the Canadian C-spine Rule have been proposed, however with strong emphasis on excluding osseous lesions. Discoligamentary injuries may be masked by unique clinical situations presenting to the emergency physician. We report on the case of a 28-year-old patient being admitted to our emergency department after a snowboarding accident, with an assumed hyperflexion injury of the cervical spine. During the initial clinical encounter the only clinical finding the patient demonstrated, was a burning sensation in the palms bilaterally. No neck pain could be elicited and the patient was not intoxicated and did not have distracting injuries. Since the patient described a fall prevention attempt with both arms, a peripheral nerve contusion was considered as a differential diagnosis. However, a high level of suspicion and the use of sophisticated imaging (MRI and CT) of the cervical spine, ultimately led to the diagnosis of a traumatic disc rupture at the C5/6 level. The patient was subsequently treated with a ventral microdiscectomy with cage interposition and ventral plate stabilization at the C5/C6 level and could be discharged home with clearly improving symptoms and without further complications.This case underlines how clinical presentation and extent of injury can differ and it furthermore points out, that injuries contracted during alpine snow sports need to be considered high velocity injuries, thus putting the patient at risk for cervical spine trauma. In these patients, especially when presenting with an unclear neurologic pattern, the emergency doctor needs to be alert and may have to interpret rigid guidelines according to the situation. The importance of correctly using CT and MRI according to both - standardized protocols and the patient's clinical presentation - is crucial for exclusion of C-spine trauma.

Effects of a low dose infusion of racemic and S-ketamine on the nociceptive withdrawal reflex in standing ponies

OBJECTIVE: To investigate the effect of plasma concentrations obtained by a low dose constant rate infusion (CRI) of racemic ketamine or S-ketamine on the nociceptive withdrawal reflex (NWR) in standing ponies. STUDY DESIGN: Prospective, blinded, cross-over study. ANIMALS: Six healthy 5-year-old Shetland ponies. METHODS: Ponies received either 0.6 mg kg(-1) racemic ketamine (group RS) or 0.3 mg kg(-1) S-ketamine (group S) intravenously (IV), followed by a CRI of 20 microg kg(-1)minute(-1) racemic ketamine (group RS) or 10 microg kg(-1)minute(-1) S-ketamine (group S) for 59 minutes. The NWR was evoked by transcutaneous electrical stimulation of a peripheral nerve before drug administration, 15 and 45 minutes after the start of the bolus injection and 15 minutes after the end of the CRI. Electromyographic responses were recorded and analysed. Arterial blood was collected before stimulation and plasma concentrations of ketamine and norketamine were measured enantioselectively using capillary electrophoresis. Ponies were video recorded and monitored to assess drug effects on behaviour, heart rate (HR), mean arterial blood pressure (MAP) and respiratory rate. RESULTS: The NWR was significantly depressed in group RS at plasma concentrations between 20 and 25 ng mL(-1) of each enantiomer. In group S, no significant NWR depression could be observed; plasma concentrations of S-ketamine (9-15 ng mL(-1)) were lower, compared to S-ketamine concentrations in group RS, although this difference was not statistically significant. Minor changes in behaviour, HR and MAP only occurred within the first 5-10 minutes after bolus drug administration in both groups. CONCLUSION: Antinociceptive activity in standing ponies, demonstrated as a depression of the NWR, could only be detected after treatment with racemic ketamine. S-ketamine may have lacked this effect as a result of lower plasma concentrations, a more rapid metabolism or a lower potency of S-ketamine in Equidae so further investigation is necessary.

Effect of discharge desynchronization on the size of motor evoked potentials: an analysis

