4.2.3. Treatment of Carpal Tunnel Syndrome

In 2017, Jerosch-Herold and colleagues published the results of large multicenter study aiming to identify prognostics factors for functional outcome and resulting costs for carpal tunnel syndrome either treated by surgical decompression or corticosteroid injection. They found a highly significant correlation between the patient-reported carpal tunnel symptom severity, depression, anxiety and the health-related QoL as assessed by the EQ-5D-3L (3-level version of EuroQol-5 dimension). The level of anxiety was also correlated with the objective carpal tunnel syndrome severity as assessed by electrophysiological evaluations, but there was no correlation of electrophysiological findings and depression [52]. Straub's group evaluated 100 hands of 67 patients, respectively, who underwent endoscopic carpal tunnel release, aiming to identify patient- and psychosocial factors associated with unsatisfactory outcomes. Out of the 8% percent of hands which were classified as unsatisfactory 75% were covered by the worker's compensatory system and in 21% of cases which were involved in litigation an unsatisfactory result was reported. Interestingly, the author concluded that various comorbid factors which were assessed, e.g., obesity, smoking or working in a job at risk did neither in isolation nor in combination result in an increased likelihood for unsatisfactory results. However, psychological factors, e.g., use of psychotropic medications or active psychiatric treatment, which were found positive in 20% of the study population, were associated with lower patient satisfaction both in isolation and combination [53]. In 2008, Lozano Calderón and colleagues conducted a retrospective survey to evaluate patient satisfaction following open carpal tunnel release and included 82 participants. They found that greater levels of depression were associated with more severe dissatisfaction following surgery and perceived disability could be predicted by depression and pain catastrophizing. The authors concluded that depression and perceived disability after carpal tunnel release can be predicted primarily by psychosocial factors like depression and insufficient coping skills [54]. Das De et al. found a significant correlation between DASH scores of patients suffering from carpal tunnel syndrome and psychosocial factors such as depression, catastrophic thinking, kinesiophobia and a punishing response by the respective patient's partner. Conversely, pain anxiety as well as solicitous or distracting responses by the respective patient's partner did not correlate with disabilities of the upper extremity in patients with carpal tunnel syndrome [55]. To summarize, these studies indicate that disease severity in patients with carpal tunnel syndrome is often directly linked to psychosocial aspects of life on the one hand whereas patients suffering from depression or anxiety are likely to experience adverse functional outcomes following carpal tunnel release.

#### *4.3. Recovery of Donor Site Morbidity following Nerve Harvest*

Ehretsman and colleagues evaluated subjective healing of nerve donor site morbidity following nerve graft harvest by means of a telephone survey. The authors evaluated possible correlations between satisfaction with donor site morbidity, both in regard to functional and cosmetic factors, and patient factors such as age, gender, involvement of worker's compensation and/or ongoing litigation. However, no statistically significant correlation with patient factors was observable [56]. Another study conducted by Miloro's group assessed patient satisfaction following sural nerve harvesting in 47 patients. In accordance with Ehretsman's results these authors did not observe any correlation between patient factor like age, gender and legal involvement and satisfaction level in regard to the donor site [57].

#### *4.4. Treatment of Painful Neuroma*

Stokvis et al. conducted a literature review aiming to identify possible prognostics factors for insufficient pain relief following neuroma treatment in 2009 [58]. They extracted ongoing worker's compensation, employment status and active litigation as predictive factors for unsuccessful treatment attempts. However, the authors stated that these factors are very difficult to consider separately, given the fact that employment status is likely more important regarding the outcome of patients undergoing surgery for painful neuroma [59,60]. Stovkis' group also emphasized Dellon's and Mackinnon's observation, that the duration of preoperative pain was significantly longer in patients who reported poor pain relief following surgery when compared to patients with satisfactory postoperative amelioration of pain [58,60]. In 2019, Lans and colleagues retrospectively analyzed 33 painful neuromas in 29 patients who underwent surgical therapy. Comparing the three treatment concepts of 1. neuroma excision with consecutive nerve repair or reconstruction; 2. neuroma excision with implantation of the proximal stump and 3. neuroma excision alone. In their study population the mean PROMIS Upper Extremity score was 45.2 ± 11.2, the mean PROMIS Pain Interference score was 54.3 ± 10.7, and the median numeric rating scale pain score was 3 (interquartile range, 1 to 5). Higher PROMIS depression scores and the surgical concept of neuroma excision alone were both independently significantly correlated with lower PROMIS Upper Extremity scores. Postoperative PROMIS Upper Extremity scores were lower in patients who underwent neuroma excision with nerve stump implantation, but this was not statistically significant. Neuroma excision alone and neuroma excision with nerve stump implantation as well as higher PROMIS Depression scores were all independently associated with higher, e.g., more severe PROMIS Pain Interference scores. Higher numeric rating scale pain scores showed a significant correlation with neuroma excision alone and neuroma excision and implantation whereas neuroma excision with consecutive nerve repair or reconstruction was associated with lower numeric rating scale pain scores [61].

