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The Polyneuropathy And Treatment with Hizentra (PATH) study required subjects with chronic inflammatory demyelinating polyneuropathy (CIDP) to show dependency on immunoglobulin G (IgG) and then be restabilized on IgG before being randomized to placebo or one of two doses of subcutaneous immunoglobulin (SCIG). Nineteen of the 51 subjects (37%) randomized to placebo did not relapse over the next 24 weeks. This article explores the reasons for this effect. A post‐hoc analysis of the PATH placebo group was undertaken. A literature search identified other placebo‐controlled CIDP trials for review and comparison. In PATH, subjects randomized to placebo who did not relapse were significantly older, had more severe disease, and took longer to deteriorate in the IgG dependency period compared with those who relapsed. Published trials in CIDP, whose primary endpoint was stability or deterioration, had a mean non‐deterioration (placebo effect) of 43%, while trials with a primary endpoint of improvement had a placebo response of only 11%. Placebo is an important variable in the design of CIDP trials. Trials designed to show clinical improvement will have a significantly lower effect of this phenomenon than those designed to show stability or deterioration.

PATH study group., In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), intravenous immunoglobulin (IVIG) is recommended to be periodically reduced to assess the need for ongoing therapy. However, little is known about the effectiveness of restabilization with IVIG in patients who worsen after IVIG withdrawal. In the Polyneuropathy And Treatment with Hizentra (PATH) study, the pre‐randomization period included sudden stopping of IVIG followed by 12 weeks of observation. Those deteriorating were then restabilized with IVIG. Of 245 subjects who stopped IVIG, 28 did not show signs of clinical deterioration within 12 weeks. Two hundred and seven received IVIG restabilization with an induction dose of 2 g/kg bodyweight (bw) IgPro10 (Privigen, CSL Behring, King of Prussia, Pennsylvania) and maintenance doses of 1 g/kg bw every 3 weeks for up to 13 weeks. Signs of clinical improvement were seen in almost all (n = 188; 91%) subjects. During IVIG restabilization, 35 subjects either did not show CIDP stability (n = 21, analyzed as n = 22 as an additional subject was randomized in error) or withdrew for other reasons (n = 14). Of the 22 subjects who did not achieve clinical stability, follow‐up information in 16 subjects after an additional 4 weeks was obtained. Nine subjects were reported to have improved, leaving a maximum of 27 subjects (13%) who either showed no signs of clinical improvement during the restabilization phase and 4 weeks post‐study or withdrew for other reasons. In conclusion, sudden IVIG withdrawal was effective in detecting ongoing immunoglobulin G dependency with a small risk for subjects not returning to their baseline 17 weeks after withdrawal., Editorial support was provided by Meridian HealthComms Ltd, funded by CSL Behring.

Mika Saarela työryhmän jäsenenä. Background Approximately two-thirds of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) need long-term intravenous immunoglobulin. Subcutaneous immunoglobulin (SCIg) is an alternative option for immunoglobulin delivery, but has not previously been investigated in a large trial of CIDP. The PATH study compared relapse rates in patients given SCIg versus placebo. Methods Between March 12, 2012, and Sept 20, 2016, we studied patients from 69 neuromuscular centres in North America, Europe, Israel, Australia, and Japan. Adults with definite or probable CIDP who responded to intravenous immunoglobulin treatment were eligible. We randomly allocated participants to 0.2 g/kg or 0.4 g/kg of a 20% SCIg solution (IgPro20) weekly versus placebo (2% human albumin solution) for maintenance treatment for 24 weeks. We did randomisation in a 1: 1:1 ratio with an interactive voice and web response system with a block size of six, stratified by region (Japan or non-Japan). The primary outcome was the proportion of patients with a CIDP relapse or who were withdrawn for any other reason during 24 weeks of treatment. Patients, caregivers, and study personnel, including those assessing outcomes, were masked to treatment assignment. Analyses were done in the intention-to-treat and per-protocol sets. This trial is registered with ClinicalTrials. gov, number NCT01545076. Findings In this randomised, double-blind, placebo-controlled trial, we randomly allocated 172 patients: 57 (33%) to the placebo group, 57 (33%) to the low-dose group, and 58 (34%) to the high-dose group. In the intention-to-treat set, 36 (63% [95% CI 50-74]) patients on placebo, 22 (39% [27-52]) on low-dose SCIg, and 19 (33% [22-46]) on high-dose SCIg had a relapse or were withdrawn from the study for other reasons (p=0.0007). Absolute risk reductions were 25% (95% CI 6-41) for low-dose versus placebo (p=0.007), 30% (12-46) for high-dose versus placebo (p=0.001), and 6% (-11 to 23) for high-dose versus low-dose (p=0.32). Causally related adverse events occurred in 47 (27%) patients (ten [18%] in the placebo group, 17 [30%] in the low-dose group, and 20 [34%] in the high-dose group). Six (3%) patients had 11 serious adverse events: one (2%) patient in the placebo group, three (5%) in the low-dose group, and two (3%) in the high-dose group; only one (an acute allergic skin reaction in the low-dose group) was assessed to be causally related. Interpretation This study, which is to our knowledge, the largest trial of CIDP to date and the first to study two administrations of immunoglobulins and two doses, showed that both doses of SCIg IgPro20 were efficacious and well tolerated, suggesting that SCIg can be used as a maintenance treatment for CIDP.

Background The efficacy of therapeutic plasma exchange (TPE) in stiff-person syndrome (SPS) is unclear. Study Design and Methods A retrospective analysis of patients diagnosed with SPS who underwent TPE and a systematic literature review were conducted. Results Nine patients with the presumptive diagnosis of SPS who underwent TPE were identified. The mean age was 55 years (range, 34-72 years) and 78% (n = 7) were female. Anti-GAD65 was present in 89% (n = 8) of the patients (range, 1.9-40,000 U/mL), and 33% (n = 3) had a history of diabetes. Forty-four percent (n = 4) of patients had previously received immunosuppressive medication and 67% (n = 6) received intravenous immune globulin. The main indication for TPE was worsening of symptoms despite treatment with first-line therapy. Seventy-eight percent of the patients (n = 7) had five TPE procedures. Seventy-eight percent (n = 7) of patients demonstrated at least minimal clinical improvement and 56% (n = 5) had a significant response. Most of the patients who demonstrated a significant response to treatment improved and their symptoms stabilized. Two patients (22%) developed adverse events, including catheter-associated infection and transient hypotension. Eighteen publications were found from the literature review, which resulted in a total of 26 patients diagnosed with SPS. Forty-two percent (n = 11) of patients had a significant symptomatic improvement after TPE treatment, and two patients (8%) developed adverse events. Conclusion TPE may benefit patients with SPS who are not responsive to first-line therapy, and it is well tolerated.

