Sensory Profiles in Patients with Low Back Pain with and Without Radiculopathy.

OBJECTIVE: During routine clinical evaluation, it can be challenging to differentiate between lumbar radiculopathy (RAD) and lower back pain with non-radicular somatic referred pain (SRP) or even axial non-radiating low back pain (LBP). The aim of this study was to characterize patients with RAD, axial LBP (aLBP), and SRP on the basis of somatosensory profiles. METHODS: Patients with LBP (n = 54) were assessed with quantitative sensory testing in the area of LBP and, in cases of RAD, additionally in the area of projecting pain. Questionnaires (PainDETECT®, EuroQol-5D, Medical Outcomes Study Sleep Scale, Hannover Functional Ability Questionnaire for Back Pain, Roland Morris Disability Questionnaire, Short Form-12 Health Survey, and Hospital Anxiety and Depression Scale) were answered by all patients. RESULTS: Patients with RAD (n = 12) had higher pain intensity scores (numeric rating scale: 5.7 ± 1.5 vs 4.1 ± 2.2; P < 0.05) and higher PainDETECT scores (14.6 ± 6.13 vs 9.7 ± 6.2; P < 0.05) than did patients with aLBP and SRP (n = 42). Patients with RAD had a more pronounced loss of small-fiber function, increased mechanical hyperalgesia, and a trend toward increased sensitivity to thermal pain in the area of LBP compared with patients with aLBP and SRP. Within patients with RAD, sensory profiles of the area of projecting pain and the area of LBP did not differ. Pressure pain hyperalgesia (measured by pressure pain threshold) and loss of mechanical detection (measured by mechanical detection threshold) in combination with the PainDETECT items numbness and prickling reached the best predictive value in detecting a radiculopathy. CONCLUSIONS: Patients with RAD demonstrated more somatosensory abnormalities than did patients with aLBP and SRP, including increased mechanical hyperalgesia and a loss of mechanical detection. The combination of pressure pain threshold, mechanical detection threshold, numbness, and prickling in the area of LBP can be a time-efficient tool to identify patients with RAD.

Motor, cognitive and mobility deficits in 1000 geriatric patients: protocol of a quantitative observational study before and after routine clinical geriatric treatment - the ComOn-study.

BACKGROUND: Motor and cognitive deficits and consequently mobility problems are common in geriatric patients. The currently available methods for diagnosis and for the evaluation of treatment in this vulnerable cohort are limited. The aims of the ComOn (COgnitive and Motor interactions in the Older populatioN) study are (i) to define quantitative markers with clinical relevance for motor and cognitive deficits, (ii) to investigate the interaction between both motor and cognitive deficits and (iii) to assess health status as well as treatment outcome of 1000 geriatric inpatients in hospitals of Kiel (Germany), Brescia (Italy), Porto (Portugal), Curitiba (Brazil) and Bochum (Germany). METHODS: This is a prospective, explorative observational multi-center study. In addition to the comprehensive geriatric assessment, quantitative measures of reduced mobility and motor and cognitive deficits are performed before and after a two week's inpatient stay. Components of the assessment are mobile technology-based assessments of gait, balance and transfer performance, neuropsychological tests, frailty, sarcopenia, autonomic dysfunction and sensation, and questionnaires to assess behavioral deficits, activities of daily living, quality of life, fear of falling and dysphagia. Structural MRI and an unsupervised 24/7 home assessment of mobility are performed in a subgroup of participants. The study will also investigate the minimal clinically relevant change of the investigated parameters. DISCUSSION: This study will help form a better understanding of symptoms and their complex interactions and treatment effects in a large geriatric cohort.

Clinical Manifestation of Acute, Subacute, and Chronic Low Back Pain in Different Age Groups: Low Back Pain in 35,446 Patients.

