Harnessing historical data to derive reference limits - A comparison of e-norms to traditionally derived reference limits.

Objective: Nerve conduction studies (NCS) require valid reference limits for meaningful interpretation. We aimed to further develop the extrapolated norms (e-norms) method for obtaining NCS reference limits from historical laboratory datasets for children and adults, and to validate it against traditionally derived reference limits. Methods: We compared reference limits obtained by applying a further developed e-norms with reference limits from healthy controls for the age strata's 9-18, 20-44 and 45-60 years old. The control data consisted of 65 healthy children and 578 healthy adults, matched with 1294 and 5628 patients respectively. Five commonly investigated nerves were chosen: The tibial and peroneal motor nerves (amplitudes, conduction velocities, F-waves), and the sural, superficial peroneal and medial plantar sensory nerves (amplitudes, conduction velocities). The datasets were matched by hospital to ensure identical equipment and protocols. The e-norms method was adapted, and reference limit calculation using both ±2 SD (original method) and ±2.5 SD (to compensate for predicted underestimation of population SD by the e-norms method) was compared to control data using ±2 SD. Percentage agreement between e-norms and the traditional method was calculated. Results: On average, the e-norms method (mean ±2 SD) produced slightly stricter reference limits compared to the traditional method. Increasing the e-norms range to mean ±2.5 SD improved the results in children while slightly overcorrecting in the adult group. The average agreement between the two methods was 95 % (±2 SD) and 96 % (±2.5 SD). Conclusions: The e-norms method yielded slightly stricter reference limits overall than ones obtained through traditional methods; However, much of the difference can be attributed to a few outlying plots where the raters found it difficult to apply e-norms correctly. The two methods disagreed on classification of 4-5% of cases. Our e-norms software is suited to analyze large amounts of raw NCS data; it should further reduce bias and facilitate more accurate ratings. Significance: With small adaptations, the e-norms method adequately replicates traditionally derived reference limits, and is a viable method to produce reference limits from historical datasets.

Estimating motor unit numbers from a CMAP scan: Repeatability study on three muscles at 15 centres.

OBJECTIVE: To assess the repeatability and suitability for multicentre studies of MScanFit motor unit number estimation (MUNE), which involves modelling compound muscle action potential (CMAP) scans. METHODS: Fifteen groups in 9 countries recorded CMAP scans twice, 1-2 weeks apart in healthy subjects from abductor pollicis brevis (APB), abductor digiti minimi (ADM) and tibialis anterior (TA) muscles. The original MScanFit program (MScanFit-1) was compared with a revised version (MScanFit-2), designed to accommodate different muscles and recording conditions by setting the minimal motor unit size as a function of maximum CMAP. RESULTS: Complete sets of 6 recordings were obtained from 148 subjects. CMAP amplitudes differed significantly between centres for all muscles, and the same was true for MScanFit-1 MUNE. With MScanFit-2, MUNE differed less between centres but remained significantly different for APB. Coefficients of variation between repeats were 18.0% for ADM, 16.8% for APB, and 12.1% for TA. CONCLUSIONS: It is recommended for multicentre studies to use MScanFit-2 for analysis. TA provided the least variable MUNE values between subjects and the most repeatable within subjects. SIGNIFICANCE: MScanFit was primarily devised to model the discontinuities in CMAP scans in patients and is less suitable for healthy subjects with smooth scans.

Influence of ergonomic factors on peripheral neuropathy under HAV exposure.

BACKGROUND: Hand-arm vibration (HAV) is a risk factor for carpal tunnel syndrome (CTS) and ulnar neuropathy at the elbow (UNE). It is unclear how ergonomic factors influence the relationship between HAV exposure and CTS and UNE. AIMS: We aimed to assess the relationship between cumulative HAV exposure and CTS and UNE in workers exposed to HAV from two tools with different ergonomic profiles. METHODS: We performed nerve conduction studies (NCSs) of the sensory and motor median and ulnar nerves and recorded symptoms indicating CTS and UNE in workers exposed to HAV from impact wrenches or from rock drills. Exposure was measured as cumulative lifetime exposure. We used linear regression adjusted for age and body mass index to assess linear relationships. RESULTS: Sixty-five workers participated (33 rock drill and 32 impact wrench operators). We found inverse linear associations between cumulative HAV exposure and median nerve sensory conduction velocity in impact wrench operators and ulnar nerve motor conduction velocity in rock drill operators (beta of 0.63 and 0.75). Based on NCS findings and symptoms, seven impact wrench operators had CTS and one UNE, and four rock drill operators had CTS and six UNE. CONCLUSIONS: Our findings indicate that ergonomic factors influence the development of CTS and UNE under HAV exposure. The ergonomic profile seems to influence which type of neuropathy workers exposed to HAV will develop. Design of occupational exposure guidelines and future studies should be based on ergonomic profile and exposure characteristics for different tools and not merely HAV.

