No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Laser heat stimulation of tiny skin areas adds valuable information to quantitative sensory testing in postherpetic neuralgia
Abstract
Patients suffering from postherpetic neuralgia often complain about hypo- or hypersensation in the affected dermatome. The loss of thermal sensitivity has been demonstrated by quantitative sensory testing as being associated with small-fiber (Aδ- and C-fiber) deafferentation. We aimed to compare laser stimulation (radiant heat) to thermode stimulation (contact heat) with regard to their sensitivity and specificity to detect thermal sensory deficits related to small-fiber dysfunction in postherpetic neuralgia. We contrasted detection rate of laser stimuli with 5 thermal parameters (thresholds of cold/warm detection, cold/heat pain, and sensory limen) of quantitative sensory testing. Sixteen patients diagnosed with unilateral postherpetic neuralgia and 16 age- and gender-matched healthy control subjects were tested. Quantitative sensory testing and laser stimulation of tiny skin areas were performed in the neuralgia-affected skin and in the contralateral homologue of the neuralgia-free body side. Across the 5 thermal parameters of thermode stimulation, only one parameter (warm detection threshold) revealed sensory abnormalities (thermal hypoesthesia to warm stimuli) in the neuralgia-affected skin area of patients but not in the contralateral area, as compared to the control group. In contrast, patients perceived significantly less laser stimuli both in the affected skin and in the contralateral skin compared to controls. Overall, laser stimulation proved more sensitive and specific in detecting thermal sensory abnormalities in the neuralgia-affected skin, as well as in the control skin, than any single thermal parameter of thermode stimulation. Thus, laser stimulation of tiny skin areas might be a useful diagnostic tool for small-fiber dysfunction.
... The second important group of currently used equipment includes radiant heat or laser stimulators (Franz et al., 2012;Svensson, Bjerring, Arendt-Nielsen, & Kaaber, 1992). Light energy is absorbed by the tissue surface, causing a rise in temperature. ...
... This technique has the major advantage that no tactile afferent fibres are activated. The disadvantages are that the generated skin temperature is not monitored, only heat tests can be performed (not cold), there is a risk of tissue damage, and the system is expensive and requires technical maintenance (Franz et al., 2012). Most lasers (including argon, CO 2 , Nd-YAG and thulium-YAG lasers) can be used intraorally, but sometimes they can only be applied in the anterior region because the rays have to pass through articulating arms. ...
Background and objective: Orofacial quantitative sensory testing (QST) is an increasingly valuable psychophysical tool for evaluating neurosensory disorders of the orofacial region. Here, we aimed to evaluate the current evidence regarding this testing method and to discuss its future clinical potential. Data treatment: We conducted a literature search in Medline, Embase and Scopus for English-language articles published between 1990 and 2019. The utilized search terms included QST, quantitative, sensory testing and neurosensory, which were combined using the AND operator with the terms facial, orofacial, trigeminal, intraoral and oral. Results: Our findings highlighted many methods for conducting QST—including method of levels, method of limits and mapping. Potential stimuli also vary, and can include mechanical or thermal stimulation, vibration or pinprick stimuli. Orofacial QST may be helpful in revealing disease pathways and can be used for patient stratification to validate the use of neurosensory profile-specific treatment options. QST is reportedly reliable in longitudinal studies and is thus a candidate for measuring changes over time. One disadvantage of QST is the substantial time required; however, further methodological refinements and the combination of partial aspects of the full QST battery with other tests and imaging methods should result in improvement.
Conclusions: Overall, orofacial QST is a reliable testing method for diagnosing pathological neurosensory conditions and assessing normal neurosensory function. Despite the remaining challenges that hinder the use of QST for everyday clinical decisions and clinical trials, we expect that future improvements will allow its implementation in routine practice.
... Todos os estudos analisados encontraram eficácia das irradiações com LBI no tratamento da NPH, chegando à conclusão de que essa terapia pode ser utilizada como terapia complementar. Apenas um estudo randomizado [15] mencionou pouca redução da neuralgia, e nenhum dos artigos, incluindo os ensaios clínicos, relatou efeitos colaterais indesejáveis. Tendo em vista que em muitos casos a terapêutica convencional com medicação é falha e não oferece qualidade de vida ao paciente, e podendo a neuralgia durar de meses a anos, a terapia a LBI mostra-se relevante. ...
... A terapia com LBI pode promover uma resposta anti-inflamatória por meio de um mecanismo que envolve a inibição de ácido araquidônico, reduzindo assim a expressão da cicloxigenase-2 (COX-2) e diminuindo a produção de prostaglandina E2, além de fatores de modulação ligados ao ácido ribonucleico de citocinas proinflamatórias. Por isso, a terapia com LBI pode melhorar o processo inflamatório provocado pelo HZ [10,14,15]. O comprimento de onda comumente utilizado varia de 600 a 900 nm. ...
Aims: To perform a literature review on the treatment of postherpetic neuralgia with low-intensity laser irradiation.
Methods: The review was conducted in November and December 2015 by searching the terms "herpes zoster", "neuralgia", "low-level laser therapy", and "low-intensity laser therapy" in the LILACS, SciELO, and Medline databases. Full articles published in Portuguese, English, German, or Spanish between 2008 and 2015 were included. Incomplete articles, those that did not directly address the topic of interest, and those appearing in the same or in different databases were excluded. In the latter case, only one article was included.
Results: Thirty-two studies were selected using the search terms. After the application of the eligibility criteria, 15 studies were read; two of them were excluded for being available in more than one database and one was eliminated for not adding relevant information. Therefore, 11 studies were included in the review: five of them conducted in the United States, two in Brazil, two in Germany, and two in Italy. There were four clinical trials, two systematic reviews and five case reports. The 11 studies found positive results after laser application, especially reduction of pain, with only one article mentioning little reduction of neuralgia. In the three studies that reported the irradiation parameters, these have not been uniform, with a medium wavelength of 740.6 nm, a medium power of 28 mW and a medium time of irradiation per point of 53.4 seconds. There was great variation in the number of sessions, with an average of about 12 sessions on alternate days.
Conclusions: The low-intensity laser therapy provided positive results to patients with postherpetic neuralgia, however there is no consensus about the parameters to be used. In view of the different protocols, it is important to perform new studies in order to standardize the low-intensity laser therapy parameters applied to postherpetic neuralgia.
... Over the last two decades, QST protocols have been developed to complement and extend the bedside neurological examination [5][6][7][8][9]. QST collectively refers to a group of procedures that assess the bs_bs_banner Pain Medicine 2014; 15: [61][62][63][64][65][66][67][68][69][70][71][72]Inc. perceptual responses to systematically applied and quantifiable sensory stimuli for the purpose of characterizing somatosensory function or dysfunction. ...
... Similarly, fibromyalgia patients require less frequent stimulation for temporal summation than healthy controls [36,70]. More recently, QST measures showed high predictive value in separating individuals with and without post-herpetic neuralgia [71]. Similarly, pressure pain sensitivity demonstrated good ability to differentiate between people with OA and healthy controls. ...
This review summarizes the scientific literature relating to the use of quantitative sensory testing (QST) for mechanism-based pain management.
A literature search was undertaken using PubMed and search terms including quantitative sensory testing, pain, chronic pain, response to treatment, outcome measure.
Studies including QST in healthy individuals and those with painful disorders were reviewed.
Publications reported on QST methodological issues including associations among measures and reliability. We also included publications on the use of QST measures in case-control studies, their associations with biopsychosocial mechanisms, QST measures predicting clinical pain, as well as predicting and reflecting treatment responses.
Although evidence suggests that QST may be useful in a mechanism-based classification of pain, there are gaps in our current understanding that need to be addressed including making QST more applicable in clinical settings. There is a need for developing shorter QST protocols that are clinically predictive of various pain subtypes and treatment responses without requiring expensive equipment. Future studies are needed, examining the clinical predictive value of QST including sensitivity and specificity for pain classification or outcome prediction. These findings could enable third-party payers' reimbursement, which would facilitate clinical implementation of QST.
