| | Quantitative sensory testing: a comprehensive protocol for clinical trialsReceived 19 October 2004; accepted 3 February 2005. Abstract 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 full protocol took 27 ±2.3 min per test area. The majority of QST parameters were normally distributed only after logarithmic transformation (secondary normalization) except for the frequency of paradoxical heat sensations, cold and heat pain thresholds, and for vibration detection thresholds. Thresholds were usually lowest over face, followed by hand, and then foot. Only thermal pain thresholds, wind-up ratio and vibration detection thresholds were not significantly dependent on the body region. There was no significant right-to-left difference for any of the QST parameters; left-to-right correlation coefficients ranged between 0.78 and 0.97, thus explaining between 61% and 94% of the variance. This study has shown that a complete somatosensory profile of one affected area and one unaffected control area, which will be necessary to characterize patients with a variety of diseases, can be obtained within 1 h. Case examples of selected patients illustrate the value of z-transformed QST data for an easy survey of individual symptom profiles. Abbreviations: ALL, Dynamic mechanical allodynia, CDT, Cold detection threshold, CPT, Cold pain threshold, DFNS, Deutscher Forschungsverbund Neuropathischer Schmerz, HPT, Heat pain threshold, MDT, Mechanical detection threshold, MPS, Mechanical pain sensitivity, MPT, Mechanical pain threshold, PHS, Paradoxical heat sensation, PPT, Pressure pain threshold, TSL, Thermal sensory limen, VDT, Vibration detection threshold, WDT, Warm detection threshold, WUR, Wind-up ratio 1. Introduction  The assessment of patients with neuropathic pain may utilize the following methods: clinical bedside examination, quantitative sensory testing (QST), questionnaires, standard electrodiagnostic studies, laser evoked potentials (LEP), functional neuroimaging (fMRI and PET), and skin biopsy (Cruccu et al., 2004, Dworkin et al., 2003). Whereas questionnaires are the formalized extension of taking the patient’s history, quantitative sensory testing refers to a set of methods that extend the traditional neurological examination of somatosensory function (Greenspan, 2001, Gracely, 1999, Haanpää et al., 1999). A great variety of quantitative testing procedures has been published, each of which allows quantifying one particular aspect of sensory function. At a consensus conference convened in September 1997 in Boston by Gary Bennett and David Borsook, it became apparent that sophisticated methods of sensory testing are available to assess all aspects of somatosensory function that may be of clinical interest (Arendt-Nielsen, 1997, Arezzo et al., 1993, Cruccu et al., 2004, Dworkin et al., 2003, Dyck et al., 1993a, Dyck et al., 1993b, Fields et al., 1998, Gescheider et al., 2001, Gracely et al., 2003, Hansson and Lindblom, 1993, Shy et al., 2003, Tölle and Baron, 2002). However, two major drawbacks limit their value: first, there is no general agreement on standard procedures and every sensory function may be assessed in a variety of ways and even the same test instrument may give different outcomes due to a variation of stimulation parameters, e.g., thermal thresholds as a function of the temperature ramp (Yarnitsky et al., 1995). Second, performing a comprehensive battery of all those tests in any given patient will eventually exceed the time constraints of clinical routine by far (i.e., a maximum of 60–90 min per patient), thus there is an urgent need for a comprehensive short form QST protocol. To address that issue we have compiled a standardized comprehensive QST battery as part of a nationwide multicenter research network (German Research Network on Neuropathic Pain-DFNS; http://www.neuro.med.tu-muenchen.de/dfns/e_index.html) that would give profiles of somatosensory function for two body areas (one affected and one normal area), and should be performed within 1 h. In contrast to other studies that restricted the assessment to thermal stimuli (Yarnitsky et al., 1995), we included both thermal and mechanical test stimuli. In this respect, our QST protocol is similar to the CASE IV system (Dyck et al., 1993b) that was developed to assess loss of somatosensory function, both in small fiber neuropathies (thermal thresholds) and in large fiber neuropathies (tactile thresholds). Our protocol extends beyond the CASE IV system, however, by also assessing parameters of increased pain sensitivity (hyperalgesia, allodynia, hyperpathia). For mechanical