Shift work, inflammation and musculoskeletal pain-The HUNT Study.

BACKGROUND: Studies have indicated that shift work, in particular night work, is associated with chronic musculoskeletal pain but the mechanisms are unclear. It has been suggested that sleep disturbance, a common complaint among shift and night workers, may induce low-grade inflammation as well as heightened pain sensitivity. AIMS: Firstly, this study was aimed to examine the cross-sectional associations between shift work, C-reactive protein (CRP) level and chronic musculoskeletal pain, and secondly, to analyse CRP as a mediator between shift work and chronic musculoskeletal pain. METHODS: The study included 23 223 vocationally active women and men who participated in the HUNT4 Survey of the Trøndelag Health Study (HUNT). Information was collected by questionnaires, interviews, biological samples and clinical examination. RESULTS: Regression analyses adjusted for sex, age and education revealed significant associations between shift work and odds of any chronic musculoskeletal pain (odd ratio [OR] 1.11, 95% confidence interval [CI] 1.04-1.19), between shift work and CRP level (OR 1.09, 95% CI 1.03-1.16) and between CRP level 3.00-10 mg/L and any chronic musculoskeletal pain (OR 1.38, 95% CI 1.27-1.51). Shift work and CRP were also associated with number of chronic pain sites. Mediation analysis indicated that shift work was indirectly associated with any chronic musculoskeletal pain through CRP (OR 1.03, 95% CI 1.01-1.06). CONCLUSIONS: The results support the hypothesis that shift work is associated with chronic musculoskeletal pain, and that systemic inflammation may be a biological mechanism linking shift work to chronic pain.

Can within-subject comparisons of thermal thresholds be used for diagnostic purposes?

OBJECTIVE: Quantitative thermal testing (QTT) is a psychophysical assessment method of small nerve fibers that relies on reference material to assess function. Normal limits for within-subject comparisons of thermal thresholds are scarce, and their association with age, height and sex is not fully elucidated. The aim of this study was to investigate the normal limits for distal-proximal- and contralateral homologous comparisons of thermal thresholds with QTT, and their association with age, sex or height. METHODS: Fifty healthy volunteers ages 20-79 participated in the experiment. Cold detection thresholds (CDT), warm detection thresholds (WDT), heat pain thresholds (HPT), and cold pain thresholds (CPT) were measured bilaterally at the thenar eminence, anterior thigh, distal medial leg and foot dorsum. Sample normal limits were calculated as (mean) ±â€¯2 SD. RESULTS: Forty-eight subjects were included in the analysis. CPT was excluded from all analyses due to a large floor-effect. Sample normal limits for side-differences ranged from 1.8 to 7.2 °C for CDT, 2.4-6.8 °C for WDT and 3.2-4.0 °C for HPT, depending on anatomical site. For distal-proximal comparisons, sample normal limits ranged from 4.0 to 8.7 °C for CDT, 6.0-14.0 °C for WDT and 4.2-9.0 °C for HPT, depending on the pairs compared. Age was associated with side-differences for CDT in the thenar eminences (p < 0.001) and distal medial legs (p < 0.002), and with 11 of 18 distal-proximal comparisons (p < 0.01). CONCLUSIONS: The normal limits for distal-proximal- and contralateral homologous thermal thresholds were wide, and thus of limited use in a clinical setting, although the reported values may be somewhat inflated by low sample-size and consequent age-pooling. Age, but not sex or height, was associated with contralateral differences in CDT in the thenar eminences and distal medial legs, and with most distal-proximal differences. SIGNIFICANCE: Due to wide normal limits, we advise caution when utilizing relative comparisons of thermal thresholds for diagnostic purposes.

