The level of agreement between the numerical rating scale and visual analogue scale for assessing pain intensity in adults with chronic pain.

The numerical rating scale and visual analogue scale are used to quantify pain intensity. However, it has not yet been explored whether these scores are interchangeable in adults with chronic pain. Data from the prospective multicentre cross-sectional INTERVAL study were used to evaluate the one-dimensionality and agreement between numerical rating scale scores and visual analogue scale scores in adults with chronic pain. Pain intensity scores using the numerical rating scale and visual analogue scale were provided by 366 patients with chronic pain for current, average, minimal and maximal pain. To evaluate whether pain intensity scales are completed in accordance with each other, the proportion of patients who satisfied the following condition was calculated: minimal pain intensity ≤ maximal pain intensity. A factor analysis confirmed the one-dimensionality of the pain measures. A significant difference was found between numerical rating scale and visual analogue scale scores for average, current, minimum and maximum pain. Intra-class correlation coefficient estimates ranged from 0.739 to 0.858 and all measures failed to show sufficient and acceptable agreement at the 95% level. The strength of agreement between pain severity categories was classified as 'moderate' for average and minimal pain and 'substantial' for current and maximal pain. The proportion of patients who scored minimal pain ≤ maximal pain was 97.5% for the numerical rating scale and 89.5% for the visual analogue scale. This study failed to show an acceptable agreement between the numerical rating scale and visual analogue scale when pain intensity was rated by adults with chronic pain, despite showing both scales measure the same information.

Potential indications for deep brain stimulation in neurological disorders: an evolving field.

Deep brain stimulation (DBS) is an established therapy for appropriately selected patients with movement disorders and neuropsychiatric conditions. Although the exact mechanisms and biology of DBS are not fully understood, it is a safe and well-tolerated therapy for many refractory cases of neuropsychiatric disease. Increasingly, DBS has been explored in other conditions with encouraging results. In this paper, available data is reviewed and new DBS targets, challenges and future directions in neurological disorders are explored. A detailed search of the medical literature discussing the potential use of DBS for neurological disorders excluding accepted indications was conducted. All reports were analyzed individually for content and redundant articles were excluded by examining individual abstracts. The level of evidence for each indication was summarized. Multiple studies report promising preliminary data regarding the safety and efficacy of DBS for a variety of neurological indications including chronic pain, tinnitus, epilepsy, Tourette syndrome, Huntington's disease, tardive dyskinesia and Alzheimer's disease. The initial results of DBS studies for diverse neurological disorders are encouraging but larger, controlled, prospective, homogeneous clinical trials are necessary to establish long-term safety and effectiveness. The field of neuromodulation continues to evolve and advances in DBS technology, stereotactic techniques, neuroimaging and DBS programming capabilities are shaping the present and future of DBS research and use in practice.

Multi-parametric analysis assists in STN localization in Parkinson's patients.

BACKGROUND: Initial subthalamic nucleus (STN) localization is based on MRI and an anatomical atlas and then refined intraoperatively using electrophysiological mapping with microelectrode recordings (IOA - intraoperative multi-unit activity) during deep brain stimulation (DBS) in Parkinson's disease (PD). IOA is time consuming and subjective. The purpose of this study was to assess the value of high frequency multi-unit background activity (MUA, frequency >500Hz), and local field potentials (LFP, frequency 5-500Hz) in detection of the STN borders. METHODS: This was a retrospective, single center study. 18 leads in ten PD patients that underwent STN DBS surgery were evaluated. IOA, MUA and LFP have been compared in detection of the STN. IOA using single train spikes analysis have been used as a gold standard. RESULTS: Both LFP in beta range (20-35Hz) and MUA increased as the microelectrode entered the STN and their increase correlated with dorsal/ventral STN borders. The differences (mean±sd) were: between IOA and MUA of the dorsal/ventral border 0.20±0.76/0.28±0.30mm; between IOA and LFP of the dorsal/ventral border 0.08±0.94/0.05±0.53mm. Using Bland-Altman statistics, only 2/36 (5.6%) differences between IOA and MUA and also 2/36 differences between IOA and LFP (one for the dorsal border and one for the ventral border) were out of ±1.96 SD line of measurement differences. Correlation between dorsal border/ventral border positions obtained by IOA and MUA was 0.86, p<0.000005/0.97, p<10(-11); by IOA and LFP was 0.78, p<0.00015/0.88, p<0.000001. CONCLUSIONS: Both MUA and LFP are characteristically elevated in the STN compared to neighboring structures. They may provide fast, real-time, objective and reliable markers of STN borders.

