A pooled number of 935 patients were included in the selected studies. Of these, 875 patients had diabetes and 1053 LEs underwent neurolysis for compressed nerves and were included in our meta-analysis.8,10,13–20 Four studies8,10,13,15 for a total of 130 patients reported the number of males (47 patients) and females (83 patients) in their study population. Four studies,8,10,15,17 for a total of 164 patients, reported the number of type 1 (73 patients) and type 2 (91 patients) diabetics in their study population.
Additionally, 4 studies8,13,15,17 for a total of 130 diabetic patients reported the mean duration of diabetes in their population, with a pooled mean of 13.87 ± 1.96 years. Six studies8,13,15–17,20 for a total of 214 patients reported the mean age of their population, the pooled mean age being 56.01 ± 7.07 years.
Regarding the method to diagnose nerve compression, 7 studies13,15–20 for a total of 762 patients relied on a positive Tinel sign to diagnose nerve compression. On the other hand, 3 studies8,10,14 for a total of 113 patients based the diagnosis of nerve compression on electrodiagnostic studies. None of the included studies based their diagnosis of nerve compression on magnetic resonance neurography findings. Five studies14,15,17–19 for a total of 745 patients used the Pressure-Specified Sensory Device, whereas 1 study13 for a total of 26 patients used the Disk-Criminator device to assess the degree of sensory impairment. One study16 including 12 patients assessed sensory impairment with both devices.
Location of Nerve Decompression
All the 1053 (100%) operated LEs had decompression of the tibial nerve at the tarsal tunnel and 1011 (96%) operated LEs had decompression of the common peroneal nerve at the fibular head and the deep peroneal nerve at the dorsum of the foot.8,10,13–20
Effect of Neurolysis on Pain
Three studies14,15,20 assessed improvement on the visual analog scale (VAS) for pain. A pooled analysis of postoperative vs preoperative VAS for pain for these 3 studies including a total of 69 LEs showed significant pain relief by >4 points on the VAS (95% CI: 4.04–6.77) after neurolysis (Fig. 2).
Four studies10,13,14,16 reported the percentage of postoperative pain relief. Pooled analysis of the 102 LEs included in these 4 studies showed that significant pain relief after neurolysis occurred in 91%, worsening of symptoms occurred in 5%, and no improvement in 4% of the LEs. The degree of improvement that constituted “significant pain relief” was not always defined in these 4 studies.
Effect of Neurolysis on Sensibility
Two studies13,14 assessed improvement on 2-point discrimination. A pooled analysis of postoperative vs preoperative 2-point discrimination for these 2 studies including a total of 59 LEs showed an improvement of 3.90 mm (95% CI: 0.13–7.67 mm) after neurolysis, from a mean of 16.16 ± 3.51 mm to a mean of 12.26 ± 3.92 mm (Fig. 3).
Furthermore, the improvement in sensibility was assessed by 4 studies.8,10,13,14 Pooled analysis of the 106 LEs included in these studies showed that sensibility improved significantly in 69% of the LEs. Similar to the pain scales, the precise degree of improvement that constitutes “significant improvement” was not always defined.
Effect of Neurolysis on Ulceration/Amputation
Two studies13,18 assessed the incidence of postoperative ulcerations. Pooled analysis of the 865 LEs included in these studies showed that the postoperative ulceration incidence was significantly reduced compared to preoperative incidence (odds ratio = 0.066, 95% CI = 0.026–0.164, P < 0.0001). With a pooled follow-up period of 27.7 ± 20.2 months, the pooled incidence of postoperative ulcerations for the 865 LEs included in these studies was 0.6%.
Furthermore, 4 studies assessed the postoperative incidence of LE amputations.13,17,18,20 After a pooled follow-up period of 19.9 ± 14.8 months, the pooled incidence of postoperative amputations for the 937 LEs included in these studies was determined to be 0.2%.
Effect of Neurolysis on Falls and Fall-associated Fractures
None of the included studies reported outcomes regarding neuropathy-associated falls and fall-associated fractures.
Effect of Neurolysis on Hospitalizations for Foot Infections
Only 1 study18 assessed the postoperative incidence of hospitalizations for foot infections (not SSI). Of 628 total patients, 4 patients (0.6%) were hospitalized postoperatively for foot infections other than SSI.
