Elena K. Krumova

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes

&NA; Neuropathic pain is accompanied by both positive and negative sensory signs. To explore the spectrum of sensory abnormalities, 1236 patients with a clinical diagnosis of neuropathic pain were assessed by quantitative sensory testing (QST) following the protocol of DFNS (German Research Network on Neuropathic Pain), using both thermal and mechanical nociceptive as well as non‐nociceptive stimuli. Data distributions showed a systematic shift to hyperalgesia for nociceptive, and to hypoesthesia for non‐nociceptive parameters. Across all parameters, 92% of the patients presented at least one abnormality. Thermosensory or mechanical hypoesthesia (up to 41%) was more frequent than hypoalgesia (up to 18% for mechanical stimuli). Mechanical hyperalgesias occurred more often (blunt pressure: 36%, pinprick: 29%) than thermal hyperalgesias (cold: 19%, heat: 24%), dynamic mechanical allodynia (20%), paradoxical heat sensations (18%) or enhanced wind‐up (13%). Hyperesthesia was less than 5%. Every single sensory abnormality occurred in each neurological syndrome, but with different frequencies: thermal and mechanical hyperalgesias were most frequent in complex regional pain syndrome and peripheral nerve injury, allodynia in postherpetic neuralgia. In postherpetic neuralgia and in central pain, subgroups showed either mechanical hyperalgesia or mechanical hypoalgesia. The most frequent combinations of gain and loss were mixed thermal/mechanical loss without hyperalgesia (central pain and polyneuropathy), mixed loss with mechanical hyperalgesia in peripheral neuropathies, mechanical hyperalgesia without any loss in trigeminal neuralgia. Thus, somatosensory profiles with different combinations of loss and gain are shared across the major neuropathic pain syndromes. The characterization of underlying mechanisms will be needed to make a mechanism‐based classification feasible.

Reference data for quantitative sensory testing (QST): refined stratification for age and a novel method for statistical comparison of group data.

&NA; Clinical use of quantitative sensory testing (QST) requires standardization. The German research network on neuropathic pain (DFNS) solves this problem by defining reference data stratified for test site, gender and age for a standardized QST protocol. In this report we have targeted two further problems: how to adjust for age‐related sensory changes, and how to compare groups of patients with the reference database. We applied a moving average across ages to define reference values per decade. This analysis revealed that women were more sensitive to heat pain independent of age. In contrast, functions were converging at older age for blunt pressure pain, but diverging for punctate mechanical pain (pin prick). The probability that an individual patient dataset is within the range of normal variability is calculated by z‐transform using site‐, gender‐ and age‐specific reference data. To compare groups of patients with reference data, we evaluated two techniques: A: paired t‐test versus fixed mean; i.e. the reference mean value is considered as the known population mean, B: non‐paired t‐test versus the reference dataset and number of cases restrained to the same number of cases as the patient data set. Simulations for various sample sizes and variances showed that method B was more conservative than method A. We present a simple way of calculating method B for data that have been z‐normalized. This technique makes the DFNS reference data bank applicable for researchers beyond the DFNS community without a need for subsampling of subjects from the database.

Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus

Summary Standards for conducting quantitative sensory testing (QST), which is a psychophysical method used to quantify somatosensory function in response to controlled stimuli in healthy subjects and patients, is discussed, and recommendations on the basis of current status of QST are presented. ABSTRACT Quantitative sensory testing (QST) is a psychophysical method used to quantify somatosensory function in response to controlled stimuli in healthy subjects and patients. Although QST shares similarities with the quantitative assessment of hearing or vision, which is extensively used in clinical practice and research, it has not gained a large acceptance among clinicians for many reasons, and in significant part because of the lack of information about standards for performing QST, its potential utility, and interpretation of results. A consensus meeting was convened by the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain (NeuPSIG) to formulate recommendations for conducting QST in clinical practice and research. Research studies have confirmed the utility of QST for the assessment and monitoring of somatosensory deficits, particularly in diabetic and small fiber neuropathies; the assessment of evoked pains (mechanical and thermal allodynia or hyperalgesia); and the diagnosis of sensory neuropathies. Promising applications include the assessment of evoked pains in large‐scale clinical trials and the study of conditioned pain modulation. In clinical practice, we recommend the use QST for screening for small and large fiber neuropathies; monitoring of somatosensory deficits; and monitoring of evoked pains, allodynia, and hyperalgesia. QST is not recommended as a stand‐alone test for the diagnosis of neuropathic pain. For the conduct of QST in healthy subjects and in patients, we recommend use of predefined standardized stimuli and instructions, validated algorithms of testing, and reference values corrected for anatomical site, age, and gender. Interpretation of results should always take into account the clinical context, and patients with language and cognitive difficulties, anxiety, or litigation should not be considered eligible for QST. When appropriate standards, as discussed here, are applied, QST can provide important and unique information about the functional status of somatosensory system, which would be complementary to already existing clinical methods.

