Neuropathy 10-15 years after Roux-en-Y gastric bypass for severe obesity: A community-controlled nerve conduction study.

Objective: We searched for long-term peripheral nerve complications 10-15 years after Roux-en-Y gastric bypass surgery (RYGB), using a comprehensive nerve conduction study (NCS) protocol. Methods: Patients (n = 175, mean age 52.0, BMI 35.2) and 86 community-controls (mean age 56.8, BMI 27.2) had NCS of one upper and lower limb. New abnormality scores from 27 polyneuropathy-relevant (PNP27s) and four carpal tunnel syndrome-relevant NCS-measures (CTS4s) were compared between groups with non-parametric statistics. Estimated prevalences were compared by 95 % confidence limits. The clinical neurophysiologist's diagnosis was retrieved from hospital records (PNP-ncs, CTS-ncs, other). Results: Abnormality score did not differ between RYGB and control groups (PNP27s: 1.9 vs 1.7, CTS4s: 0.7 vs 0.6, p > 0.29). BMI correlated weakly with CTS4s in patients (rho = 0.19, p = 0.01), and less with PNP27s (rho = 0.12, p = 0.12). Polyneuropathy (PNP-ncs) prevalence was 12 % in patients and 8 % in controls. CTS-ncs prevalence was 21 % in patients and 10 % in controls (p = 0.04). Conclusions: NCS-based abnormality scores did not differ between patients 10-15 years after RYGB and community-recruited controls, neither for PNP nor CTS. Significance: Long-term polyneuropathic complications from RYGB have probably been avoided by modern treatment guidelines. NCS-diagnosed CTS is common in overweight RYGB patients. RYGB-patients with significant neuropathic symptoms need clinical evaluation.

Diagnostic accuracy of the 5.07 monofilament test for diabetes polyneuropathy: influence of age, sex, neuropathic pain and neuropathy severity.

INTRODUCTION: There is a need for simple and cheap diagnostic tools for diabetic polyneuropathy (DPN). We aimed to assess the diagnostic accuracy of the 5.07/10 g monofilament test in patients referred to polyneuropathy assessments, as well as to examine how disease severity, age, sex and neuropathic pain (NP) impact diagnostic accuracy. RESEARCH DESIGN AND METHODS: Five Norwegian university hospitals recruited patients with diabetes aged 18-70 referred to neurological outpatient clinics for polyneuropathy assessments. The 5.07/10 g Semmes-Weinstein monofilament examination (SWME) was validated against the Toronto consensus for diagnosing diabetic neuropathies; the results were stratified by age, sex and NP. Disease severity was graded by a combined nerve conduction study (NCS) Z-score, and logistic regression was applied to assess whether disease severity was a predictor of diagnostic accuracy. RESULTS: In total, 506 patients were included in the study. Global sensitivity was 0.60 (95% CI 0.55, 0.66), specificity 0.82 (95% CI 0.75, 0.87), positive and negative predictive values were 0.86 (95% CI 0.81, 0.90) and 0.52 (95% CI 0.46, 0.58), respectively, positive and negative likelihood ratios were 3.28 (95% CI 2.37, 4.53) and 0.49 (95% CI 0.42, 0.57), respectively. The SWME was less sensitive in females (0.43), had lower specificity in patients with NP (0.56), and performed worse in patients ≥50 years. NCS-based disease severity did not affect diagnostic accuracy (OR 1.15, 95% CI 0.95, 1.40). CONCLUSIONS: This multicenter study demonstrates poor diagnostic performance for the 5.07/10 g SWME in patients with diabetes referred to polyneuropathy assessments; it is particularly unsuited for female patients and those with NP. The diagnostic accuracy of the SWME was not influenced by NCS-based disease severity, demonstrating that it does not perform better in patients with later stages of DPN. We do not recommend the use of the 5.07/10 g monofilament in the evaluation of patients with diabetes referred to polyneuropathy assessments.

Disentangling the cascade of seizure precipitants: A prospective observational study.

