Examining the Duration of Carryover Effect in Patients With Chronic Pain Treated With Spinal Cord Stimulation (EChO Study): An Open, Interventional, Investigator-Initiated, International Multicenter Study.

OBJECTIVES: Spinal cord stimulation (SCS) is a surgical treatment for severe, chronic, neuropathic pain. It is based on one to two lead(s) implanted in the epidural space, stimulating the dorsal column. It has long been assumed that when deactivating SCS, there is a variable interval before the patient perceives the return of the pain, a phenomenon often termed echo or carryover effect. Although the carryover effect has been problematized as a source of error in crossover studies, no experimental investigation of the effect has been published. This open, prospective, international multicenter study aimed to systematically document, quantify, and investigate the carryover effect in SCS. MATERIALS AND METHODS: Eligible patients with a beneficial effect from their SCS treatment were instructed to deactivate their SCS device in a home setting and to reactivate it when their pain returned. The primary outcome was duration of carryover time defined as the time interval from deactivation to reactivation. Central clinical parameters (age, sex, indication for SCS, SCS treatment details, pain score) were registered and correlated with carryover time using nonparametric tests (Mann-Whitney/Kruskal-Wallis) for categorical data and linear regression for continuous data. RESULTS: In total, 158 patients were included in the analyses. A median carryover time of five hours was found (interquartile range 2.5;21 hours). Back pain as primary indication for SCS, high-frequency stimulation, and higher pain score at the time of deactivation were correlated with longer carryover time. CONCLUSIONS: This study confirms the existence of the carryover effect and indicates a remarkably high degree of interindividual variation. The results suggest that the magnitude of carryover may be correlated to the nature of the pain condition and possibly stimulation paradigms. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT03386058.

Neurophysiological oscillatory markers of hypoalgesia in conditioned pain modulation.

Introduction: Conditioned pain modulation (CPM) is an experimental procedure that consists of an ongoing noxious stimulus attenuating the pain perception caused by another noxious stimulus. A combination of the CPM paradigm with concurrent electrophysiological recordings can establish whether an association exists between experimentally modified pain perception and modulations of neural oscillations. Objectives: We aimed to characterize how CPM modifies pain perception and underlying neural oscillations. We also interrogated whether these perceptual and/or neurophysiological effects are distinct in patients affected by chronic pain. Methods: We presented noxious electrical stimuli to the right ankle before, during, and after CPM induced by an ice pack placed on the left forearm. Seventeen patients with chronic pain and 17 control participants rated the electrical pain in each experimental condition. We used magnetoencephalography to examine the anatomy-specific effects of CPM on the neural oscillatory responses to the electrical pain. Results: Regardless of the participant groups, CPM induced a reduction in subjective pain ratings and neural responses (beta-band [15-35 Hz] oscillations in the sensorimotor cortex) to electrical pain. Conclusion: Our findings of pain-induced beta-band activity may be associated with top-down modulations of pain, as reported in other perceptual modalities. Therefore, the reduced beta-band responses during CPM may indicate changes in top-down pain modulations.

Intermittent versus continuous esketamine infusions for long-term pain modulation in complex regional pain syndrome: protocol of a randomized controlled non-inferiority study (KetCRPS-2).