pain we distinguish dynamic and two types of static hyperalgesia (Brune and Handwerker, 2004, Kilo et al., 1994, Koltzenburg et al., 1992, Ochoa and Yarnitsky, 1993). Pressure pain thresholds were included to assess both cutaneous and deep pain sensitivity (Bendtsen et al., 1996, Brennum et al., 1989, Treede et al., 2002). Based on previously published studies the design of the QST battery assembles a comprehensive list of robust and validated short form tests representing measures of all relevant submodalities of the somatosensory system, namely: •vibration detection threshold (Bolanowski et al., 1988, Fagius and Wahren, 1981, Goldberg and Lindblom, 1979, Hilz et al., 1998, Rydel and Seiffer, 1903, Talbot et al., 1968); •pressure pain threshold (Chesterton et al., 2003, Fischer, 1987, Jensen et al., 1986, Kilo et al., 1994, Kosek et al., 1999, Rolke et al., 2005). The aim of our QST protocol was to provide parameters for sensory loss (small and large fiber functions) and sensory gain (hyperalgesia, allodynia, hyperpathia). We tested the feasibility of this QST battery bilaterally over three different body regions (face, hand, foot) in a single center study for the following purposes: (1) to determine the time needed to obtain a full somatosensory profile for one test area, (2) to evaluate the psychometric properties of all parameters, (3) to propose standards for data evaluation, and (4) to prepare a form of simple data presentation for clinical use in individual patients. 2. Methods The whole battery was developed as part of the German Research Network on Neuropathic Pain (DFNS) and consists of seven tests measuring 13 parameters (Fig. 1). The tests can be grouped as follows: •thermal detection thresholds for the perception of cold, warm and paradoxical heat sensations, •thermal pain thresholds for cold and hot stimuli, •mechanical detection thresholds for touch and vibration, •mechanical pain sensitivity including thresholds for pinprick and blunt pressure, a stimulus–response-function for pinprick sensitivity and dynamic mechanical allodynia, and pain summation to repetitive pinprick stimuli. Since it was our aim to use simple hand-held devices whenever available, we did not use an automated vibrameter or pressure algometer, which are useful in specialized sensory laboratory tests. For thermal testing, no simple devices are available yet (Cruccu et al., 2004). 2.1. Subjects To evaluate the properties of the QST battery we tested a small sample of 18 healthy human subjects (9 female, 9 male, mean age 38.1±14.2 years, range 21–58 years). QST data over face (cheek), hand (dorsum) and foot (dorsum) on both sides of the body were obtained within one experimental session. All subjects were without pain medication for at least 24 h prior to the investigation. The study was approved by the local ethics committee (Landesärztekammer Rheinland-Pfalz) and all subjects had given written informed consent. 2.2. Thermal detection, thermal pain thresholds and paradoxical heat sensations The tests for thermal sensation were performed using a TSA 2001-II (MEDOC, Israel) thermal sensory testing device (Fruhstorfer et al., 1976, Yarnitsky et al., 1995). Cold detection threshold (CDT) and warm detection threshold (WDT) were measured first. The number of paradoxical heat sensations (PHS) was determined during the thermal sensory limen procedure (TSL, the difference limen for alternating cold and warm stimuli), followed by cold pain threshold (CPT), and heat pain threshold (HPT). The mean threshold temperature of three consecutive measurements was calculated. All thresholds were obtained with ramped stimuli (1 °C/s) that were terminated when the subject pressed a button. Cut-off temperatures were 0 and 50 °C. The baseline temperature was 32 °C (center of neutral range) and the contact area of the thermode was 7.84 cm2. During the experiment, the subjects were not able to watch the computer screen. All thermal tests were first demonstrated over an area that was not tested later during the QST session. 2.3. Mechanical detection threshold for modified von Frey filaments Modified von Frey filaments (MDT) was measured with a standardized set of modified von Frey hairs (Optihair2-Set, Marstock Nervtest, Germany) that exert forces between 0.25 and 512 mN (Fruhstorfer et al., 2001, Von Frey, 1896, Weinstein, 1968). The contact area of the von Frey hairs with the skin was of uniform size and shape (rounded tip, 0.5 mm in diameter) to avoid sharp edges that would facilitate nociceptor activation. The final threshold was the geometric mean of five series of ascending and descending stimulus intensities (Baumgärtner et al., 2002). 