BACKGROUND: The management of epilepsy includes appropriate antiseizure medication (ASM) treatment and careful avoidance of seizure precipitating factors. Seizure precipitants may be multiple occurring with low intensity adding to each other, thus leaving essential elements unrecognized. The aim of this study was to reveal the patients' subjective perceptions of the most important factors and to compare them with standardized measurements. METHODS: The study included 152 acute hospital admissions for seizures. The patients were asked to score the impact of various seizure precipitants as perceived by themselves on a visual analogue scale (VAS). The following items related to seizure occurrence were quantified: sleep deprivation by sleep diaries, ASM adherence by therapeutic drug monitoring, the Alcohol Use Identification Test, and the Hospital Anxiety and Depression Scale. Statistical analyses, including multiple regression, were performed to discover relationships between various parameters. RESULTS: The interaction of the various factors was high. The association between lack of sleep and hazardous drinking and anxiety was highly significant. Perceived stress correlated well with anxiety and depression. Relatively low VAS scores for missed medication in patients with identified non-adherence suggest that insufficient patient awareness is common. Low VAS-scores for alcohol in patients with harmful drinking also suggest low acknowledgment of alcohol-related seizures. High alcohol scores were associated with sleep deprivation, anxiety and depression. CONCLUSION: The circumstances leading to an epileptic seizure are complex. Stress, sleep loss, alcohol intake, and missed medication are among the most commonly reported seizure precipitants. They are often combined, and various facets of the same underlying cause may be at play. Their sequence and relative impact are often difficult to establish. Improved understanding of the cascade of events preceding a seizure can improve comprehensive personalized management of uncontrolled epilepsy.

Insufficient sleep may alter cortical excitability near the migraine attack: A blinded TMS crossover study.

BACKGROUND: Migraine is a brain disorder with a multifaceted and unexplained association to sleep. Brain excitability likely changes periodically throughout the migraine cycle. In this study we examine the effect of insufficient sleep on neuronal excitability during the course of the migraine cycle. METHODS: We examined 54 migraine patients after two nights of eight-hour habitual sleep and two nights of four-hour restricted sleep in a randomised, blinded crossover study. We performed transcranial magnetic stimulation and measured cortical silent period, short- and long-interval intracortical inhibition, intracortical facilitation and short-latency afferent inhibition. We analysed how responses changed before and after attacks with linear mixed models. RESULTS: Short- interval intracortical inhibition was more reduced after sleep restriction compared to habitual sleep the shorter the time that had elapsed since the attack (p = 0.041), and specifically in the postictal phase (p = 0.013). Long-interval intracortical inhibition was more increased after sleep restriction with time closer before the attack (p = 0.006), and specifically in the preictal phase (p = 0.034). Short-latency afferent inhibition was more decreased after sleep restriction with time closer to the start of the attack (p = 0.026). CONCLUSION: Insufficient sleep in the period leading up to a migraine attack may cause dysfunction in cortical GABAergic inhibition. The results also suggest that migraine patients may have increased need for sufficient sleep during a migraine attack to maintain normal neurological function after the attack.

Effects of insufficient sleep on sensorimotor processing in migraine: A randomised, blinded crossover study of event related beta oscillations.

BACKGROUND: Migraine has a largely unexplained connection with sleep and is possibly related to a dysfunction of thalamocortical systems and cortical inhibition. In this study we investigate the effect of insufficient sleep on cortical sensorimotor processing in migraine. METHODS: We recorded electroencephalography during a sensorimotor task from 46 interictal migraineurs and 28 controls after two nights of eight-hour habitual sleep and after two nights of four-hour restricted sleep. We compared changes in beta oscillations of the sensorimotor cortex after the two sleep conditions between migraineurs, controls and subgroups differentiating migraine subjects usually having attacks starting during sleep and not during sleep. We included preictal and postictal recordings in a secondary analysis of temporal changes in relation to attacks. RESULTS: Interictally, we discovered lower beta synchronisation after sleep restriction in sleep related migraine compared to non-sleep related migraine (p=0.006) and controls (p=0.01). No differences were seen between controls and the total migraine group in the interictal phase. After migraine attacks, we observed lower beta synchronisation (p<0.001) and higher beta desynchronisation (p=0.002) after sleep restriction closer to the end of the attack compared to later after the attack. CONCLUSION: The subgroup with sleep related migraine had lower sensorimotor beta synchronisation after sleep restriction, possibly related to dysfunctional GABAergic inhibitory systems. Sufficient sleep during or immediately after migraine attacks may be of importance for maintaining normal cortical excitability.