BACKGROUND: Complex regional pain syndrome (CRPS) is a chronic pain condition of an extremity. While achieving pain relief in CRPS is challenging, esketamine infusions can accomplish pain relief for several weeks post-infusion in a subgroup of CRPS patients. Unfortunately, CRPS esketamine protocols are very heterogeneous in advice on dosage, administration and treatment setting. Currently, no trials are available that study differences between intermittent and continuous esketamine infusions for CRPS. With the current situation of bed shortages, it is difficult to admit patients for several consecutive days for inpatient esketamine treatments. In this study, we investigate whether 6 intermittent outpatient esketamine treatments are not inferior to a continuous 6-day inpatient esketamine treatment in establishing pain relief. In addition, several secondary study parameters will be assessed in order to investigate mechanisms responsible for pain relief by esketamine infusions. Furthermore, the cost-effectiveness will be analyzed. METHODS: In this RCT, the primary objective is to demonstrate that an intermittent esketamine dosing regimen is non-inferior to a continuous esketamine dosing regimen at 3 months follow-up. We will include 60 adult CRPS patients. The inpatient treatment group receives a continuous intravenous esketamine infusion for 6 consecutive days. The outpatient treatment group receives a 6-hour intravenous esketamine infusion every 2 weeks for 3 months. Esketamine dose will be individually tailored and is started at 0.05 mg/kg/h and can be increased to a maximum of 0.2 mg/kg/h. Each patient will be followed for 6 months. The primary study parameter is perceived pain intensity, measured by an 11-point Numerical Rating Scale. Secondary study parameters are conditioned pain modulation, quantitative sensory testing, adverse events, thermography, blood inflammatory parameter, questionnaires about functionality, quality of life and mood and costs per patient. DISCUSSION: If our study reveals non-inferiority between intermittent and continuous esketamine infusions, these findings can be beneficial to increase the availability and flexibility of esketamine infusions through outpatient treatments. Furthermore, the costs of outpatient esketamine infusions could be lower than inpatient esketamine infusions. In addition, secondary parameters may predict response to esketamine treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT05212571 , date of registration 01-28-2022. PROTOCOL VERSION: Version 3, February 2022.

Heterogeneous Cortical Effects of Spinal Cord Stimulation.

OBJECTIVES: The understanding of the cortical effects of spinal cord stimulation (SCS) remains limited. Multiple studies have investigated the effects of SCS in resting-state electroencephalography. However, owing to the large variation in reported outcomes, we aimed to describe the differential cortical responses between two types of SCS and between responders and nonresponders using magnetoencephalography (MEG). MATERIALS AND METHODS: We conducted 5-minute resting-state MEG recordings in 25 patients with chronic pain with active SCS in three sessions, each after a one-week exposure to tonic, burst, or sham SCS. We extracted six spectral features from the measured neurophysiological signals: the alpha peak frequency; alpha power ratio (power 7-9 Hz/power 9-11 Hz); and average power in the theta (4-7.5 Hz), alpha (8-12.5 Hz), beta (13-30 Hz), and low-gamma (30.5-60 Hz) frequency bands. We compared these features (using nonparametric permutation t-tests) for MEG sensor and cortical map effects across stimulation paradigms, between participants who reported low (< 5, responders) vs high (≥ 5, nonresponders) pain scores, and in three representative participants. RESULTS: We found statistically significant (p < 0.05, false discovery rate corrected) increased MEG sensor signal power below 3 Hz in response to burst SCS compared with tonic and sham SCS. We did not find statistically significant differences (all p > 0.05) between the power spectra of responders and nonresponders. Our data did not show statistically significant differences in the spectral features of interest among the three stimulation paradigms or between responders and nonresponders. These results were confirmed by the MEG cortical maps. However, we did identify certain trends in the MEG source maps for all comparisons and several features, with substantial variation across participants. CONCLUSIONS: The considerable variation in cortical responses to the various SCS treatment options necessitates studies with sample sizes larger than commonly reported in the field and more personalized treatment plans. Studies with a finer stratification between responders and nonresponders are required to advance the knowledge on SCS treatment effects.

A Review of Effects of Spinal Cord Stimulation on Spectral Features in Resting-State Electroencephalography.

BACKGROUND: Spinal cord stimulation (SCS) is an effective therapy for patients with refractory chronic pain syndromes. Although studies have shown that SCS has both spinal and supraspinal effects, the current understanding of cortical effects is still limited. Neuroimaging techniques, such as magnetoencephalography (MEG) and electroencephalography (EEG), combined here as M/EEG, can reveal modulations in ongoing resting-state cortical activity. We aim to provide an overview of available literature on resting-state M/EEG in patients with chronic pain who have been treated with SCS. MATERIALS AND METHODS: We searched multiple online data bases for studies on SCS, chronic pain, and resting-state M/EEG. Primary outcome measures were changes in spectral features, combined with brain regions in which these changes occurred. RESULTS: We included eight studies reporting various SCS paradigms (tonic, burst, high-dose, and high-frequency stimulation) and revealing heterogeneity in outcome parameters. We summarized changes in cortical activity in various frequency bands: theta (4-7 Hz), alpha (7-12 Hz), beta (13-30 Hz), and gamma (30-44 Hz). In multiple studies, the somatosensory cortex showed modulation of cortical activity under tonic, burst, and high-frequency stimulation. Changes in connectivity were found in the dorsal anterior cingulate cortex, dorsolateral prefrontal cortex, and parahippocampus. CONCLUSIONS: The large heterogeneity observed in outcome measures is probably caused by the large variety in study designs, stimulation paradigms, and spectral features studied. Paresthesia-free paradigms have been compared with tonic stimulation in multiple studies. These studies suggest modulation of medial, lateral, and descending pathways for paresthesia-free stimulation, whereas tonic stimulation predominantly modulates lateral and descending pathways. Moreover, multiple studies have reported an increased alpha peak frequency, increased alpha power, and/or decreased theta power when SCS was compared with baseline, indicating modulation of thalamocortical pathways. Further studies with well-defined groups of responders and nonresponders to SCS are recommended to independently study the cortical effects of pain relief and SCS.