2.4. Mechanical pain threshold for pinprick stimuli Mechanical pain threshold (MPT) was measured using a set of seven custom-made weighted pinprick stimulators (flat contact area of 0.2 mm diameter) that exert forces between 8 and 512 mN (Baumgärtner et al., 2002, Chan et al., 1992, Magerl et al., 1998). Again using the “method of limits”, the final threshold was the geometric mean of five series of ascending and descending stimulus intensities. 2.5. Stimulus–response-functions: mechanical pain sensitivity for pinprick stimuli and dynamic mechanical allodynia for stroking light touch Mechanical pain sensitivity (MPS) was tested using the same weighted pinprick stimuli as for MPT. To obtain a stimulus–response-function, these seven pinprick stimuli were applied in a balanced order, five times each, and the subject was asked to give a pain rating for each stimulus on a 0–100 numerical rating scale (‘0’ indicating “no pain”, and ‘100’ indicating “most intense pain imaginable”). Stimulus–response-functions for dynamic mechanical allodynia (ALL) were determined using a set of three light tactile stimulators (Baumgärtner et al., 2002, LaMotte et al., 1991): a cotton wisp exerting a force of ∼3 mN, a cotton wool tip fixed to an elastic strip exerting a force of ∼100 mN, and a standardized brush (Somedic, Sweden) exerting a force of ∼200–400 mN. The three tactile stimuli were applied five times each with a single stroke of approximately 1–2 cm in length over the skin. They were intermingled with the pinprick stimuli in balanced order and subjects were asked to give a rating on the same scale as for pinprick stimuli. 2.6. Wind-up ratio – the perceptual correlate of temporal pain summation for repetitive pinprick stimuli In this test of temporal summation, the perceived magnitude of a single pinprick stimulus was compared with that of a train of 10 pinprick stimuli of the same force repeated at a 1/s rate (128 mN, when tested over face, and 256 mN, when tested over hand and foot). The train of pinprick stimuli was given within a small area of 1 cm2 and the subject was asked to give a pain rating representing the pain at the end of the train using a numerical rating scale. In contrast to the more sophisticated technique of VAS-ratings at a 1/s rate (Magerl et al., 1998) this method (modified from Sieweke et al., 1999) is likely more appropriate for clinical routine assessment. Single pinprick stimuli were alternated with a train of 10 stimuli until both were done five times at five different skin sites within the same body region. The mean pain rating of trains divided by the mean pain rating to single stimuli was calculated as wind-up ratio (WUR). 2.7. Vibration detection threshold Vibration detection threshold (VDT) test was performed with a Rydel–Seiffer tuning fork (64 Hz, 8/8 scale) that was placed over a bony prominence (cheek, processus styloideus ulnae, malleolus medialis). Vibration threshold was determined with three series of descending stimulus intensities (Fagius and Wahren, 1981, Goldberg and Lindblom, 1979, Rydel and Seiffer, 1903). 2.8. Pressure pain threshold The final test in the protocol was performed with a pressure gauge device (FDN200, Wagner Instruments, USA) with a probe area of 1 cm2 (probe diameter of 1.1 cm) that exerts pressure up to 20 kg/cm2/∼200 N/cm2/∼2000 kPa (Fischer, 1987, Kilo et al., 1994, Kosek et al., 1999, Rolke et al., 2005). The pressure pain threshold (PPT) is determined with three series of ascending stimulus intensities, each applied as a slowly increasing ramp of 50 kPa/s. 2.9. Data evaluation All data were analyzed for their distribution properties. We calculated skewness, kurtosis, Kolmogorov–Smirnov’s d for raw data and log-transformed data. The product of the geometric mean of skewness and kurtosis combined and the geometric mean of Kolmogorov–Smirnov’s d (for continuous test of normality of distribution) was calculated as a compound measure of goodness of normality. Log-transformation was considered to be superior, when the ratio for raw data to log-transformed data exceeded a factor of 3. For pain ratings to pinprick and light touch a small constant (+0.1) was added prior to log-transformation to avoid a loss of zero rating values (Bartlett, 1947, Magerl et al., 1998). All statistical calculations were performed by using the Statistica software package, release 6.0 for Windows (StatSoft Inc., USA). Differences between areas (face, hand, foot), right and left sides of the body were compared using a two-way analysis of variance for repeated