Repeatability of Quantitative Sensory Testing in Healthy Cats in a Clinical Setting With

1 Repeatability of quantitative sensory testing in healthy cats in a clinical setting with comparison to2 cats with osteoarthritis3 ES Addison1 and DN Clements24 1The Royal (Dick) School of Veterinary Studies, Hospital for Small Animals, Division of Veterinary 5 Clinical Sciences, The University of Edinburgh, Easter Bush Veterinary Centre, Roslin, Midlothian, 6 EH25 9RG, UK7 2The Royal (Dick) School of Veterinary Studies and Roslin Institute, Division of Veterinary 8 Clinical Sciences, The University of Edinburgh, Easter Bush Veterinary Centre, Roslin, Midlothian 9 EH25 9RG, UK1011 Corresponding author12 Elena Addison MA VetMB13 [email protected]14 The Royal (Dick) School of Veterinary Studies, 15 Hospital for Small Animals, 16 Division of Veterinary Clinical Sciences, 17 The University of Edinburgh, 18 Easter Bush Veterinary Centre, 19 Roslin, 20 Midlothian, 21 EH25 9RG.22 Telephone: 0131 650 76502324 Abstract25 Objectives26 The aim of this study was to evaluate the repeatability of quantitative sensory tests (QSTs) in a group27 of healthy untrained cats (n=14) and to compare those results to cats with osteoarthritis (n=7).28 Methods29 Peak vertical force (PVF) and vertical impulse (VI) were measured on a pressure plate system. 30 Thermal sensitivity was assessed using a temperature-controlled plate at 7°C and 40°C. Individual 31 paw lifts and overall duration of paw lifts were counted and measured for each limb. Paw 32 withdrawal thresholds were measured using manual and electronic von Frey monofilaments (MVF 33 and EVF respectively) applied to the metacarpal or metatarsal pads. All measurements were 34 repeated twice to assess repeatability of the tests. 35 Results36 In healthy cats all tests were moderately repeatable. When compared to cats with osteoarthritis the 37 PVF was significantly higher in healthy hindlimbs in repeat one but not in repeat two. Cats with 38 osteoarthritis of the forelimbs showed an decrease in the frequency of paw lifts on the 7°C plate 39 compared to cats with healthy forelimbs and the duration of paw lifts was significantly less than 40 healthy forelimbs in the first repeat but not in the second repeat. Osteoarthritic limbs had 41 significantly lower paw withdrawal thresholds with both MVF and EVF than healthy limbs.42 Conclusions and relevance 43 QSTs are moderately repeatable in untrained cats. Kinetic gait analysis did not permit differentiation 44 between healthy limbs and those with osteoarthritis, but thermal sensitivity testing (cold) does. 45 Sensory threshold testing can differentiate osteoarthritic and healthy limbs and may be useful in 46 diagnosis and monitoring of this condition in cats in the clinical setting.4748 Introduction49 Accurate clinical assessment of pain in cats is challenging. Osteoarthritis (OA) is a common cause of 50 chronic pain and develops with aging in this species (1). Diagnosis is complicated by the fact that 51 lameness is not a common feature (1) and early cartilaginous lesions may develop without 52 concurrent osteophytosis, which can lead to a mismatch between radiographic lesions, orthopaedic 53 examination findings and clinical signs (2). This is compounded by the lack of validated pain 54 assessment and screening tools in cats (3) which increases the difficulty in identifying those affected 55 by the chronic pain associated with OA. In a clinical setting pain assessment of cats usually involves 56 veterinary clinical examination, radiography and discussion with the owner regarding the cat’s 57 mobility and behaviour.58 The severity of radiographic lesions does not correlate with the severity of pain experienced by 59 humans with symptomatic osteoarthritis (4). Central sensitisation, which occurs in OA, has been 60 suggested as the explanation for this inconsistency (5). In chronic painful states like OA, central 61 sensitisation is due to the sustained activity of nociceptors leading to an increase in the excitability 62 of neurons within the central nervous system. This activity-dependent synaptic plasticity leads to 63 increases in synapse efficacy and reductions in inhibition causing somatosensory abnormalities such 64 as allodynia, hyperalgesia or thermal hypersensitivity at local and remote sites from the affected 65 joint (6). Central sensitisation therefore has important implications for the diagnosis and effective 66 treatment of pain. 67 Somatosensory abnormalities can be assessed using quantitative sensory tests (QSTs). QSTs involve 68 the application of mechanical, thermal or electrical