BACKGROUND: Low back pain (LBP) is a major healthcare problem causing tremendous economic costs. METHODS: Clinical manifestation of LBP was characterized in 35,446 patients. We focused on the comparison of the acute, subacute, and chronic LBP stage with regard to patients' ages, based on epidemiologic and clinical questionnaires (eg, painDETECT Questionnaire, Pain Disability Index), pain intensity, pain descriptors, and functional impairment. RESULTS: We found that neuropathic components were most frequent in chronic LBP patients at the ages of 51 to 60 years. Elderly LBP patients showed a decrease in neuropathic and an increase in nociceptive pain. The most frequently reported pain descriptors were "pressure pain" and "pain attacks" through all stages of LBP, whereas "burning" and "prickling" were most frequent in the chronic stage. Patients after back surgery presented neuropathic pain symptoms most frequently and had the highest amount of pain medication intake. CONCLUSIONS: Burning and prickling were revealed as possible indicators for LBP chronicity. Combined with pain attacks and pressure pain, these 4 pain descriptors might be a promising adjunct to pain intensity in terms of outcome parameters for future LBP studies. The decrease of neuropathic pain syndromes in the elderly might be explained by degenerative processes. The presented work provides important insights on LBP management in the acute, subacute, and chronic stages.

Pain Drawings Improve Subgrouping of Low Back Pain Patients.

BACKGROUND: Subgrouping of low back pain (LBP) patients may be improved when pain drawings are combined with the painDETECT (PD-Q) questionnaire. We hypothesized that (1) different LBP subgroups determined by their pain radiation show different clinical patterns and (2) the occurrence of neuropathic symptoms depends on pain radiation. METHODS: A total of 19,263 acute (< 6 weeks' duration), subacute (6 to 12 weeks), and chronic (> 3 months) LBP patients were allocated prospectively into 4 groups based on the location of pain drawings on a manikin and compared regarding neuropathic pain components, functionality, depression, pain intensity, and surgical interventions. All items were investigated at baseline and follow-up visits. Group I was composed of patients with axial LBP without radiating pain; group II, LBP with radiation into the thigh; group III, LBP with radiation into the shank; and group IV, LBP with radiation into the feet. Side-dependent pain radiation was assessed additionally. RESULTS: Depression, functionality, and pain intensity showed no clinically relevant differences, whereas PD-Q scores and the probability to rate positive for neuropathic pain increased with more distally radiating pain. Surgery and medication intake were most frequent in group IV. Follow-up analyses showed that only axial LBP became more neuropathic, whereas pain intensity decreased over time. CONCLUSIONS: Radicular patterns of pain drawings in LBP patients indicate severe pain conditions with the most neuropathic components, while axial LBP has the fewest. For the categorization of LBP, pain drawings help explain the underlying mechanism of pain, which might further improve mechanism-based treatment when used in clinical routines and research.

The role of cytokines and chemokines in the maintenance of chronic pain-a pilot study.

Introduction: The immune system is believed to be important in the initiation and maintenance of chronic pain. Objectives: The aim was to investigate whether patients with chronic painful polyneuropathy (PP) differ in cytokine profiles of serum and/or cerebrospinal fluid (CSF) compared with pain-free controls. Methods: Thirty-nine patients (16 women and 23 men, mean age, 69.2 ± 12.7 years, range 41-92 years) with PP (mean duration 43 ± 48.3 months) were phenotyped with quantitative sensory testing and electroneurography, and serum and CSF samples were analyzed by 40-multiplexed, bead-based cytokine immunoassays. Results were compared with 36 age- and gender-matched patients with normal pressure hydrocephalus and absence of abnormal CSF findings. Results: Compared with controls, patients with PP had lower concentrations of several proinflammatory and anti-inflammatory chemokines and cytokines in CSF, and others showed the same tendency, among these were tumor necrosis factor-α (14.1 ± 10.0 vs 23.9 ± 16.4 pg/mL, P < 0.005), interleukin (IL)-2 (0.6 ± 0.4 vs 1.2 ± 0.6 pg/mL, P < 0.0001), IL-6 (4.7 ± 6.8 vs 7.3 ± 9 pg/mL, P = 0.001), and IL-10 (7.5 ± 6.8 vs 16.8 ± 19.2 pg/mL, P < 0.01), whereas no differences were observed in serum. Conclusion: Results suggest that (1) inflammatory mediators play a minor role in the maintenance of chronic pain in contrast to initiation of acute pain, (2) chemokines/cytokines are downregulated in chronic pain, or (3) chemokines/cytokines have a protective role for nerve regeneration that is disturbed in patients with chronic pain.