Complications were reported by 6 studies (Table 5).10,13–16,20 The overall complication rate for the 138 LEs included in these studies was 22%. Specifically, the incidence of wound dehiscence was assessed by 5 studies.10,14–16,20 The pooled incidence of wound dehiscence for the 112 LEs included in these studies was 15%. Additionally, the incidence of SSI was assessed by 4 studies.10,13,14,16 The pooled incidence of SSI after neurolysis for the 112 LEs included in these studies was 6%.
Finally, the occurrence of miscellaneous complications was reported by 3 studies.10,13,20 Dellon10 reported 1 patient having loss of superficial peroneal nerve requiring foot brace. Wieman and Patel13 reported 1 patient requiring dialysis and treatment for congestive heart failure, and Knobloch et al20 reported 1 episode of venous thromboembolism. The overall incidence of the aforementioned postoperative miscellaneous complications for the 69 patients included in these studies was 4%.
The lack of published RCTs or quasi-RCTs restricts the physician caring for diabetic patients with neuropathy to rely solely on the existing observational cohort studies when considering the possibility of neurolysis for this population. We have identified 2 currently ongoing RCTs that when published will help clarify the controversy regarding this intervention. In the meantime, the meta-analytic assessment of data from nonrandomized observational studies constitutes the highest level evidence available to the clinician dealing with diabetic patients with neuropathy.
A previous systematic review performed by Chaudhry et al23 assessed the effect of neurolysis on patients with diabetic symmetric distal polyneuropathy, including diabetic patients with and without superimposed compression. They found no evidence to support the use of neurolysis in the overall diabetic population with neuropathy. However, that study has a significant limitation, which is the inclusion of patients without evidence of superimposed nerve compression. The approach first described by Dellon10 was proposed for diabetic patients with neuropathy and associated superimposed compressed nerves. Thus, the present study aimed to address this specific issue by limiting the population to diabetic patients with evidence (positive Tinel sign or electrodiagnostic studies) of superimposed nerve compression of the LEs. We believe that the pooled diabetic population (875 diabetic patients and 1053 operated LEs) along with the pooled study (1982 to 2012) and follow-up (16.8 ± 12.5 mo) periods are adequate to analyze the predefined endpoints of interest of this systematic review.
Our meta-analysis of nonrandomized observational studies shows that neurolysis significantly improves pain, sensibility, and renders a low incidence of postoperative ulcerations/amputations. Assuming a placebo effect of 30%, a change of >1.5 VAS units represents a true difference between the postoperative scores and the preoperative scores. Additionally, a true difference between scores of 4.1 to 2.6 would be clinically significant because it would bring a patient from the “moderate” down into the “mild” pain category. Thus, the observed meta-analytic pooled improvement in pain by >4 points (95% CI: 4.04–6.77) on VAS is considered clinically and statistically significant. Furthermore, the fact that pooled analysis showed significant pain relief after neurolysis occurring in 91% of the operated LEs, with worsening of symptoms in 5% and no improvement in 4%, suggests that with regard to pain, this intervention has acceptable effectiveness. Improvement on sensibility was less dramatic with a pooled significant improvement on 2-point discrimination of 3.90 mm (95% CI: 0.13–7.67 mm), occurring on 69% of the operated LEs.
Importantly, the present meta-analysis of observational studies suggests that neurolysis significantly reduces (P < 0.0001) the incidence of postoperative ulcerations when compared to the preoperative period. This statistically significant reduction on postoperative ulcerations is more evident when the pooled incidence of postoperative ulcerations for the 865 operated LEs included in these studies (0.6%) after a pooled follow-up period of 27.7 ± 20.2 months is compared to the expected lifetime occurrence of ulceration in this population (15–25%).32–34 The most likely explanations for the reduction in postoperative ulcerations are the gain of protective sensation and trophic innervation of the skin, although these were not studied directly.
