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Spinal cord stimulation (SCS) has been shown to be a safe, effective, and drug-free treatment option for many chronic pain conditions including refractory low back pain. The most commonly reported complication of SCS is equipment failure. We report a case of spinal cord injury (SCI) during SCS explant and revision. This 61-year-old female veteran complained of intermittent shock-like sensations 3-4 times a week for three months prior to her clinic visit. The device was initially implanted in 2009 secondary to neurogenic claudication with appropriate relief. The battery was replaced in 2015. Pain Management Service referred the patient to neurosurgery for replacement of the original SCS unit. Immediately following surgery she complained of severe left lower extremity pain concentrated in the medial thigh radiating into the groin and buttock. She also complained of pain, weakness and numbness in both legs (left more than right). Magnetic resonance imaging (MRI) revealed an edematous area in the left spinal cord between T11-T12. The patient was placed on steroids, ketamine infusion for pain control, and MRI the next day showed slight improvement of the edema and she was discharged home. Follow-up MRI two months later revealed mild diminution in the size of the cord edema. Her pre-operative shock-like sensations had not returned. While rare, spinal cord injury can occur and should be identified and managed expeditiously. Our case here reports for the first time an association between SCS explant/revision and syrinx formation.

Introduction: Foot drop often results from denervation of the dorsiflexor muscles in the leg. Neurological evaluation begins with lower extremity motor testing followed by electromyography needle electrode examination (EMG-NEE). We explored digital infrared thermography (IRT) as a complementary tool in diagnosing peripheral nerve disorders. Methods: Using a digital IRT camera, we recorded differences in skin surface temperatures from affected and unaffected limbs in three patients with unilateral foot drop. Denervation in the affected limb was confirmed with EMG-NEE. Results: IRT imaging revealed lower relative skin surface temperatures in regions of the leg corresponding to denervated dorsiflexor muscles for all three consecutive patients who presented to the EMG Clinic with foot drop. Conclusions: Denervation appears to cause a decrease in thermal energy output from affected muscle groups. Alongside the EMG and magnetic resonance imaging (MRI), IRT may have an important role in assessing the severity and prognosis of a nerve injury. This observation may have implications for chronic pain syndromes, such as complex regional pain syndrome (CRPS), in which thermal change is a diagnostic criterion.

BackgroundComputer-based clinical decision support (CDS) is an important component of the electronic health record (EHR). As an increasing amount of CDS is implemented, it will be important that this be accomplished in a fashion that assists in clinical decision making without imposing unacceptable demands and burdens upon the provider’s practice. ObjectiveThe objective of our study was to explore an approach that allows CDS to be clinician-friendly from a variety of perspectives, to build a prototype implementation that illustrates features of the approach, and to gain experience with a pilot framework for assessment. MethodsThe paper first discusses the project’s design philosophy and goals. It then describes a prototype implementation (Neuropath/CDS) that explores the approach in the domain of neuropathic pain and in the context of the US Veterans Administration EHR. Finally, the paper discusses a framework for assessing the approach, illustrated by a pilot assessment of Neuropath/CDS. ResultsThe paper describes the operation and technical design of Neuropath/CDS, as well as the results of the pilot assessment, which emphasize the four areas of focus, scope, content, and presentation. ConclusionsThe work to date has allowed us to explore various design and implementation issues relating to the approach illustrated in Neuropath/CDS, as well as the development and pilot application of a framework for assessment.