SUMMARY The continuing high prevalence of pain, both acute and persistent, is a public health problem. Improving pain curricula for health professionals is essential if we are to change the current ineffective practices related to pain prevention and management. An important question for all educators is whether our graduates are sufficiently competent in pain knowledge and skills to give appropriate pain care. In addition, deficiencies in our current education approaches need to be examined, including the key challenges that limit our moving the pain agenda forward. Limiting factors considered in this article include issues related to regulatory system requirements, curriculum priorities and resources, faculty qualifications and the need for collaboration with clinicians, traditional beliefs about patients and opportunities for interprofessional learning. Recent innovative advances are discussed related to curriculum resources, development of core pain competencies and creative learning models, including interprofessional ones. Suggested approaches to advocating for pain education changes are also included.

Objective The education of physicians is a fundamental obligation within medicine that must remain closely aligned with clinical care. And although medical education in pain care is essential, the current state of medical education does not meet the needs of physicians, patients, or society. To address this, we convened a committee of pain specialist medical student educators. Methods Tasked with creating systematically developed and valid recommendations for clinical education, we conducted a survey of pain medicine leadership within the American Academy of Pain Medicine (AAPM). The survey was conducted in two waves. We asked AAPM board members to rate 194 previously published pain medicine learning objectives for medical students; 79% of those eligible for participation responded. Results The “Top 5” list included the awareness of acute and chronic pain, skillfulness in clinical appraisal, promotion of compassionate practices, displaying empathy toward the patient, and knowledge of terms and definitions for substance abuse. The “Top 10” list included the major pharmacological classes as well as skills in examination, communication, prescribing, and interviewing. The “Top 20” list included the pain care of cognitively impaired populations, those with comorbid illness, and older adults. With the survey results in consideration, the committee produced a new recommended topic list for curricula in pain medicine. We strongly recommend that adequate resources are devoted to fully integrated medical curricula in pain so that students will learn not only the necessary clinical knowledge but also be prepared to address the professional, personal, and ethical challenges that arise in caring for those with pain. Conclusions We conclude that improved medical education in pain is essential to prepare providers who manifest both competence and compassion toward their patients.

Pain is prevalent in clinical settings, and yet it is relatively under-represented in the education of most students in the health professions. Because pain includes both sensory-discriminative and affective features, teaching students about pain presents unique challenges and opportunities. The present article describes the evolution of a new blueprint for clinical excellence that, among other competencies, incorporates a need for the emotional development of clinical trainees. The framework has been applied to the development and implementation of two new courses in pain. The first course is designed to provide a comprehensive foundation of medical knowledge regarding pain, while integratively introducing students to the affective dimensions of pain. The second course is designed to enhance students’ appreciation for the protean effects of pain through use of the humanities to represent medical experience. It is concluded that, to be most effective, fostering the emotional development of trainees in the health professions necessitates the incorporation of affect-focused learning objectives, educational tasks and assessment methods.

Emotional development, an important component of nascent professional competence, is likely to be shaped by specific formative experiences. This study sought to identify and gauge the impact of highly evocative experiences occurring during medical school.A 34-item list of candidate formative experiences was developed through focus group meetings of "colleges program"-affiliated student-advising faculty. The resulting survey instrument was administered to 216 graduating medical students at the Johns Hopkins University School of Medicine in 2007 and 2008 in a cohort study. Primary outcomes were exposure rates for the experiences and students' ratings of impact for those that occurred.One hundred eighty-one students (84%) responded. All events were experienced by25% of students. Two events were described by most as having tremendous impact: "finding an exceptional role model" and "identifying a perfect area of medicine." Other prevalent events with strong impact included "a special patient-care experience," "working well with a team," "seeing a patient whose life was saved," "encountering a negative role model," "seeing a patient die," "seeing a patient experience severe pain," and "a bad clinical experience." Factor analysis revealed three event clusters: "inspiring experiences," "mortality-related experiences," and "negative experiences relating to the learning environment."Specific formative experiences have especially strong impacts on medical students. Whereas the intrinsic value of such experiences should continue to drive educational design, increased awareness of the diversity and range of formative experiences will prepare educators to more effectively guide positive emotional development, enhancing personal and professional growth during medical school.

As the epidemics of obesity and diabetes expand, there are more patients with these disorders requiring elective surgery. For surgery on the extremities, peripheral nerve blocks have become a highly favorable anesthetic option when compared with general anesthesia. Peripheral blocks reduce respiratory and cardiac stresses, while potentially mitigating untreated peripheral pain that can foster physiologic conditions that increase risks for general health complications. However, local anesthetics are generally accepted to be a rare but possible cause of nerve damage, and there are no evidence-based recommendations for dosing local anesthetic nerve blocks in patients with diabetes. This is important because anesthesiologists do not want to potentially accelerate peripheral nerve dysfunction in diabetic patients at risk. This translational vignette (i) examines laboratory models of diabetes, (ii) summarizes the pharmacology of perineural adjuvants (epinephrine, clonidine, buprenorphine, midazolam, tramadol, and dexamethasone), and (iii) identifies areas that warrant further research to determine viability of monotherapy or combination therapy for peripheral nerve analgesia in diabetic patients. Conceivably, future translational research regarding peripheral nerve blocks in diabetic patients may logically include study of nontoxic injectable analgesic adjuvants, in combination, to provide desired analgesia, while possibly avoiding peripheral nerve toxicity that diabetic animal models have exhibited when exposed to traditional local anesthetics.

We compared the pathological changes in cutaneous axons and Schwann cells of individuals with nerve transection to the changes in patients with chronic neuropathies. Following axotomy there was segmentation of axons in the epidermis and dermis on the first day, and loss of axons from the skin was virtually complete by Day 11. Epidermal and small superficial dermal axons were lost before larger caliber and deeper dermal axons. Within the first 50 days following nerve transection, the denervated Schwann cells in the dermis were easily identified by their markers p75 and S100, but by 8 months they had largely disappeared. The chronic neuropathy patients had distally predominant fibre loss, with greater loss of epidermal and dermal fibres in the distal regions of the leg than proximal regions. Several patients had large axonal swellings, often alternating with axonal attenuation, even in regions with normal or nearly normal fibre densities. By electron microscopy the swellings contained accumulations of mitochondria and other particulate organelles as well as neurofilaments. These swellings are likely to represent predegenerative changes in sites of impaired axonal transport, and previous data indicate that the swellings presage fibre loss in the subsequent months. Some of the severely denervated regions had remaining Schwann cells, as judged by immunocytochemistry and by electron microscopy, but others lacked Schwann cells. By analogy with animal experiments, these regions are likely to have had more prolonged denervation. The distribution of axonal loss, the axonal swellings and the changes in Schwann cells all have implications for the design of clinical trials of agents intended to protect cutaneous innervation and to promote regeneration of cutaneous axons in peripheral neuropathies.

Background A 28-year-old woman presented to hospital after an episode of severe lower back spasms that occurred during a stressful family gathering. She had a history of progressive difficulty bending forward and increasing lumbar lordosis. Investigations Physical examination, spine MRI scan, abdominal and pelvic ultrasound, electromyogram, nerve conduction studies, cerebrospinal fluid analysis, breast examination, Pap smear, transabdominal and endovaginal ultrasound. Diagnosis Stiff-person syndrome with high titer of antibodies against glutamic acid decarboxylase. Treatment Benzodiazepines and intravenous immunoglobulins.