Allodynia, Hyperalgesia, (Quantitative) Sensory Testing and Conditioned Pain Modulation in Patients With Complex Regional Pain Syndrome Before and After Spinal Cord Stimulation Therapy.

OBJECTIVES: Complex regional pain syndrome (CRPS) is a chronic debilitating disease characterized by sensory abnormalities. Spinal cord stimulation (SCS) is an effective therapy for CRPS, but few studies have investigated the effects of SCS therapy on sensory characteristics. Therefore, this study investigated the effect of SCS on allodynia, hyperalgesia, electrical quantitative sensory testing (QST) parameters, and conditioned pain modulation (CPM) effect. MATERIALS AND METHODS: This study is part of a multicenter randomized controlled trial (ISRCTN 36655259). Patients with CRPS in one extremity and eligible for SCS were included. The outcome parameters allodynia (symptom and sign), hyperalgesia (symptom), sensory thresholds with QST, CPM effect, and pain scores were tested before and after three months of SCS (40-Hz tonic SCS). Both the CRPS-affected extremity and the contralateral, clinically unaffected extremity were used to test three sensory thresholds with electrical QST: current perception threshold (CPT), pain perception threshold (PPT), and pain tolerance threshold (PTT). The PTT also was used as a test stimulus for the CPM paradigm both before and after the conditioning ice-water test. Nonparametric testing was used for all statistical analyses. RESULTS: In total, 31 patients were included for analysis. Pain, allodynia (sign and symptom), and hyperalgesia (symptom) were all significantly reduced after SCS therapy. On the unaffected side, none of the QST thresholds (CPT, PPT, and PTT) was significantly altered after SCS therapy. However, the CPT on the CRPS-affected side was significantly increased after SCS therapy. A CPM effect was present both before and after SCS. CONCLUSIONS: Standard 40-Hz tonic SCS significantly reduces pain, hyperalgesia, and allodynia in patients with CRPS. These findings suggest that SCS therapy should not be withheld from patients who suffer from allodynia and hyperalgesia, which contradicts previous findings derived from retrospective analysis and animal research. ISRCTN Registry: The ISRCTN registration number for the study is ISRCTN 36655259.

Systematic Review and Network Meta-analysis of Neurostimulation for Painful Diabetic Neuropathy.

BACKGROUND: Different waveforms of spinal cord stimulation (SCS) have now been evaluated for the management of painful diabetic neuropathy (PDN). However, no direct or indirect comparison between SCS waveforms has been performed to date. PURPOSE: To conduct a systematic review and network meta-analysis to evaluate the effectiveness of SCS for PDN. DATA SOURCES: MEDLINE, CENTRAL, Embase, and WikiStim were searched from inception until December 2021. STUDY SELECTION: Randomized controlled trials (RCTs) of SCS for PDN were included. DATA EXTRACTION: Pain intensity, proportion of patients achieving at least a 50% reduction in pain intensity, and health-related quality of life (HRQoL) data were extracted. DATA SYNTHESIS: Significant reductions in pain intensity were observed for low-frequency SCS (LF-SCS) (mean difference [MD] -3.13 [95% CI -4.19 to -2.08], moderate certainty) and high-frequency SCS (HF-SCS) (MD -5.20 [95% CI -5.77 to -4.63], moderate certainty) compared with conventional medical management (CMM) alone. There was a significantly greater reduction in pain intensity on HF-SCS compared with LF-SCS (MD -2.07 [95% CI -3.26 to -0.87], moderate certainty). Significant differences were observed for LF-SCS and HF-SCS compared with CMM for the outcomes proportion of patients with at least 50% pain reduction and HRQoL (very low to moderate certainty). No significant differences were observed between LF-SCS and HF-SCS (very low to moderate certainty). LIMITATIONS: Limited number of RCTs and no head-to-head RCTs conducted. CONCLUSIONS: Our findings confirm the pain relief and HRQoL benefits of the addition of SCS to CMM for patients with PDN. However, in the absence of head-to-head RCT evidence, the relative benefits of HF-SCS compared with LF-SCS for patients with PDN remain uncertain.