Depression and changed pain perception: hints for a central disinhibition mechanism.

Abstract Although patients with a depressive disorder report often of pain, their sensitivity to experimental pain is controversial, probably due to differences in sensory testing methods and to the lack of normal values. Therefore, we used a standardized and validated comprehensive sensory testing paradigm to assess the peripheral and central nervous system performance in depressive patients compared to healthy controls and chronic pain patients with fibromyalgia syndrome (FMS), in which depression is a common comorbidity. Twenty‐five depressive psychiatric inpatients (pain‐free: n = 20), 35 FMS outpatients and 25 healthy controls underwent quantitative sensory testing (QST), including thermal and mechanical detection and pain thresholds, pain sensitivity and responsiveness to repetitive noxious mechanical stimuli (wind‐up). In depressive disorder (to a lesser extent also in FMS), significantly decreased cold pain thresholds and an increased wind‐up were found, although the mechanical pain thresholds and pain sensitivity were comparable to those of the healthy controls. All the detection thresholds were within the normal range in all the groups. In depressive disorder, there were no significant side differences in the detection and pain thresholds. The results contradict the former assumption of a general insensitivity to experimental pain in depressive disorder. In the mostly pain‐free patients signs of an enhanced central hyperexcitability are even more pronounced than usually found in chronic pain patients (e.g. FMS), indicating common mechanisms in depressive disorder and chronic pain in accordance with the assumption of non‐pain associated mechanisms in depressive disorder for central hyperexcitability, e.g. by inhibited serotonergic function. Furthermore, this trial demonstrates the feasibility of QST in depressive patients.

Sensory signs in complex regional pain syndrome and peripheral nerve injury.

Summary QST revealed more similarities than differences between CRPS‐I, CRPS‐II, and PNI: sensory loss occurred in 63% of CRPS‐I and sensory gain in 81% of PNI patients. Abstract This study determined patterns of sensory signs in complex regional pain syndrome (CRPS) type I and II and peripheral nerve injury (PNI). Patients with upper‐limb CRPS‐I (n = 298), CRPS‐II (n = 46), and PNI (n = 72) were examined with quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain. The majority of patients (66%–69%) exhibited a combination of sensory loss and gain. Patients with CRPS‐I had more sensory gain (heat and pressure pain) and less sensory loss than patients with PNI (thermal and mechanical detection, hypoalgesia to heat or pinprick). CRPS‐II patients shared features of CRPS‐I and PNI. CRPS‐I and CRPS‐II had almost identical somatosensory profiles, with the exception of a stronger loss of mechanical detection in CRPS‐II. In CRPS‐I and ‐II, cold hyperalgesia/allodynia (28%–31%) and dynamic mechanical allodynia (24%–28%) were less frequent than heat or pressure hyperalgesia (36%–44%, 67%–73%), and mechanical hypoesthesia (31%–55%) was more frequent than thermal hypoesthesia (30%–44%). About 82% of PNI patients had at least one type of sensory gain. QST demonstrates more sensory loss in CRPS‐I than hitherto considered, suggesting either minimal nerve injury or central inhibition. Sensory profiles suggest that CRPS‐I and CRPS‐II may represent one disease continuum. However, in contrast to recent suggestions, small fiber deficits were less frequent than large fiber deficits. Sensory gain is highly prevalent in PNI, indicating a better similarity of animal models to human patients than previously thought. These sensory profiles should help prioritize approaches for translation between animal and human research.