Accuracy of neuropathic pain measurements in patients with symptoms of polyneuropathy: validation of painDETECT, Self-Completed Leeds Assessment of Neuropathic Symptoms and Signs, and Douleur Neuropathique 4.

ABSTRACT: Pain is a common symptom in patients referred to polyneuropathy assessment. Diagnostic evaluation and choice of treatment may depend on whether the pain is likely to be neuropathic or not. This study aimed to investigate the diagnostic accuracy of 3 tools commonly used to differentiate between neuropathic and nonneuropathic pain. To accomplish this, we included patients with bilateral distal lower extremity pain, referred to neurological outpatient clinics at 5 Norwegian University hospitals for polyneuropathy assessment. The patients filled in Norwegian versions of painDETECT, the Self-Completed Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS), and the clinician-rated Douleur Neuropathique 4 (DN4). All patients underwent a clinical examination and nerve conduction measurements and were classified according to the NeuPSIG neuropathic pain criteria (reference standard). In total, 729 patients were included, of which 63% had neuropathic pain by the reference standard. Only DN4 demonstrated high sensitivity (0.87), whereas all 3 tools had low specificity (≤0.65). Importantly, the tools' predictive ability was unsatisfactory; The probability of getting a correct test result was 3 quarters at best, and at worst, no better than two fifths. Consequently, we show that neither DN4, painDETECT, nor S-LANSS can be confidently used to assess neuropathic pain in a neurological outpatient population with symptoms of polyneuropathy.

Sleep restriction alters cortical inhibition in migraine: A transcranial magnetic stimulation study.

OBJECTIVE: Migraine is a primary headache disorder with a well-known association with insufficient sleep. However, both the underlying pathophysiology of the disease and the relationship with sleep is still unexplained. In this study, we apply transcranial magnetic stimulation to investigate possible mechanisms of insufficient sleep in migraine. METHODS: We used a randomised, blinded crossover design to examine 46 subjects with migraine during the interictal period and 29 healthy controls. Each subject underwent recordings of cortical silent period, short- and long-interval intracortical inhibition, intracortical facilitation and short-latency afferent inhibition after both two nights of habitual eight-hour sleep and two nights of restricted four-hour sleep. RESULTS: We found reduced cortical silent period duration after sleep restriction in interictal migraineurs compared to controls (p = 0.046). This effect was more pronounced for non-sleep related migraine (p = 0.002) and migraine with aura (p = 0.017). The sleep restriction effect was associated with ictal symptoms of hypersensitivity such as photophobia (p = 0.017) and overall silent period was associated with premonitory dopaminergic symptoms such as yawning (p = 0.034). CONCLUSIONS: Sleep restriction reduces GABAergic cortical inhibition during the interictal period in individuals with migraine. SIGNIFICANCE: Sleep related mechanisms appear to affect the pathophysiology of migraine and may differentiate between migraine subgroups.

Pain thresholds and suprathreshold pain after sleep restriction in migraine - A blinded crossover study.

OBJECTIVE: There is an unexplained association between disturbed sleep and migraine. In this blinded crossover study, we investigate if experimental sleep restriction has a different effect on pain thresholds and suprathreshold pain in interictal migraineurs and controls. METHODS: Forearm heat pain thresholds and tolerance thresholds, and trapezius pressure pain thresholds and suprathreshold pain were measured in 39 interictal migraineurs and 31 healthy controls after two consecutive nights of partial sleep restriction and after habitual sleep. RESULTS: The effect of sleep restriction was not significantly different between interictal migraineurs and controls in the primary analyses. Pressure pain thresholds tended to be lower (i.e., increased pain sensitivity) after sleep restriction in interictal migraineurs compared to controls with a 48-hour preictal-interictal cut-off (p = 0.061). We found decreased pain thresholds after sleep restriction in two of seven migraine subgroup comparisons: heat pain thresholds decreased in migraineurs with lower pain intensity during attacks (p = 0.005) and pressure pain thresholds decreased in migraineurs with higher severity of photophobia during attacks (p = 0.031). Heat pain thresholds tended to decrease after sleep restriction in sleep-related migraine (p = 0.060). Sleep restriction did not affect suprathreshold pain measurements in either group. CONCLUSION: This study could not provide strong evidence for an increased effect of sleep restriction on pain sensitivity in migraineurs compared to healthy controls. There might be a slightly increased effect of sleep restriction in migraineurs, detectable using large samples or more pronounced in certain migraine subgroups.