Electrical neurostimulation for the treatment of chronic pruritus: A systematic review.

Approximately one fifth of the world population experiences continuous itch for 6 weeks or more during their life, that is chronic itch. It is diverse in its aetiologies, and it is notoriously hard to treat. Because itch and pain have largely overlapping pathophysiology and the demonstrated efficacy of neurostimulation in treatment of selected chronic pain conditions, we conducted a systematic review to investigate whether neurostimulation could be an effective treatment for chronic itch. We identified two randomized controlled trials and 17 open label studies or case reports investigating various neurostimulation modalities for the treatment of refractory itch of various aetiologies. Transcutaneous electrical nerve stimulation (TENS) was the most investigated modality (n = 17), and in the largest number of conditions. Other modalities were cutaneous field stimulation (n = 2), painscrambler (n = 1), transcranial direct current stimulation (n = 1) and peripheral nerve field stimulation (n = 1). Atopic dermatitis was the most studied condition (n = 5). Despite the large heterogeneity in used stimulation paradigms and outcome parameters, all studies reported a positive effect of at least one neurostimulation modality. Our review indicates that electrical neurostimulation could be considered for the treatment of refractory chronic itch of selected aetiologies, such as atopic dermatitis or burn pruritus. However, better understanding of the mechanisms of action of the neurostimulation modalities and regimens in various pruritic conditions is necessary.

Neural and behavioral correlates of human pain avoidance in participants with and without episodic migraine.

ABSTRACT: The innate motivation to avoid pain can be disrupted when individuals experience uncontrollable stress, such as pain. This can lead to maladaptive behaviors, including passivity, and negative affect. Despite its importance, motivational aspects of pain avoidance are understudied in humans and their neural mechanisms vastly unknown. Rodent models suggest an important role of the periaqueductal gray, but it is unknown whether it subserves a similar role in humans. Furthermore, it is unclear whether pain avoidance is associated with individual differences in pain coping. Using functional magnetic resonance imaging, networks underlying pain avoidance behavior were examined in 32 participants with and without episodic migraine. Pain avoidance behavior was assessed using an adaptation of the incentive delay task. In each trial of the task, participants tried to avoid a painful stimulus and receive a nonpainful one instead while the difficulty to succeed varied across trials (3 difficulty levels: safe, easy, and difficult). After unsuccessful pain avoidance on the preceding trial, participants showed reduced pain avoidance behavior, especially in the difficult condition. This reduction in behavior was associated with higher helplessness scores only in participants with migraine. Higher helplessness in participants with migraine was further correlated with a stronger decrease in activation of cortical areas associated with motor behavior, attention, and memory after unsuccessful pain avoidance. Of these areas, specifically posterior parietal cortex activation predicted individual's pain avoidance behavior on the next trial. The results link individual pain coping capacity to patterns of neural activation associated with altered pain avoidance in patients with migraine.

Modulation of the Somatosensory Evoked Potential by Attention and Spinal Cord Stimulation.