stimuli to an area to assess sensory and/or pain 69 pathways (7). Two studies have evaluated these in dogs demonstrating increased sensory sensitivity 70 in those with OA (8, 9), which is likely to reflect the presence of central sensitisation. Increased 71 sensory sensitivity with a reduction in paw withdrawal threshold has also been identified in cats with72 OA using a von Frey anaesthesiometer (10, 11). In these studies cats were trained for gait analysis 73 across a pressure plate system and they were partially restrained in a mesh cage for paw withdrawal 74 threshold assessment.75 Clinical application of QSTs has the potential to aid diagnosis of osteoarthritis in cats and to help 76 evaluate the efficacy of treatment. Experimental studies have demonstrated good repeatability of 77 these tests in an experimental setting (10) but to the authors’ knowledge no studies have evaluated 78 the application of QSTs to untrained cats in a clinical setting.79 The purpose of this study was to evaluate the repeatability of QSTs in a clinical setting in healthy 80 untrained cats and to further investigate the somatosensory abnormalities that are present in cats 81 with osteoarthritis to assess clinical utility in aiding diagnosis of this condition. It was hypothesised 82 that QSTs would be repeatable in untrained cats and that cats with osteoarthritis would 83 demonstrate lower paw withdrawal thresholds and cold hypersensitivity, similar to findings in dogs.8485 Materials and methods86 The study design was approved by the University of Edinburgh Veterinary Ethical Review Committee 87 (Reference 14/12). Prior to a cat’s enrolment in the study, all assessments were explained in detail 88 to the owner and written consent was obtained. All tests were readily escapable.89 Phenotyping 90 Cats were recruited from February 2013 to November 2014. All owners completed a questionnaire 91 (see Appendix) assessing mobility, activity levels, grooming habits and temperament. Activities were 92 scored from 0 to 4 (0 = no problem completing the activity; 1 = a little problematic; 2 = quite 93 problematic; 3 = severely problematic; 4 = impossible). The presence of lameness or resentment to 94 being handled was scored as 0 if negative and 1 if positive. The owner was asked if the cat sought 95 seclusion, which was scored as 0 if they never sought seclusion; 1 if rarely; 2 if occasionally; 3 if often96 and 4 if all the time. The owner was also asked regarding the cat seeking interaction with family 97 members and was scored as 0 if interaction occurred all the time; 1 if it occurred often; 2 if it 98 occurred occasionally; 3 if it occurred rarely and 4 if it never occurred. 99 All cats underwent a full physical and orthopaedic examination by both authors to assess for any 100 orthopaedic or neurological disease. Painful joints were identified and noted for each cat if present.101 Medical records and radiographic/computed tomography (CT) images were reviewed in cats with 102 painful joints to assess for the presence of osteoarthritis and response to analgesia.103 Cats were placed into the ‘healthy’ group if there was no evidence of activity/mobility impairment 104 from the questionnaire and were deemed to be in good general health following veterinary 105 examination. Cats were placed into the ‘osteoarthritis’ group if there was clear activity/mobility 106 impairment from the questionnaire; consistent joint pain on examination, evidence of osteoarthritis 107 in those joints on radiographic examination or computed tomography scan and/or positive 108 improvement in mobility with a course of meloxicam. In those cats treated with meloxicam this 109 medication was stopped 48 hours prior to testing. As the half-life is 24 hours (12), therapeutic 110 concentrations should not have been present. No cats received opioid analgesia.111 Kinetic gait analysis112 A Tekscan pressure walkway (Tekscan, Boston, MA, USA) consisting of two sensing tiles connected 113 together to form a single low-profile 1 m x 0.5 m pressure walkway containing 1.4 sensels per cm2 114 was used. Two ‘Tekscan EH-2 Evolution’ handles were used to connect the walkway to a laptop 115 computer, allowing kinetic data to be analysed using proprietary software (Walkway v7.02, Tekscan, 116 Inc. South Boston, USA). The walkway was calibrated as per manufacturer guidelines and a 117 proprietary equilibration file (20 PSI) was used when gathering data. The data was collected in a 118 quiet room with two cardboard boards on either side of the long edge of the walkway with exits at 119 the front and back of the walkway. The cats were encouraged