Importance There is a need for more effective pharmacotherapy for chronic pain, including pain in inherited erythromelalgia (IEM) in which gain-of-function mutations of sodium channel Na V 1.7 make dorsal root ganglion (DRG) neurons hyperexcitable. Objective To determine whether pain in IEM can be attenuated via pharmacotherapy guided by genomic analysis and functional profiling. Design, Setting, and Participants Pain in 2 patients with IEM due to the Na V 1.7 S241T mutation, predicted by structural modeling and functional analysis to be responsive to carbamazepine, was assessed in a double-blind, placebo-controlled study conducted from September 2014 to April 21, 2015. Functional magnetic resonance imaging assessed patterns of brain activity associated with pain during treatment with placebo or carbamazepine. Multielectrode array technology was used to assess the effect of carbamazepine on firing of DRG neurons carrying S241T mutant channels. Main Outcomes and Measures Behavioral assessment of pain; functional magnetic resonance imaging; and assessment of firing in DRG neurons carrying S241T mutant channels. Results This study included 2 patients from the same family with IEM and the S241T Na V 1.7 mutation. We showed that, as predicted by molecular modeling, thermodynamic analysis, and functional profiling, carbamazepine attenuated pain in patients with IEM due to the S241T Na V 1.7 mutation. Patient 1 reported a reduction in mean time in pain (TIP) per day during the 15-day maintenance period, from 424 minutes while taking placebo to 231.9 minutes while taking carbamazepine (400 mg/day), and a reduction in total TIP over the 15-day maintenance period, from 6360 minutes while taking placebo to 3015 minutes while taking carbamazepine. Patient 2 reported a reduction in mean TIP per day during the maintenance period, from 61 minutes while taking placebo to 9.1 minutes while taking carbamazepine (400 mg then 200 mg/day), and a reduction in total TIP, from 915 minutes while taking placebo over the 15-day maintenance period to 136 minutes while taking carbamazepine. Patient 1 reported a reduction of mean episode duration, from 615 minutes while taking placebo to 274.1 minutes while taking carbamazepine, while patient 2 reported a reduction of the mean episode duration from 91.5 minutes while taking placebo to 45.3 minutes while taking carbamazepine. Patient 1, who had a history of night awakenings from pain, reported 101 awakenings owing to pain while taking placebo during the maintenance period and 32 awakenings while taking carbamazepine. Attenuation of pain was paralleled by a shift in brain activity from valuation and pain areas to primary and secondary somatosensory, motor, and parietal attention areas. Firing of DRG neurons expressing the S241T Na V 1.7 mutant channel in response to physiologically relevant thermal stimuli was reduced by carbamazepine. Conclusions and Relevance Our results demonstrate that pharmacotherapy guided by genomic analysis, molecular modeling, and functional profiling can attenuate neuropathic pain in patients carrying the S241T mutation.

Following the recent withdrawal of several prominent drugs from US and European markets because of detrimental drug-drug interactions, metabolic drug interactions have received considerable attention in the pharmaceutical industry. In turn, the question of drug safety has received significant legal, regulatory and commercial emphasis, bringing this issue to the forefront of both industry and government drug agendas. The value of predicting the drug interactions of compounds as early as possible in the drug discovery process for all therapeutic areas cannot be underestimated. From 1964 to 1999, approximately 8% of the drugs approved by the FDA were later withdrawn from the US market. Pharmaceutical companies are facing increasing pressure to prove the long-term safety of their products, and this is complicated by the fact that animal models are not perfectly predictive of human responses, and may provide contradictory information. The failure to address safety concerns successfully during the drug optimization process may result in companies withdrawing any approved drugs from the market; drug safety issues not only present human health consequences, but also have a negative economic and public relations impact on the pharmaceutical industry. This paper discusses the significance of drug interactions, and addresses strategies to evaluate the potential of a drug candidate for drug interactions.

Myelin-forming glial cells transplanted into the demyelinated spinal cord can form compact myelin and improve conduction properties. However, little is known of the expression and organization of voltage-gated ion channels in the remyelinated central axons or whether the exogenous cells provide appropriate signaling for the maturation of nodes of Ranvier. Here, we transplanted olfactory ensheathing cells from green fluorescent protein (GFP)-expressing donor rats [GFP-olfactory ensheathing cells (OECs)] into a region of spinal cord demyelination and found extensive remyelination, which included the development of mature nodal, paranodal, and juxtaparanodal domains, as assessed by ultrastructural, immunocytochemical, and electrophysiological analyses. In remyelinated axons, Nav1.6 was clustered at nodes, whereas Kv1.2 was aggregated in juxtaparanodal regions, recapitulating the distribution of these channels within mature nodes of uninjured axons. Moreover, the recruitment of Navand Kvchannels to specific membrane domains at remyelinated nodes persisted for at least 8 weeks after GFP-OEC transplantation.In vivoelectrophysiological recordings demonstrated enhanced conduction along the GFP-OEC-remyelinated axons. These findings indicate that, in addition to forming myelin, engrafted GFP-OECs provide an environment that supports the development and maturation of nodes of Ranvier and the restoration of impulse conduction in central demyelinated axons.