With some developments, QST could become a cost-effective and clinically useful component of pain assessment and diagnosis, which can further our progress toward the goal of mechanism-based personalized pain management.
... Vogel et al. [14] used these techniques to investigate the role of hypersensitivity in NeP development after SCI. Ultra-late LEPs are technically more difficult to record than late LEPs, only a few studies assessed their usefulness in patients with postherpetic neuralgia and depression [15,16] but none in central NeP after SCI. ...
Abstract Study design An experimental study. Objectives To investigate the changes in somatosensory functions using the combined application of quantitative sensory testing (QST), contact heat-evoked potentials (CHEPs) and laser-evoked potentials (LEPs) studies in individuals with spinal cord injury (SCI) in relation to neuropathic pain (NeP). Setting Centre for Pain Medicine, Swiss Paraplegic Centre, Nottwil, Switzerland. Methods Individuals with SCI were compared: 12 with NeP (SCI NeP) and 12 without NeP (SCI no NeP). Tools used were QST, CHEPs, LEPs and self-reported questionnaires. Tests were applied to the control (hand) and test (dermatome of altered sensation) sites, and compared to the able-bodied group. Results QST, LEPs and CHEPs assessments showed abnormalities both on the test and control sites, which did not differ between the groups with SCI. QST showed higher prevalence of allodynia in SCI NeP. CHEPs and LEPs demonstrated diminished amplitudes in both groups with SCI in comparison to able-bodied individuals. Only reaction time (RT) analysis revealed the difference of SCI NeP from the other two groups, expressed in partially preserved responses to the laser C-fibre stimulations. Conclusions Combination of assessments in our study allowed to examine spinothalamic and dorsal column functions in individuals with SCI. Changes in QST, CHEPs and LEPs were detected below the level of injury independent of NeP and at the control site indicating modifications in sensory processing rostral to the spinal lesion. Analysis of RT during laser stimulation could be an essential component when evaluating the somatosensory functions related to NeP in persons with SCI.
https://rdcu.be/cdysv
... Instead, raw data are shown. Certification of our laboratory by the DFNS (Reg: 36180814) and previous research with separate control groups 8,23,24 documents the validity of this approach. ...
A comprehensive functional recovery is one of the criteria for successful replantation of an amputated limb. Functionality of a replanted limb is strongly dependent on its regained sensibility. In previous studies concerning the sensibility of replanted limbs, only a few somatosensory submodalities were examined in small samples. The purpose of the present study is to provide a full pattern of somatosensory symptoms following replantation. Quantitative Sensory Testing (QST) was carried out according to a standardized protocol in a sample of 15 patients who underwent replantation of their upper limb proximal to the radiocarpal joint (macroreplantation). Results indicate that most of these patients showed a specific somatosensory profile characterized by thermal and mechanical hypoesthesia and hyperalgesia in response to pressure pain, while no single case of hyperalgesia to heat pain occurred. This distinct profile of impaired somatosensation shares some features of the somatosensory profile of neuropathic pain syndromes. Patients' limbs that were replanted many years before the present QST showed more sensory deficits than patients with more recent replantations. This knowledge might be helpful in the development of more specific and more successful rehabilitation programs with replanted patients, and improve the behavioral function of the replanted limb.
... This lack of systematic variation alone is sufficient to explain the lack of a significant correlation. However, it is exactly this small data range of some of the QST parameters, particularly in healthy subjects, which makes QST a suitable measure to detect both deviations from the norm, as may be seen in patients, 8,39,40 as well as changes induced by treatments. The question of how stable a measure is can be answered by analyzing how similar two measurements are, and this question is best answered by using the LoAs. ...
Background
Quantitative sensory testing (QST) is a diagnostic tool for the assessment of the somatosensory system. To establish QST as an outcome measure for clinical trials, the question of how similar the measurements are over time is crucial. Therefore, long-term reliability and limits of agreement of the standardized QST protocol of the German Research Network on Neuropathic Pain were tested.
Methods
QST on the lower back and hand dorsum (dominant hand) were assessed twice in 22 healthy volunteers (10 males and 12 females; mean age: 46.6±13.0 years), with sessions separated by 10.0±2.9 weeks. All measurements were performed by one investigator. To investigate long-term reliability and agreement of QST, differences between the two measurements, correlation coefficients, intraclass correlation coefficients (ICCs), Bland–Altman plots (limits of agreement), and standard error of measurement were used.
Results
Most parameters of the QST were reliable over 10 weeks in healthy volunteers: Almost-perfect ICCs were observed for heat pain threshold (hand) and mechanical pain sensitivity (back). Substantial ICCs were observed for heat pain threshold (back), pressure pain threshold (back), mechanical pain sensitivity (hand), and vibration detection threshold (back and hand). Some QST parameters, such as cold detection threshold, exhibited low ICCs, but also very low variability. Generally, QST measures exhibited narrow limits of agreement in the Bland–Altman plots.
Conclusion
The standardized QST protocol of the German Research Network on Neuropathic Pain is feasible to be used in treatment trials. Moreover, defining a statistically meaningful change is possible, which is a prerequisite for the use of QST in clinical trials as well as in long-term investigations of disease progression.
... Due to the nature of the data, results of emotional report are presented only descriptively. With regard to ratings of valence and arousal as well as data of physiological reactivity, an analytic approach reported by Franz et al. (42) was adapted to examine potential differences between R.B. and the control group. In this sense, R.B. 's values were z-transformed [z = (value R.B. − mean controls )/SD controls ] to establish a relation to the standard distribution of the norm population (neurotypical control group). ...
Limbic encephalitis (LE) is an autoimmune-mediated disorder that affects structures of the limbic system, in particular, the amygdala. The amygdala constitutes a brain area substantial for processing of emotional, especially fear-related signals. The amygdala is also involved in neuroendocrine and autonomic functions, including skin conductance responses (SCRs) to emotionally arousing stimuli. This study investigates behavioral and autonomic responses to discrete emotion evoking and neutral film clips in a patient suffering from LE associated with contactin-associated protein-2 (CASPR2) antibodies as compared to a healthy control group. Results show a lack of SCRs in the patient while watching the film clips, with significant differences compared to healthy controls in the case of fear-inducing videos. There was no comparable impairment in behavioral data (emotion report, valence, and arousal ratings). The results point to a defective modulation of sympathetic responses during emotional stimulation in patients with LE, probably due to impaired functioning of the amygdala.
... Secondly, we tested only nociceptive processing of Aδ-fibre-mediated input to laser heat simulation. So our study could be extended to the investigation of C-fibre-mediated input (e.g., using tiny skin area stimulation and recordings of ultra-late LEPs; (Opsommer et al., 2001;Franz et al., 2012)) because of the crucial role of C-fibres for chronic pain (e.g., central sensitization). ...
Background:
Based upon studies using mechanical pin-prick, pressure, electrical or heat stimuli applied to painful and/or pain-free parts of the body, chronic low back pain (CLBP) has been shown to be associated with generalized and enhanced pain sensitivity and altered brain responses to noxious stimuli. To date, no study examined the processing of noxious laser heat pulses, which are known to selectively excite thermal nociceptors located in the superficial skin layers, in CLBP.
Methods:
We studied laser heat pain thresholds (LHPTs) and nociceptive laser-evoked brain electrical potentials (LEPs) following skin stimulation of the pain-affected back and the pain-free abdomen using noxious laser heat stimulation in 16 CLBP patients and 16 age- and gender-matched healthy controls (HCs).
Results:
We observed no statistically significant differences in LHPTs between CLBP patients and HCs, neither on the back nor on the abdomen. Furthermore, we found no evidence for altered brain responses between CLBP patients and HCs in response to stimulation of the back and abdomen in single-trial latencies and amplitudes of LEP components (N2, P2).