The factors inducing normally innervated Schwann cells in peripheral nerve to divide are poorly understood. Transection of the fourth and fifth lumbar ventral roots (L4/5 ventral rhizotomy) of the rat is highly selective, sparing unmyelinated axons and myelinated sensory axons; Wallerian degeneration is restricted to myelinated efferent fibers. We found that L4/5 ventral rhizotomy prompted many normally innervated nonmyelinating (Remak) Schwann cells to enter cell cycle; myelinating Schwann cells of intact (sensory) axons did not. Three days after L4/5 ventral rhizotomy, [3H]thymidine incorporation into Remak Schwann cells increased 30-fold. Schwann cells of degenerating efferents and endoneurial cells also incorporated label. Increased [3H]thymidine incorporation persisted at least 10 d after ventral rhizotomy. Despite Remak Schwann cell proliferation, the morphology of unmyelinated nerve (Remak) bundles was static. Seven days after L5 ventral rhizotomy, Remak Schwann cells in the L5-predominant lateral plantar nerve increased slightly; endoneurial cells doubled. Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive nuclei increased dramatically in peripheral nerve after L5 ventral rhizotomy; many of these were macrophage nuclei. In summary, we find that the degeneration of myelinated motor axons produced signals that were mitogenic for nonmyelinating Schwann cells with intact axons but not for myelinating Schwann cells with intact axons.

Stiff-person syndrome (SPS) is a rare neurologic disorder with autoimmune features. It is characterized by progressive, severe muscle rigidity or stiffness most prominently affecting the spine and lower extremities.Superimposed muscle spasms result in simultaneous contraction of agonist and antagonist muscles which are detectable by electromyography (EMG) and relieved by administration of benzodiazepines. The exacerbation of SPS by emotional stressors often results in the referral of these patients for psychiatric assessment although this was more common before the discovery of an association with antibodies to glutamic acid decarboxylase (GAD antibodies). Formerly known as stiff-man syndrome, the female to male ratio is 2:1 and the principle paraneoplastic variant is associated with breast cancer. Although rare, this is a disease of middle age that severely curtails the functional capacity of those it strikes. It is frequently associated with diabetes and other autoimmune diseases. IVIg is recently demonstrated to be effective in the treatment of SPS; diazepam remains useful in managing the symptoms.This article summarizes the history of SPS, describes important clinical features, discusses management, touches upon areas of uncertainty, and postulates some avenues for research.

Recent advances in regeneration and pain research have revealed gaps in the understanding of normal C-fiber anatomy. In the rat PNS, C-fiber axons assemble into Remak bundles, but beyond this, features of C-fiber organization are not defined. Systematic sampling and quantitation reveals that Remak bundles exiting from the L5 dorsal root ganglion (DRG) contain large numbers of axons, for example, 56% of unmyelinated axons were in bundles of >20 axons. This is different from distal nerve segments such as the hindpaw plantar nerve where the median number of axons per bundle is 3. The cross-sectional area of unmyelinated axons in dorsal root was homogeneous near the DRG but variability in axonal area increased near the spinal cord (p = 0.00001) and the mean axonal area was unchanged. Unmyelinated axons in peripheral nerve were almost always isolated from one another by Schwann cell processes; however, in dorsal root 7% to 9% of unmyelinated axons were immediately adjacent within pockets containing 2 or more axons. Remak bundles in the distal peripheral nerve clustered with other Remak bundles. We observe that multiple unmyelinated axons are juxtaposed within the C-fiber/Remak bundle and that the close association of afferent axons may have important functional implications.

Motoneurons reinnervate the distal stump at variable rates after peripheral nerve transection and suture. In the rat femoral nerve model, reinnervation is already substantial 3 weeks after repair, but is not completed for an additional 7 weeks. However, this “staggered regeneration” can be temporally compressed by application of 20 Hz electrical stimulation to the nerve for 1 hr. The present experiments explore two possible mechanisms for this stimulation effect: (1) synchronization of distal stump reinnervation and (2) enhancement of regeneration speed. The first possibility was investigated by labeling all motoneurons that have crossed the repair at intervals from 4 d to 4 weeks after rat femoral nerve transection and suture. Although many axons did not cross until 3–4 weeks after routine repair, stimulation significantly increased the number crossing at 4 and 7 d, with only a few crossing after 2 weeks. Regeneration speed was studied by radioisotope labeling of transported proteins and by anterograde labeling of regenerating axons, and was not altered by stimulation. Attempts to condition the neuron by stimulating the femoral nerve 1 week before injury were also without effect. Electrical stimulation thus promotes the onset of motor axon regeneration without increasing its speed. This finding suggests a combined approach to improving the outcome of nerve repair, beginning with stimulation to recruit all motoneurons across the repair, followed by other treatments to speed and prolong axonal elongation.

An L5 spinal nerve ligation (SNL) in the rat leads to behavioral signs of mechanical hyperalgesia. Our recent finding that an L5 dorsal root rhizotomy did not alter the mechanical hyperalgesia following an L5 SNL suggests that signals originating from the proximal stump of the injured nerve are not essential. We postulate that Wallerian degeneration of L5 nerve fibers leads to altered properties of adjacent intact nociceptive afferents. To investigate the role of degeneration in sensory versus motor fibers, five injury models were examined concurrently in a blinded fashion. An L5 ganglionectomy produced a selective lesion of sensory fibers. An L5 ventral root rhizotomy produced a selective lesion of motor fibers. The three control lesions included: (1) SNL with L5 dorsal root rhizotomy; (2) L5 dorsal root rhizotomy; and (3) exposure of the L5 roots without transection (sham). Paw withdrawal thresholds to mechanical stimuli were measured at three sites in the rat hindpaw corresponding to the L3, L4, and L5 dermatomes. Both the ganglionectomy and the ventral rhizotomy produced a significant, lasting (>or=20 d) decrease of mechanical withdrawal thresholds that was comparable to that produced by the SNL lesion. The L5 dorsal rhizotomy, by itself, produced a short lasting (

Chronic pain represents an immense clinical problem. With tens of millions of people in the United States alone suffering from the burden of debilitating chronic pain, there is a moral obli- gation to reduce this burden by improving the understanding of pain and treatment mechanisms, developing new therapies, optimizing and testing existing therapies, and improving access to evidence-based pain care. Here, we present a goal-oriented research agenda describing the American Pain Society's vision for pain research aimed at tackling the most pressing issues in the field. Perspective: This article presents the American Pain Society's view of some of the most important research questions that need to be addressed to advance pain science and to improve care of patients with chronic pain. a 2014 by the American Pain Society

Stiff-man syndrome (SMS) is a rare disease of progressive muscle stiffness, most common in middle age, often associated with autoimmunity to glutamic acid decarboxylase (GAD) and responsive to treatment with GABA agonists. Diagnosis is established by clinical characteristics and confirmed by EMG or antibody testing. Anti-GAD antibodies are present in 60% of those with SMS and antiamphiphysin antibodies are found in fewer than 10%. The production of antibodies has an unclear relationship to the pathological processes of the disease. GABA receptors and GABA receptor mRNAs are found in high density in the spinal cord laminae and identify possible sites of dys-function in SMS. At some spinal cord synapses, GABA co-localizes with glycine, a neurotransmitter implicated in hyperekplexia. Failure of spinal cord reflexes explains the symptoms of SMS, but electrophysiological studies have not yet identified a single locus of inhibitory failure. Immunomodulation may alter the disease course, but consistently effective treatments for SMS await development.