Cocaethylene is a naturally occurring cocaine derivative that has been used as a tool in both clinical studies of cocaine reward and as a potential model compound for agonist substitution therapy in cocaine dependence. It is equipotent to cocaine at inhibiting dopamine uptake in-vitro and in-vivo. Because it has been reported that local anesthetic properties may influence the reinforcing effects of dopamine uptake inhibitors, we investigated the local anesthetic properties of cocaethylene as well as isopropylcocaine, another potential pharmacological tool in studies of cocaine reward and agonist substitution therapy. We compared the efficacy of nerve impulse blockade by lidocaine, cocaine, cocaethylene and isopropylcocaine using rat sciatic nerves and dorsal roots (DRs). Nerves were placed in a modified sucrose gap chamber and repetitively stimulated at high frequency. The amplitude of compound action potentials (CAPs) at the beginning and end of each stimulus train was measured before and after exposure to each compound. All compounds produced concentration-dependent and use-dependent decrements in CAP amplitude, but cocaethylene and isopropylcocaine at medium to high concentration (0.375-1.875 mM) showed a more prolonged block after washout relative to cocaine or lidocaine. Patch clamp studies on dorsal root ganglion (DRG) neurons indicated a use-dependent blockade of sodium channels. These studies provide a more complete understanding of the pharmaocology of potential agonist treatment candidates, and suggest a mechanism whereby cocaethylene produces a decreased euphoria in humans compared to cocaine.

Background: Transcranial magnetic stimulation (TMS) provides a noninvasive method of examining cortical inhibitory and excitatory processes and cortical excitability in awake subjects. There is evidence from clinical and electroencephalographic (EEG) data that cortical excitability may be abnormal in some psychiatric populations. Chronic cocaine abuse influences a number of neurotransmitters that are involved in the excitatory/inhibitory balance of the cerebral cortex. This pilot study was conducted to ascertain the possible utility of TMS in examining cortical excitability in a population of chronic cocaine abusers. Methods: The right and left motor thresholds of ten cocaine-dependent subjects, according to DSM-IV, and ten normal control subjects were examined using single pulse TMS. Results: The resting motor thresholds resulting from stimulation of the right or the left motor cortical regions were significantly elevated in cocaine-dependent subjects compared with matched control subjects. Conclusions: These pilot data suggest that chronic cocaine use significantly alters cortical excitability in the direction of increased inhibition or decreased excitability. We hypothesize that this observation reflects adaptation to those effects of cocaine intoxication that promote cortical excitability and seizures.

The cross-sectional area of cholinergic neurons stained immunohistochemically for choline acetyltransferase were measured in the striatum of infants, young adults, aged individuals and patients with Alzheimer's disease. Cholinergic neurons were distributed throughout the caudate nucleus and the putamen and displayed no significant variations in size across the two structures. The cross-sectional area of striatal cholinergic neurons was smaller in infants as compared with all the other groups examined. No significant changes were observed in the size of these neurons as a consequence of aging or Alzheimer's disease.