Conclusion:
The results are in contrast to previous studies showing hypersensitivity to different experimental noxious stimuli (e.g., contact heat). We argue that these discrepancies may be due to low spatial and temporal summation within the central nervous system following laser heat stimulation. Our results indicate important methodological differences between laser heat and thermode stimulation that should be taken into account when interpreting results, such as from thermal quantitative sensory testing.
... caused by a multiple TFD or a lesion is needed to change the tactile detection thresholds. An experimental study in postherpetic neuralgia patients demonstrates that the parameters of the quantitative sensory testing including VFHT [20] are not sensitive enough to detect minor sensory abnormalities [31]. ...
Temporary functional deafferentation is of interest to become an additional tool in neurorehabilitative treatments. Temporary functional deafferentation is known to improve sensory and motor outcomes in chronic stroke patients and healthy subjects. The present study soughts to indicate differences in the efficiency of pharmacologically induced temporary functional deafferentation between chronic stroke patients and matched healthy subjects. 46 chronic stroke patients and 20 age- and gender-matched healthy subjects were deafferented on one forearm by an anesthetic cream. Somatosensory performance was assessed using von-Frey Hair testing and Grating orientation task; motor performance was assessed by means of a shape-sorter-drum task. Grating orientation task and shape-sorter-drum task were significantly improved during temporary functional deafferentation in stroke patients but not in healthy subjects. Von-Frey Hair testing revealed no improvement of absolute tactile thresholds during temporary functional deafferentation in both groups. Furthermore, the stroke patients showed deficits at baseline measurement in all assessments except the von-Frey Hair test. Temporary functional deafferentation of a forearm by an anesthetic cream results in improvements of motor performance and somatosensory discrimination in stroke patients but not in healthy subjects. Therefore, it is reasonable to test in a next step whether temporary functional deafferentation might become an additional tool in motor rehabilitation of post stroke patients.
... For example, Bragard et al. [1] averaged 600 trials to obtain identifiable C-fibre LEPs. Similarly, Franz et al. [8] collected 196 trials at each stimulation site to examine the diagnostic usefulness of C-fibre LEPs in postherpetic neuralgia. Finally, without the ability to control the target temperature, selectively activating lowthreshold C-fibre afferents can be difficult because the temperature reached by the stimulus is not only determined by the power and duration of the laser pulse, but also by the possibly drifting baseline skin temperature, as well as changes in power density, for example due to variations in beam incidence. ...
C‐fibre laser‐evoked potentials can be obtained reliably at single‐subject level from the hand and foot using a temperature‐controlled CO2 laser combined with an adaptive algorithm based on reaction times. ABSTRACT: Brain responses to the activation of C‐fibres are obtained only if the co‐activation of Aδ‐fibres is avoided. Methods to activate C‐fibres selectively have been proposed, but are unreliable or difficult to implement. Here, we propose an approach combining a new laser stimulator to generate constant‐temperature heat pulses with an adaptive paradigm to maintain stimulus temperature above the threshold of C‐fibres but below that of Aδ‐fibres, and examine whether this approach can be used to record reliable C‐fibre laser‐evoked brain potentials. Brief CO2 laser stimuli were delivered to the hand and foot dorsum of 10 healthy subjects. The stimuli were generated using a closed‐loop control of laser power by an online monitoring of target skin temperature. The adaptive algorithm, using reaction times to distinguish between late detections indicating selective activation of unmyelinated C‐fibres and early detections indicating co‐activation of myelinated Aδ‐fibres, allowed increasing the likelihood of selectively activating C‐fibres. Reliable individual‐level electroencephalogram (EEG) responses were identified, both in the time domain (hand: N2: 704 ± 179 ms, P2: 984 ± 149 ms; foot: N2: 1314 ± 171 ms, P2: 1716 ± 171 ms) and the time‐frequency (TF) domain. Using a control dataset in which no stimuli were delivered, a Receiver Operating Characteristics analysis showed that the magnitude of the phase‐locked EEG response corresponding to the N2‐P2, objectively quantified in the TF domain, discriminated between absence vs presence of C‐fibre responses with a high sensitivity (hand: 85%, foot: 80%) and specificity (hand: 90%, foot: 75%). This approach could thus be particularly useful for the diagnostic workup of small‐fibre neuropathies and neuropathic pain.
... Experimentally, PHS can be induced by selective conduction blockade in A-fibers, and it is facilitated by peripheral sensitization experimentally [42][43][44]. Similar changes have been previously reported at the hand in patients with fibromyalgia, peripheral arterial occlusion, acute complex regional pain syndrome, and postherpetic neuralgia [16,42,[45][46][47]. PHS together with a hyperalgesia to mechanical stimuli are interpreted as signs of a deficiency of pain inhibitory systems and/or altered integration of somatosensory stimuli [43,46,48,49]. ...
Chronic low back pain (CLBP) was shown to be associated with pathophysiological changes at several levels of the sensorimotor system. Changes in sensory thresholds have been reported but complete profiles of Quantitative Sensory Testing (QST) were only rarely obtained in CLBP patients. The aim of the present study was to investigate comprehensive QST profiles in CLBP at the painful site (back) and at a site distinct from their painful region (hand) and to compare these data with similar data in healthy controls. We found increased detection thresholds in CLBP patients compared to healthy controls for all innocuous stimuli at the back and extraterritorial to the painful region at the hand. Additionally, CLBP patients showed decreased pain thresholds at both sites. Importantly, there was no interaction between the investigated site and group, i.e. thresholds were changed both at the affected body site and for the site distinct from the painful region (hand). Our results demonstrate severe, widespread changes in somatosensory sensitivity in CLBP patients. These widespread changes point to alterations at higher levels of the neuraxis or/and to a vulnerability to nociceptive plasticity in CLBP patients.
Wir berichten über eine veröffentlichte Studie [5], in der die Eignung zweier thermischer Stimulationsverfahren, namentlich der Thermodenstimulation sowie der Laserstimulation, im Rahmen der mechanismenorientierten Schmerz-diagnostik untersucht wurde. Die ge-wonnenen Erkenntnisse sind mit Blick auf die quantitative sensorische Testung (QST; [11]) und des darin verwandten Thermodenverfahrens klinisch bedeut-sam.
This study aimed at evaluating the performance of a battery of morphological and functional tests for the assessment of small nerve fiber loss in asymptomatic diabetic neuropathy (DNP). Patients diagnosed for ≥10 years with type 1 (n = 10) or type 2 (n = 13) diabetes mellitus (DM) without conventional symptoms or signs of DNP were recruited and compared with healthy controls (n = 18) and patients with overt DNP (n = 5). Intraepidermal nerve fiber density (IENFd) was measured with PGP9.5 immunostaining on punch skin biopsies performed at the distal leg. Functional tests consisted of quantitative sensory testing (QST) for light-touch, cool, warm and heat pain detection thresholds and brain-evoked potentials with electrical (SEPs) and CO(2) laser stimulation [laser-evoked potentials (LEPs)] of hand dorsum and distal leg using small (0.8 mm(2)) and large (20 mm(2)) beam sizes. Results confirmed a state of asymptomatic DNP in DM, but only at the distal leg. Defining a critical small fiber loss as a reduction of IENFd ≤-2 z scores of healthy controls, this state prevailed in type 2 (30%) over type 1 DM (10%) patients despite similar disease duration and current glycemic control. LEPs with the small laser beam performed best in terms of sensitivity (91%), specificity (83%) and area-under-the ROC curve (0.924). Although this performance was not statically different from that of warm and cold detection threshold, LEPs offer an advantage over QST given that they bypass the subjective report and are therefore unbiased by perceptual factors.