#### **5. A Perspective on Experimental Insights**

In addition to clinical studies, psychosocial aspects of peripheral nerve injuries have also been studied in preclinical models, e.g., rodents. Using a spared nerve injury (SNI) model Norman et al. tested the hypotheses that peripheral nerve injury is causative for depression by induction of inflammatory processes in the brain and these neuroinflammatory changes are further exacerbated in case of stress exposure prior to nerve injury. The authors found their presumptions to be confirmed as they observed that injury of the

common peroneal and tibial nerve caused mechanical allodynia and depressive behavior in mice, as well as an increased expression of interleukin-1b (IL-1b) and glial fibrillary acidic protein (GFAP). The mechanical allodynia was more severe in mice which were exposed to increased stress by chronic physical constraint two weeks prior to the experimental surgery. Treatment of these animals with a corticosteroid synthesis inhibitor prior to physical constraint eliminated the aforementioned effects, proving that psychosocial factors, e.g., the experience of increased stress directly influences the severity of symptoms following peripheral nerve injury [62].

Besides individual psychological factors like depression, social factors have also been identified to play an important role in symptom severity in rats with peripheral nerve injury. Raber and Devor used a neuroma model of neuropathic pain caused by sciatic nerve injury to investigate pain phenotype in two distinct rat strains. When rats with high (HA) and low (LA) pain phenotype and autotomy-behavior, e.g., gnawing of the toes or entire paws in consequence to nerve injury, were housed together, LA rats showed high levels of autotomy even when they were familiar with the HA preoperatively. The observed autotomy in LA rats was also independent of the performance of autotomy by the HA rats. Interestingly, even the contact with cage bedding soiled by HA rats was sufficient to induce moderate levels of autotomy in LA rats even in the absence of HA rats [63]. Another study investigated the effects of ongoing social stress (OSS) on mechanical sensitivity and cold allodynia in a rat model of chronic constriction injury (CCI) of the sciatic nerve. Rats which experienced ongoing social stress by twice-weekly exchange of their cage mates did not display significant changes in mechanical sensitivity. In regard to cold allodynia, rats with CCI and OSS were less susceptible during the early phase of the observation period when compared to rats which underwent CCI surgery only. At later time points however, rats with CCI + OSS were more susceptible to cold stimuli compared to the CCI rats. In addition, in the former group enhanced glial cell activation, pro-inflammatory cytokine expression and higher neurotrophic factor mRNA levels were observable [64].

#### **6. Discussion**

In this work we reviewed the current body of knowledge in regard to the interplay of psychosocial factors and peripheral nerve lesions as well as these factors' predictive value of functional outcome following peripheral nerve injury. Our work emphasizes that psychological factors like depression, pain-catastrophizing and anxiety are both influenced by peripheral nerve lesions and also significant predictors of functional recovery and QoL after peripheral nerve surgery in patients suffering from PNI. The same applies to social factors, e.g., employment status or worker's compensation. These findings underpin the need for personalized treatment concepts involving not only surgeons but also psychologists, occupational therapists, and others. As was pointed out by Kaltenbrunner and other authors [65,66] there are large differences between countries in regard to the regulatory framework of disability cases and rehabilitation measures to facilitate the affected individuals return to work. Notably, this not only applies to the transatlantic comparison, but also within the smaller perimeter of the European Union, indicating the need to consider the country-dependent differences when developing treatment and rehabilitation concepts for patients with PNIs.

Patients with depression, pain catastrophizing and anxiety are usually at risk to experience poor outcomes following PNI, reporting higher levels of pain and disability as well as lower satisfaction [54]. Vice versa, the rate of symptoms of clinical depression among patients suffering from PNI is alarmingly high, reaching almost 40%, which is more than twice the numbers reported in the general population, ranging between 10% and 20%, depending on the studied population [38,67,68]. In case of brachial plexus injuries, even more than 50% of patients could be suffering from depression, underpinning the need for adequate treatment strategies beyond surgical intervention in this group of patients [69,70]. In conclusion, screening for depression and referral of patients for psychological and/or psychiatric counseling or treatment is advised for surgeons and any other profession

involved in the treatment of patients with PNIs, especially in case of a planned operative intervention [38]. However, it might be demanding to identify such patients since they might show a tendency to conceal their depression, afraid of the social stigma which might come with diagnosed mental illness [17,71]. Circling back to the aforementioned cross-country differences regarding post-injury rehabilitation and return to work, the same applies to mental health care systems. Again, significant differences are not only observable when comparing mental health care systems worldwide [72] but also within the European Union [73]. These observations emphasize that the interplay of psychosocial factors and peripheral nerve lesions extends beyond the affected patients' ways of living but are also heavily influenced by significant differences between countries regarding their health care system.

In our opinion, the findings reported by Ehretsman [56] and Miloro [57] deserve special emphasis, as both authors reported that donor site morbidity following nerve harvest was not correlated with any of the psychosocial factors they assessed. Although nerve graft harvesting can be considered as nerve lesion, it is interesting to note that sequalae of these "non-accidental" nerve injuries seem not to be correlated with psychosocial factors as it is the case with traumatic nerve lesions or compression neuropathies. As possible explanation for this observation we would like to suggest that patients who undergo nerve graft harvest choose this procedure voluntarily and without the experience of a "loss of control" associated with traumatic nerve injuries. It was shown that the feelings of uncontrollability or helplessness are associated with an increase in psychological vulnerabilities [74–76] and pain levels [77,78]. The patient's impression of being in control of the situation leading to a nerve lesion, e.g., sural nerve harvest, might be protective of adverse functional outcome following these procedures.