Experimental sleep restriction increases latency jitter in pain elicited cortical responses.

OBJECTIVE: Previous studies have shown increased pain scores to painful stimulation after experimental sleep restriction, but reduced or unchanged magnitude of the event related potentials (ERPs) when averaged in the time-domain. However, some studies found increased response magnitude when averaging in the time-frequency domain. The aim of this study was to determine whether ERP-latency jitter may contribute to this discrepancy. METHODS: Ninety painful electrical stimuli were given to 21 volunteers after two nights of 50% sleep restriction and after two nights of habitual sleep. ERPs were analyzed in the time-domain (N2-and P2-peaks) and time-frequency domain (power spectral density). We quantified latency jitter by the mean consecutive difference (MCD) between single-trial peak latencies and by phase locking value (PLV) across trials. RESULTS: P2-MCD increased from 20.4 ± 2.1 ms after habitual sleep to 24.3 ± 2.2 ms after sleep restriction (19%, p = 0.038) and PLV decreased from 0.582 ± 0.015 after habitual sleep to 0.536 ± 0.015 after sleep restriction (7.9%, p = 0.009). We found no difference for N2-MCD. CONCLUSIONS: Our results indicate that partial sleep restriction increase latency jitter in cortical responses to experimental pain. SIGNIFICANCE: Latency jitter may contribute to the discrepancies between ERP-responses in the time-frequency domain and time-domain. Latency jitter should be considered when ERPs are analyzed.

Conditioned pain modulation is not decreased after partial sleep restriction.

BACKGROUND: Sleep problems have been identified as a risk factor for several chronic pain conditions. Reduced sleep has been related to increased pain perception and it has been hypothesized that reduced pain inhibition may explain this. The aim of this study was to determine if sleep restriction (SR) affects heat pain perception and conditioned pain modulation (CPM). METHODS: In a paired cross-over design with two conditions (2 nights habitual sleep (HS) vs. 2 nights 50% SR) CPM was tested in 22 healthy individuals (14 women, 8 men). The test stimulus (TS) was 2-min contact heat stimulation (47  ± 1.3  °C) to the volar forearm. TS was delivered before and during a 7 °C cold pressor test (conditioning stimulus, CS) to the contralateral hand. RESULTS: TS was perceived as more painful after SR compared to after HS (p < 0.001). A stronger inhibitory CPM was found after SR versus after HS (p < 0.001). CONCLUSIONS: The results indicate that SR leads to increased heat pain perception, but not reduced inhibitory CPM. This contradicts general assumptions on the relation between SR and the CPM effect.

Recommendations on practice of conditioned pain modulation (CPM) testing.

Protocols for testing conditioned pain modulation (CPM) vary between different labs/clinics. In order to promote research and clinical application of this tool, we summarize the recommendations of interested researchers consensus meeting regarding the practice of CPM and report of its results.

A large conditioned pain modulation response is not related to a large blood pressure response: a study in healthy men.

BACKGROUND: Endogenous pain modulation has been studied with the conditioned pain modulation (CPM) paradigm with large differences in the magnitude of the CPM effect. We hypothesized that differences in CPM effects might be associated with differences in blood pressure responses to the conditioning stimulus when comparing the CPM effects using two different conditioning stimuli. METHODS: A single-blind repeated-measures design with block-randomization was applied on 25 healthy male subjects. The test stimulus (TS; tonic heat pain for 120 s) was first presented alone, thereafter in parallel with a conditioning stimulus (CS). Conditioning stimuli were either a cold pressor test (CPT) or equally painful ischaemic muscle pain (ISC), both lasting 120 s. Finger blood pressure and heart rate were recorded continuously. Data were analysed in a linear mixed model framework with CS type (CPT or ISC) and conditioning (TS or TS + CS) as independent factors. RESULTS: An inhibitory CPM effect was found for both types of conditioning (p < 0.001). The CPM effect was larger during CPT conditioning compared with ISC conditioning (p = 0.001). No association with the concomitant cardiovascular response (blood pressure and heart rate) was found (p > 0.34). CONCLUSION: Cold pressor pain CS induces larger CPM effects than ischaemic pain CS. The larger CPM effect is, however, not associated with a larger blood pressure response. Other factors related to the CS should be investigated to understand why different CS modalities give different CPM effects.