This study evaluates the additional use of laser-evoked potentials (LEP) and quantitative sensory testing (QST) in the sensory assessment of spinal lesions. Four consecutive patients with spinal lesions verified by MRI and clinical evidence for mild spinothalamic tract involvement were included. The electrophysiological workup [somatosensory evoked potentials (SEP) and LEP] was compared to QST. Electrophysiology and QST were reassessed after about 6 months. LEP detected impaired spinothalamic tract function in 7/8 examinations. QST pointed to spinothalamic tract lesions by loss of thermal function (3/8); most frequent positive sensory signs (3/8) were paradoxical heat sensations. LEP and QST results were concordant in 6/8 examinations. SEPs were abnormal in 2/8 examinations. Congruent results between SEP and both LEP and QST were obtained in 3/8 examinations. LEP detected more deficits than any single QST parameter or their combination but additional QST allows the detection of positive sensory signs. The diagnostic gain of SEP was limited.
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.
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.
In the syndrome of post-herpetic neuralgia (PHN), the nature of the sensory disturbance and its relationship both to the severity and cause of the pain is controversial. To address these issues, sensory mapping and quantitative thermal sensory testing was carried out four times in separate sessions on 35 subjects with established PHN. All subjects had pain affecting the torso or extremities and brush-evoked allodynia. Each session included rating of ongoing pain, mapping of the area of any sensory disturbance and the area of greatest pain, grading of allodynia severity within the area of greatest ongoing pain, and quantitative testing of thermal sensation in both the painful and the contralateral unaffected mirror-image skin. The severity of allodynia was positively correlated with reported ongoing pain severity. As a group, subjects had a sensory deficit to thermal stimuli in PHN skin compared with unaffected mirror-image skin. However, the magnitude of the heat pain sensory deficit was inversely correlated with both pain intensity and severity of allodynia. In fact, 12 subjects had heat hyperalgesia in their region of maximum pain. Compared with the 23 subjects with heat hypoalgesia, the group of 12 heat hyperalgesic subjects had significantly higher pain ratings and allodynia severity. Sensory loss was less strongly, but still inversely related to pain severity for the thermal modalities of innocuous warming, cooling and cold pain. This implies that there is no simple relationship between loss of peripheral nerve function and spontaneous or evoked pain. Rather, the preservation of several sensory modalities in their area of maximal pain suggests that in some PHN patients, activity in primary afferent nociceptors that remain connected to both their peripheral and central targets contributes significantly to ongoing pain. Although other mechanisms are likely to contribute to the pain, the demonstrated responsivity of PHN to topical agents including local anaesthetics, capsaicin, and non-steroidal anti-inflammatory drugs, supports this proposed mechanism of pain generation.
The aim of this study was to examine the recovery of sensory function in myocutaneous flaps comparing 2 test methods. Eight flaps in 7 patients were examined by using clinical neurological test procedures (CNT) in comparison with psychophysics and evoked brain potentials (LEP) following infrared laser stimuli. The authors found that only 3 out of 8 flaps in 7 patients exhibited signs of reinnervation when tested with CNT. Three grades of reinnervation appeared in 7 flaps when tested with the laser. Grade 1 indicated the recovery of unmyelinated C-fiber function in 7 flaps accounting for the ability to discriminate laser intensities by different degrees of warmth. Grade 2 appeared in 3 of these flaps and was characterized by the additional ability to sense pinprick pain and the elicitation of late components of LEP mediated by thinly myelinated A delta-nociceptors. Grade 3 involved the additional sensibility for superficial touch indicating the recovery of thickly myelinated A beta-fibers noted in 2 of these flaps. The authors conclude that the LEP method is more sensitive than standard neurological test procedures to objectively document early signs of reinnervation after reconstructive flap surgery. This result is promising to investigate greater patient populations comparing different surgical techniques in future studies.
We have compiled a comprehensive QST protocol as part of the German Research Network on Neuropathic Pain (DFNS) using well established tests for nearly all aspects of somatosensation. This protocol encompasses thermal as well as mechanical testing procedures. Our rationale was to test for patterns of sensory loss (small and large nerve fiber functions) or gain (hyperalgesia, allodynia, hyperpathia), and to assess both cutaneous and deep pain sensitivity. The practicality of the QST protocol was tested in 18 healthy subjects, 21–58 years, half of them female. All subjects were tested bilaterally over face, hand and foot. We determined thermal detection and pain thresholds including a test for the presence of paradoxical heat sensations, mechanical detection thresholds to von Frey filaments and a 64-Hz tuning fork, mechanical pain thresholds to pinprick stimuli and blunt pressure, stimulus-response-functions for pinprick and dynamic mechanical allodynia (pain to light touch), and pain summation (wind-up ratio) using repetitive pinprick stimulation.
The nationwide multicenter trials of the German Research Network on Neuropathic Pain (DFNS) aim to characterize the somatosensory phenotype of patients with neuropathic pain. For this purpose, we have implemented a standardized quantitative sensory testing (QST) protocol giving a complete profile for one region within 30 min. To judge plus or minus signs in patients we have now established age- and gender-matched absolute and relative QST reference values from 180 healthy subjects, assessed bilaterally over face, hand and foot. We determined thermal detection and pain thresholds including a test for paradoxical heat sensations, mechanical detection thresholds to von Frey filaments and a 64 Hz tuning fork, mechanical pain thresholds to pinprick stimuli and blunt pressure, stimulus/response-functions for pinprick and dynamic mechanical allodynia, and pain summation (wind-up ratio). QST parameters were region specific and age dependent. Pain thresholds were significantly lower in women than men. Detection thresholds were generally independent of gender. Reference data were normalized to the specific group means and variances (region, age, gender) by calculating z-scores. Due to confidence limits close to the respective limits of the possible data range, heat hypoalgesia, cold hypoalgesia, and mechanical hyperesthesia can hardly be diagnosed. Nevertheless, these parameters can be used for group comparisons. Sensitivity is enhanced by side-to-side comparisons by a factor ranging from 1.1 to 2.5. Relative comparisons across body regions do not offer advantages over absolute reference values. Application of this standardized QST protocol in patients and human surrogate models will allow to infer underlying mechanisms from somatosensory phenotypes.
The objective of this article is to provide evidence-based recommendations for the management of patients with herpes zoster
(HZ) that take into account clinical efficacy, adverse effects, impact on quality of life, and costs of treatment. Systematic
literature reviews, published randomized clinical trials, existing guidelines, and the authors' clinical and research experience
relevant to the management of patients with HZ were reviewed at a consensus meeting. The results of controlled trials and
the clinical experience of the authors support the use of acyclovir, brivudin (where available), famciclovir, and valacyclovir
as first-line antiviral therapy for the treatment of patients with HZ. Specific recommendations for the use of these medications
are provided. In addition, suggestions are made for treatments that, when used in combination with antiviral therapy, may
further reduce pain and other complications of HZ.
Publisher Summary It is generally held that non-corpuscular fine sensory endings (free nerve endings) arise from slowly conducting (group III and group IV) fibers, whereas corpuscular nerve endings are the sensory end formations of fast conducting fibers. The sensory axons of non-corpuscular free endings are not accompanied by other cellular structures than the terminal Schwann cells. The terminal Schwann cells of group III fibers do not produce a myelin sheath. In articular tissues, group III fibers lose their myelin sheath already within the most distal portion of the peripheral nerves. The endings of mechanosensitive afferents are connected to the structures that are able to transmit the mechanical stimuli, for example, stretch. In the knee joint, low-threshold mechanosensory endings are found in loose connective tissue composed of fibroblasts, thin collagenous fibers, and fat cells, whereas the endings of high-threshold (nociceptive) afferents seem to be embedded in dense collagenous tissue such as the fibrous capsule or ligaments. The rigidity of the surrounding tissue and its resistance to stretch may determine the mechanical sensitivity of the sensory endings, and hence the mechanical threshold of the afferent units.