Introduction: Spinal Cord Stimulation (SCS) is a last-resort treatment for patients with intractable chronic pain in whom pharmacological and other treatments have failed. Conventional tonic SCS is accompanied by tingling sensations. More recent stimulation protocols like burst SCS are not sensed by the patient while providing similar levels of pain relief. It has been previously reported that conventional tonic SCS can attenuate sensory-discriminative processing in several brain areas, but that burst SCS might have additional effects on the medial, motivational-affective pain system. In this explorative study we assessed the influence of attention on the somatosensory evoked brain responses under conventional tonic SCS as well as burst SCS regime. Methods: Twelve chronic pain patients with an implanted SCS device had 2-weeks evaluation periods with three different SCS settings (conventional tonic SCS, burst SCS, and sham SCS). At the end of each period, an electro-encephalography (EEG) measurement was done, at which patients received transcutaneous electrical pulses at the tibial nerve to induce somatosensory evoked potentials (SEP). SEP data was acquired while patients were attending the applied pulses and while they were mind wandering. The effects of attention as well as SCS regimes on the SEP were analyzed by comparing amplitudes of early and late latencies at the vertex as well as brain activity at full cortical maps. Results: Pain relief obtained by the various SCS settings varied largely among patients. Early SEP responses were not significantly affected by attention nor SCS settings (i.e., burst, tonic, and sham). However, late SEP responses (P300) were reduced with tonic and burst SCS: conventional tonic SCS reduced P300 brain activity in the unattended condition, while burst SCS reduced P300 brain activity in both attended and unattended conditions. Conclusion: Burst spinal cord stimulation for the treatment of chronic pain seems to reduce cortical attention that is or can be directed to somatosensory stimuli to a larger extent than conventional spinal cord stimulation treatment. This is a first step in understanding why in selected chronic pain patients burst SCS is more effective than tonic SCS and how neuroimaging could assist in personalizing SCS treatment.

Effect of intravenous low-dose S-ketamine on pain in patients with Complex Regional Pain Syndrome: A retrospective cohort study.

OBJECTIVE: The objective of this study was to assess the effectiveness of a low-dose intravenous S-ketamine treatment on refractory pain in patients with Complex Regional Pain Syndrome (CRPS). METHODS: In this retrospective study, patients with CRPS who received intravenous S-ketamine from March 2010 to April 2019 were included. According to our inpatient protocol, S-ketamine dose was increased until pain reduction was achieved or side effects were observed. Maximum dose was 14 mg/h and treatment duration was 7 days. Primary outcome parameters were pain scores (Numeric Rating Scale) at baseline (T0), end of infusion (T1), and approximately 4 weeks postinfusion (T2). Patients were categorized as responder/nonresponder at T1 and T2. Patients were considered a responder in case there was pain score reduction of greater than or equal to 2 points or if treatment was reported as successful. RESULTS: Forty-eight patients were included. Mean disease duration was 5 years (interquartile range [IQR] = 6 years). Median pain score significantly decreased from 8 (IQR = 2) at T0 to 6 (IQR = 4) at T1 (p < 0.001). At T1, 62% of the patients were responders. At T2, 48% of the patients remained a responder. A significant proportion of the responders at T1 turned into nonresponders at T2 (p = 0.03). CONCLUSION: In a group of patients with CRPS with refractory pain, low-dose intravenous S-ketamine treatment resulted in effective pain relief during infusion. Although a significant proportion of initial responders became nonresponders at follow-up, half of the patients were still a responder at ~ 4 weeks postinfusion. Further research is needed to investigate mechanisms responsible for pain relief by S-ketamine infusions and to ascertain possible predictors of response to the treatment.

Spinal cord stimulation for the management of painful diabetic neuropathy: a systematic review and meta-analysis of individual patient and aggregate data.

ABSTRACT: Spinal cord stimulation (SCS) has been suggested as a treatment option for patients with painful diabetic neuropathy (PDN). We conducted a systematic review and undertook a meta-analysis on individual patient data from randomised controlled trials (RCTs) to assess the effectiveness of SCS for the management of PDN. Electronic databases were searched from inception to May 2020 for RCTs of SCS for PDN. Searches identified 2 eligible RCTs (total of 93 patients with PDN) and 2 long-term follow-up studies of one of the RCTs. Individual patient data were obtained from the authors of one of these RCTs. Meta-analysis showed significant and clinically meaningful reductions in pain intensity for SCS compared with best medical therapy alone, pooled mean difference (MD) -3.13 (95% confidence interval [CI]: -4.19 to -2.08) on a 10-point scale at the 6-month follow-up. More patients receiving SCS achieved at least a 50% reduction in pain intensity compared with best medical therapy, pooled risk ratio 0.08 (95% CI: 0.02-0.38). Increases were observed for health-related quality of life assessed as EQ-5D utility score (pooled MD 0.16, 95% CI: 0.02-0.30) and visual analogue scale (pooled MD 11.21, 95% CI: 2.26-20.16). Our findings demonstrate that SCS is an effective therapeutic adjunct to best medical therapy in reducing pain intensity and improving health-related quality of life in patients with PDN. Large well-reported RCTs with long-term follow-up are required to confirm these results.