to walk across with positive 120 reinforcement with food, toys or the presence of their bed, basket or owner. The cats walked across 121 the walkway at their own (self-governed) speed. This was repeated until five valid trials were 122 obtained. Trials were excluded if the cat ran, trotted, paused, stopped or turned their head on the 123 walkway. Only trials with a velocity in the central 50% of the cat’s comfortable speed were used. The124 peak vertical force (PVF), vertical impulse (VI) and velocity were calculated. PVF and VI were 125 expressed as a percent of body weight (BW). Symmetry indices were calculated using the following 126 formula (13):127 SI1 = 200 x ((PVF1-PVF2)/(PVF1+PVF2))128 ‘SI’ stands for symmetry index and PVF1 was the higher value and PVF2 was the lower value. A SI of 129 0 indicated perfect symmetry. A second SI was also used, which has been used in a previous study 130 with kinetic gait analysis in cats (14):131 SI2 = PVF2/PVF1132 With this index a SI of one indicated perfect symmetry.133 Cut-off values used to differentiate between lame and normal dogs were evaluated to assess utility 134 in cats, which were as follows (13):135 Cut-off value for lameness = mean SI + (2 x standard deviation)136 Thermal sensitivity 137 The custom designed thermal platform (Figure 1) was manufactured in-house to provide a level 138 1000mm x 500mm x 15mm aluminium platform which could be controlled at 7ºC (cold plate) or 139 40ºC (hot plate). The cooling and heating was achieved using Peltier elements with the ‘back’ surface140 of the elements being maintained at room temperature with computer processor coolers. The 141 platform contained 18 Peltier elements and associated processor coolers which were arranged in six 142 rows of three each. Twenty-one calibrated temperature sensors were mounted in the platform and 143 the temperature readings from the six sensors surrounding each group of three Peltier elements 144 were used to stabilise the temperature in that area of the platform. The Peltier elements were 145 driven by six reversible switching drivers and proportional control is provided by pulse width 146 modulation of the drive signals and the choice of cooling or heating for each channel. The whole 147 system was controlled by a PIC microcontroller which acquired and displayed the temperature 148 measurements at each temperature sensor. The surface temperature was confirmed on the top of 149 the platform at multiple random points prior to use with a digital thermometer. 150 Cats were placed onto the plate at each temperature and after 10 seconds of habituation the 151 number of times and duration that each paw was lifted clear of the plate surface was recorded over 152 80 seconds. The plate was escapable (by walking off) in all directions at all times. A period of at least 153 five minutes with rest on a surface at room temperature occurred between testing at each 154 temperature.155 Paw withdrawal threshold156 Paw withdrawal threshold was assessed with von Frey monofilaments. In the first test manual von 157 Frey monofilaments (MVF) were used (Touch Test® Sensory Evaluators, North Coast Medical & 158 Rehabilitation products, Gilroy, USA) (Figure 2). The filament was applied to the palmar or plantar 159 aspect of the metacarpal or metatarsal pad respectively, when the cat was standing with minimal 160 manual restraint. A negative response was no paw withdrawal with buckling of the filament. A 161 positive response was the cat withdrawing its paw prior to the filament buckling. The threshold 162 sensitivity (measured in grams) was defined as the filament which induced a paw withdrawal at least163 three times in six repeated measurements.164 In the second test an electronic von Frey device (EVF) was used (Model 2391, IITC Life Science, 165 California, USA) (Figure 3). This had a rigid probe (0.8mm diameter tip) on a hand-held force 166 transducer (800g internal load cell) with a threshold monitoring anaesthesiometer which gave 167 readings in grams. The probe was applied to the same area as described above. The force of the 168 probe was steadily increased until paw withdrawal was elicited or the maximum value of 400g was 169 reached. This was repeated three times and the average of the three readings was used in the 170 analysis.171 Repeatability172 All tests were repeated on a second separate occasion (minimum of two hours between tests) to 173 evaluate repeatability.174 Statistical analysis175 Data analysis was performed using three types of statistical software (Microsoft Excel 2010, 176 Microsoft Corporation, Reading, Berkshire, UK; Minitab 