Cold-evoked potentials in Fabry disease and polyneuropathy.

Background: Fabry disease (FD) causes cold-evoked pain and impaired cold perception through small fiber damage, which also occurs in polyneuropathies (PNP) of other origins. The integrity of thinly myelinated fibers and the spinothalamic tract is assessable by cold-evoked potentials (CEPs). In this study, we aimed to assess the clinical value of CEP by investigating its associations with pain, autonomic measures, sensory loss, and neuropathic signs. Methods: CEPs were examined at the hand and foot dorsum of patients with FD (n = 16) and PNP (n = 21) and healthy controls (n = 23). Sensory phenotyping was performed using quantitative sensory testing (QST). The painDETECT questionnaire (PDQ), FabryScan, and measures for the autonomic nervous system were applied. Group comparisons and correlation analyses were performed. Results: CEPs of 87.5% of the FD and 85.7% of the PNP patients were eligible for statistical analysis. In all patients combined, CEP data correlated significantly with cold detection loss, PDQ items, pain, and autonomic measures. Abnormal CEP latency in FD patients was associated with an abnormal heart frequency variability item (r = -0.684; adjusted p = 0.04). In PNP patients, CEP latency correlated significantly with PDQ items, and CEP amplitude correlated with autonomic measures (r = 0.688, adjusted p = 0.008; r = 0.619, adjusted p = 0.024). Furthermore, mechanical pain thresholds differed significantly between FD (gain range) and PNP patients (loss range) (p = 0.01). Conclusions: Abnormal CEPs were associated with current pain, neuropathic signs and symptoms, and an abnormal function of the autonomic nervous system. The latter has not been mirrored by QST parameters. Therefore, CEPs appear to deliver a wider spectrum of information on the sensory nervous system than QST alone.

Capsaicin treatment in neuropathic pain: axon reflex vasodilatation after 4 weeks correlates with pain reduction.

ABSTRACT: Capsaicin, an agonist at the transient receptor potential vanilloid 1, is used for the topical treatment of peripheral neuropathic pain. Reversible receptor defunctionalization and degeneration and subsequent regeneration of cutaneous nociceptors are discussed as its mechanism of action. Here, we hypothesize an accelerated functional recovery of a subclass of nociceptive afferents, the peptidergic vasoactive nociceptors, as the potential cause of capsaicin analgesia. In this noninterventional exploratory trial, 23 patients with peripheral neuropathic pain were treated with one topical high-concentration capsaicin application. Baseline pain ratings, comorbidities, and quality of life were assessed. Functional laser speckle contrast analysis (heat-evoked neurogenic vasodilatation to assess functional properties of peptidergic nociceptors) and quantitative sensory testing were performed in the affected skin. Four weeks after treatment, functional laser speckle contrast analysis and questionnaires were repeated. Telephone interviews were conducted at weeks 2, 10, and 12. Topical capsaicin treatment induced a significant reduction in pain intensity with a maximum at 4 weeks. At the same time, heat-evoked neurogenic vasodilatation was on average similar to pretreatment values. Half of the patients not only showed a functional recovery but also an improvement in vasodilatation, indicating regeneration of nerve fibers. Patients with improved heat-evoked neurogenic vasodilatation at week 4 showed a greater pain reduction than those with deterioration. The degree of vasodilatation significantly correlated with pain reduction. These findings suggest that (1) regeneration of peptidergic nociceptors may be the mechanism behind capsaicin-induced analgesia and (2) that a disease-modifying effect of capsaicin on these fibers already occurs 4 weeks after application.

Test-retest reliability of a simple bedside-quantitative sensory testing battery for chronic neuropathic pain.