Supraspinal stimulation for treatment of refractory pain.

Refractory pain syndromes often have far reaching effects and are quite a challenge for primary care providers and specialists alike to treat. With the help of site-specific neuromodulation and appropriate patient selection these difficult to treat pain syndromes may be managed. In this article, we focus on supraspinal stimulation (SSS) for treatment of intractable pain and discuss off-label uses of deep brain stimulation (DBS) and motor cortex stimulation (MCS) in context to emerging indications in neuromodulation. Consideration for neuromodulatory treatment begins with rigorous patient selection based on exhaustive conservative management, elimination of secondary gains, and a proper psychology evaluation. Trial stimulation prior to DBS is nearly always performed while trial stimulation prior to MCS surgery is symptom dependent. Overall, a review of the literature demonstrates that DBS should be considered for refractory conditions including nociceptive/neuropathic pain, phantom limb pain, and chronic cluster headache (CCH). MCS should be considered primarily for trigeminal neuropathic pain (TNP) and central pain. DBS outcome studies for post-stroke pain as well as MCS studies for complex regional pain syndrome (CRPS) show more modest results and are also discussed in detail.

Measurement of free fatty acids in cerebrospinal fluid from patients with hemorrhagic and ischemic stroke.

Free fatty acid (FFA) concentrations in cerebrospinal fluid (CSF) from patients with ischemic and hemorrhagic stroke (n=25) and in contemporary controls (n=73) were examined using HPLC. Concentrations of CSF FFAs from ischemic and hemorrhagic stroke patients obtained within 48 h of the insult were significantly greater than in control patients. Higher concentrations of polyunsaturated fatty acids (PUFAs) in CSF obtained within 48 h of insult were associated with significantly lower (P<0.05) admission Glasgow Coma Scale scores and worse outcome at the time of hospital discharge, using the Glasgow Outcome Scale (P<0.01).

Effects of immunosuppressants, calcineurin inhibition, and blockade of endoplasmic reticulum calcium channels on free fatty acid efflux from the ischemic/reperfused rat cerebral cortex.

Elevated levels of free fatty acids (FFA) have been implicated in the pathogenesis of neuronal injury and death induced by cerebral ischemia. This study evaluated the effects of immunosuppressants agents, calcineurin inhibitors and blockade of endoplasmic reticulum (ER) calcium channels on free fatty acid formation and efflux in the ischemic/reperfused (I/R) rat brain. Changes in the extracellular levels of arachidonic, docosahexaenoic, linoleic, myristic, oleic and palmitic acids in cerebral cortical superfusates during four-vessel occlusion-elicited global cerebral ischemia were examined using a cortical cup technique. A 20-min period of ischemia elicited large increases in the efflux of all six FFAs, which were sustained during the 40 min of reperfusion. Cyclosporin A (CsA) and trifluoperazine, which reportedly inhibit the I/R elicited opening of a mitochondrial permeability transition (MPT) pore, were very effective in suppressing ischemia/reperfusion evoked release of all six FFAs. FK506, an immunosuppressant which does not directly affect the MPT, but is a calcineurin inhibitor, also suppressed the I/R-evoked efflux of FFAs, but less effectively than CsA. Rapamycin, a derivative of FK506 which does not inhibit calcineurin, did not suppress I/R-evoked FFA efflux. Gossypol, a structurally unrelated inhibitor of calcineurin, was also effective, significantly reducing the efflux of docosahexaenoic, arachidonic and oleic acids. As previous experiments had implicated elevated Ca(2+) levels in the activation of phospholipases with FFA formation, agents affecting endoplasmic reticulum stores were also evaluated. Dantrolene, which blocks the ryanodine receptor (RyR) channel of the ER, significantly inhibited I/R-evoked release of docosahexaenoic, arachidonic, linoleic and oleic acids. Ryanodine, which can either accentuate or block Ca(2+) release, significantly enhanced ischemia/reperfusion-elicited efflux of linoleic acid, with non-significant increases in the efflux of myristic, arachidonic, palmitic and oleic acids. Xestospongin C, an inhibitor of the inositol triphosphate (IP(3)R) channel, failed to affect I/R-evoked FFA efflux. Thapsigargin, an inhibitor of the Ca(2+)-ATPase ER uptake pump, elicited significant elevations in the efflux of myristic, arachidonic and linoleic acids, in the absence of ischemia. Collectively, the data suggest an involvement of both ER and mitochondrial Ca(2+) stores in the chain of events which lead to PLA(2) activation and FFA formation.