Reference values for quantitative sensory testing in children and adolescents: developmental and gender differences of somatosensory perception.

&NA; The Quantitative Sensory Testing (QST) protocol of the German research network on neuropathic pain (DFNS) encompassing all somatosensory modalities assesses the functioning of different nerve fibers and of central pathways. The aim of our study was: (1) to explore, whether this QST protocol is feasible for children, (2) to detect distribution properties of QST data and the impact of body site, age and gender and (3) to establish reference values for QST in children and adolescents. The QST protocol of the DFNS with modification of instructions and pain rating was used in 176 children aged 6.12–16.12 years for six body sites. QST was feasible for children over 5 years of age. ANOVAs revealed developmental, gender and body site differences of somatosensory functions similar to adults. The face was more sensitive than the hand and/or foot. Younger children (6–8 years) were generally less sensitive to all thermal and mechanical detection stimuli but more sensitive to all pain stimuli than older (9–12 years) children, whereas there were little differences between older children and adolescents (13–17 years). Girls were more sensitive to thermal detection and pain stimuli, but not to mechanical detection and pain stimuli. Reference values differ from adults, but distribution properties (range, variance, and side differences) were similar and plausible for statistical factors. Our results demonstrate that the full QST protocol is feasible and valid for children over 5 years of age with their own reference values.

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Reference data for the trunk and application in patients with chronic postherpetic neuralgia

Summary A new set of reference data on the trunk for male and female healthy subjects is presented and applied to patients with postherpetic neuralgia. ABSTRACT Age‐ and gender‐matched reference values are essential for the clinical use of quantitative sensory testing (QST). To extend the standard test sites for QST—according to the German Research Network on Neuropathic Pain—to the trunk, we collected QST profiles on the back in 162 healthy subjects. Sensory profiles for standard test sites were within normal interlaboratory differences. QST revealed lower sensitivity on the upper back than the hand, and higher sensitivity on the lower back than the foot, but no systematic differences between these trunk sites. Age effects were significant for most parameters. Females exhibited lower pressure pain thresholds (PPT) than males, which was the only significant gender difference. Values outside the 95% confidence interval of healthy subjects (considered abnormal) required temperature changes of >3.3–8.2 °C for thermal detection. For cold pain thresholds, confidence intervals extended mostly beyond safety cutoffs, hence only relative reference data (left‐right differences, hand‐trunk differences) were sufficiently sensitive. For mechanical detection and pain thresholds, left‐right differences were 1.5–2.3 times more sensitive than absolute reference data. The most sensitive parameter was PPT, where already side‐to‐side differences >35% were abnormal. Compared to trunk reference data, patients with postherpetic neuralgia exhibited thermal and tactile deficits and dynamic mechanical allodynia, mostly without reduced mechanical pain thresholds. This pattern deviates from other types of neuropathic pain. QST reference data for the trunk will also be useful for patients with postthoracotomy pain or chronic back pain.

Lidocaine patch (5%) produces a selective, but incomplete block of Aδ and C fibers

Summary Topical lidocaine (5%) induced a selective, but only partial blockade of Ad‐ and C‐fibers of variable magnitude in healthy subjects, with significantly increased thermal detection and mechanical pain thresholds and decreased mechanical pain sensitivity. Abstract Topical lidocaine (5%) leads to sufficient pain relief in only 29%–80% of treated patients, presumably by small‐fiber block. The reasons for nonresponse are unclear; it may be due to different underlying pain mechanisms or partly insufficient anesthetic effect. Using quantitative sensory testing (QST) following the protocol of the DFNS (German Research Network on Neuropathic Pain), this study aims to assess the type and extent of somatosensory changes after lidocaine application in healthy volunteers. Twenty‐six healthy volunteers underwent QST on the volar forearm, including thermal and mechanical detection and pain thresholds, twice before (for baseline retest reliability) and once after 6‐hour simultaneous application with lidocaine patch 5% and contralateral placebo in a double‐blinded manner. Pre and post differences of QST parameters were analyzed by paired t‐test (Bonferroni‐corrected alpha 0.0023). QST profiles did not change between the 2 baseline measurements and after the placebo application. Lidocaine application led to a significant change of only the small‐fiber‐associated thresholds (increase of thermal detection and mechanical pain thresholds, decrease of mechanical pain sensitivity). Tactile detection thresholds representing Aβ function remained unchanged. Interindividually, the extent of the small‐fiber block varied widely (eg, thermal detection thresholds: in 54% of the subjects there were only minimal changes; in only 8% were there changes of >60% of the maximal achievable value). Topical lidocaine (5%) induces thermal hypoesthesia and pinprick hypoalgesia, suggesting an isolated but only partial block of Aδ and C fibers of unpredictable extent. Further studies must analyze the influencing factors and determine whether patients with poor analgesic effect, in particular, are those with insufficient small‐fiber block.