Another interesting finding was the correlation between picking "no comment" when asked about a possible childhood trauma and pain reported at the current and next visit. The same applies to the predictive value of a positive history childhood trauma for nextvisit sadness and depression. It has been suggested that this correlation is caused by trauma-induced changes to the brain of abused or traumatized children [47,79,80]. In this context, one should consider the fact that about 10% of American youth have experienced at least one episode of sexual assault and 9–19% were subject to physical abuse or a physical assault by the respective caregiver [81]. Although a history of childhood trauma does not necessarily cause pain, sadness and depression, the likelihood of seeing an abused person with PNI at the inpatient or outpatient clinic is relatively high.

As several studies reviewed in this work have pointed out there are distinct variations regarding the impact of PNIs on psychosocial factors depending on their severity. Patients with distal, single-site compression neuropathies will likely experience fewer negative psychosocial effects that patients with distal traumatic injuries of both the median and ulnar nerve, dual compression neuropathies or TOS. As was emphasized by Wojtkiewicz these findings bear several implications for clinical practice, as patients suffering from the aforementioned conditions should be counseled regarding the impact of such PNIs on their psychosocial and occupational status prior to surgical treatment [17]. The ability to return to work (RTW) is another exemplary psychosocial factor, as it is primarily affected by PNI but also has an impact on functional recovery in patients with PNI. Knowledge of this interplay is of high value when an individual treatment and rehabilitation plan is conceptualized for the patient as patients with more complex injuries, e.g., combined nerve injuries of the upper extremity are at high risk not to return to work. In consequence functional recovery in these patients might also be poor, given their inability to pursue their profession as desired [34]. Considering the exorbitant indirect costs of low productivity which exceed direct health costs by more than 100% in case of upper extremity PNIs [14,82–84] an adequate prognostic assessment and a personalized interdisciplinary treatment are of outmost relevance. A battery of structured preoperative assessment tools such as the PROMIS-29 and EQ-5D [85] are suited to determine the impact of peripheral nerve injuries on patient-reported QoL. The healthcare team involved in treatment of patients with PNI should consist of expert not only in surgical treatment of nerve injuries, but also specialist for physical as well as emotional adaptation and resilience, e.g., hand therapists, occupational therapists, psychologist, and social workers [86].

Wojtkiewicz summarized the evidence gathered in the literature regarding the influence of pain caused by PNIs on patient-reported disability [17,18,38,87–90]. Pain levels can be assessed by the BPI Short Form, NEO-FFI, PCS and the MPQ. A more personalized pain-assessment is possible via pain drawings [91]. It was shown that these drawings are affected by pain and depression in patients with cervical degenerative disc disease [92] or cervical spine nerve involvement in chronic whiplash-associated disorders [93]. They are also a feasible and reliable tool to assess neuropathic pain following spinal cord injury [94]. Pain drawings are also predictive of functional outcome in patients undergoing surgical treatment for degenerative disc disease in the cervical spine [95]. Use of a related assessment-tool named CALA to visualize pain in upper limbs amputees has been published by Prahm et al. [96], but there is yet no published large patient sample study evaluating the value of pain drawings in patient with peripheral nerve lesions in general. Given the high prevalence of neuropathic pain of up to 10% in society and its deleterious impact on physical and psychical function [47], a more personalized assessment tool might be a valuable addition to the armamentarium of diagnostic and prognostic instruments.

To summarize our findings, coaching, and providing emotional support to patients suffering from PNI can be effective to help them adapting a positive mindset, overcome severe psychological distress, and eventually adapting to their new situation, even if the functional outcome following surgical treatment is not more than mediocre. It must be emphasized that objective impairment, e.g., severe paresis, or diminished sensibility does not inevitably result in the same level of subjective disability. This observation has been beautifully condensed by Ring who had reconstructed the median nerve in a female nurse following complete iatrogenic laceration: "Credit goes to her (the patient's) spirit, adaptation and resiliency; not my knife or suture" [86].

#### **7. Conclusions**

Psychosocial factors play an important role in case of PNI. They are not only directly affected by PNI but also have significant predictive value of functional outcome following surgical treatment. Careful psychological assessment can help to identify patients at risk for unsatisfactory functional recovery and persistent disability following surgical treatment. The interplay of psychosocial factors and PNIs should be kept in mind in regard to personalized treatment concepts for these patients.

**Author Contributions:** Conceptualization, J.C.H., C.P., J.K. and A.D.; methodology and literature research, J.C.H., L.F.D. and J.R.; writing—original draft preparation, J.C.H., L.F.D., N.W., M.B. and J.R.; writing—review and editing, H.L., C.P., J.K. and A.D.; supervision, J.K. and A.D. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Acknowledgments:** We acknowledge support by Open Access Publishing Fund of University of Tübingen.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

