Neuropathic Donor-Site Pain following Radial Forearm Free Flap Harvest: A Multicenter Study on Incidence, Prognostic Factors, and Quality of Life.

BACKGROUND: The radial forearm free flap (RFFF) is widely used and is considered one of the workhorse flaps in oncologic head and neck reconstructions. However, the potential for significant donor-site morbidity remains a major drawback. Although various donor-site problems have been reported, the incidence of neuropathic pain and possible predicting factors remain unclear. This study aimed to identify the incidence, prognostic factors, and impact on quality of life of neuropathic pain following RFFF harvest. METHODS: In this multicenter, cross-sectional study, 167 patients who underwent an RFFF reconstruction between 2010 and 2020 were included. Baseline characteristics were collected by medical charts. All patients received questionnaires to measure patient's pain (Doleur Neuropathique 4 and visual analog scale, pain), hand function (Patient-Reported Wrist and Hand Evaluation), and quality of life (EuroQol 5D). Multiple logistic regression was used to identify prognostic factors associated with outcomes. RESULTS: A total of 114 patients (68%) completed the questionnaire. Neuropathic pain was present in 18% of all patients. Donor-site wound problems, mostly tendon exposure, occurred in 32% and was significantly correlated with neuropathic pain (p = 0.003). Neuropathic pain was significantly associated with poorer quality of life (p < 0.001) and poorer hand function (p < 0.001). CONCLUSION: Almost one-fifth of all patients deal with neuropathic pain following RFFF harvest. Neuropathic pain is significantly correlated with poorer hand function and a poorer quality of life. Therefore, future research should focus on analyzing surgical factors such as the management of wound problems and primary denervation to improve hand function and quality of life of these patients.

Prevalence of post-traumatic neuropathic pain after digital nerve repair and finger amputation.

INTRODUCTION: Post-traumatic neuropathic pain is a major factor affecting the quality of life after finger trauma and is reported with considerable variance in the literature. This can partially be attributed to the different methods of determining neuropathic pain. The Douleur Neuropathique 4 (DN4) has been validated to be a reliable and non-invasive tool to assess the presence of neuropathic pain. This study investigated the prevalence of neuropathic pain after finger amputation or digital nerve repair using the DN4 questionnaire. METHODS: Patients with finger amputation or digital nerve repair were identified between 2011 and 2018 at our institution. After a minimal follow-up of 12 months, the short form DN4 (S-DN4) was used to assess neuropathic pain. RESULTS: A total of 120 patients were included: 50 patients with 91 digital amputations and 70 patients with 87 fingers with digital nerve repair. In the amputation group, 32% of the patients had pain, and 18% had neuropathic pain. In the digital nerve repair group, 38% of the patients had pain, and 14% had neuropathic pain. Secondly, of patient-, trauma-, and treatment-specific factors, only the time between trauma and surgery had a significant negative influence on the prevalence of neuropathic pain in patients with digital nerve repair. CONCLUSION: This study shows that persistent pain and neuropathic pain are common after finger trauma with nerve damage. One of the significant prognostic factors in developing neuropathic pain is treatment delay between trauma and time of digital nerve repair, which is of major clinical relevance for surgical planning of these injuries.

Prevention is better than cure: Surgical methods for neuropathic pain prevention following amputation - A systematic review.

BACKGROUND: Pain after amputation can be known as residual limb pain (RLP) or phantom limb pain (PLP); however, both can be disabling in daily life with reported incidences of 8% for finger amputations and up to 85% for major limb amputations. The current treatment is focused on reducing the pain after neuropathic pain occurs. However, surgical techniques to prevent neuropathic pain after amputation are available and effective, but they are underutilized. The purpose of the review is to investigate the effects of techniques during amputation to prevent neuropathic pain. METHODS: A systematic review was performed in multiple databases (Embase, Medline, Web of Science, Scopus, Cochrane, and Google Scholar) and following the PRISMA guidelines. Studies that reported surgical techniques to prevent neuropathic pain during limb amputation were included. RESULTS: Of the 6188 selected studies, 13 eligible articles were selected. Five articles reported techniques for finger amputation: neurovascular island flap, centro-central union (CCU), and epineural ligatures, and flaps. For finger amputations, the use of prevention techniques resulted in a decrease of incidences from 8% to 0-3% with CCU being the most beneficial. For major limb amputations, the incidences for RLP were decreased to 0 to 55% with TMR and RPNI and compared to 64-91% for the control group. Eight articles reported techniques for amputations on major limbs: targeted muscle reinnervation (TMR), targeted nerve implantation, concomitant nerve coaptation, and regenerative peripheral nerve interface (RPNI). CONCLUSIONS: Based on the current literature, we state that during finger and major limb amputation, the techniques to prevent neuropathic pain and PLP should be performed.