How to Identify Responders and Nonresponders to Dorsal Root Ganglion-Stimulation Aimed at Eliciting Motor Responses in Chronic Spinal Cord Injury: Post Hoc Clinical and Neurophysiological Tests in a Case Series of Five Patients.

OBJECTIVE: While integrity of spinal pathways below injury is generally thought to be an important factor in the success-rate of neuromodulation strategies for spinal cord injury (SCI), it is still unclear how the integrity of these pathways conveying the effects of stimulation should be assessed. In one of our institutional case series of five patients receiving dorsal root ganglion (DRG)-stimulation for elicitation of immediate motor response in motor complete SCI, only two out of five patients presented as responders, showing immediate muscle activation upon DRG-stimulation. The current study focuses on post hoc clinical-neurophysiological tests performed within this patient series to illustrate their use for prediction of spinal pathway integrity, and presumably, responder-status. MATERIALS AND METHODS: In a series of three nonresponders and two responders (all male, American Spinal Injury Association [ASIA] impairment scale [AIS] A/B), a test-battery consisting of questionnaires, clinical measurements, as well as a series of neurophysiological measurements was performed less than eight months after participation in the initial study. RESULTS: Nonresponders presented with a complete absence of spasticity and absence of leg reflexes. Additionally, nonresponders presented with close to no compound muscle action potentials (CMAPs) or Hofmann(H)-reflexes. In contrast, both responders presented with clear spasticity, elicitable leg reflexes, CMAPs, H-reflexes, and sensory nerve action potentials, although not always consistent for all tested muscles. CONCLUSIONS: Post hoc neurophysiological measurements were limited in clearly separating responders from nonresponders. Clinically, complete absence of spasticity-related complaints in the nonresponders was a distinguishing factor between responders and nonresponders in this case series, which mimics prior reports of epidural electrical stimulation, potentially illustrating similarities in mechanisms of action between the two techniques. However, the problem remains that explicit use and report of preinclusion clinical-neurophysiological measurements is missing in SCI literature. Identifying proper ways to assess these criteria might therefore be unnecessarily difficult, especially for nonestablished neuromodulation techniques.

Induced oscillatory signaling in the beta frequency of top-down pain modulation.

BACKGROUND: Induced synchronized brain activity, particularly in the beta-frequency range, has rarely been investigated in human electrophysiological studies of attentional modulation of the perception of nociceptive stimuli. METHODS: We measured time-resolved brain responses to nociceptive stimuli in healthy subjects (final data set: n = 17) using magnetoencephalography (MEG). In addition to investigating evoked responses as previous studies, we tested whether synchronized beta activity induced by nociceptive stimuli differs between 2 attentional conditions. Subjects were presented simultaneously with 2 stimulus modalities (pain-producing intraepidermal electrical stimuli and visual stimuli) in 2 different experimental conditions, ie, "attention to pain" and "attention to color." Pain ratings between conditions were compared using a 2-sided paired-sample t test; MEG data were analyzed with Brainstorm. RESULTS: Pain ratings were significantly higher in the "attention to pain" compared with the "attention to color" condition. Peak amplitudes of the evoked responses were significantly larger in the "attention to pain" condition bilaterally in the insula and secondary somatosensory cortex, and in the primary somatosensory cortex (SI) contralateral to stimulation. Induced responses to painful stimuli were significantly stronger in contralateral SI in the beta-frequency range in the "attention to pain" condition. CONCLUSIONS: This study replicates previous reports w.r.t. the attentional modulation of evoked responses and suggests a functional role of induced oscillatory activity in the beta frequency in top-down modulation of nociceptive stimuli.

Breath analysis in detecting epilepsy.