Der Deutsche Schmerzfragebogen (DSF) wurde von Mitgliedern des Arbeitskreises “Standardisierung und ...konomisierung in der
Schmerztherapie” der Deutschen Gesellschaft zum Studium des Schmerzes (DGSS) zwischen 1993 und 1997 entwickelt und validiert.
Im einzelnen erfasst der DSF in einer modularen Konzeption folgende wesentliche Komponenten des Schmerzes:
Identifizierende Daten zur Person; Krankenversicherung, Hausarzt etc.
Eine ausführliche subjektive Schmerzbeschreibung (Lokalisation, Charakteristik, zeitlicher Verlauf, Intensität etc.).
Schmerzlindernde und -verstärkende Bedingungen, Begleitsymptome.
Die subjektive Schmerzempfindung (Schmerzempfindungsskala, SES©).
Die schmerzbedingte Beeinträchtigung (Pain Disability Index).
Das Ausmaß depressiver Symptomatik (Allgemeine Depressionsskala, ADS©).
Den Krankheitsverlauf (Umfang der bisherigen Behandlung, Medikamenteneinnahme, vorbehandelnde Ärzte und Institutionen).
Die medizinische und psychologische/psychiatrische Komorbidität.
Die Schul-/Berufsausbildung, derzeitige Arbeitssituation und Rentenstatus; privater sozialer Status.
Einschränkungen in der gesundheitsbezogenen Lebensqualität (Short-Form-36©).
Inhaltliche Validität und Praktikabilität des DSF wurden multizentrisch an über 3000 Patienten überprüft. Der Vergleich mit
den externen Kriterien ärztliche und psychologisch-psychiatrische Diagnosen und der ärztlichen Einordnung der Schmerzchronifizierung
nach dem Mainzer Stadienmodell (MPSS) belegt eine gute inhaltliche Validität und Zuverlässigkeit der Patientenangaben im Fragebogen.
Die überwiegende Mehrzahl der Patienten bewerteten den DSF als ihre Schmerzkrankengeschichte vollständig erfassend, übersichtlich
und nicht zu schwierig.
Der Deutsche Schmerzfragebogen der DGSS ist ein gut überprüftes Screeninginstrument zur Erfassung der Multidimensionalität
des Schmerzes. Als Datenbasis für Verlaufsuntersuchungen (follow-up) sowie eine interne und externe Qualitätssicherung ist
ein solches, validiertes und modellgeleitetes Instrument unverzichtbar. Der DSF kann über die Deutsche Gesellschaft zum Studium
des Schmerzes (www.dgss.org) bezogen werden und wird im Computerprogramm “Qualitätssicherung in der Schmerztherapie” (QUAST)
der DGSS als Basismodul mit Auswertungsroutine eingesetzt.
The German pain questionnaire (DSF) has been developed and validated by the Task force on "Standardization and Economy in
Pain Management" of the German Chapter of the International Association for the Study of Pain (DGSS). The concept of the DSF
is based on a bio (medical) - psycho - social pain model. The modular approach to pain assessment consists of:
demographic data,
pain variables (e. g. pain sites, temporal characteristics, duration, intensity),
pain associated symptoms,
affective and sensory qualities of pain
(adjective list by Geissner, SES©),
pain relieving and intensifying factors,
previous pain treatment procedures,
pain-related disability (Pain Disability Index by Tait et al.),
depression test CES-D (Center for Epidemiological Studies Depression Test),
comorbid conditions,
social factors (educational level, occupation, retirement status, compensation and/or litigation status, disability for work),
health related quality of life (SF-36©).
Practicability and content validity were tested in some 3000 patients. Comparison with external criteria (e. g. medical and
psychiatric-psychological diagnoses, physician-determined chronicity of pain) proved good content validity and excellent reliability
of patients statements in the questionnaire.
The great majority of patients stated that the DSF covered their pain history completely and in an orderly fashion. Difficulty
to answer the questions was considered low.
The German pain questionnaire is a reliable and valid instrument for recording the multidimensional experience of pain. Data
from such questionnaires are indispensable for follow-up studies and internal and external quality assessments. The DSF can
be ordered from the German Society for the Study of Pain (www.dgss.org) and is a core instrument of the computer program "quality
assurance in pain management" (QUAST) of this society.
This study analyzed the relationship between the density of intraepidermal nerve fibers (IENF) and the characteristics of either nociceptive laser-evoked potentials (LEPs) or contact heat-evoked potentials (CHEPs) in patients with painful sensory polyneuropathy with the aim to determine which parameters of LEPs and CHEPs more reliably reflect IENF loss. A total of 96 patients and 35 healthy volunteers took part in the study. Based on clinical examination, nerve conduction tests, and quantitative sensory testing, we identified 52 patients with small-fiber neuropathy (SFN), 40 with mixed (small-fiber and large-fiber) neuropathy (MFN), and 4 who were excluded from the analysis because of no evidence of involvement of small fibers. The latency of the N2 was delayed for both LEPs and CHEPs in patients with MFN and for CHEPs only in patients with SFN. The amplitude of the vertex N2/P2 potential was similarly reduced in both types of neuropathy, but LEPs were more frequently absent than CHEPs in MFN patients (68% vs 40%). In general, latency and amplitude of LEPs and CHEPs were well correlated with IENF density. SFN patients were characterized by abnormal EPs and slightly decreased but morphologically abnormal IENF. MFN patients were characterized by frequently absent LEPs and CHEPs and a rather severe IENF loss. The correlation between nociceptive evoked potentials (laser-evoked potentials and contact heat-evoked potentials) and skin biopsy aids in the diagnosis of painful neuropathies.
We have revised the previous EFNS guidelines on neuropathic pain (NP) assessment, which aimed to provide recommendations for the diagnostic process, screening tools and questionnaires, quantitative sensory testing (QST), microneurography, pain-related reflexes and evoked potentials, functional neuroimaging and skin biopsy.
We have checked and rated the literature published in the period 2004-2009, according to the EFNS method of classification for diagnostic procedures.
Most of the previous recommendations were reinforced by the new studies. The main revisions relate to: (i) the new definition of NP and a diagnostic grading system; (ii) several new validated clinical screening tools that identify NP components, and questionnaires which assess the different types of NP; (iii) recent high-quality studies on laser-evoked potentials (LEPs) and skin biopsy.
History and bedside examination are still fundamental to a correct diagnosis, whilst screening tools and questionnaires are useful in indicating probable NP; QST is also useful for indicating the latter, and to assess provoked pains and treatment response. Amongst laboratory tests, LEPs are the best tool for assessing Adelta pathway dysfunction, and skin biopsy for assessing neuropathies with distal loss of unmyelinated nerve fibres.
This study aimed to assess thermal and mechanical perception and pain thresholds in primary idiopathic restless legs syndrome and secondary restless legs syndrome associated with small fibre neuropathy. Twenty-one patients (age: 53.4 + or - 8.4, n = 3, male) with primary restless legs syndrome and 13 patients (age: 63.0 + or - 8.2, n = 1, male) with secondary restless legs syndrome associated with small fibre neuropathy were compared with 20 healthy subjects (age: 58.0 + or - 7.0; n = 2, male). Differential diagnosis of secondary restless legs syndrome associated with small fibre neuropathy was based on clinical symptoms and confirmed with skin biopsies in all patients. A comprehensive quantitative sensory testing protocol encompassing thermal and mechanical detection and pain thresholds, as devised by the German Research Network on Neuropathic Pain, was performed on the clinically more affected foot between 2 pm and 1 am when restless legs syndrome symptoms were present in all patients. Patients with primary restless legs syndrome showed hyperalgesia to blunt pressure (P < 0.001), pinprick (P < 0.001) and vibratory hyperaesthesia (P < 0.001). Patients with secondary restless legs syndrome associated with small fibre neuropathy showed thermal hypoaesthesia to cold (Adelta-fibre mediated) and warm (C-fibre mediated) (all P < 0.001) and hyperalgesia to pinprick (P < 0.001). Static mechanical hyperalgesia in primary and secondary restless legs syndrome is consistent with the concept of central disinhibition of nociceptive pathways, which might be induced by conditioning afferent input from damaged small fibre neurons in secondary restless legs syndrome.