The development of acetylcholinesterase (AChE) activity within cortical neurons of the rat brain was investigated using a histochemical method. The fate of these neurons in later stages of development was studied in animals in which AChE within cortical axons (mostly cholinergic) had been depleted by lesions of the cholinergic neurons of the basal forebrain or by injections of diisopropyl fluorophosphate. We designated neurons with medium to high intensity of reaction product as AChEH and neurons with a low intensity of reaction product as AChEL. Four groups of AChEH cortical neurons were detected: (1) AChEH Cajal-Retzius cells were present in layer I at birth (P0) and decreased steadily in number until none could be detected at P17 or thereafter. (2) AChEH neurons within layer VI and underlying white matter were present at P0, peaked in number and staining intensity at P8-P9, showed a moderate decrease in number at P11-P13 and a further decrease into adulthood. (3) AChEH polymorphic intracortical neurons appeared at P3-P4 in deep cortical layers and by P9 were present in layers II-VI. They continued to increase in number through P11-P14 at which time they displayed the adult pattern and were found in all cortical areas. (4) A large population of AChEH pyramidal neurons appeared at P1-P4, peaked at P8-P10 and was no longer visible at P21. In the adult cerebral cortex, few pyramidal neurons displayed AChE activity and these were almost always of the AChEL type. These results indicate that the AChE within cortical neurons is developmentally regulated and that the content of this enzyme helps to differentiate cortical neurons into distinct populations. The transient expression of AChE activity within cortical neurons suggests a role for this enzyme in the development of the cerebral cortex.

Objective: Maternally inherited diabetes and deafness (MIDD) syndrome is a rare mitochondrial disorder characterized by progressive sensorineural hearing loss and diabetes mellitus. Case reports also exist of patients with additional clinical features typically associated with mitochondrial disorders, such as retinopathy, seizures, and stroke-like episodes. We present the clinical, imaging, histopathologic and genetic data for a patient diagnosed with MIDD following evaluation for new-onset myoclonus. To our knowledge, this is the first case to describe MIDD syndrome in association with myoclonus. Background MIDD syndrome is a mitochondrial genetic disorder caused by a heteroplasmic A3243G transition of mtDNA. The same mutation has also been associated with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS). It has not been previously associated with myoclonus. Design/Methods: We report the clinical characteristics of a patient diagnosed with MIDD syndrome after initially seeking medical attention for myoclonus, and present the results of a comprehensive literature review. Results: A 57-year-old man developed intermittent myoclonic jerks in his right arm. He had a past history of sensorineural hearing loss developing in his late 20s, and diabetes mellitus developing in his 30s. On exam, he was found to have subtle proximal muscle weakness, as well as peripheral neuropathy. EEG demonstrated rare generalized spike-and-wave discharges. He was started on valproic acid, with resolution of myoclonus. Subsequently, a muscle biopsy demonstrated ragged-red fibers. Genetic testing confirmed the A3243G mtDNA mutation. Given his clinical picture, a diagnosis of MIDD syndrome was established. Conclusions: MIDD syndrome should be considered in patients presenting with a clinical syndrome of sensorineural hearing loss and diabetes mellitus. Additional features of mitochondrial disorders, such as myopathy, neuropathy, and myoclonus may be present. Valproic acid may be an effective treatment of myoclonus. In addition, treatment with coenzyme Q10 may be of modest benefit in slowing progression of neurologic deterioration. Disclosure: Dr. Blondin has nothing to disclose. Dr. Vortmeyer has nothing to disclose. Dr. Tokuno has nothing to disclose.

The authors contemplated to find optimum conditions to manufacture ethylene oxide and glycol by the chlorohydrine method. It was found that high yield of ethylenechlorohydrine was obtainable in circulating type reaction column, whereby violenter agitation promotes higher yield when 20% excess of ethylene was introduced. Further investigations were made to establish direct chlorination condition with result in high yield, by using untreated gaseous chlorine generated by electrolysis of brine. When a horizontal type reactor and same type of providing nets at the bottom were employed, by using calcium hydroxide as dehydrochloric acid, optimum conditions on holding time, amount of blow-in steam and temperature at the outlet of dephlegmeter were also investigated and decided. Both catalytic and high pressure process manufacturing ethylene glycol were investigated and optimum conditions for molecular ratio of water to ethylene oxide, temperature, time, pressure and neutralization of catalyst were decided.