Pain sensitivity in young adults with juvenile idiopathic arthritis: a quantitative sensory testing study.

BACKGROUND: To study for the first-time, pain perception, pain sensitivity, and self-reported pain in young adults with long disease duration of juvenile idiopathic arthritis (JIA) compared with controls. METHODS: Children from Central Norway diagnosed with JIA between 1997 and 2004 were included consecutively in a population-based prospective study. Children with onset 1997-2000 were part of the Nordic JIA cohort. Controls were age- and sex-matched. In 2015-2017, study visits with investigator-blinded quantitative sensory testing (QST) comprising cold and warm detection thresholds (CDT/WDT), cold and heat pain thresholds (CPT/HPT), pressure pain threshold (PPT), and a suprathreshold heat pain test were performed. We constructed separate multilevel models for each variable of detection and pain thresholds with interaction between groups and site adjusted for the effect of age and sex. RESULTS: Among 96 young adults with JIA, 71% were female, median age was 22.7 years, disease duration was 16.1 years, and 47% had oligoarticular disease. Among 109 controls, 71% were female, and median age was 23.5 years. Participants with JIA had lower pressure pain thresholds (PPTs) (95% CI) compared to controls, upper limb 888 (846,930) versus 1029 (999,1059) kPa and lower limb 702 (670,734) versus 760 (726,794) kPa. Participants with inactive disease had the lowest PPTs and cold pain thresholds (CPTs), compared to those in remission off medication and those with active disease. Minor differences were found regarding CDT/WDT and CPT/HPT in JIA compared to controls. The median (IQR) temperature needed to evoke pain = 6 on a 0-10 numeric rating scale (NRS) in the suprathreshold heat pain tests were lower in JIA than in controls (46 °C (45-47 °C) versus 47 °C (46-48 °C)). We found no associations between self-reported pain and pain thresholds. CONCLUSIONS: Our results indicate for the first time that young adults with long disease duration of JIA may have altered pain perception and sensitivity compared to controls. A clinical implication may be the importance of early treatment to quickly achieve pain-free remission and avoid long-term pain sensitization.

Fluctuations of sensorimotor processing in migraine: a controlled longitudinal study of beta event related desynchronization.

BACKGROUND: The migraine brain seems to undergo cyclic fluctuations of sensory processing. For instance, during the preictal phase, migraineurs experience symptoms and signs of altered pain perception as well as other well-known premonitory CNS-symptoms. In the present study we measured EEG-activation to non-painful motor and sensorimotor tasks in the different phases of the migraine cycle by longitudinal measurements of beta event related desynchronization (beta-ERD). METHODS: We recorded electroencephalography (EEG) of 41 migraine patients and 31 healthy controls. Each subject underwent three EEG recordings on three different days with classification of each EEG recording according to the actual migraine phase. During each recording, subjects performed one motor and one sensorimotor task with the flexion-extension movement of the right wrist. RESULTS: Migraine patients had significantly increased beta-ERD and higher baseline beta power at the contralateral C3 electrode overlying the primary sensorimotor cortex in the preictal phase compared to the interictal phase. We found no significant differences in beta-ERD or baseline beta power between interictal migraineurs and controls. CONCLUSION: Increased preictal baseline beta activity may reflect a decrease in pre-activation in the sensorimotor cortex. Altered pre-activation may lead to changes in thresholds for inhibitory responses and increased beta-ERD response, possibly reflecting a generally increased preictal cortical responsivity in migraine. Cyclic fluctuations in the activity of second- and third-order afferent somatosensory neurons, and their associated cortical and/or thalamic interneurons, may accordingly also be a central part of the migraine pathophysiology.

Pain Sensitivity and Thermal Detection Thresholds in Young Adults Born Preterm With Very Low Birth Weight or Small for Gestational Age at Term Compared With Controls.