17, Minitab Ltd., Coventry, UK; MedCalc 177 version 16.4.3, MedCalc Software, Ostend, Belgium).178 All data was analysed to assess if it was parametric or non-parametric. Left versus right limbs were 179 evaluated in the healthy group using the Mann-Whitney U test or the paired Student t-test (for non-180 parametric and parametric data respectively). Repeatability was assessed in the healthy group using 181 the Wilcoxon-signed rank test or paired Student t-test (for non-parametric and parametric data 182 respectively) to evaluate for differences between the first and second repeat. Bland-Altman plots 183 were then performed for each test. 184 The overall score for the questionnaire was assessed between healthy cats and those with arthritis. 185 A Mann-Whitney U test was performed to evaluate the difference in score. Each score for each 186 activity was then assessed between the two groups using the Fishers Exact Test.187 As the cats in the osteoarthritis group had different joints affected statistical analysis was performed188 to evaluate differences between healthy limbs and those limbs affected by osteoarthritis. 189 Differences between limbs were assessed using the Mann-Whitney U test or the two-sample 190 Student t-test (for non-parametric and parametric data respectively). A Bonferroni correction was 191 applied to correct for multiple comparisons.192193 Results194 Phenotyping195 23 cats in total were recruited for the study with 16 cats in the healthy group and seven cats in the 196 OA group. Two cats in the healthy group were excluded as they both had a painful left elbow joint on197 orthopaedic examination, leaving 14 cats in total in this group. 198 The median score of the questionnaire of healthy cats was two and that of the OA cats was 14. The 199 questionnaire score was significantly higher for the OA group (p=0.0030). On individual activity 200 assessment walking (p=0.0001), running (p=0.0010) and jumping (p=0.0001) scored significantly 201 higher in the OA group in comparison to the healthy group.202 Five cats in the OA group were being treated with meloxicam, which was stopped 48 hours prior to 203 testing. One cat in this group also had inflammatory bowel disease, which was well controlled on 204 low-dose prednisolone (1mg (0.27mg/kg) orally every 24 hours). This cat developed vomiting if the 205 prednisolone was stopped; therefore treatment was continued during testing. Another cat in the OA 206 group had been diagnosed with alimentary small cell lymphoma, which was treated with 207 dexamethasone (0.16mg/kg subcutaneously every two weeks). Testing was performed at the end of 208 the two week period, prior to a repeat dexamethasone injection. Neither of these two cats had any 209 abdominal discomfort on examination prior to testing. All cats in the OA group had radiographic 210 (n=2) or CT (n=4) evidence of OA in the painful joint except one cat, which had painful joints and a 211 significant improvement in mobility with treatment with meloxicam (the owner had declined 212 imaging). Joints affected included the hip joint (bilateral; two cats); the stifle joint (unilateral; two 213 cats); the shoulder joint (unilateral one cat; bilateral one cat) and the elbow joint (unilateral one cat; 214 bilateral one cat).215 Signalment216 11 cats were male (seven healthy; four OA) and 10 were female (seven healthy; three OA). 20 cats 217 were neutered (14 healthy; six OA) and one cat was entire (OA). 13 cats were domestic short- or 218 longhair (11 healthy; two OA) and eight cats were represented by the following breeds: British 219 Shorthair (two healthy); Birman (one healthy); Bengal (one OA); Maine Coon (three OA) and Persian 220 (two OA). There was no significant difference between the gender, breed or neuter status between 221 healthy and OA groups. 222 The median age of the healthy group was seven years one month and of the OA group was 12 years. 223 The OA group was significantly older than the healthy group (p=0.0394).224 Repeat testing225 The second repeat of the tests was performed on the same day for all cats except six who were not 226 available for same day testing. Repeat testing performed on the same day was performed at least 227 two hours apart. Three healthy cats had the second repeat tests performed four, six and 26 weeks 228 after the first session. Three OA cats had the second repeat tests performed 15 weeks after the first 229 session. One cat with OA was not available for second repeat tests.230 Tests in healthy cats 231 Table 1 summarises mean/median values and confidence intervals for each test. In the kinetic gait 232 analysis the