Introduction: The sensory phenotype is believed to provide information about the underlying pathophysiological mechanisms and to be used in the diagnosis and treatment of chronic neuropathic pain. However, the use of standardized quantitative sensory testing (QST) protocols is limited due to high expenditures of time and costs. Thus, a simple bedside-QST battery was recently developed showing good agreement when compared with laboratory QST. The aim of this study was to preliminary validate this bedside-QST protocol. Methods: Patients experiencing chronic pain with neuropathic features (n = 60) attended 3 visits. During the first visit, laboratory QST and bedside-QST were performed by the same trained investigator. Three hours and 3 weeks later, bedside-QST was repeated. Patients completed questionnaires regarding their pain (intensity, quality), depression/anxiety, and quality of life. Test-retest reliability and convergent/divergent validity were investigated. Results: Most of the bedside-QST parameters, including also those recommended in our first study as being indicative for sensory phenotypes, revealed a moderate to excellent test-retest reliability. Overall, results for short-term reliability and interval-scaled parameters were slightly better. Most of the bedside-QST parameters did not correlate with the depression and anxiety score, suggesting a good divergent validity. Conclusions: Bedside-QST has good criterion and divergent validity as well as reliability. This battery consists of 5 low-cost devices that can be quickly and easily used to characterize the sensory phenotype of patients with neuropathic pain. A combination of bedside-QST parameters can be used to investigate patients' subgroups with specific pathophysiological mechanisms and to identify treatment responders.

Differential Expression of microRNAs in Serum of Patients with Chronic Painful Polyneuropathy and Healthy Age-Matched Controls.

Polyneuropathies (PNP) are the most common type of disorder of the peripheral nervous system in adults. However, information on microRNA expression in PNP is lacking. Following microRNA sequencing, we compared the expression of microRNAs in the serum of patients experiencing chronic painful PNP with healthy age-matched controls. We have been able to identify four microRNAs (hsa-miR-3135b, hsa-miR-584-5p, hsa-miR-12136, and hsa-miR-550a-3p) that provide possible molecular links between degenerative processes, blood flow regulation, and signal transduction, that eventually lead to PNP. In addition, these microRNAs are discussed regarding the targeting of proteins that are involved in high blood flow/pressure and neural activity dysregulations/disbalances, presumably resulting in PNP-typical symptoms such as chronical numbness/pain. Within our study, we have identified four microRNAs that may serve as potential novel biomarkers of chronic painful PNP, and that may potentially bear therapeutic implications.

The association of self-reported symptoms of central sensitization and sleep disturbances in neuropathic pain.

Introduction: Patients with neuropathic pain (NP) report a higher impairment of quality of life and sleep than patients with chronic pain without neuropathic characteristics. These include somatosensory peculiarities like allodynia, a surrogate marker for central sensitization. Objectives: This study aimed to investigate the relation between symptoms of central sensitization and sleep disturbances in patients with NP. Methods: Within this cross-sectional study, data sets of 3339 patients with chronic NP syndromes (painful diabetic polyneuropathy, n = 543; postherpetic neuralgia, n = 1480) or complex regional pain syndromes (CRPS, n = 1316) were analyzed. Neuropathic pain symptoms were assessed with the painDETECT questionnaire (PD-Q), depression with the Patient Health Questionnaire-9, and sleep impairment with items of the Medical Outcomes Study Sleep Scale in 4 subscales. The association of demographic/clinical data, somatosensory phenotype, depression, and pain intensity with sleep impairment was assessed by unadjusted Spearman correlation analyses and multivariable regression analyses. Results: Sleep impairment was observed in all pain aetiologies although with some significant differences in the single sleep items. The intensity of the individual PD-Q items differed to some extent between the 3 pain entities, whereas the PD-Q sum score was similar. Thermal hyperalgesia and burning assessed by the PD-Q were significantly associated with sleep disturbance, adequacy, and quantity but not with sleep somnolence. Only depression and self-reported allodynia had a significant relation to all 4 sleep elements. Conclusion: Beside depression, allodynia as a surrogate marker hints to a possible impact of central sensitization on the sleep disruption of patients with NP.

Development of a bedside tool-kit for assessing sensitization in patients with chronic osteoarthritis knee pain or chronic knee pain after total knee replacement.

