Efficacy of therapeutic plasma exchange for treatment of stiff-person syndrome.

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.

Recommendations for a new curriculum in pain medicine for medical students: toward a career distinguished by competence and compassion.

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.

Core competencies for pain management: results of an interprofessional consensus summit.

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.

Selected statins produce rapid spinal motor neuron loss in vitro.

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 < 2 µM. Profound neurite loss was observed after 4 days exposure in culture. Other statins were found to produce toxic effects at much higher concentrations. In contrast, no such toxicity was observed for cultured Schwann cells or cortical neurons. 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.

A new program in pain medicine for medical students: integrating core curriculum knowledge with emotional and reflective development.

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.

Degeneration of myelinated efferent fibers prompts mitosis in Remak Schwann cells of uninjured C-fiber afferents.

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.

Electrical stimulation promotes motoneuron regeneration without increasing its speed or conditioning the neuron.

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.

Degeneration of myelinated efferent fibers induces spontaneous activity in uninjured C-fiber afferents.

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.

Mechanical hyperalgesia after an L5 ventral rhizotomy or an L5 ganglionectomy in the rat.

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 (

A pain research agenda for the 21st century.

UNLABELLED: 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 obligation 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.

Current challenges in pain education.

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.

Pain education in North American medical schools.

UNLABELLED: 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.

Formative experiences of emerging physicians: gauging the impact of events that occur during medical school.

PURPOSE: 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. METHOD: 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. RESULTS: One hundred eighty-one students (84%) responded. All events were experienced by >25% 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." CONCLUSIONS: 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.

Future considerations for pharmacologic adjuvants in single-injection peripheral nerve blocks for patients with diabetes mellitus.

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.

Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 (p < 0.0000001) with cervical involvement more likely, p < or = 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. CONCLUSIONS: 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.

Cognitive expertise, emotional development, and reflective capacity: clinical skills for improved pain care.

UNLABELLED: 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.

The tibial neuroma transposition (TNT) model of neuroma pain and hyperalgesia.

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.