Differential effects of phospholipase inhibitors on free fatty acid efflux in rat cerebral cortex during ischemia-reperfusion injury.

Free fatty acid (FFA) elevation in the brain has been shown to correlate with the severity of damage in ischemic injury. The etiology of this increase in FFA remains unclear and has been hypothesized to result from phospholipase activation. This study examines the effects of specific phospholipase inhibitors on FFA efflux during ischemia-reperfusion injury. A four-vessel occlusion model of cerebral ischemia was utilized to assess the effects of PLA(2) and PLC inhibitors on FFA efflux from rat cerebral cortex. In addition, FFA efflux from non-ischemic cortices exposed to PLA(2) and PLC was measured. Concentrations of arachidonic, docosahexaenoic, linoleic, myristic, oleic, and palmitic acids in cortical superfusates were determined using high performance liquid chromatography (HPLC). Exposure to the non-selective PLA(2) inhibitor 4-bromophenylacyl bromide (BPB) significantly inhibited FFA efflux during ischemia-reperfusion injury (P<0.01 arachidonic, oleic and palmitic; P<0.05 all others); exposure to the PLC inhibitor U73122 had no observed effect. The effects of the Ca(2+)-dependent PLA(2) inhibitor arachidonyl trifluoromethyl ketone (AACOCF(3)) mirrored the effects of BPB and led to reductions in all FFA levels (P<0.01 arachidonic, oleic and palmitic; P<0.05 all others). Exposure to the secretory PLA(2) inhibitor 3-(3-acetamide-1-benzyl-2-ethyl-indolyl-5-oxy) propane sulfonic acid (LY311727) and to the Ca(2+)-independent PLA(2) inhibitor bromoenol lactone (BEL) had only minimal effects on FFA efflux. Application of both PLA(2) and PLC to non-ischemic cortices resulted in significant increases in efflux of all FFA (P<0.05). The study suggests that FFA efflux during ischemia-reperfusion injury is coupled to activation of Ca(2+)-dependent PLA(2) and provides further evidence of the potential neuroprotective benefit of Ca(2+)-dependent PLA(2) inhibitors in ischemia.

Inhibition of Na(+)/Ca(2+) exchange by KB-R7943, a novel selective antagonist, attenuates phosphoethanolamine and free fatty acid efflux in rat cerebral cortex during ischemia-reperfusion injury.

Reversal of the Na(+)/Ca(2+) exchanger (NCX) occurs during ischemia-reperfusion injury as a result of changes in intracellular pH and sodium concentration. Inhibition of NCXs has been shown to be neuroprotective in vitro. In this study, we evaluated the effects of KB-R7943 (50 microM), a specific inhibitor of the reverse mode of NCX, applied topically onto rat cerebral cortex prior to and during ischemia. Amino acid and free fatty acid levels in cortical superfusates, withdrawn at 10-min intervals from bilateral cortical windows, were analyzed by high-performance liquid chromatography. During a 20-min period of ischemia in control animals, there were significant increases in all amino acids and in all FFAs. Following reperfusion, all FFAs remained significantly elevated. Application of KB-R7943 (50 microM) significantly inhibited effluxes of phosphoethanolamine, but had no effect on glutamate, aspartate, taurine or GABA levels. KB-R7943 also resulted in significant reductions in levels of myristic, docosahexaenoic and arachidonic acid during ischemia and in reperfusion levels of arachidonic and docosahexaenoic acids. These data indicate that inhibition of Na(+)/Ca(2+) exchange likely prevented the activation of phospholipases that usually occurs following an ischemic insult as evidenced by its attenuation of phosphoethanolamine and free fatty acid efflux. The inhibition of phospholipases may be an essential component of the neuroprotective benefits of Na(+)/Ca(2+) exchange inhibitors in ischemia-reperfusion injury and may provide a basis for their possible use in therapeutic strategies for stroke.

Inhibition of Na(+)/H(+) exchange by SM-20220 attenuates free fatty acid efflux in rat cerebral cortex during ischemia-reperfusion injury.