Postherpetic neuralgia is an exceptionally drug-resistant neuropathic pain. To investigate the pathophysiological mechanisms underlying postherpetic neuralgia we clinically investigated sensory disturbances, pains and itching, with an 11-point numerical rating scale in 41 patients with ophthalmic postherpetic neuralgia. In all the patients we recorded the blink reflex, mediated by non-nociceptive myelinated Abeta-fibers, and trigeminal laser evoked potentials (LEPs) related to nociceptive myelinated Adelta- and unmyelinated C-fiber activation. We also sought possible correlations between clinical sensory disturbances and neurophysiological data. Neurophysiological testing yielded significantly abnormal responses on the affected side compared with the normal side (P<0.001). The blink reflex delay correlated with the intensity of paroxysmal pain, whereas the Adelta- and C-LEP amplitude reduction correlated with the intensity of constant pain (P<0.01). Allodynia correlated with none of the neurophysiological data. Our study shows that postherpetic neuralgia impairs all sensory fiber groups. The neurophysiological-clinical correlations suggest that constant pain arises from a marked loss of nociceptive afferents, whereas paroxysmal pain is related to Abeta-fiber demyelination. These findings might be useful for a better understanding of pain mechanisms in postherpetic neuralgia.
The effect of compression-ischaemia nerve block on psychophysical thresholds for warm sensation and heat-induced pain was studied on 19 normal human volunteers. Although those two sensory submodalities should be predicted to block simultaneously, based on the fact that both are served by unmyelinated primary afferents, it was actually found that warm sensation was much more vulnerable to compression-ischaemia than heat-induced pain. This is interpreted as resulting from different summation requirements for each of the two sensory modalities; sensation of warmth depends on spatial summation to a larger extent than heat-induced pain. Such differential vulnerability is in line with recent clinical studies reporting deterioration of warm sensation associated with preservation of heat pain in peripheral nerve disorders caused by diabetes, ageing and other neuropathic processes.
A combined light and electron microscope study of the normal sural nerve in 7 people aged 15-59 years is reported. Qualitative and quantitative studies of the Schwann cells and fibroblasts, myelinated and unmyelinated fibres are made in isolated fascicles. Schwann cells predominate over fibroblasts in the ratio of about 9-1. Most Schwann cells, almost 80%, are attached to unmyelinated fibres. Factors influencing the densities of these cells per cross sectional area are discussed. Some ultrastructural features of the myelinated fibres are described and their numbers per sq.mm and frequency distribution of their sizes are produced. An indirect method is proposed for assessing the mean internodal length for earch of the myelinated fibre size populations in cross sections of fascicles of normal nerves by estimating the proportion of myelinated segments cut through their nucleus. The ultrastructure of unmyelinated fibres is described and the identification of axons of extreme diameter is discussed. Their densities and size frequency histograms are the first to be reported in man by systematic electron microscope studies. The average ratio of unmyelinated to myelinated fibre density is about 3.7:1 though it varies in the fascicles of the different individuals. The implications of axonal diameter in the presence of myelin are commented on.
Under normal conditions acute stimulation and sensitization of polymodal nociceptive C-fibres cause pain and, due to afferent axon reflex activation, a local skin vasodilatation, flare reaction and skin temperature increase. Two questions arise: (i) Do sensitized C-nociceptors signal allodynia in chronic postherpetic neuralgia? (ii) If not, does ongoing peripheral nociceptive C-fibre input maintain a central process that accounts for allodynia? Ten patients with postherpetic neuralgia and tactile allodynia and 10 control subjects were studied using a laser Doppler perfusion monitor. Peripheral nociceptive C-fibre function was assessed by quantitative measurement of the axon reflex vasodilatation and flare reaction induced by histamine iontophoresis and compared with non-neural vasodilatation induced by local skin heating. Resting skin temperature, skin resistance and resting skin blood flow were the same in the allodynic area and the contralateral homologous skin area. The histamine responses (vasodilatation and flare) were significantly reduced or nearly abolished in the allodynic area compared with the contralateral side, whereas the temperature-dependent vasodilatation in patients and the histamine responses in healthy controls showed no side differences. C-fibre mediated pain and itch sensations were also decreased in the allodynic area. These findings indicate a considerable impairment of cutaneous nociceptive C-fibre function in the allodynic area. Allodynic stimuli of 20 s did not cause any local blood flow change. Impairment of C-fibre function was positively correlated with intensity of neuropathic pain. We conclude that sensitized nociceptive C-fibres are not involved in signalling allodynia. Changes in CNS processing may occur after zoster infection that strengthen the synaptic ties between central pain signalling pathways and low-threshold mechanoreceptors with A beta-fibres. This altered central processing is not maintained by ongoing cutaneous nociceptive C-fibre input, at least in some patients with postherpetic neuralgia. On the contrary, an anatomical synaptic reorganization depending on afferent C-fibre degeneration seems to be more likely, particularly in advanced stages of postherpetic neuralgia.
In 12 zoster patients who had developed postherpetic neuralgia with dynamic mechanical allodynia and in six zoster patients who had recovered without pain, the functional role of nociceptive C-fibers in allodynia was assessed by quantifying axon reflex reactions induced by histamine iontophoresis within allodynic regions and in their contralateral sites. In patients with postherpetic neuralgia, histamine responses were reduced or abolished within allodynic areas, indicating degeneration of nociceptive C-fibers. In patients who recovered without pain, histamine responses were bilaterally identical, indicating complete regeneration of nociceptive C-fibers. These results demonstrate that sensitized nociceptive C-fibers are not involved in signaling and maintenance of allodynia. Alteration in CNS processing may reorganize synaptic ties between central pain-signaling pathways and mechanoreceptive A beta-fibers depending on afferent C-fiber degeneration rather than ongoing C-fiber input.
In this study, it is reported that CO2 laser heat stimulation of tiny skin surface area (0.15 mm2) provides a unique method to directly and selectively activate C-fibre as assessed by the ultra-late brain potentials (peak latencies: N810, P996) evoked consistently across a set of stimulus energy levels. On a larger surface area (15.5 mm2), low energy stimulation also resulted in minute ultra-late potential, while higher intensities induced only late potentials related to A-delta fibre activity (peak latencies: N247, P394). The selective activation of C afferent sensory terminals in the skin by stimulation of tiny surface area is explained by their relative high density and lower activation threshold.
The relationship between deafferentation, sensory function, and pain was explored in 18 subjects with chronic postherpetic neuralgia (PHN). Subjective thresholds for warmth, cooling, and heat pain were measured quantitatively in painful skin areas and compared with normal contralateral skin. The severity of allodynia was graded in the affected area. Two 3-mm punch biopsies were taken from the most painful skin area and one from unaffected contralateral mirror-image skin. Immunofluorescence with the axonal marker PGP 9.5 revealed a reduction in density of innervation of the epidermis, the dermal-epidermal junction, and the eccrine sweat glands in PHN skin. In painful PHN skin, the reduction in innervation density was positively correlated with the magnitude of the thermal sensory deficits. However, loss of cutaneous innervation was inversely correlated with allodynia, indicating that surviving cutaneous primary afferent nociceptors that are spontaneously active and/or sensitized contribute to PHN pain and allodynia.