Metabolic and endocrine neuropathies, although generally well characterized clinically and electrophysiologically, represent an area in which improved mechanistic understanding is still needed. Although in most cases early detection and reversal of underlying abnormalities is the most effective therapeutic intervention, there are clinical states where metabolic abnormalities may persist for decades without complete resolution, e.g., chronic renal or hepatic failure in the absence of transplantation. In these instances, there remains a compelling clinical impetus for scientific advances in this area.

The efficacy of therapeutic plasma exchange (TPE) in stiff-person syndrome (SPS) is unclear.A retrospective analysis of patients diagnosed with SPS who underwent TPE and a systematic literature review were conducted.Nine patients with the presumptive diagnosis of SPS who underwent TPE were identified. The mean age was 55 years (range, 34-72 years) and 78% (n = 7) were female. Anti-GAD65 was present in 89% (n = 8) of the patients (range, 1.9-40,000 U/mL), and 33% (n = 3) had a history of diabetes. Forty-four percent (n = 4) of patients had previously received immunosuppressive medication and 67% (n = 6) received intravenous immune globulin. The main indication for TPE was worsening of symptoms despite treatment with first-line therapy. Seventy-eight percent of the patients (n = 7) had five TPE procedures. Seventy-eight percent (n = 7) of patients demonstrated at least minimal clinical improvement and 56% (n = 5) had a significant response. Most of the patients who demonstrated a significant response to treatment improved and their symptoms stabilized. Two patients (22%) developed adverse events, including catheter-associated infection and transient hypotension. Eighteen publications were found from the literature review, which resulted in a total of 26 patients diagnosed with SPS. Forty-two percent (n = 11) of patients had a significant symptomatic improvement after TPE treatment, and two patients (8%) developed adverse events.TPE may benefit patients with SPS who are not responsive to first-line therapy, and it is well tolerated.

Objective: The objective of this project was to develop core competencies in pain assessment and management for prelicensure health professional education. Such core pain competencies common to all prelicensure health professionals have not been previously reported. Methods: An interprofessional executive committee led a consensus-building process to develop the core competencies. An in-depth literature review was conducted followed by engagement of an interprofessional Competency Advisory Committee to critique competencies through an iterative process. A 2-day summit was held so that consensus could be reached. Results: The consensus-derived competencies were categorized within four domains: multidimensional nature of pain, pain assessment and measurement, management of pain, and context of pain management. These domains address the fundamental concepts and complexity of pain; how pain is observed and assessed; collaborative approaches to treatment options; and application of competencies across the life span in the context of various settings, populations, and care team models. A set of values and guiding principles are embedded within each domain. Conclusions: These competencies can serve as a foundation for developing, defining, and revising curricula and as a resource for the creation of learning activities across health professions designed to advance care that effectively responds to pain

A number of antidepressants are essential for the treatment of chronic pain; these are referred to as the “pain-active” antidepressants. As a group, these agents manifest noradrenergic modulation. They have a number of advantages in this context: well-documented efficacy, mechanism or mechanisms of action that are complimentary to other agents used for persistent pain, distinctive and unique side effect profiles, excellent long-term tolerability, and a spectrum of cost-range options. Because the onset of action for the pain-active antidepressants can take days to weeks, these drugs are generally not appropriate for acute pain treatment with notable exceptions. It is because of their numerous advantages including efficacy and tolerability for long-term usage that antidepressants have become a staple of medical management of chronic pain.

Patient–physician interactions are increasingly influenced by the extraordinary diversification of populations and rapid expansion of medical knowledge that characterize our modern era. By contrast, the patient–physician interaction models currently used to teach medical trainees have little capacity to address these twin challenges. We developed a new model of patient–physician interaction to explicitly address these problems. Historically, models of patient–physician interaction viewed patient autonomy and the manifestation of clearly defined health care-related values as tightly linked, and it was assumed that patients’ medical knowledge was low. Unfortunately, this does not adequately represent patients such as 1) the highly educated non-medical specialist who possesses little familiarity with health-related values but is highly autonomous, and 2) the patient from a non-Western background who may have well-established health care-related values but a low sense of personal independence. In addition, it is evident to us that the assumption that all patients possess little medical knowledge can create alienation between patient and physician, e.g. the well-informed patient with a rare disease. We propose a paradigm that models autonomy, health care-related values formation, and medical knowledge as varying from patient to patient. Four examples of patient types are described within the context of the model based on clinical experience. We believe that adopting this model will have implications for optimizing patient–physician interactions and teaching about patient-centered care. Further research is needed to identify relevant patient types within this framework and to assess the impact on health care outcomes.

Knowledgeable and compassionate care regarding pain is a core responsibility of health professionals associated with better medical outcomes, improved quality of life, and lower healthcare costs. Education is an essential part of training healthcare providers to deliver conscientious pain care but little is known about whether medical school curricula meet educational needs. Using a novel systematic approach to assess educational content, we examined the curricula of Liaison Committee on Medical Education-accredited medical schools between August 2009 and February 2010. Our intent was to establish important benchmark values regarding pain education of future physicians during primary professional training. External validation was performed. Inclusion criteria required evidence of substantive participation in the curriculum management database of the Association of American Medical Colleges. A total of 117 U.S. and Canadian medical schools were included in the study. Approximately 80% of U.S. medical schools require 1 or more pain sessions. Among Canadian medical schools, 92% require pain sessions. Pain sessions are typically presented as part of general required courses. Median hours of instruction on pain topics for Canadian schools was twice the U.S. median. Many topics included in the International Association for the Study of Pain core curriculum received little or no coverage. There were no correlations between the types of pain education offered and school characteristics (eg, private versus public). We conclude that pain education for North American medical students is limited, variable, and often fragmentary. There is a need for innovative approaches and better integration of pain topics into medical school curricula. Perspective This study assessed the scope and scale of pain education programs in U.S. and Canadian medical schools. Significant gaps between recommended pain curricula and documented educational content were identified. In short, pain education was limited and fragmentary. Innovative and integrated pain education in primary medical education is needed.