The objective of this prospective long-term follow-up study was to investigate whether somatosensory function is altered among young adults born preterm with very low birth weight (VLBW; ≤1,500 g) or small for gestational age (SGA; <10th percentile) at term. In a blinded quantitative sensory testing protocol, we determined thermal detection, thermal pain, and pressure pain thresholds and the response to prolonged supra-threshold heat among 51 VLBW, 66 term SGA, and 86 term-born controls (birth weight ≥10th percentile) at 28 years. Self-reported chronic pain was also investigated. Except for increased sensitivity to cool in the term SGA group versus controls, we found no significant group differences regarding thermal or pain thresholds. Overall, male participants had higher pain thresholds, and no significant interactions of group and sex were observed (P > .14). Within the VLBW group, neonatal mechanical ventilation was associated with reduced sensitivity to cool, and length of mechanical ventilation correlated with lower pressure pain thresholds. The response to prolonged supra-threshold heat was similar between the groups, and the prevalence of self-reported chronic pain was not reliably different. In conclusion, low birth weight young adults were as sensitive to thermal and pain stimuli as term-born, normal birth weight controls, with the same sex differences. PERSPECTIVE: To our knowledge, this is the first report on thermal and pain sensitivity among young adults born preterm with VLBW or SGA at term. The negative results from a comprehensive quantitative sensory testing protocol oppose previous findings of altered sensory perception among children and adolescents born preterm.

Habituation of laser-evoked potentials by migraine phase: a blinded longitudinal study.

BACKGROUND: Migraineurs seem to have cyclic variations in cortical excitability in several neurophysiological modalities. Laser-evoked potentials (LEP) are of particular interest in migraine because LEP specifically targets pain pathways, and studies have reported different LEP-changes both between and during headaches. Our primary aim was to explore potential cyclic variations in LEP amplitude and habituation in more detail with a blinded longitudinal study design. METHODS: We compared N1 and N2P2 amplitudes and habituation between two blocks of laser stimulations to the dorsal hand, obtained from 49 migraineurs with four sessions each. We used migraine diaries to categorize sessions as interictal (> one day from previous and to next attack), preictal (< one day before the attack), ictal or postictal (< one day after the attack). Also, we compared 29 interictal recordings from the first session to 30 controls. RESULTS: N1 and N2P2 amplitudes and habituation did not differ between preictal, interictal and postictal phase sessions, except for a post hoc contrast that showed deficient ictal habituation of N1. Habituation is present and similar in migraineurs in the interictal phase and controls. CONCLUSIONS: Hand-evoked LEP amplitudes and habituation were mainly invariable between migraine phases, but this matter needs further study. Because hand-evoked LEP-habituation was similar in migraineurs and controls, the present findings contradict several previous LEP studies. Pain-evoked cerebral responses are normal and show normal habituation in migraine.

Does pain sensitivity change by migraine phase? A blinded longitudinal study.

Objective Studies suggest that pain thresholds may be altered before and during migraine headaches, but it is still debated if a central or peripheral dysfunction is responsible for the onset of pain in migraine. The present blinded longitudinal study explores alterations in thermal pain thresholds and suprathreshold heat pain scores before, during, and after headache. Methods We measured pain thresholds to cold and heat, and pain scores to 30 seconds of suprathreshold heat four times in 49 migraineurs and once in 31 controls. Sessions in migraineurs were categorized by migraine diaries as interictal, preictal (≤one day before attack), ictal or postictal (≤one day after attack). Results Trigeminal cold pain thresholds were decreased ( p = 0.014) and pain scores increased ( p = 0.031) in the ictal compared to the interictal phase. Initial pain scores were decreased ( p < 0.029), and the temporal profile showed less adaptation ( p < 0.020) in the preictal compared to the interictal phase. Hand cold pain thresholds were decreased in interictal migraineurs compared to controls ( p < 0.019). Conclusion Preictal heat hypoalgesia and reduced adaptation was followed by ictal trigeminal cold suballodynia and heat hyperalgesia. Our results support that cyclic alterations of pain perception occur late in the prodromal phase before headache. Further longitudinal investigation of how pain physiology changes within the migraine cycle is important to gain a more complete understanding of the pathogenic mechanisms behind the migraine attack.

Visual evoked potentials in migraine: Is the "neurophysiological hallmark" concept still valid?