The Na(+)/H(+) exchanger (NHE) is activated during ischemia-reperfusion in an effort to restore intracellular pH to normal levels. Inhibition of NHE with non-selective amiloride derivatives has been shown to be neuroprotective and to attenuate free fatty acid efflux during ischemia-reperfusion. We evaluated the effects of SM-20220 (20 microM), a highly selective and specific NHE inhibitor, applied topically onto rat cerebral cortex prior to and during a 20-min period of ischemia. SM-20220 application significantly reduced the ischemia-evoked efflux of myristic, palmitic, and arachidonic acids during both ischemia and reperfusion with significant decreases in linoleic and docosahexaenoic levels during reperfusion. This study confirms the importance of NHEs in eliciting free fatty acid efflux, inhibition of which may be an essential component of the neuroprotective benefits of NHE inhibitors in ischemia-reperfusion injury.

Complications of head injury.

Management of head injury is based on two concepts, proper treatment of the acute insult and the prevention and treatment of secondary insults. The head injured patient is subject to both intracranial and extracranial secondary insults. This paper will review complications related to the central nervous system as well as the pulmonary, infectious, gastrointestinal, and psychiatric complications frequently seen following traumatic brain injury. Complications following head trauma lead to significant acute and chronic morbidity and mortality. It is essential that clinicians be able to recognize and treat these complications in order to more effectively manage head trauma, improve outcome, and care for patients.

The role of vertebroplasty in metastatic spinal disease.

Many advances have been made in the treatment of metastatic spinal disease over the last few decades. Radiotherapy offers benefit and pain relief to many patients; however, this modality provides minimal vertebral stabilization. Surgical management consists of decompression and complex fusions. Vertebroplasty offers an adjuvant therapy to both radiotherapy and surgery by providing additional stabilization and pain relief. The results of case studies suggest that including vertebroplasty in the management of these patients is beneficial. In this article the authors review the role of vertebroplasty in metastatic spinal disease.

Quantification of free fatty acids in human cerebrospinal fluid.

Free fatty acids (FFA) in cerebrospinal fluid (CSF) are well-recognized markers of brain damage in animal studies. Information is limited regarding human CSF in both normal and pathological conditions. Samples of CSF from 73 patients, who had undergone lumbar puncture for medically indicated reasons, came from a core laboratory upon completion of ordered tests. Using high performance liquid chromatography, mean FFA concentrations (microg/L +/- SEM) were: arachidonic 26.14 +/- 3.44; docosahexaenoic 60.74 +/- 5.70; linoleic 105.07 +/- 10.98; myristic 160.38 +/- 16.17; oleic 127.91 +/- 10.13; and palmitic 638.34 +/- 37.27. No differences in FFA concentrations were seen with gender, race, age, and/or indication for lumbar puncture. This is the first study to document normal human CSF FFA concentrations in a large series. Further characterization of FFA in pathological conditions may provide markers for evaluating clinical treatments and assisting in prognostication of neurological disease.

Adenosine receptor mediated stimulation of intracellular calcium in acutely isolated astrocytes.

The characteristics of adenosine receptors found in glial fibrillary acid protein (GFAP)-positive astrocytes acutely isolated from the cerebral cortices of 4- to 12-day old rats were examined by evaluating the effects of adenosine and its analogues on intracellular calcium levels. First, these effects were compared with those seen in primary astrocytic cultures, and it was found that acutely isolated astrocytes showed much greater sensitivity to adenosine than their cultured counterparts. Then, the adenosine evoked calcium responses in acutely isolated cells were evaluated under various conditions. The responses to adenosine were not inhibited by papaverine, an uptake blocker, or by removal of extracellular calcium. U73122, a phospholipase C inhibitor, was able to completely inhibit the adenosine response. The receptor inhibitor 3-isobutyl-1-methylxanthine inhibited the calcium response to adenosine, providing evidence that the response is not coupled to the xanthine-insensitive A3 receptor. The stimulatory action of NECA, a non-selective analogue, was blocked neither by the A2A-selective receptor antagonist 8-(3-chlorostyryl) caffeine nor by the A1-selective receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine. The A2B receptor antagonist alloxazine, however, was able to completely inhibit the increase in intracellular calcium produced by NECA. Taken together, these data suggest that the adenosine-evoked calcium response in acutely isolated astrocytes is coupled to the A2B receptor.