OBJECTIVE: Motor evoked potentials (MEPs) after transcranial magnetic brain stimulation (TMS) are smaller than CMAPs after peripheral nerve stimulation, because desynchronization of the TMS-induced motor neurone discharges occurs (i.e. MEP desynchronization). This desynchronization effect can be eliminated by use of the triple stimulation technique (TST; Brain 121 (1998) 437). The objective of this paper is to study the effect of discharge desynchronization on MEPs by comparing the size of MEP and TST responses. METHODS: MEP and TST responses were obtained in 10 healthy subjects during isometric contractions of the abductor digiti minimi, during voluntary background contractions between 0% and 20% of maximal force, and using 3 different stimulus intensities. Additional data from other normals and from multiple sclerosis (MS) patients were obtained from previous studies. RESULTS: MEPs were smaller than TST responses in all subjects and under all stimulating conditions, confirming the marked influence of desynchronization on MEPs. There was a linear relation between the amplitudes of MEPs vs. TST responses, independent of the degree of voluntary contraction and stimulus intensity. The slope of the regression equation was 0.66 on average, indicating that desynchronization reduced the MEP amplitude on average by one third, with marked inter-individual variations. A similar average proportion was found in MS patients. CONCLUSIONS: The MEP size reduction induced by desynchronization is not influenced by the intensity of TMS and by the level of facilitatory voluntary background contractions. It is similar in healthy subjects and in MS patients, in whom increased desynchronization of central conduction was previously suggested to occur. Thus, the MEP size reduction observed may not parallel the actual amount of desynchronization.

Corticospinal output and loss of force during motor fatigue

The objective of this study was to analyze central motor output changes in relation to contraction force during motor fatigue. The triple stimulation technique (TST, Magistris et al. in Brain 121(Pt 3):437-450, 1998) was used to quantify a central conduction index (CCI = amplitude ratio of central conduction response and peripheral nerve response, obtained simultaneously by the TST). The CCI removes effects of peripheral fatigue from the quantification. It allows a quantification of the percentage of the entire target muscle motor unit pool driven to discharge by a transcranial magnetic stimulus. Subjects (n = 23) performed repetitive maximal voluntary contractions (MVC) of abductor digiti minimi (duration 1 s, frequency 0.5 Hz) during 2 min. TST recordings were obtained every 15 s, using stimulation intensities sufficient to stimulate all cortical motor neurons (MNs) leading to the target muscle, and during voluntary contractions of 20% of the MVC to facilitate the responses. TST was also repetitively recorded during recovery. This basic exercise protocol was modified in a number of experiments to further characterize influences on CCI of motor fatigue (4 min exercise at 50% MVC; delayed fatigue recovery during local hemostasis, "stimulated exercise" by 20 Hz trains of 1 s duration at 0.5 Hz during 2 min). In addition, the cortical silent period was measured during the basic exercise protocol. Force fatigued to approximately 40% of MVC in all experiments and in all subjects. In all subjects, CCI decreased during exercise, but this decrease varied markedly between subjects. On average, CCI reductions preceded force reductions during exercise, and CCI recovery preceded force recovery. Exercising at 50% for 4 min reduced muscle force more markedly than CCI. Hemostasis induced by a cuff delayed muscle force recovery, but not CCI recovery. Stimulated exercise reduced force markedly, but CCI decreased only marginally. Summarized, force reduction and reduction of the CCI related poorly quantitatively and in time, and voluntary drive was particularly critical to reduce the CCI. The fatigue induced reduction of CCI may result from a central inhibitory phenomenon. Voluntary muscle activation is critical for the CCI reduction, suggesting a primarily supraspinal mechanism.

Is carotid endarterectomy a trainee operation?

BACKGROUND: Recent dramatic changes in surgical training resulting from working-hour regulations may lead to lack of competence. Traditionally, carotid surgery has been the domain of specialists. This study was designed to compare the outcome of carotid endarterectomy performed by vascular surgical trainees versus vascular surgeon (VS). METHODS: A retrospective study of 1,379 consecutive patients who underwent carotid endarterectomy as the sole procedure under local or general anesthesia (from 1995-2004) was performed. All patients were admitted to the intensive care unit for 24 hours. Trainees performed 475 (34.5%) and vascular specialists performed 904 (65.5%) operations. RESULTS: Patient characteristics with regard to preoperative neurological status were similar. Trainees operated on 61.4% symptomatic patients and VS on 56.8% (P = 0.09). Shunt use did not differ (16% trainee vs. 17.8% VS). Clamping time and total operating time were longer among trainees (41.9 vs. 33.5 min, P < 0.001; and 121.2 vs. 101.8 min, P < 0.001, respectively). Postoperative stroke and death rates (3.2% vs. 3.1% and 0.4% vs. 0.9%, respectively) did not differ. Peripheral nerve complications were more common among trainees (12.2% vs. 6.5%; P < 0.0001); 99.6% of these nerve injuries had resolved at 3 months' follow-up. CONCLUSIONS: Carotid endarterectomy can be performed safely by a trainee vascular surgeon when assisted and supervised by a specialist vascular surgeon.