Higher incidences of neuropathic pain and altered sensation following radial forearm free flap: A systematic review.

BACKGROUND: The radial forearm free flap (RFFF) has been used extensively for complex tissue defect reconstructions; however, the potential for significant donor-site morbidity remains a major drawback. Despite an abundance of literature on donor-site morbidities, no consensus has been reached on exact incidences of sensory morbidities that vary largely between 0% and 46%. Incidences of neuropathic pain in the donor site following RFFF still lack, even though clinical experience shows it often occurs. Therefore, the purpose of this systematic review was to identify the incidence of neuropathic pain and altered sensation in the hand following harvesting of a RFFF. METHODS: A systematic search was performed in multiple databases (Embase, Medline, Cochrane, Web of Science, and Google Scholar). Studies from 1990 onwards that reported donor-site morbidities following harvest of the RFFF were included. Analyzed parameters included hand pain, hypoesthesia, cold intolerance, hyperesthesia, neuroma formation, paresthesia, sharp sensation loss, light sensation loss, and defect closure. RESULTS: Of the 987 selected studies, 51 eligible articles were selected. The mean level of evidence was 3 (SD 0.6). Twenty articles reported pain as a donor-site morbidity, and the mean incidence of pain reported was 23% (SD 7.8). Hypoesthesia was reported by 37 articles and had a mean incidence of 34% (SD 25). Locations of pain and hypoesthesia included, amongst others, the area of the radial sensory nerve and the skin graft area. The mean incidences of cold intolerance and hyperesthesia were 13% (SD 13) and 16% (SD 15), respectively. CONCLUSION: The results of this systematic review suggest that 23% of all patients are dealing with neuropathic pain in the donor-site following harvest of an RFFF. Future studies should therefore focus on the prognostic factors and preventive measures of neuropathic pain to further improve clinical outcomes of this widely used flap.

The prevalence of radiographic thumb base osteoarthritis: a meta-analysis.

INTRODUCTION: Osteoarthritis (OA) affects millions of people worldwide. In hand OA, the thumb base is the most affected single joint. The reported radiographic prevalence ranges from 0 to 100%, making the true radiographic prevalence unclear. Hence, we conducted a meta-analysis on the age and sex-specific prevalence of radiographic thumb base OA. METHODS: We performed a search in Embase, Medline Ovid, Web of Science Core Collection, Cochrane Central Register of Trials, and Google Scholar. We included studies of the general population that reported thumb base OA for males and females separately based on a hand radiograph and reported the age of these groups. Using meta-regression, we estimated the odds ratio (OR) of having radiographic thumb base OA for age and sex, while adjusting for within-study correlation. RESULTS: The initial search yielded 4,278 articles; we finally included 16 studies that reported the age- and sex-stratified prevalence. Taken together, there were 104 age and gender specific-prevalence rates that could be derived from the 16 studies. The prevalence of radiographic OA for the 50-year-old male and female participants was 5.8% and 7.3%, respectively, while the respective prevalence for 80-year-old male and female participants was 33.1% and 39.0%. We found an OR for having radiographic OA of 1.06 (95%CI [1.055-1.065], p < 0.001) per increasing year of age, and 1.30 (95%CI: 1.05-1.61], p = 0.014) for females. CONCLUSION: In the general population, radiographic thumb base OA is more prevalent in females and is strongly associated with age.

Mirror-image pain after nerve reconstruction in rats is related to enhanced density of epidermal peptidergic nerve fibers.

Mirror-image pain is a phenomenon in which unprovoked pain is detected on the uninjured contralateral side after unilateral nerve injury. Although it has been implicated that enhanced production of nerve growth factor (NGF) in the contralateral dorsal root ganglion is important in the development of mirror-image pain, it is not known if this is related to enhanced expression of nociceptive fibers in the contralateral skin. Mechanical and thermal sensitivity in the contralateral hind paw was measured at four different time points (5, 10, 20 and 30weeks) after transection and immediate end-to-end reconstruction of the sciatic nerve in rats. These findings were compared to the density of epidermal (peptidergic and non-peptidergic) nerve fibers on the contralateral hind paw. Mechanical hypersensitivity of the contralateral hind paw was observed at 10weeks PO, a time point in which both subgroups of epidermal nerve fibers reached control values. Thermal hypersensitivity was observed with simultaneous increase in the density of epidermal peptidergic nerve fibers of the contralateral hind paw at 20weeks PO. Both thermal sensitivity and the density of epidermal nerve fibers returned to control values 30weeks PO. We conclude that changes in skin innervation and sensitivity are present on the uninjured corresponding side in a transient pain model. Therefore, the contralateral side cannot serve as control. Moreover, the current study confirms the involvement of the peripheral nervous system in the development of mirror-image pain.