Impaired spatial body representation in complex regional pain syndrome type 1 (CRPS I).

Summary Supraspinal mechanisms involved in complex regional pain syndrome may contribute to an exacerbation of the “normal” leftward bias of visuospatial attention due to an impaired spatial body representation. ABSTRACT Recently, a shift of the visual subjective body midline (vSM), a correlate of the egocentric reference frame, towards the affected side was reported in patients with complex regional pain syndrome (CRPS). However, the specificity of this finding is as yet unclear. This study compares 24 CRPS patients to 21 patients with upper limb pain of other origin (pain control) and to 24 healthy subjects using a comprehensive test battery, including assessment of the vSM in light and dark, line bisection, hand laterality recognition, neglect‐like severity symptoms, and motor impairment (disability of the arm, shoulder, and hand). Statistics: 1‐way analysis of variance, t‐tests, significance level: 0.05. In the dark, CRPS patients displayed a significantly larger leftward spatial bias when estimating their vSM, compared to pain controls and healthy subjects, and also reported lower motor function than pain controls. For right‐affected CRPS patients only, the deviation of the vSM correlated significantly with the severity of distorted body perception. Results confirm previous findings of impaired visuospatial perception in CRPS patients, which might be the result of the involvement of supraspinal mechanisms in this pain syndrome. These mechanisms might accentuate the leftward bias that results from a right‐hemispheric dominance in visuospatial processing and is known as pseudoneglect. Pseudoneglect reveals itself in the tendency to perceive the midpoint of horizontal lines or the subjective body midline left of the centre. It was observable in all 3 groups, but most pronounced in CRPS patients, which might be due to the cortical reorganisation processes associated with this syndrome.

Left is where the L is right. Significantly delayed reaction time in limb laterality recognition in both CRPS and phantom limb pain patients.

The body schema is based on an intact cortical body representation. Its disruption is indicated by delayed reaction times (RT) and high error rates when deciding on the laterality of a pictured hand in a limb laterality recognition task. Similarities in both cortical reorganisation and disrupted body schema have been found in two different unilateral pain syndromes, one with deafferentation (phantom limb pain, PLP) and one with pain-induced dysfunction (complex regional pain syndrome, CRPS). This study aims to compare the extent of impaired laterality recognition in these two groups. Performance on a test battery for attentional performance (TAP 2.0) and on a limb laterality recognition task was evaluated in CRPS (n=12), PLP (n=12) and healthy subjects (n=38). Differences between recognising affected and unaffected hands were analysed. CRPS patients and healthy subjects additionally completed a four-day training of limb laterality recognition. Reaction time was significantly delayed in both CRPS (2278±735.7ms) and PLP (2301.3±809.3ms) compared to healthy subjects (1826.5±517.0ms), despite normal TAP values in all groups. There were no differences between recognition of affected and unaffected hands in both patient groups. Both healthy subjects and CRPS patients improved during training, but RTs of CRPS patients (1874.5±613.3ms) remain slower (p<0.01) than those of healthy subjects (1280.6±343.2ms) after four-day training. Despite different pathomechanisms, the body schema is equally disrupted in PLP and CRPS patients, uninfluenced by attention and pain and cannot be fully reversed by training alone. This suggests the involvement of complex central nervous system mechanisms in the disruption of the body schema.