Objective. Improvements in clinical pain care have not matched advances in scientific knowledge, and innovations in medical education are needed. Several streams of evidence indicate that pain education needs to address both the affective and cognitive dimensions of pain. Our aim was to design and deliver a new course in pain establishing foundation-level knowledge while comprehensively addressing the emotional development needs in this area. Setting. One hundred eighteen first-year medical students at Johns Hopkins School of Medicine. Outcome Measures. Performance was measured by multiple-choice tests of pain knowledge, attendance, reflective pain portfolios, and satisfaction measures. Results. Domains of competence in pain knowledge included central and peripheral pain signalling, pharmacological management of pain with standard analgesic medications, neuromodulating agents, and opioids; cancer pain, musculoskeletal pain, nociceptive, inflammatory, neuropathic, geriatric, and pediatric pain. Socio-emotional development (portfolio) work focused on increasing awareness of pain affect in self and others, and on enhancing the commitment to excellence in pain care. Reflections included observations on a brief pain experience (cold pressor test), the multidimensionality of pain, the role of empathy and compassion in medical care, the positive characteristics of pain-care role models, the complex feelings engendered by pain and addiction including frustration and disappointment, and aspirations and commitments in clinical medicine. The students completing feedback expressed high levels of interest in pain medicine as a result of the course. Discussion. We conclude that a 4-day pain course incorporating sessions with pain specialists, pain medicine knowledge, and design-built elements to strengthen emotional skills is an effective educational approach. Summary. Innovations in medical education about pain are needed. Our aim was to design and deliver a new course for medical students addressing both the affective and cognitive dimensions of pain. Combining small-group sessions with pain specialists, active-learning approaches to pain knowledge, and design-built elements to strengthen emotional skills was highly effective.

To report the clinical, electrodiagnostic, and pathologic findings in 3 patients who presented with complex regional pain syndrome as their primary manifestation of peripheral nerve vasculitis.Case series.Outpatient clinic in a tertiary care academic medical center.Patient 1 was a 39-year-old woman with a 9-year history of non-length-dependent severe burning pain and swelling in her extremities. Patient 2 was a 67-year-old man with a 2-year history of severe burning pain and swelling in an extremity after a fall. Patient 3 was a 74-year-old man with a 6-month history of severe allodynic pain and atrophy of the right hand after a viral illnessIn all 3 cases, clinical and electrodiagnostic testing were suggestive of multiple mononeuropathies. Nerve biopsy either confirmed vasculitis (patient 1) or was suggestive of angiopathy (patients 2 and 3). Immunomodulative therapy led to marked clinical improvement in all 3 cases.To our knowledge, this is the first report demonstrating that the inflammatory nerve injury seen with peripheral nerve vasculitis can result in complex regional pain syndrome. Clinical and electrodiagnostic assessments can help in the identification and management of these patients.

Stiff-person syndrome (SPS), formerly Stiff-man syndrome, is a rare autoimmune disease usually exhibiting severe spasms and thoracolumbar stiffness, with very elevated glutamic acid decarboxylase antibodies (GAD Ab). A paraneoplastic variant, less well characterized, is associated with amphiphysin antibodies (amphiphysin Ab). The objective of this study was to identify distinctive clinical features of amphiphysin Ab-associated SPS.Records associated with 845 sera tested in the Yale SPS project were examined, and 621 patients with clinically suspected SPS were included in the study. Clinical characteristics were assessed with correction for multiple comparisons.In all, 116 patients had GAD antibodies and 11 patients had amphiphysin Ab; some clinical information was available for 112 and 11 of these patients, respectively. Patients with amphiphysin Ab-associated SPS were exclusively female; mean age was 60. All except one had breast cancer; none had diabetes. Compared to patients with GAD Ab-associated SPS, those with amphiphysin Ab were older (p = 0.02) and showed a dramatically different stiffness pattern (p0.0000001) with cervical involvement more likely, por = 0.001. Electromyography showed continuous motor unit activity or was reported positive in eight. Benzodiazepines at high dose (average 50 mg/day diazepam) were partially effective. Four patients were steroid responsive and tumor excision with chemotherapy produced marked clinical improvement in three of five patients.Amphiphysin Ab-associated stiff-person syndrome is strongly associated with cervical region stiffness, female sex, breast cancer, advanced age, EMG abnormalities, and benzodiazepine responsiveness. The condition may respond to steroids and can dramatically improve with cancer treatment.

The overarching goal of medical training is to nurture the growth of knowledgeable, caring, and insightful clinicians guided by the ideals of medical professionalism. Recent definitions of professional competence identify essential clinical skills, including cognitive expertise, emotional competence, and reflective capacity. This modern framework reflects the increasingly complex nature of the patient-clinician interaction, in which the clinician must exchange diagnostic information while supportively engaging the patient on a deeper, affective level. The affective dimension can be particularly potent when pain is the primary symptom, as it is for the majority of medical visits. Unfortunately, however, current models of professionalism, used as an early guide for medical trainees to develop an understanding of the clinical exchange, largely focus on interactions in the cognitive domain. To emphasize the importance of emotions in professional development, we propose the Cognitive and Emotional Preparedness Model, which describes the clinical encounter occurring on two channels, one cognitive and the other emotional, and stresses the importance of multidimensional development in preparing the clinician to (1) communicate clinical information, (2) provide emotional support, and (3) actively reflect on experiences for continued improvement. Together, acquisition of knowledge, emotional development, and reflective skill will improve the clinical interaction. Perspective The proficiency of medical trainees in developing clinical skills profoundly shapes patient satisfaction and treatment outcomes. This article reviews the cognitive, emotional, and reflective development of medical trainees and presents a model illustrating how clinical development impacts pain care. For improved efficacy, pain education should be calibrated to students' developmental needs.

Peripheral nerve injury may lead to the formation of a painful neuroma. In patients, palpating the tissue overlying a neuroma evokes paraesthesias/dysaesthesias in the distribution of the injured nerve. Previous animal models of neuropathic pain have focused on the mechanical hyperalgesia and allodynia that develops at a location distant from the site of injury and not on the pain from direct stimulation of the neuroma. We describe a new animal model of neuroma pain in which the neuroma was located in a position that is accessible to mechanical testing and outside of the innervation territory of the injured nerve. This allowed testing of pain in response to mechanical stimulation of the neuroma (which we call neuroma tenderness) independent of pain due to mechanical hyperalgesia. In the tibial neuroma transposition (TNT) model, the posterior tibial nerve was ligated and transected in the foot just proximal to the plantar bifurcation. Using a subcutaneous tunnel, the end of the ligated nerve was positioned just superior to the lateral malleolus. Mechanical stimulation of the neuroma produced a profound withdrawal behavior that could be distinguished from the hyperalgesia that developed on the hind paw. The neuroma tenderness (but not the hyperalgesia) was reversed by local lidocaine injection and by proximal transection of the tibial nerve. Afferents originating from the neuroma exhibited spontaneous activity and responses to mechanical stimulation of the neuroma. The TNT model provides a useful tool to investigate the differential mechanisms underlying the neuroma tenderness and mechanical hyperalgesia associated with neuropathic pain.