median velocity was 65cm/s with a range of 14.2-112.8cm/s. Hindlimbs bore 80.92% of 233 the weight of the forelimbs in the first repeat and 79.25% of the weight in the second repeat, 234 consistent with previous reports (15). The PVF and VI were significantly higher for the forelimbs than235 the hindlimbs (PVF: p<0.0001 repeat one; p=0.0007 repeat two; VI: p=0.0248 repeat one; p=0.0156 236 repeat two).237 Table 2 summarises the symmetry index results for the PVF of the forelimbs and hindlimbs in healthy238 cats. Using the cut-off values for lameness one healthy cat was falsely classed as forelimb lame in 239 repeat one and another healthy cat was falsely classed as hindlimb lame in repeat two. This was 240 identified in the same cats for both symmetry indices. The duration of time to obtain five valid trials 241 varied with the individual cat. For repeat one the median time was 12 minutes (range: 6-22 minutes)242 and for repeat two the median time was 15 minutes (range: 6-55 minutes).243 The frequency of paw lifts on the cold and hot plates were significantly higher in the forelimbs than 244 the hindlimbs in repeat two (cold: p=0.0074; hot: p=0.0029), but not in repeat one (cold: p=0.0767; 245 hot: p=0.0795). The duration of the paw lifts for both plates were significantly higher for the 246 forelimbs than the hindlimbs in both repeats however (cold: p=0.0036 repeat one; p=0.0009 repeat 247 two; hot: p=0.0123 repeat one; p=0.0001 repeat two). There was no significant difference between 248 paw withdrawal threshold sensitivity between forelimbs and hindlimbs.249 There was no significant difference between left and right forelimbs or hindlimbs in any test. 250 Repeatability251 There was no difference in the mean or median value between repeat one and repeat two of any 252 test. Bland-Altman plots (see Figure 4 and Appendix) demonstrated moderate repeatability of all 253 tests; however there were large limits of agreement for all tests due to individual variability between254 repeats. The largest variability was present for the MVF and EVF. 255 Healthy versus osteoarthritic limbs256 See Table 1 for mean/median values and confidence intervals for each test. Table 3 contains the p-257 values for each test. In hindlimbs with OA, PVF was significantly lower than healthy hindlimbs in 258 repeat one (p=0.0017), but not in repeat two. There was no significant difference in the PVF 259 between healthy and OA forelimbs. There was no significant difference in the VI between healthy 260 and OA forelimbs or hindlimbs. Table 4 summarizes the symmetry index results for the PVF of the 261 forelimbs and hindlimbs in OA cats. Using the cut-off values for lameness identified in the healthy 262 cat group, one cat with right shoulder joint OA and one cat with right stifle joint OA were identified 263 as lame in repeat one. In repeat two one cat with bilateral shoulder joint OA (worse on the left side) 264 was identified as lame and the cat with right stifle joint OA was again identified as lame. Of the four 265 bilaterally affected cats only one cat was identified as lame in one repeat using both symmetry 266 indices. Of the three unilaterally affected cats, two cats were identified as lame using both symmetry267 indices. The duration of time to obtain five valid trials varied with the individual cat, similarly with 268 the healthy cats. For repeat one the median time was seven minutes (range: 3-17 minutes) and for 269 repeat two the median time was nine minutes (range: 5-13 minutes). There was no significant 270 difference in the length of time to obtain five valid trials between healthy and osteoarthritic cats.271 On the cold plate in forelimbs with OA the frequency of paw lifts was significantly less than healthy 272 forelimbs (p=0.0021 repeat one; p=0.0107 repeat two). The duration of paw lifts was significantly 273 less than healthy forelimbs in the first repeat (p=0.0025) but not in the second repeat. There was no 274 significant difference in either the frequency or duration of paw lifts between healthy and OA 275 hindlimbs on the cold plate. There was no significant difference between healthy and OA forelimbs 276 or hindlimbs in the frequency or duration of paw lifts on the hot plate.277 OA limbs had significantly lower paw withdrawal thresholds with both MVF and EVF than healthy 278 limbs (MVF: p<0.0001 repeat one; p=0.0016 repeat two; EVF: p=0.0150 repeat one; p<0.0001 repeat 279 two). An arbitrary threshold of 150g for EVF paw withdrawal gave a sensitivity of 0.82 (repeat one) 280 and 0.67 (repeat two); and a specificity of 0.81 (repeat one) and 0.89 (repeat two) for discriminating 281 OA versus healthy limbs. 