Sensory Abnormalities in Post-surgical Peripheral Neuropathy

Overview

The concept of normality is a cornerstone in medical practice and research. As an example, in clinical chemistry, a laboratory value based on a plasma sample exceeding the +/- 1.96 x standard deviation (SD) range, referenced from normative material, is, per definition, outside the normal range (the reference interval). Obviously, a number of reasons for this deviation may exist. The sample value could reflect a "true" pathological condition but could also be caused by error, e.g., technical measurement error, drug-interaction error, random error, or reflect a value occurring in 5% of the healthy population. Conversely, a sample value in the normal range evidently does not exclude a pathological condition. The reference interval is calculated from a large number of healthy subjects sampled across age, anthropometrics, ethnicity, and gender. Normative reference intervals are certainly of help, particularly in the screening of subjects, but may be of limited value in the detailed assessment of pathophysiological processes. Also, increasing the number of analyses in a subject expands the risk of making a type I error (acquiring "false" positive results). The likelihood of one or more type I errors in the analysis of 10 different laboratory values in one subject is impressive 46% (\[1 - 0.95\^10\] =0.46). It is well-known that multiple measurements are commonly performed in medical practice and research, but corrected significance levels are not always used.

Quantitative sensory testing (QST) is defined as perceptually quantifiable responses to graded chemical (capsaicin), electrical, mechanical (pressure, punctate, vibratory, and light touch), or thermal (cool, warmth, cold pain, and heat pain) stimuli. Thus, QST is a psychophysical method primarily assessing small nerve fiber function in the skin. The method is ubiquitously used for the assessment of peripheral neuropathies, e.g., chemotherapy-induced neuropathy, painful diabetic polyneuropathy, post-herpetic neuralgia, and post-surgical neuropathy. Sensory mapping and QST are essential tools in grading definite or probable neuropathic pain, as stated in the definition: "Demonstration of the distinct neuroanatomically plausible distribution by at least one confirmatory test." Thus, examining somatosensory profiles in chronic post-surgical pain (CPSP) could be an important step in distinguishing the pathophysiologic components behind the transition from acute to chronic pain. However, determining when a measured variable is abnormal is obviously of prime importance in somatosensory research. During the last decade, the German Research Network on Neuropathic Pain (DFNS) has acquired normative sensory data from healthy individuals using a standardized testing protocol. Clearly, a deviating sensory response from an individual with a painful peripheral neuropathy could be evaluated by use of these normative data and eventually be classified as an abnormal response (absolute approach). However, other alternatives exist that, hypothetically, might provide improved diagnostic specificity and sensitivity. First, in unilateral sensory deficits (mono-neuropathies), assessments at the contralateral side are possible, allowing a comparison with the pathological side (relative approach). The within-subject variances (WSV) are often significantly smaller than the between-subject variances (BSV) in QST assessments. In a normative study including thermal assessments (n = 100), the WSV and the BSV ranged between 18-23% and 77-82% of the total variance, respectively. Correspondingly, in a study of individuals with post-thoracotomy pain syndrome, the estimated WSV and BSV were 5-28% and 72-95%, respectively. Thus, scenarios using the subject as their own control may reduce data variability and improve diagnostic efficacy. However, the use of a contralateral homologous area as a control area in sensory testing has been questioned by several authors. The occurrence of mirror image sensory dysfunction (MISD) may affect contralateral assessments, requiring a distant control area. Second, instead of using healthy controls in pain studies, the use of post-surgical pain-free individuals as controls (e.g. post-groin hernia repair, post-thoracotomy) has been recommended in chronic post-surgical pain studies. In spite of the importance of selecting an optimally controlled research design, the research group is only aware of one QST study addressing the control-group problem, i.e., a study including individuals with complex regional pain syndrome type I (CRPS I) restricted to one extremity. The study examined the validity of using the contralateral side as a control compared to using normative data from healthy individuals. The study recommended that the contralateral side in CPRS I individuals should be used as a control (relative approach). Thus, it may be inferred that the following approaches are available for evaluating sensory data from an anticipated pathological site: an empirical approach (á priori set reference values), an absolute approach (comparing the subject's pathological side with normative data), and a relative approach (comparing the subject's side-to-side differences with normative data). The present study has a prospective, observational, three-cohort design comparing somatosensory profiles from a cohort with groin hernia repair (GHR) associated CPSP (P-GHR; n = 70) across two standard cohorts: one surgical cohort without CPSP (NP-GHR; n = 54) and another healthy non-surgical cohort (NOP; n = 54). Testing sites are the surgical groin, with the comparator sites, the non-surgical groin, and the lower arm. The QST assessments are compared across cohorts (P-GHR, NP-GHR, NOP), testing sides (surgical side, non-surgical side), and testing sites (groins, arm). The statistical processing is by linear mixed-effects models and z-transformations, using the NOP cohort as reference material. The main objective is: \* To characterize and interpret the pathophysiologic substrate behind the somatosensory profiles in individuals with GHR-associated CPSP using relevant controls Other objectives are: * To examine the somatosensory data repeatability * To determine the diagnostic efficiency of QST in identifying GHR-associated somatosensory abnormalities * To compare the somatosensory testing efficacy of the absolute approach compared to the relative approach, using normative healthy controls * To examine contralateral somatosensory abnormalities in individuals with/without GHR-associated CPSP