The authors assessed the ability of the neurophilin compound, timcodar dimesylate, to accelerate the return of epidermal nerve fiber density (ENFD) after a standardized nerve injury in a randomized double blind, placebo controlled trial. While there was no difference in the regeneration rate between the treatment and placebo arms, the baseline ENFD (p = 0.006), height (p = 0.02), and race (p = 0.03) were associated with the regeneration rate.

Stiff-person syndrome (SPS) is a rare disease of severe progressive muscle stiffness in the spine and lower extremities with superimposed muscle spasms triggered by external stimuli. Patients with SPS are often referred for psychiatric evaluation and the psychiatrist may be the first to diagnosis SPS. Psychosocial stressors often precede the first manifestations of the disease; depression, anxiety, and alcohol abuse are comorbid illnesses. The identification of an association with antibodies to glutamic acid decarboxylase (GAD) was invaluable for definitively establishing a pathological basis for the disease; antibodies to amphiphysin and gephyrin are also found in cases of SPS but at much lower frequencies. Whether the antibodies inhibit GAD activity in vivo, target GAD-expressing neurons for immune-mediated destruction, are part of a wider immune process, or are merely a marker for destruction of GAD-expressing neurons by an independent neurodegenerative process is not yet clear. Both electromyography and the detection of GAD antibodies are useful in establishing a diagnosis of SPS. Treatment of SPS includes the use of immunomodulating therapies (plasmapheresis and intravenous immunoglobulins) and symptomatic treatment with benzodiazepines and baclofen. The use of tricyclic antidepressants and rapid withdrawal from therapy should be avoided.

Unmyelinated nerve fibers (Remak bundles) in the rodent sciatic nerve typically contain multiple axons. This study asked whether C-fiber bundles contain axons arising from more than one type of neuron. Most small neurons of the lumbar dorsal root ganglion (DRG) are either glial cell line-derived neurotrophic factor dependent or nerve growth factor dependent, binding either isolectin B4 (IB4) or antibodies to calcitonin gene-related peptide (CGRP), respectively. Injection of IB4-conjugated horseradish peroxidase into a lumbar DRG resulted in intense labeling of IB4 axons, with very low background. Visualized by confocal fluorescence, IB4-binding and CGRP-positive nerve fibers originating from different DRG neurons came together and remained closely parallel over long distances, suggesting that these two types of axon occupy the same Remak bundle. With double-labeling immunogold electron microscopy (EM), we confirmed that IB4 and CGRP axons were distinct and were found together in single Remak bundles. Previous studies indicate that some DRG neurons express both CGRP and IB4 binding. To ensure that our immunogold results were not a consequence of coexpression, we studied large populations of unmyelinated axons by using quantitative single-label EM. Tetramethylbenzidine, a chromogen with strong intrinsic signal amplification of IB4-horseradish peroxidase, labeled as many as 52% of unmyelinated axons in the dorsal root. Concomitantly, 97% of the Remak bundles with more than one axon contained at least one IB4-labeled axon. Probabilistic modeling using binomial distribution functions rejected the hypothesis that IB4 axons segregate into IB4-specific bundles (P < 0.00001). We conclude that most Remak bundle Schwann cells simultaneously support diverse axon types with different growth factor dependences.

Since the 2011 Institute of Medicine (IOM) report on the status of pain and pain care in America, there has been a renewed appreciation for the scope of the pain “epidemic” ⇓. Many solutions have been proposed, but it is clear that no one specialty or discipline can address the needs of 100 million people with pain in the United States alone, much less the many, many more hundreds of millions suffering from conditions causing chronic pain around the globe. The number of pain care specialists remains small compared with the needs for pain care, but in truth, much of the most-needed pain care can be managed effectively by skillful, knowledgeable, and compassionate primary care providers and members of their clinical teams. The biggest barrier to primary care clinicians more effectively managing pain is that most of them are not trained to assess and manage even common problems such as back pain, headache, or …

Five hundred seventy-six patients with suspected stiff-person syndrome (SPS) underwent immunocytochemistry (ICC). Of these, 286 underwent radioimmunoassay (RIA) for glutamic acid decarboxylase (GAD) antibodies; 116 were GAD antibody positive by one or both tests. Ninety-six percent of those positive by ICC had RIA values several standard deviations above normal. RIA did not correlate with age or illness duration. Marked elevations of RIA for GAD antibodies were characteristic of ICC-confirmed SPS, and modest elevations were not.

We demonstrated recently that uninjured C-fiber nociceptors in the L4 spinal nerve develop spontaneous activity after transection of the L5 spinal nerve. We postulated that Wallerian degeneration leads to an alteration in the properties of the neighboring, uninjured afferents from adjacent spinal nerves. To explore the role of degeneration of myelinated versus unmyelinated fibers, we investigated the effects of an L5 ventral rhizotomy in rat. This lesion leads to degeneration predominantly in myelinated fibers. Mechanical paw-withdrawal thresholds were assessed with von Frey hairs, and teased-fiber techniques were used to record from single C-fiber afferents in the L4 spinal nerve. Behavioral and electrophysiological data were collected in a blinded manner. Seven days after surgery, a marked decrease in withdrawal thresholds was observed after the ventral rhizotomy but not after the sham operation. Single fiber recordings revealed low-frequency spontaneous activity in 25% of the C-fiber afferents 8-10 d after the lesion compared with only 11% after sham operation. Paw-withdrawal thresholds were inversely correlated with the incidence of spontaneous activity in high-threshold C-fiber afferents. In normal animals, low-frequency electrocutaneous stimulation at C-fiber, but not A-fiber, strength produced behavioral signs of secondary mechanical hyperalgesia on the paw. These results suggest that degeneration in myelinated efferent fibers is sufficient to induce spontaneous activity in C-fiber afferents and behavioral signs of mechanical hyperalgesia. Ectopic spontaneous activity from injured afferents was not required for the development of the neuropathic pain behavior. These results provide additional evidence for a role of Wallerian degeneration in neuropathic pain.

Stiff-person syndrome (SPS), a neurologic disorder of severe progressive stiffness and spasms of legs and spine, is frequently associated with the production of autoimmune antibodies.1 Immunologic therapies, including plasmapheresis and IV immunoglobulin, usually do not produce a permanent improvement in symptoms and treatment frequently requires benzodiazepines.2,3⇓ High-dose benzodiazepine therapy is effective, but is often worrisome, particularly in patients who do not have a positive antibody test to support the clinical diagnosis. To date, three autoantigens have been associated with SPS.4 It is likely that there are patients in whom specific antibodies are not yet identified. We present an antibody-negative patient with clinical SPS whose symptoms improved significantly in response to the anticonvulsant tiagabine, an inhibitor of GABA catabolism.5 A 39-year-old woman presented with …

Ligation and transection of the L5 spinal nerve in the rat lead to behavioral signs of pain and hyperalgesia. Discharge of injured nociceptors has been presumed to play a role in generating the pain. However, A fibers, but not C fibers, in the injured L5 spinal nerve have been shown to develop spontaneous activity. Moreover, an L5 dorsal root rhizotomy does not reverse this pain behavior, suggesting that signals from other uninjured spinal nerves are involved. We asked if abnormal activity develops in an adjacent, uninjured root. Single nerve fiber recordings were made from the L4 spinal nerve after ligation and transection of the L5 spinal nerve. Within 1 d of the lesion, spontaneous activity developed in approximately half of the C fiber afferents. This spontaneous activity was at a low level (median rate, seven action potentials/5 min), originated distal to the dorsal root ganglion, and was present in nociceptive fibers with cutaneous receptive fields. The incidence and level of spontaneous activity were similar 1 week after injury. The early onset of spontaneous activity in uninjured nociceptive afferents could be the signal that produces the central sensitization responsible for the development of mechanical hyperalgesia. Because L4 afferents comingle with degenerating L5 axons in the peripheral nerve, we hypothesize that products associated with Wallerian degeneration lead to an alteration in the properties of the adjacent, uninjured afferents.