Increased baroreflex sensitivity and heart rate variability in migraine patients.

OBJECTIVES: We investigated whether spontaneous baroreflex sensitivity and heart rate variability (HRV) are different in migraine patients compared to healthy controls. MATERIAL AND METHODS: Sixteen female migraine patients without aura aged 18-30 years and 14 age-matched healthy female controls were included. Continuous finger blood pressure and ECG were measured supine during paced breathing in the laboratory. Continuous finger blood pressure was measured the following 24-h period. Spontaneous baroreflex sensitivity (time-domain cross correlation baroreflex sensitivity) as well as HRV parameters were calculated. RESULTS: Spontaneous baroreflex sensitivity measured in the 24-h period was increased in patients (20.6 ms/mmHg) compared to controls (15.7 ms/mmHg, P = 0.031). HRV parameters were increased during paced breathing in patients (P < 0.045). CONCLUSIONS: The results suggest that central hypersensitivity in migraine also includes cardiovascular reactivity and may be important for the understanding of the mechanisms for the effect of antihypertensive drugs for migraine prophylaxis.

Two novel SCN9A mutations causing insensitivity to pain.

The sensation of pain is important and there may be serious consequences if it is missing. Recently, the genetic basis for a channelopathy characterised by a congenital inability to experience pain has been described and channelopathy-associated insensitivity to pain has been proposed as a suitable name for this condition. Different mutations in the SCN9A gene causing loss of function of the voltage-gated sodium channel Nav1.7 have been reported in patients with this rare disease. Here we describe a woman with insensitivity to pain with two novel mutations in the SCN9A gene, coding for the Nav1.7 channel. We also discuss the finding of anosmia which apparently is a common feature in these patients.

Thermal pain thresholds are decreased in the migraine preattack phase.

BACKGROUND AND PURPOSE: Migraine patients may have cutaneous allodynia during attacks. In order to investigate if pain physiology changes in the preattack phase we estimated heat pain and cold pain detection threshold (HPT and CPT) on three different days in 41 migraine patients and 28 controls. METHODS: A thermode was applied at four sites bilaterally: forehead, face, neck, and hand. A subgroup of 11 migraine patients had been tested within 24 h before their next attack and in the interictal phase. RESULTS: In the preattack phase, HPT was lower compared with the paired interictal recording for the hand (44.8 degrees C vs. 45.9 degrees C, P = 0.009), neck (46.8 degrees C vs. 48.2 degrees C, P = 0.02), and forehead (45.1 degrees C vs. 46.3 degrees C, P = 0.02). Neck and hand CPT were higher in the preattack phase than interictally (10 degrees C vs. 7.3 degrees C, P = 0.01 and 11.6 degrees C vs. 9.4 degrees C, P = 0.06, respectively). Preattack forehead changes were most apparent on the headache side of the subsequent attack. DISCUSSION: Subclinical preattack thermal pain hypersensitivity seems to be a feature of the process that leads to a migraine attack.

A unilateral sympathetic blockade does not affect stress-related pain and muscle activity in patients with chronic musculoskeletal pain.

OBJECTIVE: Chronic musculoskeletal pain is often exacerbated by mental and social stress. The association between stress and musculoskeletal pain is potentially mediated by peripheral sympathetic nerves, either directly or indirectly through muscle activity. In the present study we wanted to determine whether sympathetic blockade could affect either the pain or the muscular activity experienced during mental stress in patients with chronic musculoskeletal pain. METHODS: We performed a unilateral anaesthetic blockade of the lower cervical sympathetic ganglion (ganglion stellatum) in 18 patients with chronic musculoskeletal pain (10 with fibromyalgia and eight with chronic shoulder/neck pain). After the blockade the patients performed a 60-minute stressful task with low-grade mental stress that has induced pain and muscle activity in earlier experiments. Surface electromyography (SEMG) of the forehead, temples, neck, and shoulders, and heart rate and blood pressure were recorded together with ratings of pain. RESULTS: We did not find any side or sidextime effect for pain or muscular activity in any of the four muscle groups (p>0.12). CONCLUSION: We investigated the potential involvement of peripheral sympathetic nerves in stress-related musculoskeletal pain. A peripheral sympathetic block did not affect pain and muscle responses to a stressful task. Other explanatory models should be implemented and tested experimentally to further investigate the clinical impression that mental stress exacerbates pain in patients with chronic musculoskeletal pain.