measures (ANOVA). Post hoc comparisons were calculated using LSD-post hoc tests (LSD=least significant difference). Log-data of thresholds were retransformed to linear values representing the original unit of each test. 2.10. Z-transformation of QST data to create profiles of sensory changes To compare a patient’s QST data profile with control data independent of the different units of measurement across QST parameters, the patient data were Z-transformed for each single parameter by using the following expression (Glass and Stanley, 1970, Gauss, 1863): This procedure results in a QST profile where all parameters are presented as standard normal distributions (zero mean, unit variance). For clarity of data presentation we adjusted the algebraic sign of Z-score values for each parameter so that it reflects the patient’s sensitivity for this parameter. Z-values above “0” indicate a gain of function when the patient is more sensitive to the tested stimuli compared with controls, while Z-scores below “0” indicate a loss of function referring to a lower sensitivity of the patient. Thus, elevations of threshold (CDT, WDT, TSL, HPT, CPT, MDT, MPT, VDT, PPT) resulted in negative Z-scores, whereas increases in ratings (MPS, ALL, WUR) resulted in positive Z-scores. Paradoxical heat sensations (PHS) were interpreted as a loss of thermodiscriminative function resulting in negative Z-scores. Even though QST specialists are familiar with the concept of threshold elevations, we decided to use this procedure, because the general readership may find it conceptually easier to think in terms of gain or loss of sensory function. After this Z-transformation it is straightforward to compare a single patient with the group mean of healthy controls, since the 95% confidence interval (CI) of a standard normal distribution is defined as follows: 3. Results It was possible to obtain all QST data in all 18 healthy subjects at all sites tested. The testing procedures were easily feasible with a mean duration of 27.0±2.3 min for the full QST protocol tested over one test area. Thus, assessing six sites in healthy subjects took about 3 h. In patients, assessment of two sites (one affected, one normal area) is expected to be finished within 1 h. 3.1. QST report form QST data were entered into an EXCEL-spreadsheet (Microsoft, USA) automatically generating thresholds and average ratings, and numbers of observed symptoms (in the case of PHS). These data are summarized in a single sheet QST report form which eases comparison of the test and control areas (Fig. 2). 3.2. The majority of QST parameters are lognormally distributed Some QST parameters were not normally distributed, but normal distribution was achieved by logarithmic transformation (secondary normal distribution). A typical example is shown in Fig. 3 (warm detection thresholds in the hand dorsum). Table 1 comprises skewness, kurtosis and Kolmogorov–Smirnov’s d as markers to test for normality of distribution in raw and log-transformed data. Based on a weighted comparison of distribution parameters we recommend to execute log-transformation in the following QST parameters: CDT, WDT, TSL, MDT, MPT, MPS, ALL, WUR, and PPT. | a Paradoxical heat sensation (PHS) and allodynia (ALL) did not significantly occur in healthy subjects. bRecommendation on data transformation for allodynia (pain to light touch) was derived from patient studies and from studies of experimentally induced hyperalgesia (Baumgärtner et al., 2002, Magerl et al., 2001). |
3.3. QST procedures show highly significant differences across test areas There were highly significant differences between test areas for most QST parameters (Table 2), except for cold pain threshold (CPT), heat pain threshold (HPT), wind-up ratio (WUR), and vibration detection threshold (VDT). Differences between test areas could not be assessed for paradoxical heat sensations (PHS) and dynamic mechanical allodynia (ALL) because there was no significant occurrance of these parameters in healthy subjects. Mean value differences across areas are illustrated in Table 1. Thresholds were usually lowest over face, followed by hand and foot with the exceptions of vibration detection threshold presenting the highest sensitivity in the hand (Table 1), and stimulus–response-function for pinprick presenting highest sensitivity over face, followed by foot, then hand. No differences were found between body sides (Table 2), and there were no interactions between test area and body side. These findings confirm that each area of the body needs its own set of QST reference data. Due to the narrow age range and small number of healthy subjects in the present study we did not address age or gender differences. 