ABSTRACT: Different pathophysiological mechanisms contribute to the pain development in osteoarthritis (OA). Sensitization mechanisms play an important role in the amplification and chronification of pain and may predict the therapeutic outcome. Stratification of patients according to their pain mechanisms could help to target pain therapy. This study aimed at developing an easy-to-use, bedside tool-kit to assess sensitization in patients with chronic painful knee OA or chronic pain after total knee replacement (TKR). In total, 100 patients were examined at the most affected knee and extrasegmentally by the use of 4 standardized quantitative sensory testing parameters reflecting sensitization (mechanical pain threshold, mechanical pain sensitivity, dynamic mechanical allodynia, and pressure pain threshold), a bedside testing battery of equivalent parameters including also temporal summation and conditioned pain modulation, and pain questionnaires. Machine learning techniques were applied to identify an appropriate set of bedside screening tools. Approximately half of the patients showed signs of sensitization (46%). Based on machine learning techniques, a composition of tests consisting of 3 modalities was developed. The most adequate bedside tools to detect sensitization were pressure pain sensitivity (pain intensity at 4 mL pressure using a 10-mL blunted syringe), mechanical pinprick pain sensitivity (pain intensity of a 0.7 mm nylon filament) over the most affected knee, and extrasegmental pressure pain sensitivity (pain threshold). This pilot study presents a first attempt to develop an easy-to-use bedside test to probe sensitization in patients with chronic OA knee pain or chronic pain after TKR. This tool may be used to optimize individualized, mechanism-based pain therapy.

The pandemic's effect on a patient cohort with painful polyneuropathy in 2020: A longitudinal study on pain, mood, and everyday life.

In the early phase of the COVID pandemic 2020, we demonstrated how patients with painful polyneuropathy, against our expectations, did not experience a deterioration of their neuropathic pain. We hypothesized that our assessed measures, that is, pain intensity and characteristics, emotional wellbeing, and everyday life, would deteriorate in the further course of the pandemic according to the phases of disaster management. Thus, the aim of our study was to investigate patients repeatedly under varying pandemic conditions from March until December 2020. Sixty-three patients were investigated with validated questionnaires (brief pain inventory [BPI], neuropathic pain symptom inventory [NPSI], pain catastrophizing scale [PCS], patient-reported outcomes measurement information system [PROMIS] pain interference/sleep disturbance/fatigue/ depression/anxiety, EuroQol 5 dimensions 5 level version [EQ-5D-5L]) and a pandemic-specific, self-designed questionnaire. The data from the beginning of the pandemic with severe restrictions, during summer with loosened regulations and from December 2020 with reinstalled, severe restrictions were compared with an observational design. Patients reported higher pain severity when restrictions were lower. Sleep, mood, and quality of life did not change in the course of the pandemic in the validated measures. Pain interference significantly decreased during the study independent from restrictions. Patients who reported medical disadvantages had a lower quality of life upon EuroQol 5 dimension (EQ-5D) and were significantly more worried about their health. The perception of pain intensity was dependent on pandemic severity. Sleep, mood, and quality of life did not change significantly in validated measures. Continued medical care seems decisive to prevent worsening of pain and quality of life.

Revealing the time course of laser-evoked potential habituation by high temporal resolution analysis.

BACKGROUND AND OBJECTIVES: Reduced laser-evoked potential (LEP) habituation indicates abnormal central pain processing. But the paradigm (four stimulation blocks a 25 stimuli) is time consuming and potentially omits important information on the exact habituation time course. This study examined whether a high temporal resolution (HTR) analysis (dividing the four stimulation blocks into 12 analysis blocks) can answer the following questions: (a) After how many stimuli does LEP habituation occur? (b) Is there a difference in LEP habituation in younger versus older subjects? (c) Is HTR applicable on radiculopathy patients? METHODS: EEG data of 129 subjects were included. Thirty-four young healthy and 28 advanced-aged healthy subjects were tested with LEPs on the hand dorsum. Thirty-seven radiculopathy patients and 30 controls were tested with LEPs on the L3 dermatome. The EEG data of the hand dorsa have been analysed conventionally and with HTR analysis. The applicability of HTR has been tested on radiculopathy patients and respective controls. RESULTS: HTR was well feasible in young healthy subjects and revealed a strong habituation effect during the first 25 stimuli (i.e. within the first 5 min). After approximately 48 stimuli, no further significant habituation was detectable. LEP amplitudes were higher in young subjects. HTR was unsuitable for elderly subjects and middle-aged radiculopathy patients. CONCLUSIONS: In young healthy subjects, HTR allows a shortening of the test protocol while providing a detailed information on the time course of LEP habituation. A shorter protocol might be useful for the applicability of the LEP paradigm for clinical and experimental settings as well as pharmacological studies. SIGNIFICANCE: The usage of high temporal resolution (HTR) analysis in young healthy subjects enables a short test protocol and provides the exact time course of laser-evoked potential habituation. This can be useful for the examination of neurological conditions affecting younger patients and for pharmacological studies. HTR was inapplicable in advanced-aged subjects and patients with radiculopathy.