There is a coalescing trend in several areas of pain research. Studies endeavoring to measure the extent to which individuals differ in ascribing pain intensity to noxious stimuli are occurring in areas of pain research as diverse as self-assessment questionnaires, genetics, functional neuro-imaging and psychophysics. The article in this issue of Pain by Ruscheweyh et al [1] highlights two important points relating to the measurement of individual responses to pain. The first is a point of terminology, the second is a point of critical importance in pain neurobiology: the extent to which responses to imagined stimuli predict clinically-relevant pain outcomes [2]. A variety of terms have been applied to describe inter-individual differences in responsiveness to controlled noxious stimuli and painful experiences: pain sensitivity, pain hypersensitivity, pain responsivity, pain perception, pain reactivity, pain responsiveness and central pain processing are among those commonly used. Of these, ‘pain sensitivity’ is the term most widely used to describe the tendency of individuals to vary in the extent to which they respond to noxious stimuli. A survey of this term in Pubmed indicates that ‘pain sensitivity’ was used infrequently prior to 1973 but became the subject in many studies from the late 1970s onwards [3]. A related term, pain hypersensitivity, presumably indicating abnormally increased sensitivity to pain, is much less frequently used. There are many instances however, where ‘pain sensitivity’ is not chosen by authors to describe the responsiveness of individuals to pain. The potential reasons for this may be several. For example, the broader use of ‘sensitivity’ in discourse carries the connotation of emotionality. In addition, sensitivity in other technical applications focuses on assessing the capacity to distinguish the presence of especially small stimulus perturbations. The term ‘pain perception’, also widely used since the 1970s, carries the same implicit meaning of measuring responses to small amounts of pain. The term ‘pain reactivity’ seems to have had a history in the psychological literature of the mid-twentieth century but found later application to describe both biobehavioral and neurohumoral responses in animal and human studies of pain [4]. The use of the term ‘pain responsivity’ began in 1981 and became more widespread in the 1990s. Presumably, the word responsivity was chosen to reference the notion that responsivity is measured by assessing responses to a particular nociceptive stimulus. One reason that broader use of this term may not be optimal is that in engineering applications, responsivity has a particular meaning: it is the derivative (or slope) of the stimulus-response curve. Given the limitations described here, it is timely to re-consider the value of ‘pain responsiveness’ as a term of reference. ‘Pain responsiveness’ was first used in published pain research in 1977 [5] and has been subject to a steady stream of citations since that time. Pain responsiveness appropriately conveys the quality of being responsive to pain and directly alludes to the process of measuring pain responsiveness by obtaining an estimate of the individual's response to a noxious stimulus. As an added point in favor of wider usage, ‘pain responsiveness’ is potentially less laden with implied meaning than ‘pain sensitivity’. In the search for new measures of pain responsiveness, the use of a questionnaire that solicits pain ratings in response to imagined pain-provoking experiences [1] challenges traditional ‘physical’ approaches, where objective stimuli are employed to elicit reproducible responses. In the laboratory setting, diverse psychophysical parameters are sampled for the purposes of understanding both central and peripheral pain processing. Among these, dynamic psychophysical measures have become quite popular; changes in temporal summation and endogenous analgesia capabilities are now considered as representative of the individual's pain responsiveness, especially since abnormalities are observed in both established and idiopathic pain syndromes [6]. Ruscheweyh et al [1] report the development of a 17-item questionnaire seeking to gauge ‘pain sensitivity’. The items in the questionnaire invite the respondent to imagine the occurrence of an unexpected pain-provoking experience, e.g., trapping one's finger in a drawer, and rate the degree of pain that would result. Diverse noxious stimuli are represented, including heat, cold, pressure and acid. The items were selected to represent a range of anticipated pain intensities. A primary score was calculated as the mean of the pain-provoking item responses (14 of the total). In mature adult respondents, the instrument showed good internal consistency. The performance of the instrument was compared to a battery of psychophysical measures of pain thresholds and intensities tested in medical students. There was no correlation with psychophysical pain threshold measures, however the correlation with the composite score of experimental pain intensity ratings was strong (r = 0.56) and stable when re-tested. Although the practical advantages of using a self-filled questionnaire over device- and technician-dependent psychophysical test are obvious, fundamental questions remain [7]. In which settings does an assessment of responses to imagined stimuli have the potential to substitute for actual psychophysical testing? To what degree does chronic pain distort self-awareness of pain responses and limit the utility of self-assessment measures? Are individuals capable of effectively integrating sensory disturbances, e.g. peripheral nerve injuries, into the pain percept? To what extent is there an overlap between pain-related catastrophizing and the parameters of an instrument like the PSQ [1]? And perhaps most controversially, to what extent is there a unitary quality of pain responsiveness that influences pain responses across various nociceptive modalities? The results of Ruschweyeh et al [1] indicate that prompting patients to imagine pain scenarios may be more effective in eliciting correlates of psychophysically-determined pain responsiveness than are more global self-assessments, however the full value of this conceptualization will only be revealed when it is tested against clinical pain. Pain responsiveness is clearly going to be a major study field in the near future. Studies that evaluate pain responsiveness by use of diverse approaches as well as actual psychophysical paradigms, understood within the contexts of pain symptomatology, clinical prognostication, diagnosis and therapeutic outcomes will give the answers.

Pain is a leading reason for seeking medical care, but the management of pain is often felt to be inadequate. A good place to start tackling this problem is in the training of future doctors. This Training Matters article provides excellent advice for neurologists who are involved in the teaching of pain and its management.