3.5. QST profiles of Z-transformed data in selected patients To illustrate the potential use of QST profiles, Fig. 4 presents QST profiles of three selected patients. Some of the Z-values were beyond the 95% confidence interval (grey zone) of healthy subjects showing three different patterns of sensory changes. Patient A (vibration induced vasospastic syndrome), a 64-year-old man, complained about intermittent Raynaud-syndrome and painless dysesthesia of the right hand after working for more than 20 years using a chain-saw. Sensory conduction velocities of the median and ulnar nerves were pathologically reduced, motor conduction velocity was normal corresponding to the lack of a motor deficit. Autonomic testing revealed normal sudomotor function, but a slightly reduced heart rate variability. The QST profile shows combined sensory loss for large fiber (MDT, VDT) and small fiber mediated stimuli (CDT, WDT, TSL). Patient B (small fiber neuropathy), a 60-year-old woman, suffered for more than 1 year from a severe burning pain over feet with a stocking distribution. Mean pain rating was 50 on a 0–100-numerical rating scale. Conventional neurography over legs only demonstrated a reduced amplitude (2.4 mV) of the peroneal nerve but normal motor conduction velocity (51.8 m/s) of that nerve. Somatosensory evoked potentials (SEP) of the tibial nerve were normal (latency 41.0 ms, amplitude 1.5 μV). Motor evoked potentials (MEP) were normal for hands and feet. The QST profile of this patient shows a loss of sensory function only for thermal detection thresholds (CDT, WDT, TSL), which are mediated by small nerve fibers. Cooling stimuli during the TSL procedure were often mistaken as heating stimuli (paradoxical heat sensations). Patient C (chronic low back pain attributed to facet joint arthropathy), a 45-year-old woman, complained about permanent low-back pain of fluctuating intensity for 7 years. Mean pain rating was 60 on a 0–100 numerical rating scale. Clinically, there was neither sensory nor motor loss attributable to any spinal root. Pain increased upon dorsiflexion of the back, and paraspinal segments L4 and L5 overlying the facet joints were sensitive to local pressure bilaterally. The QST profile of this patient shows a sensory gain beyond the normal range for cold pain threshold (CPT), for sharp stimuli (MPT, MPS), and blunt pressure (PPT). 4. Discussion Our study shows that the present QST protocol consisting of seven previously published tests examining altogether 13 QST parameters covering all somatosensory channels was feasible within a reasonable time of about 1 h for two symmetrical areas of the body. Differences in thresholds over different body areas indicate the need for calculating QST reference data for each area, and for presenting data of individual patients relative to those reference data. The lack of a side difference over all areas suggests that side-to-side testing may give the most sensitive results. Further studies need to evaluate this QST battery regarding inter-observer reliability, repeatability within defined time intervals, and validity for mechanism-based diagnoses in patients with chronic pain (Hansson et al., 2001, Jensen and Baron, 2003, Woolf et al., 1998). 4.1. QST parameters vary significantly over areas As in previous studies the body area over which QST parameters were tested had a significant effect on most QST parameters (CDT, WDT, TSL, MDT, MPT, MPS, PPT). Generally lowest thresholds were found over face, followed by hand and foot. The same regional differences were seen in thermal pain thresholds (CPT, HPT) but just failed to be significant due to the limited sample size. These differences may not always represent true regional differences, since stimuli, which were applied as increasing ramps of temperature or pressure (CDT, WDT, TSL, CPT, HPT, PPT) always included reaction time artefacts, following the rule that the longer the distance to the brain, the larger the reaction time artefact (see, e.g., Tillman et al., 1995, Yarnitsky and Ochoa, 1991). In contrast, the higher sensitivity of the hand to vibratory stimuli documented in previous studies (e.g., Goldberg and Lindblom, 1979) just missed significance in our data (p=0.08) and may even be underestimated due to a reaction time artefact, since it was measured as a disappearance threshold. The pain thresholds for pinprick stimuli (MPT) constituted another exception from the rule, since MPT was lower over foot than hand, likely because the hands usually are more exposed to environmental influences than feet, e.g., ultraviolet radiation and exhibit a significant thickening of the epidermis resulting in a higher mechanical resistance to stimuli causing shear stress by very localized strong indentations (Holbrook and Odland, 1974, Plewig and Marples, 1970). 