The anatomical relationship of the superficial radial nerve and the lateral antebrachial cutaneous nerve: A possible factor in persistent neuropathic pain.

The superficial branch of the radial nerve (SBRN) is known for developing neuropathic pain syndromes after trauma. These pain syndromes can be hard to treat due to the involvement of other nerves in the forearm. When a nerve is cut, the Schwann cells, and also other cells in the distal segment of the transected nerve, produce the nerve growth factor (NGF) in the entire distal segment. If two nerves overlap anatomically, similar to the lateral antebrachial cutaneous nerve (LACN) and SBRN, the increase in secretion of NGF, which is mediated by the injured nerve, results in binding to the high-affinity NGF receptor, tyrosine kinase A (TrkA). This in turn leads to possible sprouting and morphological changes of uninjured fibers, which ultimately causes neuropathic pain. The aim of this study was to map the level of overlap between the SBRN and LACN. Twenty arms (five left and 15 right) were thoroughly dissected. Using a new analysis tool called CASAM (Computer Assisted Surgical Anatomy Mapping), the course of the SBRN and LACN could be compared visually. The distance between both nerves was measured at 5-mm increments, and the number of times they intersected was documented. In 81% of measurements, the distance between the nerves was >10 mm, and in 49% the distance was even <5 mm. In 95% of the dissected arms, the SBRN and LACN intersected. On average, they intersected 2.25 times. The close (anatomical) relationship between the LACN and the SBRN can be seen as a factor in the explanation of persistent neuropathic pain in patients with traumatic or iatrogenic lesion of the SBRN or the LACN.

Innervation mapping of the hind paw of the rat using Evans Blue extravasation, Optical Surface Mapping and CASAM.

BACKGROUND: Although numerous studies investigate sensory regeneration and reinnervation of the hind paw of the rat after nerve damage, no comprehensive overview of its normal innervation is present in literature. The Evans Blue extravasation technique is a well-known technique to study patterns of skin innervation. This technique has been performed differently by various groups but was never used to study the entire skin innervation in rats' hind paw including all three branches of the sciatic nerve and the saphenous nerve in detail. NEW METHOD: In this paper, we have used the Evans Blue extravasation technique to chart the skin areas innervated by the sural, peroneal, tibial and/or saphenous nerves, which together innervate the entire hind paw of the rat, and use a new technique to analyze the distribution, overlap and variability of the results. The technique is based on analysis of whole hind paws using Optical Surface Mapping (OSM) in combination with the Computer Assisted Surgical Anatomy Mapping (CASAM) technology. RESULTS: While the plantar hind paw is mainly innervated by the tibial nerve, the dorsal hind paw is supplied by the sural, peroneal and the saphenous nerve. COMPARISON WITH EXISTING METHODS: Although our results basically concur with the general nerve-specific innervation of the rat hind paw, they show considerable detail in their areas of overlap as well as in the amount of variability between animals. CONCLUSION: These results will be invaluable to study and evaluate patterns of innervation and reinnervation of intact and damaged nerve fibers.

Thermo-sensitive TRP channels in peripheral nerve injury: a review of their role in cold intolerance.

One of the sensory complications of traumatic peripheral nerve injury is thermal intolerance, which manifests in humans mainly as cold intolerance. It has a major effect on the quality of life, and adequate therapy is not yet available. In order to better understand the pathophysiological background of thermal intolerance, we focus first on the various transient receptor potential (TRP) channels that are involved in temperature sensation, including their presence in peripheral nerves and in keratinocytes. Second, the role of thermo-sensitive TRP channels in cold and heat intolerance is described showing three different mechanisms that contribute to thermal intolerance in the skin: (a) an increased expression of TRP channels on nerve fibres and on keratinocytes, (b) a lower activation threshold of TRP channels and (c) the sprouting of non-injured nerve fibres. Finally, the data that are available on the effects of TRP channel agonists and antagonists and their clinical use are discussed. In conclusion, TRP channels play a major role in temperature sensation and in cold and heat intolerance. Unfortunately, the available pharmaceutical agents that successfully target TRP channels and counteract thermal intolerance are still very limited. Yet, our focus should remain on TRP channels since it is difficult to imagine a reliable treatment for thermal intolerance that will not involve TRP channels.

Disordered conditioned pain modulation system in patients with posttraumatic cold intolerance.