A modality-specific somatosensory evoked potential test protocol for clinical evaluation: A feasibility study.

OBJECTIVE: We aimed to establish an objective neurophysiological test protocol that can be used to assess the somatosensory nervous system. METHODS: In order to assess most fiber subtypes of the somatosensory nervous system, repetitive stimuli of seven different modalities (touch, vibration, pinprick, cold, contact heat, laser, and warmth) were synchronized with the electroencephalogram (EEG) and applied on the cheek and dorsum of the hand and dorsum of the foot in 21 healthy subjects and three polyneuropathy (PNP) patients. Latencies and amplitudes of the modalities were assessed and compared. Patients received quantitative sensory testing (QST) as reference. RESULTS: We found reproducible evoked potentials recordings for touch, vibration, pinprick, contact-heat, and laser stimuli. The recording of warm-evoked potentials was challenging in young healthy subjects and not applicable in patients. Latencies were shortest within Aß-fiber-mediated signals and longest within C-fibers. The test protocol detected function loss within the Aß-fiber and Aδ-fiber-range in PNP patients. This function loss corresponded with QST findings. CONCLUSION: In this pilot study, we developed a neurophysiological test protocol that can specifically assess most of the somatosensory modalities. Despite technical challenges, initial patient data appear promising regarding a possible future clinical application. SIGNIFICANCE: Established and custom-made stimulators were combined to assess different fiber subtypes of the somatosensory nervous system using modality-specific evoked potentials.

Protective role of natural killer cells in neuropathic pain conditions.

ABSTRACT: During the past few years, the research of chronic neuropathic pain has focused on neuroinflammation within the central nervous system and its impact on pain chronicity. As part of the ERA-Net NEURON consortium, we aimed to identify immune cell patterns in the cerebrospinal fluid (CSF) of patients with herpes zoster neuralgia and patients with polyneuropathy (PNP), which may contribute to pain chronicity in these neuropathic pain conditions. Cerebrospinal fluid of 41 patients (10 herpes zoster and 31 PNP) was analyzed by flow cytometry identifying lymphocyte subsets: CD4+ (T-helper cells), CD8+ (cytotoxic T cells), CD19+ (B cells), and CD56+ (natural killer [NK]) cells. At baseline and at follow-up, the somatosensory phenotype was assessed with quantitative sensory testing. In addition, the patients answered epidemiological questionnaires and the PainDETECT questionnaire. Immune cell profiles and somatosensory profiles, as well as painDETECT questionnaire scores, were analyzed and correlated to determine specific immune cell patterns, which contribute to chronic pain. We found a negative correlation (P = 0.004, r = -0.596) between the frequency of NK cells and mechanical pain sensitivity (MPS), one of the most relevant quantitative sensory testing markers for central sensitization; a high frequency of NK cells correlated with low MPS. The analysis of the individual follow-up showed a worsening of the pain condition if NK-cell frequency was low. Low NK-cell frequency is associated with signs of central sensitization (MPS), whereas high NK-cell frequency might prevent central sensitization. Therefore, NK cells seem to play a protective role within the neuroinflammatory cascade and may be used as a marker for pain chronicity.

Sensory bedside testing: a simple stratification approach for sensory phenotyping.