4.2. Z-score QST profiles for easy data analysis and presentation The abundance of tested parameters in the QST protocol of the DFNS indicates the need for an easily applicable standard presentation. At the same time, a standard presentation has to account for the fact that different parameters come in different units of measurement and possible data ranges differ vastly across variables (e.g., 0–3 for PHS vs. 0.0–31.9 °C for CPT). Moreover, a clear definition of hyper- and hypophenomena is essential, if QST is to gain wider acceptance. Grouping under the heading of “abnormal finding” as often done in the existing literature is of little value and may potentially obscure a view on mechanisms of a pathology (Hansson et al., 2001). All of these requirements are fulfilled by the Z-transformed QST profiles as presented for three selected patients in Fig. 4. To enable the reader to interpret the meaning of a deviation from normality, we adjusted the signs of the Z-score values in such a way that they specify uniformly whether a change represents gain or loss of sensitivity. For example, a drop in pain threshold and an increase in suprathreshold pain ratings both indicate a gain in pain sensitivity with positive Z-scores (e.g., in MPT and MPS in patient C). This way, we have chosen to present QST data according to the general concept of “loss or gain of sensory function”, which has a longstanding tradition throughout the neurological sciences. We suggest to use Z-transformed QST data (i.e., data presentation as values from a standard normal distribution of a reference database) in order to judge the significance of sensory changes in a single patient with reference to healthy controls. The Z-transformation has to be done separately for each QST parameter and for each area tested. Most of the QST parameters required a logarithmic data transformation to conform to a normal (Gaussian) distribution. For mechanical pain thresholds to blunt and pricking stimuli, and for pain ratings this transformation had previously been identified as adequate (e.g., Magerl et al., 1998, Rolke et al., 2005). We have now extended those findings to mechanical and thermal detection thresholds (cf. Haanpää et al., 1999, Weinstein, 1968), but not thermal pain thresholds. Logarithmic transformation of the latter are inadequate, since the temperature scale is arbitrary and there is no natural zero in the stimulus dimension. In contrast, the wind-up ratio (Price et al., 1994, Vierck et al., 1997) like all ratios follows a geometrical distribution, which is adequately accounted for by logarithmic transformation (cf. Magerl et al., 1998). In the resulting Z-score QST profile the differences between different areas like hands or feet become irrelevant due to site-specific normalization. Therefore, this type of data presentation will allow at-a-glance identification of symptom patterns, e.g., to identify local vs. bilateral or generalized alterations of the somatosensory system. Localized changes can easily be judged compared to an unaffected control area, while generalized changes can only be identified using absolute reference values. 4.3. Strengths and limitations of quantitative sensory testing Quantitative sensory tests are psychophysical in nature, with an objective physical stimulus but a subjective report from a patient or control subject as the response. In contrast to electrophysiological, imaging and biopsy techniques, QST requires cooperation from the subject. The size of the effects of malingering and other non-organic factors on QST findings is currently unresolved (Shy et al., 2003), eliminating its use in medico-legal matters. On the other hand, QST can assess both large and small fiber function as illustrated in patients A and B, whereas standard electrophysiology is limited to large fibers (Cruccu et al., 2004). Laser-evoked potentials allow functional assessment of small fibers, but appear to be insensitive to gain of function (Treede et al., 2003). Thus, hyperalgesia and allodynia are domains for QST as illustrated in patient C. Other small fiber tests (sudomotor, heart rate variability) assess the autonomic but not sensory system. The high side-to-side correlations of all QST parameters predict that short-term test–retest reliability within