Furthermore, pooled data analysis showed that the postoperative incidence of amputations (0.2%) after a pooled follow-up period of 19.9 ± 14.8 months was significantly reduced compared to the expected incidence of postoperative amputations (10–15%).35 In the diabetic population, amputation of the LEs is the result of 2 phenomena that may exist independently or coexist: ischemia due to peripheral vascular disease vs loss of protective sensation (which exposes the patient to inadvertent trauma with the subsequent development of ulcerations, soft-tissue infection, and necrosis). All the patients in our study population had an ankle-brachial index >0.7, making ischemia an unlikely cause of amputation. Hence, the reduced postoperative incidence of amputations is likely due to the gain of protective sensation with a subsequent lower incidence of ulceration, infection, and soft-tissue necrosis. Alternatively, some sort of surgical selection bias might explain the reduction on the postoperative incidence of ulcerations because only patients without significant peripheral vascular disease were deemed candidates for neurolysis.
Unfortunately, none of the included studies assessed the effect of neurolysis on prevention of neuropathy-associated falls and fall-induced fractures, whereas only one assessed its effect on postoperative incidence of hospitalizations for foot infections other than SSI. This study found this incidence to be 0.6%, a significant decrease when compared to the 3.7% incidence at 2 years reported by previous studies on diabetics undergoing the best available, intensive primary foot care.36 This can be explained by the same mechanism that decreases the incidence of postoperative ulceration/amputation in this population.
Finally, but equally important, neurolysis for diabetic patients with compressed nerves of the LEs is associated with a 22% overall complication rate. Wound dehiscence (15%) is the most common complication after neurolysis, followed by SSI (6%) and miscellaneous complications (4%). All but one of the patients included in this systematic review and meta-analysis healed appropriately and did not progress to amputation of the extremities affected by delayed wound healing.
Although the present study includes the ideal patient population, the subjectivity inherent to some of the endpoints assessed (pain and sensibility) along with some methodological flaws of the included observational studies lower the strength of data interpretation and the conclusions reached. The overall clinical relevance score of the included articles (70%) clearly demonstrates the importance of the population and intervention. Nevertheless, the methodological quality score (50%) reflects how poor our attempts have been toward elucidating the real impact of this clinically relevant intervention. Furthermore, in these 10 included studies, the side of surgery (generally more symptomatic), the number of nerves operated upon, the endpoints, and the follow-up differed. Nine of the 10 included studies were not blinded,10,13–20 and 1 study was blinded only to the technician recording sensation measurements.8
All of the above justify the need for RCTs to further assess the effect of neurolysis on diabetic patients with compressed nerves of the LEs. To date, there are several ongoing RCTs worldwide; however, there is no consensus as to the ideal RCT design to determine the effect of neurolysis on this population. The following RCT designs could be considered:
- Patients are randomized to receive either actual decompression surgery or sham operation; experimental group = unilateral neurolysis; control group = unilateral sham surgery; all patients will have unilateral surgery.
- Patients are randomized to receive either actual decompression surgery or no operation; experimental group = unilateral neurolysis; control group = no surgery, optimized medical and podiatric care; half the patients will have unilateral surgery, and the half will receive no surgery.
- Limbs are randomized to receive either actual decompression surgery or sham operation; experimental group = unilateral neurolysis; control group = contralateral sham surgery; all patients will have bilateral surgery.
- Limbs are randomized to receive either actual decompression surgery or no operation; experimental group = unilateral neurolysis; control group = contralateral limb receives no surgery, but receives optimized medical and podiatric care; all patients will have unilateral decompression surgery, without contralateral surgery.
Sham surgery in the control group can be used to blind the patients and account for the placebo effect; study designs without sham surgery will not have blinding. Additionally, in study designs with a sham surgery, someone other than the surgeon should do the follow-up, such that both the patient and the evaluator would be blinded. The control and experimental groups should receive optimized medical and podiatric care during the preoperative and postoperative periods. Additional evaluations of the economic implications of this intervention are also warranted.
Meta-analytic assessment of observational (prospective and retrospective) studies shows that neurolysis significantly improves symptoms and natural history of diabetic patients with superimposed compressed nerves on the LE. RCTs and subsequent meta-analysis of RCTs have not yet been published and will further enlighten the use of neurolysis on diabetic patients with superimposed nerve compression.
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