INTRODUCTION: Stratification of patients according to the individual sensory phenotype has been suggested a promising method to identify responders for pain treatment. However, many state-of-the-art sensory testing procedures are expensive or time-consuming. OBJECTIVES: Therefore, this study aimed to present a selection of easy-to-use bedside devices. METHODS: In total, 73 patients (39 m/34 f) and 20 controls (11 m/9 f) received a standardized laboratory quantitative sensory testing (QST) and a bedside-QST. In addition, 50 patients were tested by a group of nonexperienced investigators to address the impact of training. The sensitivity, specificity, and receiver-operating characteristics were analyzed for each bedside-QST parameter as compared to laboratory QST. Furthermore, the patients' individual sensory phenotype (ie, cluster) was determined using laboratory QST, to select bedside-QST parameters most indicative for a correct cluster allocation. RESULTS: The bedside-QST parameters "loss of cold perception to 22°C metal," "hypersensitivity towards 45°C metal," "loss of tactile perception to Q-tip and 0.7 mm CMS hair," as well as "the allodynia sum score" indicated good sensitivity and specificity (ie, ≳70%). Results of interrater variability indicated that training is necessary for individual parameters (ie, CMS 0.7). For the cluster assessment, the respective bedside quantitative sensory testing (QST) parameter combination indicated the following agreements as compared to laboratory QST stratification: excellent for "sensory loss" (area under the curve [AUC] = 0.91), good for "thermal hyperalgesia" (AUC = 0.83), and fair for "mechanical hyperalgesia" (AUC = 0.75). CONCLUSION: This study presents a selection of bedside parameters to identify the individual sensory phenotype as cost and time efficient as possible.

The early influence of COVID-19 pandemic-associated restrictions on pain, mood, and everyday life of patients with painful polyneuropathy.

INTRODUCTION: The SARS-Cov-2 pandemic requires special attention on its psychological effects and the impact on patients with chronic pain. OBJECTIVES: This study aimed at examining the influence of the COVID-19 pandemic-associated regulations initiated by the German government on pain intensity and characteristics, emotional well-being, and everyday life of patients with painful polyneuropathy. METHODS: Forty-three patients (well assessed with questionnaires before the pandemic and without change of their health status between baseline and current assessment) were investigated with validated, self-reported questionnaires and COVID-19-specific items 2 weeks after the regulations came into effect. RESULTS: Pain intensity remained stable or even improved like the neuropathic pain symptom inventory total score (t0: 33.54 ± 20.48 vs t1: 27.38 ± 16.16, P = 0.008). Only 11.6% reported a pandemic-associated pain worsening. Rumination scores of the Pain Catastrophizing Scale were lower during t1 compared to before the pandemic regulations (t0: 7.81 ± 4.70, t1: 6.49 ± 4.39; P = 0.030). Interestingly, pain ratings for the last 7 days were higher in patients with a changed social life compared to those without (-1.63 ± 1.60 vs 0.31 ± 1.83; P = 0.01). Quality of life was decreased and helplessness increased in those with higher pain ratings. CONCLUSION: Results suggest a shift of attention from the chronic pain condition towards the imminent threat of a global pandemic. As the impacts of the pandemic are persistent and evolving, the development of the measured parameters in the forthcoming weeks will be of great interest.

Bridging the Gap Between Vessels and Nerves in Fabry Disease.

PURPOSE: Fabry disease frequently includes pain as an early disease feature, which was characterized as a dysfunctional processing of somatosensory information in various studies. The pathomechanism involves the mutation in the x-chromosomal GLA-gene and a consequent reduction of the α-galactosidase. This results in an insufficient reduction of globotriaosylceramide (GL3). Interestingly, an accumulation of GL3 was shown in both vascular endothelial cells and nerve tissue. This implicates that both an endothelial and nerve-dependent dysfunction may be considered as prominent mechanisms in pain pathogeneses. PATIENTS AND METHODS: The exploration of endothelial and C-fiber-dependent microcirculatory changes was conducted in a healthy cohort (n = 22) and in patients with polyneuropathy (n = 21) and Fabry disease (n = 15). Microcirculatory measurements were conducted using a laser speckle contrast analysis (LASCA) in combination with a thermoprobe controlling system, which applied a constant heat stimulus (42°C). Additionally, nerve fiber function was assessed via Quantitative Sensory Testing and heart rate variability (HRV). RESULTS: The results indicated a characteristic perfusion profile in the control group as well as both patient groups. Fabry patients had the smallest increase of endothelial-dependent perfusion as compared to the others [% increase as compared to Fabry: control + 129% (p = 0.002), PNP + 126% (p = 0.019)]. The sensory testing indicated a dysfunctional processing of A-delta fibers in Fabry disease as compared to healthy controls [cold detection threshold (CDT): p = 0.004, mechanical pain threshold (MPT): p = 0.007] and PNP patients (MPT: p = 0.001). CONCLUSION: Our results point to both an endothelial and a nerve-dependent dysfunction in Fabry disease. Therefore, not only direct changes in nerve fiber tissue may contribute to an altered sensory processing. Indeed, evidence of a perfusion change in vasa nervorum could also contribute to the dysfunctional processing of sensory information, which likely occurs under physical stress.