the same day should be high. However, formal determination of test–retest reliability over different time ranges (1 day, 1 month, 1 year) as well as inter-observer reliability are needed to assess the overall reliability of this QST protocol. As mentioned in the recent American Academy of Neurology guideline (Shy et al., 2003), the inter-observer reliability will depend on the quality of training personnel to administer this QST battery in a standardized fashion. Future studies should show reproducible results on both healthy subjects and patients. Such studies are under way in the German Research Network on Neuropathic Pain (DFNS). Validation of a procedure such as QST requires comparison with a gold standard. This is not an easy task, because QST is not suggested to be a diagnostic test for one particular disease entity. Instead, we and others hope that QST will help in the mechanism-based diagnosis of pain (cf. Baron and Saguer, 1995, Baumgärtner et al., 2002, Fields et al., 1998, Hansson et al., 2001, Jensen and Baron, 2003, Woolf et al., 1998). Such mechanisms could include sensory deafferentation, central sensitization or peripheral sensitization. Although the patients presented in Fig. 4 lend themselves for a tentative mechanism-based interpretation, at present this interpretation is largely based on conjecture and analogy. Studies on a preclinical level in human surrogate models of pain and hyperalgesia with known mechanisms of symptom induction are needed to be able to connect a distinct pattern of sensory changes with an underlying mechanism and hence establish discriminative validity. Such studies are already under way (e.g., Gustorff et al., 2004, Lang et al., 2004). An advantage of the QST protocol presented here is that it covers nearly all aspects of somatosensation and hence can be used to identify the QST patterns for a wide variety of mechanisms. On a clinical level, external validity may be tested in defined clinical cases and against other (objective) methods of assessment as was also suggested for all QST in the current AAN Guidelines (Shy et al., 2003). Validation against gold-standards is only possible, where they exist (e.g., clinical neurophysiology for large fiber neuropathy). In reality, for many clinical situations there is at best a “brass standard”. In particular, small fiber neuropathy cannot be identified at all by standard clinical neurophysiology or light-microscope nerve biopsy, and skin punch biopsy or laser evoked potentials are only an emerging possible standard (Cruccu et al., 2004). Along the same lines of clinical research, specificity and sensitivity have to be estimated to establish the relative importance of QST and other tests (as instructive examples see Fitzek et al., 2001, Jääskeläinen et al., 2004). 4.4. Conclusions and clinical implications The QST protocol of the DFNS, as described here, packed an unprecedented wide range of tests, covering nearly all aspects of somatosensation, into one short form QST battery that is feasible both technically and within the time constraints of clinical assessment. None of the components in this QST battery is a new invention. We intentionally included only tests that had some previous evidence for their validity and sensitivity. Distribution properties of these QST parameters and adequate data transformation rules were established, which form the basis of a simple way of data presentation as Z-score QST profiles. This work has now to be extended to establish a population-based reference database, which is currently developed by a nation-wide multi-center study (DFNS – German Research Network on Neuropathic Pain). Such a database will provide data on the age and gender-dependence of all QST parameters. Inter-observer and test–retest reliability have to be established to confirm the adequacy of this QST protocol. Once validated with known neural mechanisms and against external standards, this protocol is expected to help in the mechanism-based diagnosis of neuropathic pain. 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a Institute of Physiology and Pathophysiology, Johannes Gutenberg-University, Saarstr. 21, D-55099 Mainz, Germany b Department of Neurology, Johannes Gutenberg-University, Mainz, Germany c Department of Anatomy and Developmental Biology, University College, London, UK  Corresponding author. Tel.: +49 6131 3925715; fax: +49 6131 3925902.
PII: S1090-3801(05)00027-3 doi:10.1016/j.ejpain.2005.02.003 © 2005 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Inc. All rights reserved. |
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