282283 Discussion284 This study investigated the clinical utility of kinetic gait analysis, thermal sensitivity testing with a 285 temperature plate and paw withdrawal testing with two types of von Frey monofilaments in healthy 286 untrained cats. All tests were shown to be moderately repeatable; however there was an element of287 individual variability for all tests, which was particularly notable when using the von Frey 288 monofilaments.289 The particular tests used in this study were evaluated because they have been shown to discriminate290 osteoarthritis in limbs in dogs (8). Ethical approval was obtained prior to commencement of the 291 study. With respect to the thermal sensitivity testing, hot and cold temperature thresholds were 292 chosen that would not cause pain or injury. A previous study has demonstrated that the noxious 293 heat stimulus in cats is greater than 43°C; therefore a temperature below this threshold was chosen 294 (16). Literature regarding cold pain thresholds is limited. Nociceptors responsive to cold 295 temperatures in cat skin start to discharge between 15 and 20°C, with higher rates of discharge <5°C 296 (17). The second threshold with a temperature of 7°C, although cold, is warmer than ground 297 temperature during the winter, which many cats would be exposed to when roaming outdoors. 298 Overall safety of exposure to certain temperatures is not just reliant on the temperature alone; it is 299 also a function of the duration of exposure. Thermal testing in this study was therefore designed to 300 be of short duration and easily escapable. All cats were closely monitored and no adverse behaviour 301 or discomfort was identified for any cat during testing.302 Kinetic gait analysis has been used in several previous studies in cats (10, 11, 14, 15); however cats 303 have either been acclimatised for at least 30 minutes in the room with the pressure plate or trained 304 to walk across it with or without a leash. In this study cats were completely naïve to the pressure 305 plate with no level of training. Although our analysis found the results repeatable it was a very time 306 consuming test in some cats in order to obtain five valid trials. Some cats were easily motivated by 307 the positive reinforcement; however in other cats the positive reinforcement was much less 308 effective and it took nearly an hour to get five trials. Therefore in some cats this may be a 309 challenging test to perform in a clinical scenario due to the variable response to positive 310 reinforcement. 311 The symmetry index, which is regularly used in dogs, seems to be less useful in the cat. Two healthy 312 cats were classed as lame when this index was applied. SI2 was used for comparative purposes as it 313 has been assessed in normal cats in a previous study (14). They identified a mean SI on 0.97 with a 314 standard deviation of 0.02 for both forelimbs and hindlimbs. In our study the mean SIs and standard 315 deviations were more variable. Without leash training the cats may not be walking ‘perfectly’ across 316 the plate. Very slight changes in speed or the cat looking around the room without an obvious head 317 turn could lead to the increased variability seen, which on two occasions was enough for the healthy318 cats to be classed as ‘lame’ using this approach.319 In contrast to dogs, which have been shown to have cold hypersensitivity with stifle OA (8), we 320 found some evidence of cold hyposensitivity in cats in forelimbs with osteoarthritis. Increased 321 sensory sensitivity is not always reported with central sensitisation in humans; indeed tactile and 322 thermal hyposensitivity have been reported with knee OA alongside pressure hyperalgesia in the 323 same areas (5). The reason for this has been suggested to be due to the descending inhibitory 324 systems which may become activated to counteract the enhanced excitation of peripheral afferents 325 to noxious stimuli. Therefore the sensitivity of afferents to innocuous stimuli may also be reduced 326 (5).327 The cold hyposensitivity was only identified in the forelimbs in this study. The reason for this could 328 be due to the methodology. If the cats wanted to move on the temperature plate they often moved 329 their forelimbs and pivoted on their hindlimbs. This is likely to be the reason for the increased 330 frequency and duration of paw lifts observed in the forelimbs in comparison to the hindlimbs. 