Peripheral nerve blocks have become a popular anesthetic option in the peri-operative management of patients with diabetes mellitus (Types 1 and 2), since blocks provide better postoperative analgesia than does general anesthesia, while avoiding the cardiopulmonary and insulin-resistance effects of general anesthesia. Despite widespread clinical application of peripheral nerve blocks, important limits persist in our knowledge concerning their use in these patients. First, whether local anesthetics themselves are more toxic to peripheral nerves in diabetic and other preneuropathic patients is unknown, although this has been suggested by a recent report of sensorimotor nerve damage for patients with previously undiagnosed polyneuropathy.1 Second, we do not know whether the dose of local anesthetic for effective peripheral nerve block differs in the presence of diabetes mellitus. Third, a recent report suggests that standard (nerve stimulator) approaches to localizing nerves for injection exhibit reduced effectiveness in diabetic patients.2 In this issue of Anesthesiology, Rigaud et al.3 take an essential step toward better understanding of the suggested problem related to needle localization using nerve stimulators in the presence of diabetes mellitus. Rigaud et al. first show that in normal dogs, nerve stimulation with electrical current levels in the range of 0.33–1.0 mA results in needle placement sufficiently close to the sciatic nerve in 23 of 24 insertions, with unwanted epineural penetration occurring in 1 of these nerve trials. Of note, the lower threshold for electrical perineural stimulation (i.e., 0.50 mA) did not result in distinguishably better needle positioning. The authors then demonstrate that – in the presence of hyperglycemia induced by streptozotocin and alloxan –low-threshold (0.5 mA) stimulation in the hyperglycemic animals uniformly resulted in intraneural injections. The hyperglycemic animals were unfortunately not tested with high-threshold (i.e., 1.0 mA, or higher) electrical current. The application of the study findings directly to diabetic patients, however, is problematic due to the uncertainty of relevance of acute changes in streptozotocin-hyperglycemia in animals to long standing diabetes mellitus in people. Nonetheless, these preliminary observations provide the impetus for future research into the safety of nerve stimulation to guide needle placement for peripheral nerve blocks in patients with diabetes mellitus. Follow up studies will need to address a number of important questions regarding the implications of hyperglycemia and diabetes mellitus for the utility, conduct, and safety of local anesthetics in peripheral nerve blocks. Well-designed studies in this area would likely be considered highly significant for funding by the Foundation for Anesthesia Education and Research and the American Society for Regional Anesthesia and Pain Medicine. A central problem is the use of animal models to emulate the clinical conditions of human diabetes mellitus. There is currently no perfect research model for diabetes mellitus, let alone diabetic neuropathy. Perhaps the closest diabetes mellitus model to the human condition is the naturally occurring diabetes mellitus that develops in rhesus monkeys fed an ad libitum diet.4 These primates develop Type 2 diabetes mellitus following several years of over-feeding; however the expenses associated with this model system make it impractical for most research questions. One interesting recently-reported Type 2 diabetic rat strain is the Zucker Diabetic Fatty rat5, and an example of a useful Type 1 diabetic mouse model involves autoimmunity of the NOD/SCID mouse to a glutamic acid decarboxylase peptide.6 Generally, these small animal models have been derived by selective breeding. While these strains are valuable for study, they also have particular characteristics that may or may not pertain to desired abnormalities in glucose metabolism. Recently, mouse models for obesity and Type 2 diabetes mellitus have been reviewed7; these models involve genetic manipulation to create transgenic mice with selective disruption of various genes related to insulin signal transduction. For example, mice with complete loss of insulin receptors die shortly after birth, and selective knock-out approaches have been used for understanding the role of the insulin receptor in various organs. However, whether any such mouse models develop peripheral neuropathy is unknown. Streptozotocin-induced hyperglycemia is quite rapid, and has the advantage that studies can be done with treated and untreated animals examined in parallel. This approach has been used in a wide range of species (e.g., rat, pig, dog). At higher doses, streptozotocin is associated with damage to liver and kidneys8, yet streptozotocin-induced diabetes models9 are still in widespread use, despite limitations when using behavioral study methods (e.g., nociceptive testing) due to end organ damage. Most pertinently, however, streptozotocin models are known to develop peripheral neuropathy. The study of the potential for nerve damage in hyperglycemic dogs reported by Rigaud et al. in this issue3 is one example of the usefulness of the streptozotocin model. The next questions to be addressed have immediate clinical relevance. First is whether the use of ultrasound for needle localization is equally (or more) effective when compared with electrical stimulation at higher thresholds, as one may suspect based on the case report by Sites et al.2 One can now assume thousands of similar cases per day that are not reported in the literature, given the extent of the obesity-diabetes mellitus (i.e., Type 2) epidemic, and the increasing popularity of ultrasound-guided neurolocation. Secondly, is the use of local anesthetics inherently safe in hyperglycemia and diabetes mellitus whether or not the epineurium is penetrated? Concerns regarding perineural local anesthetic toxicity are not new. In 1992, an important bench science report by Kalichmann and Calcutt landed on the pages of Anesthesiology.10 This report concluded that in rat, the traditional local anesthetics procaine and lidocaine were highly toxic (based on light microscopy) to the sciatic nerve in animals that were hyperglycemic following exposure to streptozotocin.10 Given the prevalence and increasing incidence of diabetes mellitus, it is surprising that no one to date has followed up on the 1992 toxicity study10 with an appropriate dose-response evaluation of any local anesthetics for neuropathic conditions such as sustained hyperglycemia or diabetes mellitus. Such studies should have been considered a research priority based on this 1992 report, and are therefore long overdue. If local anesthetics are indeed toxic in the setting of diabetes mellitus at doses that are considered safe in healthy patients, then another potential avenue for basic research would involve the co-administration of perineural adjuvants which may include one or more of the following: clonidine, dexmedetomidine, buprenorphine, midazolam, tramadol, ketamine, ziconotide, and/or etanercept, but probably not dexamethasone. If such multimodal perineural adjuvants reduce local anesthetic toxicity and/or reduce the required local anesthetic dose in neuropathic (and preneuropathic) patients, then a potentially important public health advance would be possible. In the meantime, given the increasing incidence, prevalence, and associated neuropathic risks of diabetes mellitus, studies are urgently needed to determine whether or not high-threshold electrical current will help avoid intraneural injection in the diabetic nerve. Once this is known, we will have a better perspective as to whether perineural imaging technologies2 with or without electrical stimulation would be a logical way to partially protect patients with diabetes mellitus from unintentional nerve injury.

Background Hmg-CoA reductase inhibitors (statins) are widely used to prevent disease associated with vascular disease and hyperlipidemia. Although side effects are uncommon, clinical observations suggest statin exposure may exacerbate neuromuscular diseases, including peripheral neuropathy and amyotrophic lateral sclerosis. Although some have postulated class-effects, prior studies of hepatocytes and myocytes indicate that the statins may exhibit differential effects. Studies of neuronal cells have been limited. Methods We examined the effects of statins on cultured neurons and Schwann cells. Cultured spinal motor neurons were grown on transwell inserts and assessed for viability using immunochemical staining for SMI-32. Cultured cortical neurons and Schwann cells were assessed using dynamic viability markers. Results 7 days of exposure to fluvastatin depleted spinal motor neurons in a dose-dependent manner with a KD of Conclusions It is known from pharmacokinetic studies that daily treatment of young adults with fluvastatin can produce serum levels in the single micromolar range. We conclude that specific mechanisms may explain neuromuscular disease worsening with statins and further study is needed.