Ultrasound-guided block of sciatic and femoral nerves: an anatomical study

The sheep is a popular animal model for human biomechanical research involving invasive surgery on the hind limb. These painful procedures can only be ethically justified with the application of adequate analgesia protocols. Regional anaesthesia as an adjunct to general anaesthesia may markedly improve well-being of these experimental animals during the postoperative period due to a higher analgesic efficacy when compared with systemic drugs, and may therefore reduce stress and consequently the severity of such studies. As a first step 14 sheep cadavers were used to establish a new technique for the peripheral blockade of the sciatic and the femoral nerves under sonographic guidance and to evaluate the success rate by determination of the colorization of both nerves after an injection of 0.5 mL of a 0.1% methylene blue solution. First, both nerves were visualized sonographically. Then, methylene blue solution was injected and subsequently the length of colorization was measured by gross anatomical dissection of the target nerves. Twenty-four sciatic nerves were identified sonographically in 12 out of 13 cadavers. In one animal, the nerve could not be ascertained unequivocally and, consequently, nerve colorization failed. Twenty femoral nerves were located by ultrasound in 10 out of 13 cadavers. In three cadavers, signs of autolysis impeded the scan. This study provides a detailed anatomical description of the localization of the sciatic and the femoral nerves and presents an effective and safe yet simple and rapid technique for performing peripheral nerve blocks with a high success rate.

Desmoplastic small round cell tumor: A rare cause of a progressive brachial plexopathy.

Introduction: Desmoplastic small round cell tumor (DSRCT) is an uncommon, embryonic-type neoplasm, typically presenting as an abdominal mass in young men. A single case of DSRCT arising in the peripheral nervous system has been reported. Methods: The clinical course, imaging, electrophysiological, intraoperative, histopathological, molecular findings, and postoperative follow-up are reported. Results: A 43-year-old man presented with slowly progressive right brachial plexopathy. Magnetic resonance imaging revealed an enlarged medial cord with heterogeneous contrast enhancement. Histology showed a "small round cell" neoplasm with a polyphenotypic immunoprofile, including epithelial and mesenchymal markers. A pathognomonic fusion of Ewing sarcoma breakpoint region 1 and Wilms tumor 1 genes (EWSR1/WT1) was present. Treatment involved gross total excision and local radiotherapy. Conclusion: Our findings confirm the occurrence of DSRCT as a primary peripheral nerve tumor. Despite its usually very aggressive clinical course, prolonged recurrence-free survival may be reached. Histomorphology and immunoprofile of DSRCT may lead to misdiagnosis as small cell carcinoma. © 2013 Wiley Periodicals, Inc.

Cultivation and expansion of canine Schwann cells using reexplantation

Despite the numerous available possibilities for the surgical treatment of peripheral nerve lesions found in the dog, the success of these treatments is often unsatisfactory. It has been proven that Schwann cells (SC) have a positive influence on the regeneration of nerve stumps. Implanting a guidance channel seeded with autologous SC at the lesion site could be a new therapeutic approach. The aim of this research was to investigate the in vitro cultivation and expansion of canine SC as the main requirement for the treatment referred to above. Biopsies were carried out on 17 nerve samples originating from dogs of different breed, age, gender and condition. The reexplantation method was employed, followed by dissociation using hyaluronidase, collagenase and trypsin and further expansion. The samples were divided into six groups which were treated with a varying combination of mitogens (forskolin, bovine PEX, choleratoxin, heregulin). To obtain the quantities of SC, the specimens were immunostained by a p75-antibody. By employing a growing number of agents it was possible to obtain an increase in both the quantity of cells and purity of cultures. A maximum of 16x10(5) cells per millilitre of suspension was achieved. The largest SC purity measured 27.1%. The maximum SC quantity achieved was 43.3x10(4) SC per millilitre.

Neurotisation zur Behandlung von peripheren Nervenverletzungen beim Hund: 5 Fälle

Five dogs with peripheral nerve injuries (3 radial nerve and 2 peroneal nerve paralysis) were presented at the Small Animal Clinic of the Freie University in Berlin, Germany and were treated with a new surgical technique. The patients were examinated clinically, neurologically and an electromyographic examination was performed. The surgical technique consisted in a direct transposition of a sound nerve in a paralysed muscle. After 12 weeks, 4 dogs were able to use their leg in a correct fashion. One dog showed an improvement of the clinical signs but remained unable to bear weight on his leg.