OBJECTIVE: Lack of habituation is considered a neurophysiological hallmark of migraine. However, the results of visual evoked potential (VEP) studies have been discrepant, possibly because of different stimulation parameters and lack of blinding. Hence, there is a need for independent confirmation of lack of VEP habituation in migraine. In this blinded study we applied 16' checks to supplement our previous findings with 8', 31', 62' and 65' checks. METHODS: VEPs in 41 interictal migraineurs and 30 controls were compared. VEPs were recorded in six blocks of 100 single responses. Linear N70-P100 amplitude change over blocks (habituation slope) was compared with an independent samples Student's t-test. RESULTS: Amplitude decline over blocks was observed in both groups. Habituation slope was not significantly different between controls (-0.43 ± 0.54 µV/block) and migraineurs (-0.29 ± 0.35 µV/block) (p=0.33). CONCLUSION: VEP habituation with 16' checks did not differ in migraineurs and controls. This is in agreement with previous findings with other stimulation parameters. It is therefore unlikely that use of different stimulation parameters could explain the discrepant results of previous studies. No studies that applied blinding during recording of VEP have found lack of habituation in migraineurs. SIGNIFICANCE: Lack of VEP habituation cannot be considered a reliable neurophysiological hallmark in migraine.

Modulation of visual evoked potentials by high-frequency repetitive transcranial magnetic stimulation in migraineurs.

OBJECTIVE: High-frequency repetitive transcranial magnetic stimulation (rTMS) modulates cortical excitability. We investigated its effect on visual evoked potentials (VEPs) in migraine. METHODS: Thirty-two headache-free controls (CO), 25 interictal (MINT) and 7 preictal migraineurs (MPRE) remained after exclusions. VEPs to 8' and 65' checks were averaged in six blocks of 100 single responses. VEPs were recorded before, directly after and 25min after 10Hz rTMS. The study was blinded for diagnosis during recording and for diagnosis and block number during analysis. First block amplitudes and habituation (linear amplitude change over blocks) were analysed with repeated measures ANOVA. RESULTS: With 65' checks, N70-P100 habituation was reduced in MINT compared to CO after rTMS (p=0.013). With 8' checks, habituation was reduced in MPRE compared to MINT and CO after rTMS (p<0.016). No effects of rTMS on first block amplitudes were found. CONCLUSION: RTMS reduced habituation only in migraineurs, indicating increased responsivity to rTMS. The magnocellular visual subsystem may be affected interictally, while the parvocellular system may only be affected preictally. SIGNIFICANCE: Migraineurs may have increased responsiveness to rTMS because of a cortical dysfunction that changes before a migraine attack.

Visual evoked potentials in interictal migraine: no confirmation of abnormal habituation.

OBJECTIVE: We intended to study the effect of check size on visual evoked potential habituation in interictal migraine, using the faster 3 per second reversal rate and an improved analytic procedure with block-number blinding. BACKGROUND: Habituation in migraineurs has been extensively studied with visual evoked potentials. Despite discrepant results, possibly related to the use of different stimulus conditions, lack of habituation in the period between attacks is presently considered to be a neurophysiological hallmark of migraine. METHODS: Midoccipital monocular visual evoked potentials were recorded and analyzed in 27 interictal migraineurs and 34 healthy controls using a blinded study design. Small 8' checks and large 65' checks were applied in random order, both with 3 reversals per second. Six consecutive blocks of 100 responses were recorded for each check size. N70-P100 and P100-N145 peak-to-peak amplitudes were measured. Regression slopes across the 6 blocks, supplemented by last block/first block ratio and repeated measures analysis of variance with amplitude as the dependent variable, were used to test for habituation. RESULTS: N70-P100 habituation to small and large checks was observed in controls (mean slope -0.30 and -0.11 µV/block) and interictal migraineurs (-0.32 and -0.26 µV/block). P100-N145 habituation to small checks in controls (mean slope -0.39 µV/block) and to small and large checks in interictal migraineurs (-0.38 and -0.17 µV/block) was also observed. None of the habituation measures were significantly different between healthy controls and migraineurs (F < 1.6, P > .18). The check-size effect was similar in the 2 groups (F < 2.3, P > .14). CONCLUSION: Reversal rate and check-size differences do not seem to explain the discrepant visual evoked potential habituation results in the migraine literature. Furthermore, no differences in first block amplitudes or N70, P100, and N145 latencies between healthy controls and migraineurs were found. We recommend blinded evaluation designs in future habituation studies in migraine.