Shingles can cause chronic neuropathic pain (postherpetic neuralgia) long after skin lesions heal. To investigate its causes, we quantitated immunolabeled sensory neurites in skin biopsies from 18 subjects with and 16 subjects without postherpetic neuralgia after unilateral shingles. Subjects rated the intensity of their pain. Punch skin biopsies were evaluated from the site of maximum pain or shingles involvement, the homologous contralateral location, and a site on the back, distant from shingles involvement. Sections were immunostained with anti-PGP9.5 antibody, a pan-axonal marker, and the density of epidermal and dermal neurites determined. The group with postherpetic neuralgia had a mean density of 339 +/- 97 neurites/mm2 in shingles-affected epidermis compared with a density of 1,661 +/- 262 neurites/mm2 for subjects without pain. Neurite loss was more severe in epidermis than dermis. Unexpectedly, the group with pain had also lost half of the neurites in contralateral epidermis. Contralateral damage occurred despite the lack of contralateral shingles eruptions or pain, correlated with the presence and severity of ongoing pain at the shingles site, and did not extend to the distant site. Thus, the pathophysiology of postherpetic neuralgia pain may involve a new bilateral mechanism.
Postherpetic neuralgia (PHN) is a common and often devastatingly painful condition. It is also one of the most extensively investigated of the neuropathic pains. Patients with PHN have been studied using quantitative testing of primary afferent function, skin biopsies, and controlled treatment trials. Together with insights drawn from an extensive and growing literature on experimental models of neuropathic pain these patient studies have provided a preliminary glimpse of the pain-generating mechanisms in PHN. It is clear that both peripheral and central pathophysiological mechanisms contribute to PHN pain. Some PHN patients have abnormal sensitization of unmyelinated cutaneous nociceptors (irritable nociceptors). Such patients characteristically have minimal sensory loss. Other patients have pain associated with small fiber deafferentation. In such patients pain and temperature sensation are profoundly impaired but light moving mechanical stimuli can often produce severe pain (allodynia). In these patients, allodynia may be due to the formation of new connections between nonnociceptive large diameter primary afferents and central pain transmission neurons. Other deafferentation patients have severe spontaneous pain without hyperalgesia or allodynia and presumably have lost both large and small diameter fibers. In this group the pain is likely due to increased spontaneous activity in deafferented central neurons and/or reorganization of central connections. These three types of mechanism may coexist in individual patients and each offers the possibility for developing new therapeutic interventions.
Sensory loss and allodynia are hallmark signs of postherpetic neuralgia (PHN). We set out to investigate how frequently these signs are present in patients with acute herpes zoster (HZ) and what their prognostic value might be. We assessed pain, mechanical allodynia, and sensitivity to pinprick in 113 immunocompetent patients with HZ of a median duration of 5 days. Follow-up visits took place at 2 weeks, 6 weeks, 3 months, and 6 months. When first seen, 87 (77%) patients reported ongoing pain and 48/107 (45%) had allodynia. Twenty-eight (25%) patients had pain at 3 months (and were considered to have developed PHN), while 14 (12%) patients had pain at 6 months. Allodynia tended to subside quickly in most patients. Reduced sensitivity to pinprick was less common. Mechanical allodynia and pinprick hypesthesia were strongly associated with the development of PHN. They merit addition to the list of potential risk factors for PHN although they cannot be used as a predictive rule for an individual patient. By contrast, lack of allodynia in the early stages of HZ predicts good recovery by three months.
Ultralate (C-fibres) laser evoked potentials (LEP) can be obtained by stimulation of a tiny skin surface area (0.23 mm(2)). Since their generators are unknown up to now, we performed brain source analyses of ultralate LEPs using high resolution electroencephalography (64 channels) and a realistic head model that was based on individual magnetic resonance images. Ultralate LEPs were characterized by a negative-positive complex with a large positive component maximal at the vertex. Source analysis revealed that ultralate LEPs could be explained by two dipole sources in the upper bank of the contralateral and ipsilateral Sylvian fissure (SII) and one dipole in the median region corresponding to the anterior cingulate gyrus.
Quantitative sensory testing of heat pain sensation has become an important tool to evaluate small caliber afferent nerve function in peripheral neuropathy. In earlier studies, we found that topical application of capsaicin in humans results in the loss of epidermal nerve fibers (ENFs) with a corresponding decrease in detection of heat pain sensation. Capsaicin may therefore be a useful model for developing optimal psychophysical testing procedures for detection of neuropathy in its early stages. Here we determined the influence of thermal probe (thermode) size in detecting the diminished heat pain sensation following capsaicin application. Twelve healthy volunteers applied 0.075% capsaicin topically to the volar forearm four times daily for 7 days. Psychophysical measures of heat pain, mechanical (sharp) pain, and tactile threshold were obtained daily from untreated control skin and from capsaicin-treated skin during capsaicin application, and once weekly for 5 weeks following discontinuation of capsaicin. Heat pain sensation was assessed using a large (30 x 30 mm) and small (3 x 3 mm) thermode and different algorithms to assess pain threshold and suprathreshold heat pain. Skin biopsies were obtained and were processed for immunohistochemical localization of (ENFs) using the pan neuronal marker protein gene product 9.5. Capsaicin produced a rapid decrease in the number of ENFs, with nearly complete disappearance after 3 days of treatment. Heat pain evoked by the small, but not the large, thermode decreased dramatically after capsaicin treatment. The sensation of heat pain returned toward normal after 2--3 weeks following discontinuation of capsaicin treatment concordant with gradual reinnervation of the epidermis. Regression analysis indicated that the sensation of heat pain evoked by the small thermode correlated much better with the number of ENFs than heat pain evoked by the large thermode. The detection of sharp pain decreased moderately after capsaicin treatment. Assessment of heat pain sensation using small thermodes has potential for detecting sensory deficits in early stages of small fiber neuropathy.
The mechanisms of chronic neuropathic pain are not well understood. Postherpetic neuralgia (PHN), which occurs in some patients after shingles (herpes zoster), was used to investigate the neural determinants of chronic pain. Skin biopsies were obtained from 38 adults with or without PHN at least 3 months after healing of shingles on the torso. Vertical sections were immunolabeled against PGP9.5, a pan-axonal marker, to measure the density of remaining nerve endings in skin previously affected by shingles. All axons that end in the epidermis are nociceptors, neurons that transmit pain messages. The densities ranged between 2 and 3976 neurites/mm2 skin surface, but the overlap between subjects and without PHN was small. Of 19 subjects without PHN, 17 had more than 670 neurites/mm2 skin surface area (mean +/- SEM = 1569 +/- 230), and 18 of 19 subjects with PHN had 640 or fewer neurites/mm2 (mean +/- SEM = 367 +/- 92). PHN may be a 'phantom-skin' pain associated with loss of nociceptors. This threshold of approximately 650 neurites/mm2 skin surface was not detected in previous studies that used summary statistics. It implies that the absence of pain after shingles may require the preservation of a minimum density of primary nociceptive neurons, and that the density of epidermal innervation may provide an objective correlate for the presence or absence of PHN pain.
To investigate (1) the scalp topography of ultralate laser evoked potentials (LEPs) related to C-fibre activation, which can directly be obtained by thulium YAG (Tm YAG) laser stimulation of tiny skin surface areas (about 0.23 mm(2)) and (2) the influence of the performance of a motor task on ultralate LEPs.
Laser stimuli were applied to the dorsum of the left hand. LEPs were recorded with 58 scalp electrodes from 9 healthy subjects in two different conditions, with and without a reaction time (RT) task (press a button upon detection).
On high resolution electroenchephalogram recordings, ultralate LEPs were characterized by a broad positive component (peak latency: 1133+/-91 ms) with maximum amplitude about the vertex. Moreover, the performance of a RT task had no influence on latency, amplitude and topographical patterns of two maps chosen at the positive peak latency in ultralate LEPs. Nevertheless, a negative inflexion (latency 1300 ms) appeared after the positive component in the task condition possibly reflecting movement-related potentials.