Long-term hyperexcitability of sensory and motor axons in Aplysia californica: Induction by axotomy, serotonin, and transient depolarization

Neuropathic pain is a debilitating neurological disorder that may appear after peripheral nerve trauma and is characterized by persistent, intractable pain. The well-studied phenomenon of long-term hyperexcitability (LTH), in which sensory somata become hyperexcitable following peripheral nerve injury may be important for both chronic pain and long-lasting memory formation, since similar cellular alterations take place after both injury and learning. Though axons have previously been considered simple conducting cables, spontaneous afferent signals develop from some neuromas that form at severed nerve tips, indicating intrinsic changes in sensory axonal excitability may contribute to this intractable pain. Here we show that nerve transection, exposure to serotonin, and transient depolarization induce long-lasting sensory axonal hyperexcitability that is localized to the treated nerve segment and requires local translation of new proteins. Long-lasting functional plasticity may be a general property of axons, since both injured and transiently depolarized motor axons display LTH as well. Axonal hyperexcitability may represent an adaptive mechanism to overcome conduction failure after peripheral injury, but also displays key features shared with cellular analogues of memory including: site-specific changes in neuronal function, dependence on transient, focal depolarization for induction, and requirement for synthesis of new proteins for expression of long-lasting effects. The finding of axonal hyperexcitability after nerve injury sheds new light on the clinical problem of chronic neuropathic pain, and provides more support for the hypothesis that mechanisms of long-term memory storage evolved from primitive adaptive responses to injury. ^

Targeting Histone deacetylases (HDAC) for the treatment of soft tissue sarcoma

Targeting Histone deacetylases (HDAC) for the treatment of genetically complex soft tissue sarcoma Histone deactylase inhibitors (HDACi) are a new class of anticancer therapeutics; however, little is known about HDACi or the individual contribution of HDAC isoform activity in soft tissue sarcoma (STS). We investigated the potential efficacy of HDACi as monotherapy and in combination with chemotherapy in a panel of genetically complex STS. We found that HDACi combined with chemotherapy significantly induced anti-STS effects in vitro and in vivo. We then focused our study of HDACi in malignant peripheral nerve sheath tumor (MPNST), a subtype of highly aggressive, therapeutically resistant, and commonly fatal malignancies that occur in patients with neurofibromatosis type-1 (NF1) or sporadically. The therapeutic efficacy of HDACi was investigated in a panel of NF1-associated and sporadic MPNST cell lines. Our results demonstrate the NF1-assocaited cohort to be highly sensitive to HDACi while sporadic cell lines exhibited resistance. HDACi-induced productive autophagy was found to be a mode of resistance and inhibiting HDACi-induced autophagy significantly induced pro-apoptotic effects of HDACi in vitro and in vivo. HDACs are not a single enzyme consisting of 11 currently known isoforms. HDACis used in these studies inhibit a variety of these isoforms, namely class I HDACs which include HDAC1, 2, 3, and 8. Recently, HDAC8-specific inhibitors (HDAC8i) have been created and tested in various cancer cell lines. Lastly, the potential therapeutic efficacy of HDAC8i was investigated in human (NF1-associated and sporadic) and NF1-associated murine-derived MPNST. HDAC8i abrogated cell growth in human and murine-derived MPNST cells. Similar to the pattern noticed with pan-HDACis NF1-associated cells, especially murine-derived, were more sensitive to HDAC8i compared to human sporadic MPNST cell lines. S-phase arrest was observed in human and murine MPNST cells, independent of p53 mutational and NF1 status. HDAC8i induced apoptosis is all cell lines tested, with a more pronounced effects in human and murine-derived NF1-associated cells. Most importantly, HDAC8i abrogated murine-derived MPNST xenograft growth in vivo. Taken together, these findings support the evaluation of pan-HDACi and isoform-specific inhibitors as a novel therapy to treat MPNST, including in combination with autophagy blocking combination regimens in particular for patients with sporadic MPNST.