The aim of this proof of concept study is to investigate if an electronic nose (eNose) is able to make a distinction between breath profiles of diagnosed epilepsy patients and epilepsy-free control subjects. An eNose is a non-invasive device, with a working mechanism that is based on the presence of volatile organic compounds (VOCs) in exhaled breath. These VOCs interact with the sensors of the eNose, and the eNose has to be trained to distinguish between breath patterns from patients with a specific disease and control subjects without that disease. During the measurement participants were asked to breathe through the eNose for five minutes via a disposable mouthpiece. Seventy-four epilepsy patients and 110 control subjects were measured to train the eNose and create a classification model. To assess the effects of anti-epileptic drugs (AEDs) usage on the classification, additional test groups were measured: seven patients who (temporarily) did not use AEDs and 11 patients without epilepsy who used AEDs. The results show that an eNose is able to make a distinction between epilepsy and control subjects with a sensitivity of 76%, a specificity of 67%, and an accuracy of 71%. The results of the two additional groups of subjects show that the created model classifies one out of seven epilepsy patients without AEDs and six out of 13 patients without epilepsy but with AEDs correctly. In this proof of concept study, the AeonoseTM is able to differentiate between epilepsy patients and control subjects. However, the number of false positives and false negatives is still high, which suggests that this first model is still mainly based on the usage of various AEDs.

Predicting success of vagus nerve stimulation (VNS) from EEG symmetry.

PURPOSE: Vagus nerve stimulation (VNS) has shown to be an effective treatment for drug resistant epilepsy, with achieving more than 50% seizure reduction in one third of the treated patients. In order to predict which patients will profit from VNS, we previously found that a low pairwise derived Brain Symmetry Index (pdBSI) could potentially predict good responders to VNS treatment. These findings however have to be validated before they can be generalized. METHODS: 39 patients (age 18-68 years) with medically intractable epilepsy who were referred for an implanted VNS system were included. Routine EEG registrations, recorded before implantation, were analyzed. Artefact-free epochs with eyes open and eyes closed were quantitatively analyzed. The pdBSI was tested for relation with VNS outcome one year after surgery. RESULTS: Twenty-three patients (59%) obtained a reduction in seizure frequency, of whom ten (26%) had a reduction of at least 50% (good responders) and thirteen (33%) a reduction of less than 50% (moderate responders). Sixteen patients without seizure reduction are defined as non-responders. No significant differences were found in the pdBSI of good responders (mean 0.27), moderate responders (mean 0.26) and non-responders (mean 0.25) (p>0.05). Besides seizure reduction, many patients (56%) reported additional positive effects of VNS in terms of seizure duration, seizure intensity and/or postictal recovery. CONCLUSION: EEG features that correlate with VNS therapy outcome may enable better patient selection and prevent unnecessary VNS surgery. Contrary to earlier findings, this validation study suggests that pdBSI might not be helpful to predict VNS therapy outcome.

Effect of Burst Stimulation Evaluated in Patients Familiar With Spinal Cord Stimulation.

OBJECTIVE: Spinal cord stimulation (SCS) is used for treating intractable neuropathic pain. It has been suggested that burst SCS (five pulses at 500 Hz, delivered 40 times per second) suppresses neuropathic pain at least as well as conventional tonic SCS, but without evoking paraesthesia. The efficacy of paraesthesia-free high and low amplitude burst SCS for the treatment of neuropathic pain in patients who are already familiar with tonic SCS was evaluated. MATERIALS AND METHODS: Forty patients receiving conventional (30-120 Hz) tonic SCS for at least six months were included. All patients received high and low amplitude burst SCS, for a two-week period in a double blind randomized crossover design, with a two-week period of tonic stimulation in between. The average visual analogue scale (VAS) scores for pain during the last three days of each stimulation period were evaluated as well as quality of life (QoL) scores, and patient's preferences. RESULTS: Average VAS score for pain were lower during high (40, p = 0.013) and low amplitude burst stimulation (42, p = 0.053) compared with tonic stimulation (52). QoL scores did not differ significantly. At the individual level 58% of the patients experienced significant additional pain reduction (>30% decrease in VAS for pain) during high and/or low amplitude burst stimulation. Eleven patients preferred tonic stimulation, fifteen high, and fourteen low amplitude burst stimulation. CONCLUSION: Burst stimulation is in general more effective than tonic stimulation. Individual patients can highly benefit from burst stimulation; however, the therapeutic range of burst stimulation amplitudes requires individual assessment.