Tm YAG laser stimulation of tiny skin surface areas allows recording the dynamic scalp topography of ultralate (C-fibres) LEPs, with or without the performance of a RT task.
Baseline and follow-up data from 4 samples of immunocompetent patients with herpes zoster who participated in clinical trials of the antiviral agent famciclovir were examined (N = 1778). In both univariate and multivariate analyses, severe rash (ie, >50 lesions, defined as papules, vesicles, or crusted vesicles) was significantly associated with older age, male sex, severe pain, primary involvement of nontrigeminal dermatomes, and a greater number of affected dermatomes. In addition, severe rash predicted the presence of pain 3 months later. The results indicate that severe rash is more common in patients with herpes zoster who are older and who have more severe acute pain and confirm that severe rash is a risk factor for prolonged pain.
The German pain questionnaire (DSF) has been developed and validated by the Task force on "Standardization and Economy in Pain Management" of the German Chapter of the International Association for the Study of Pain (DGSS). The concept of the DSF is based on a bio (medical) - psycho - social pain model. The modular approach to pain assessment consists of:demographic data,pain variables (e. g. pain sites, temporal characteristics, duration, intensity),pain associated symptoms,affective and sensory qualities of pain (adjective list by Geissner, SESCopyright ),pain relieving and intensifying factors,previous pain treatment procedures,pain-related disability (Pain Disability Index by Tait et al.),depression test CES-D (Center for Epidemiological Studies Depression Test),comorbid conditions,social factors (educational level, occupation, retirement status, compensation and/or litigation status, disability for work),health related quality of life (SF-36Copyright ). Practicability and content validity were tested in some 3000 patients. Comparison with external criteria (e. g. medical and psychiatric-psychological diagnoses, physician-determined chronicity of pain) proved good content validity and excellent reliability of patients statements in the questionnaire. The great majority of patients stated that the DSF covered their pain history completely and in an orderly fashion. Difficulty to answer the questions was considered low. The German pain questionnaire is a reliable and valid instrument for recording the multidimensional experience of pain. Data from such questionnaires are indispensable for follow-up studies and internal and external quality assessments. The DSF can be ordered from the German Society for the Study of Pain (www.dgss.org) and is a core instrument of the computer program "quality assurance in pain management" (QUAST) of this society.
In contrast to the function of the visual or auditory pathways which are electrophysiologically accessible by visual or auditory evoked potentials, the somatosensory pathway cannot be investigated as a whole by conventional somatosensory evoked potentials (SEP), because these only reflect function of large fibers, dorsal columns, medial lemniscus and their thalamo-cortical projections mediating sensations like touch and vibration. The other half of the somatosensory system, signaling temperature and pain perception, uses a different set of afferents and different central pathways, the function of which is accessible by laser-evoked potentials (LEPs). LEP can document lesions of the spinothalamic tract and (lateral) brainstem and of thalamo-cortical projections conveying thermo-nociceptive signals. In the peripheral nerve, LEP can help distinguish between large and small fiber neuropathies. The rapid heating of the skin by infrared laser pulses can easily be applied to non-glabrous skin in any dermatome. In recent years, many clinical studies have demonstrated that LEP can supply evidence for establishing clinical diagnoses when deficits of the nociceptive system are present. This review outlines principles and recording techniques for LEP in patients and compiles typical LEP findings in patients with lesions due to different diseases at various levels of the nociceptive pathways. Limitations for the use of LEP are pointed out, too, like the uncertainty of lesion location along these pathways and the fact that LEP can reliably show correlates of reduced nociceptive function but only rarely of enhanced transmission (like in hyperalgesia).
This review presents and discusses the leading arguments justifying the use of high power laser stimulators to explore the nociceptive system. To grasp the particularity of such stimulators, fundamentals concerning the interaction of low-energy radiation with the skin will be recalled and focused on the optimal match between the wavelength of the emitting source and the thermophysical properties of the skin. This knowledge shall allow us to discuss critical characteristics of laser stimulators. Study of the cutaneous spectrum of receptors showed that laser stimulators allow the selective activation of A(delta) and C-fiber nociceptors. We will present different methods, which increase the selectivity of the laser stimulation, restricting the activation to isolated C-fiber nociceptors. These methods open new perspectives in the study of the cerebral processing of signals ascending through A(delta) and/or C nociceptors and should contribute to a better understanding of their central interaction and integration in normal and pathological states.
Pain can be induced by thermal, chemical, and mechanical stimulation in animals and man. Of the thermal stimulation modalities, heat is the most commonly used, as a variety of reliable stimulation techniques are available. Heat is a natural stimulus modality to evoke pain, and it has been used to study animal nociception and human pain perception for (a) examining the mechanisms of tissue injury and sensitisation and (b) quantifying the therapeutic effects of pharmacological, physical, and psychological interventions. This paper summarises the current understanding of the physiology and psychophysical response to painful heat stimulation in humans. By understanding the underlying mechanisms, new methods of heat stimulation may be developed for basic and clinical applications. Traditionally, contact heat, indirect thermal heat by focused light bulb, and laser pulses have been the methods used to induce heat pain in humans for experimental and clinical studies. The following lasers have been used in pain research: argon (488-515 nm), copper vapour (510-577 nm), semiconductor (e.g. 970 nm), neodymium-YAG (1064 nm), thulium-YAG (2000 nm), and CO(2) (10,600 nm).
We evaluated the reliability of laser-evoked potentials (LEPs) as a diagnostic tool in patients with post-herpetic neuralgia (PHN), i.e. a chronic painful condition that causes small-diameter fibre dysfunction. Furthermore, we sought information on pathophysiology of PHN pain.
We recorded 'late' LEPs after stimulation of the supraorbital, upper cervical, lower cervical, upper thoracic, mid thoracic, and lower thoracic territories in 12 control subjects and 40 patients with PHN. We also determined the correlation of LEP data with age, duration of disease, and severity and quality of pain.
At all stimulation sites, laser pulses invariably evoked high-amplitude brain potentials related to small-myelinated (A-delta) fibre activation. The laser perceptive threshold and LEP latency correlated with the distance of the dermatome from the brain (P<0.001). In patients, the perceptive threshold was higher and the LEP amplitude was lower in the affected dermatome than on the contralateral side (P<0.001). We found no significant LEP-clinical correlation except for a correlation between LEP abnormality and age.
Being sensitive and reliable in assessing sensory function also in proximal dermatomes, LEPs are a promising diagnostic tool in radiculopathies. Although PHN severely impairs small myelinated fibres, the lack of a significant correlation between LEP abnormalities and pain suggests that pain in PHN does not chiefly arise from a dysfunction of small-myelinated afferents.
Thermal and nociceptive cutaneous stimuli activate the brain via two types of nerve fibers, slightly myelinated Adelta-fibers with moderate conduction velocity and unmyelinated C-fibers with slow conduction velocity. Differences in central processing upon selective stimulation of these two fiber types in healthy human subjects still remain poorly understood. By means of event-related functional magnetic resonance imaging the present study investigated brain activation in response to stimulation of Adelta- and C-fibers in healthy subjects. We used the stimulation of tiny skin areas to perform a selective stimulation upon cutaneous C-fibers. Besides similar activation in several brain areas in response to both kinds of stimulation, we observed pronounced brain activation to selective C-fiber stimulation as compared to Adelta-fiber stimulation in the right frontal operculum and anterior insula. Based on a putative function of these structures we suggest that the C-fiber system might be engaged in homeostatic and interoceptive functions in a manner other than the Adelta-fiber system, producing a signal of greater emotional salience.
Beck-Depressions-Inventar (BDI) [German]. Goettingen: Hogrefe
- M Hautzinger
- M Bailer
- H Worall
- F Keller
Hautzinger M, Bailer M, Worall H, Keller F. Beck-Depressions-Inventar (BDI)
[German]. Goettingen: Hogrefe; 1995.