Learning -dependent plasticity of movement representations in the primate primary motor cortex

Primary motor cortex (M1) is involved in the production of voluntary movement and contains a complete functional representation, or map, of the skeletal musculature. This functional map can be altered by pathological experiences, such as peripheral nerve injury or stroke, by pharmacological manipulation, and by behavioral experience. The process by which experience-dependent alterations of cortical function occur is termed plasticity. In this thesis, plasticity of M1 functional organization as a consequence of behavioral experience was examined in adult primates (squirrel monkeys). Maps of movement representations were derived under anesthesia using intracortical microstimulation, whereby a microelectrode was inserted into the cortex to electrically stimulate corticospinal neurons at low current levels and evoke movements of the forelimb, principally of the hand. Movement representations were examined before and at several times after training on behavioral tasks that emphasized use of the fingers. Two behavioral tasks were utilized that dissociated the repetition of motor activity from the acquisition of motor skills. One task was easy to perform, and as such promoted repetitive motor activity without learning. The other task was more difficult, requiring the acquisition of motor skills for successful performance. Kinematic analysis indicated that monkeys used a consistent set of forelimb movements during pellet extractions. Functional mapping revealed that repetitive motor activity during the easier task did not produce plastic changes in movement representations. Instead, map plasticity, in the form of selective expansions of task-related movement representations, was only produced following skill acquisition on the difficult task. Additional studies revealed that, in general, map plasticity persisted without further training for up to three months, in parallel with the retention of task-related motor skills. Also, extensive additional training on the small well task produced further improvements in performance, and further changes in movement maps. In sum, these experiments support the following three conclusions regarding the role of M1 in motor learning. First, behaviorally-driven plasticity is learning-dependent, not activity-dependent. Second, plastic changes in M1 functional representations represent a neural correlate of acquired motor skills. Third, the persistence of map plasticity suggests that M1 is part of the neural substrate for the memory of motor skills. ^

A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain

Alterations in sodium channel expression and function have been suggested as a key molecular event underlying the abnormal processing of pain after peripheral nerve or tissue injury. Although the relative contribution of individual sodium channel subtypes to this process is unclear, the biophysical properties of the tetrodotoxin-resistant current, mediated, at least in part, by the sodium channel PN3 (SNS), suggests that it may play a specialized, pathophysiological role in the sustained, repetitive firing of the peripheral neuron after injury. Moreover, this hypothesis is supported by evidence demonstrating that selective “knock-down” of PN3 protein in the dorsal root ganglion with specific antisense oligodeoxynucleotides prevents hyperalgesia and allodynia caused by either chronic nerve or tissue injury. In contrast, knock-down of NaN/SNS2 protein, a sodium channel that may be a second possible candidate for the tetrodotoxin-resistant current, appears to have no effect on nerve injury-induced behavioral responses. These data suggest that relief from chronic inflammatory or neuropathic pain might be achieved by selective blockade or inhibition of PN3 expression. In light of the restricted distribution of PN3 to sensory neurons, such an approach might offer effective pain relief without a significant side-effect liability.

Causalgia, pathological pain, and adrenergic receptors

Control of expression of molecular receptors for chemical messengers and modulation of these receptors’ activity are now established as ways to alter cellular reaction. This paper extends these mechanisms to the arena of pathological pain by presenting the hypothesis that increased expression of α-adrenergic receptors in primary afferent neurons is part of the etiology of pain in classical causalgia. It is argued that partial denervation by lesion of peripheral nerve or by tissue destruction induces a change in peripheral nociceptors, making them excitable by sympathetic activity and adrenergic substances. This excitation is mediated by α-adrenergic receptors and has a time course reminiscent of experimental denervation supersensitivity. The change in neuronal phenotype is demonstrable after lesions of mixed nerves or of the sympathetic postganglionic supply. Similar partial denervations also produce a substantial increase in the number of dorsal root ganglion neurons evidencing the presence of α-adrenergic receptors. The hypothesis proposes the increased presence of α-adrenergic receptors in primary afferent neurons to result from an altered gene expression triggered by cytokines/growth factors produced by disconnection of peripheral nerve fibers from their cell bodies. These additional adrenergic receptors are suggested to make nociceptors and other primary afferent neurons excitable by local or circulating norepinephrine and epinephrine. For central pathways, the adrenergic excitation would be equivalent to that produced by noxious events and would consequently evoke pain. In support, evidence is cited for a form of denervation supersensitivity in causalgia and for increased expression of human α-adrenergic receptors after loss of sympathetic activity.