331 Therefore with this test it would be more challenging to pick up differences in thermal sensitivity in 332 the hindlimbs. Alternatively, another interpretation could be that cats with OA are less mobile and 333 more reluctant to move around. However this is not the case identified with similar methodology in 334 dogs with OA and in the kinetic gait analysis there was no significant difference in the velocity of cats335 with OA in comparison to healthy cats. Although placing cats on the temperature plate is a quick and336 easy test, its clinical utility may be relatively limited given that it was only discriminatory for cats 337 with forelimb lameness.338 Increased sensory sensitivity with a lower paw withdrawal threshold as measured using von Frey 339 monofilaments allowed consistent differentiation between OA and healthy limbs. This was a 340 relatively quick and easy test to perform using both electronic and manual techniques. They also 341 allow for quantification of pain by identification of allodynia, which has important implications for 342 analgesia treatment. Paw withdrawal thresholds in cats consistent with allodynia have been 343 reported to be 40g for the forelimbs and 50g for the hindlimbs (10, 11). In our study however there 344 was no significant difference in paw withdrawal threshold between forelimbs and hindlimbs. 345 Applying these thresholds to our EVF dataset revealed that no healthy cats had allodynia, whereas 346 33% of OA cats in repeat one and 45% of OA cats in repeat two had thresholds suggestive of 347 allodynia. In comparison of MVF to EVF the authors felt that the EVF was superior due to its 348 continuous data measurement, the fact that allodynia was incorrectly identified in some healthy cats349 with MVF, and the much shorter time it took to perform the EVF test.350 This study has several limitations. The sample size is small; therefore type II errors may have 351 occurred. There was also no imaging of the healthy cats prior to enrolment into the study. This was 352 not performed as there was no clinical justification to do so for the benefit of these cats, which were353 perceived to be healthy. In addition, due to the mismatch between radiographic signs and 354 macroscopic lesions (2), negative radiographic findings would not have definitively ruled out the 355 presence of OA in these cats. The OA group itself was very heterogeneous with different joints 356 affected and some cats being either bilaterally or unilaterally affected. The majority of cases of OA in357 cats are primary and related to aging, therefore a more homogeneous group would be very 358 challenging to obtain. There were also differences in time between the first and second repeats as 359 not all cats were available for same-day testing. Although the latter two points are valid limitations, 360 the purpose of the study was to evaluate the use of these tests in a clinical setting and this more 361 closely approximates what can be achieved clinically. Finally two cats in the OA group had other 362 medical conditions – one had inflammatory bowel disease and the other had alimentary small cell 363 lymphoma. Both cats had good long term control of the conditions with low-dose steroids and 364 showed no pain on abdominal palpation. As the conditions were not perceived to be causing chronic365 pain it is unlikely that they would be causing central sensitisation in these patients in comparison to 366 the joints with OA, where obvious pain was identified on clinical examination. 367 In conclusion all QSTs were found to be moderately repeatable in healthy untrained cats. Kinetic gait368 analysis did not permit differentiation between osteoarthritic and healthy limbs and had relatively 369 limited clinical utility for diagnosis of this condition. In contrast to findings in dogs, cats demonstrate 370 some evidence of cold hyposensitivity with osteoarthritis. Paw withdrawal threshold measured using371 von Frey monofilaments allowed consistent differentiation between osteoarthritic and healthy limbs372 and may aid diagnosis of this condition in combination with clinical examination and a history of 373 impaired mobility.374375 Acknowledgements 376 We would like to thank the owners and staff at the Hospital for Small Animals for their help with this377 study . 378 Funding 379 This research received no specific grant from any funding agency in the public, commercial, or not-380 for-profit sectors.381 Conflict of interest 382 The authors do not have any potential conflicts of interest to declare.383384 References385 1. Lascelles BD. Feline degenerative joint disease. Vet Surg. 2010;39(1):2-13.386 2. Freire M, Robertson I, Bondell HD, Brown J, Hash J, Pease AP, et al. 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