Stratification of patients with unclassified pain in the FabryScan database.

PURPOSE: Fabry disease belongs to lysosomal storage disorders and can be successfully treated today. On the contrary, the correct diagnostic classification of its symptoms can be challenging and most patients suffer from pain for years, until they are diagnosed correctly. The aim of this project was to characterize patients with unclassified extremity pain and to present a simple algorithm for a retrospective stratification approach. PATIENTS AND METHODS: The FabryScan includes a bedside-test and a questionnaire, consisting of 10 symptom-orientated and anamnestic questions. For the stratification of patients according to the likelihood for Fabry disease two different approaches were conducted. First, a prospective subgrouping based on the previously invented FabryScan evaluation system was conducted. The second retrospective approach consisted of a factor analysis and a subsequent two-way cluster analysis. Further on, 4 patients diagnosed with Fabry disease were stratified according to both approaches. RESULTS: In total, 183 completed datasets were included in the statistical analysis. The first approach prospectively classified patients into 3 subgroups (n=40 [likely], n=96 [possible], n=47 [unlikely]) according to the FabryScan evaluation system. The second approach retrospectively stratified patients into 3 subgroups (n=47 [cluster 1], n=95 [cluster 2], n=41 [cluster 3]). Finally, the Fabry patients were sorted to the subgroups, indicative for the highest possibility of Fabry disease in both stratification approaches A and B. CONCLUSION: Both stratification approaches sorted patients with confirmed Fabry disease to the subgroups, indicative for the highest likelihood for Fabry. These results indicate validity of the initially selected FabryScan outcome parameters.

Cold-evoked potentials versus contact heat-evoked potentials-Methodological considerations and clinical application.

BACKGROUND: Previous studies investigated cold-evoked potentials (CEPs) for the assessment of the integrity of cold-mediating A-delta fibres and the spinothalamic tract. Nevertheless, several methodological questions remained unanswered to proceed to clinical application. How do latencies and amplitudes vary between CEPs and contact heat-evoked potentials (CHEPs)? Are there differences between variable and fixed thermode positions or between glabrous and hairy skin? Are CEPs recordable in patients with abnormal cold processing? METHODS: A total of 16 healthy subjects were tested with CEPs and CHEPs at the face, hand and foot. Variable and fixed thermode positions, hairy and glabrous skin were compared. Three patients with abnormal cold processing were tested with CEPs and quantitative sensory testing. RESULTS: Compared to CEPs, CHEPs latencies were significantly longer at all locations, amplitudes were significantly larger at the face and the hand whilst comparable at the foot. CEPs and CHEPs did not differ significantly between variable and fixed thermode positions using inter stimulus intervals of 8-12 s. CEP latencies were increased by around 20% at the glabrous skin. Patients with known abnormal cold processing (central pain, polyneuropathy, Fabry's disease) showed increased N2 latencies as compared to normal controls. CONCLUSIONS: Inter stimulus intervals of 8-12 s allow the use of a fixed thermode position for reliable CEPs/CHEPs recording. Hairy skin stimulation results in faster latencies as compared to glabrous skin, without influencing EP amplitudes. In patients with abnormal cold processing, CEPs are recordable and increased latencies may be expected as compared to healthy controls and the healthy contralateral side. SIGNIFICANCE: Cold-evoked potentials are an innovative, non-invasive technique to assess cold detection and processing objectively. This study shows that CEP can be recorded from the hairy and glabrous skin, regardless of using fixed or variable thermode positions. Loss of A-delta fibre function leads to an increased CEP latency, consistent with loss of cold detection in the QST.