Stress-induced pain and muscle activity in patients with migraine and tension-type headache.

We recorded deep pain and surface electromyographic (EMG) responses to stress in 22 migraineurs during headache-free periods, 18 patients with tension-type headache (TTH), and 44 healthy controls. Sixty minutes of cognitive stress was followed by 30 min relaxation. EMG and pain (visual analogue scale) in the trapezius, neck (splenius), temporalis and frontalis areas were recorded. TTH patients had higher pain responses in temporalis and frontalis (with similar trends for trapezius and splenius) and more potentiation of pain during the test than controls. Migraine patients developed more pain in the splenius and temporalis than controls. Muscle pain responses were more regional (more pain in the neck and trapezius compared with the temporalis and frontalis) in migraine than in TTH patients. TTH patients had delayed pain recovery in all muscle regions compared with controls, while migraine patients had delayed pain recovery in a more restricted area (trapezius and temporalis). EMG responses were not different from controls in headache patients, and EMG responses did not correlate with pain responses. TTH patients had delayed EMG recovery in the trapezius compared with controls and migraine patients. These results support the concept that (probably central) sensitization of pain pathways and the motor system is important in TTH. Less pronounced and more regional (either peripheral or central) trigeminocervical sensitization seems to be important in migraine. Surface-detectable muscular activation does not seem to be causal for pain during cognitive stress either in migraine or in TTH.

Pain induced by low-grade stress in patients with fibromyalgia and chronic shoulder/neck pain, relation to surface electromyography.

The mechanisms of pain causation in fibromyalgia (FMS) and chronic shoulder/neck pain (SNP) are still debated. We wanted to compare muscle activity and pain development during and after low-grade mental stress in FMS and SNP patients. Twenty-three women with FMS, 29 women with chronic SNP and 35 healthy women performed a stressful task lasting 60 min followed by a 30 min recovery period. We recorded surface electromyography over the trapezius, neck, temporalis and frontalis muscles. Subjects reported their pain at the corresponding locations together with the development of fatigue and perceived tension. Significant differences between FMS and SNP groups were not observed either for muscular or subjective responses. SNP patients and controls responded with more pain in the trapezius and neck regions than in the forehead, in contrast to FMS patients who had a more generalized pain response. Development of pain, tension and fatigue was not related to muscle activity for any group. We conclude that FMS and SNP patients have similar pain and electromyographic responses. The results suggest that similar pathophysiological mechanisms are involved although the responses are more generalised in FMS than in SNP patients. Muscular activity did not explain the pain which developed during the stressful task for either group. Pain lasted longer during recovery in both FMS and SNP patients compared to healthy controls, possibly a result of disease-related sensitisation in pain pathways.

[Prescription of central nervous system stimulants]. / Forskrivning av sentralstimulerende medikamenter.

BACKGROUND: The Child and Adolescent Unit at Nordland Psychiatric Hospital has conducted a review of the prescription practice in its region with regard to central nervous system stimulants. MATERIAL AND METHODS: Data were collected from the region's pharmacies on the type of drug, the type of medical practitioners prescribing them, and patients's sex, age and community of residence. RESULTS: The total numbers of users of Ritalin/Dexamin (methylphenidate/dextroamphetamine) were 199 children (under 18) and 21 adults (above 18). The male/female ratio was 4:1, boys between 8 and 13 being the largest group. Users in the below-18 group constituted 0.35% of their age group in our region. Prescriptions to children were in 188 out of 199 cases written by child psychiatrists or paediatricians. Prescription patterns in the seven local hospital areas in the region were almost identical, with one area forming an exception. INTERPRETATION: This survey suggest that because of insufficient knowledge of the diagnostic criteria for attention deficit/hyperactivity disorders, many children with this type of problems do not get the treatment they may need. Adequate treatment based on competent diagnostic assessment is assumed to relieve distress and counteract the development of further problems. Similar surveys in other Norwegian regions would enable us to compare prescription practice nation-wide.