BACKGROUND: Conditioned pain modulation (CPM) is a phenomenon of 'pain inhibiting pain' that is important for understanding idiopathic pain syndromes. Because the pathophysiology of posttraumatic cold intolerance is still unknown but it could involve similar mechanisms as idiopathic pain syndromes, we evaluated the functioning of the CPM system in patients with posttraumatic cold intolerance compared to healthy controls. METHODS: Fourteen healthy controls and 24 patients diagnosed with cold intolerance using the Cold Intolerance Symptom Severity questionnaire were included in the study. Of the 24 patients with cold intolerance, 11 had a nerve lesion and 13 an amputation of one or more digits. To quantify the CPM, pain threshold for mechanical pressure was measured at the affected region as a baseline measure. Then, the contralateral hand received a cold stimulus of ice water to evoke the noxious conditioning. After the cold stimulus, the pain threshold for mechanical pressure was determined again. RESULTS: The absolute and relative changes in algometer pressure (CPM effect) between pre- and post-conditioning were significantly smaller in the cold intolerance group compared to the control group (absolute p = 0.019, relative p = 0.004). The CPM effect was significantly different between the control group and the subgroups of nerve lesion (p = 0.003) and amputation patients (p = 0.011). CONCLUSIONS: In this study, we found a CPM effect after a cold stimulus in both controls and patients. A significant weaker CPM effect compared to the controls was found, as in other chronic pain conditions. The CPM system within patients with cold intolerance is altered.

Cold-induced vasodilatation in cold-intolerant rats after nerve injury.

PURPOSE: Cold-induced vasodilatation (CIVD) is a cyclic regulation of blood flow during prolonged cooling of protruding body parts. It is generally considered to be a protective mechanism against local cold injuries and cold intolerance after peripheral nerve injury. The aim of this study was to determine the role of the sympathetic system in initiating a CIVD response. METHODS: Eight rats were operated according to the spared nerve injury (SNI) model, eight underwent a complete sciatic lesion (CSL) and six underwent a sham operation. Prior to operation, 3, 6 and 9 weeks postoperatively, both hind limbs were cooled and the skin temperature was recorded to evaluate the presence of CIVD reactions. Cold intolerance was determined using the cold plate test and mechanical hypersensitivity measured using the Von Frey test. RESULTS: No significant difference in CIVD was found comparing the lateral operated hind limb for time (preoperatively and 3, 6 and 9 weeks postoperatively; p = 0.397) and for group (SNI, CSL and Sham; p = 0.695). SNI and CSL rats developed cold intolerance and mechanical hypersensitivity. CONCLUSION: Our data show that the underlying mechanisms that initiate a CIVD reaction are not affected by damage to a peripheral nerve that includes the sympathetic fibres. We conclude that the sympathetic system does not play a major role in the initiation of CIVD in the hind limb of a rat. CLINICAL RELEVANCE: No substantial changes in the CIVD reaction after peripheral nerve injury imply that the origin of cold intolerance after a traumatic nerve injury is initiated by local factors and has a more neurological cause. This is an important finding for future developing treatments for this common problem, as treatment focussing on vaso-regulation may not help diminish symptoms of cold-intolerant patients.

Thermoregulation in peripheral nerve injury-induced cold-intolerant rats.

PURPOSE: Cold intolerance is defined as pain after exposure to non-painful cold. It is suggested that cold intolerance may be related to dysfunctional thermoregulation in upper extremity nerve injury patients. The purpose of this study was to examine if the re-warming of a rat hind paw is altered in different peripheral nerve injury models and if these patterns are related to severity of cold intolerance. METHODS: In the spared nerve injury (SNI) and complete sciatic lesion (CSL) model, the re-warming patterns after cold stress exposure were investigated preoperatively and at 3, 6 and 9 weeks postoperatively with a device to induce cooling of the hind paws. Thermocouples were attached on the dorsal side of the hind paw to monitor re-warming patterns. RESULTS: The Von Frey test and cold plate test indicated a significantly lower paw-withdrawal threshold and latency in the SNI compared to the Sham model. The CSL group, however, had only significantly lower paw-withdrawal latency on the cold plate test compared to the Sham group. While we found no significantly different re-warming patterns in the SNI and CSL group compared to Sham group, we did find a tendency in temperature increase in the CSL group 3 weeks postoperatively. CONCLUSION: Overall, our findings indicate that re-warming patterns are not altered after peripheral nerve injury in these rat models despite the fact that these animals did develop cold intolerance. This suggests that disturbed thermoregulation may not be the prime mechanism for cold intolerance and that, other, most likely, neurological mechanisms may play a more important role. CLINICAL RELEVANCE: There is no direct correlation between cold intolerance and re-warming patterns in different peripheral nerve injury rat models. This is an important finding for future developing treatments for this common problem, since treatment focussing on vaso-regulation may not help diminish symptoms of cold-intolerant patients.