ORIGINAL RESEARCH
Nerve Conduction Studies After Decompression in Painful Diabetic Polyneuropathy Joanne F. M. Macaré van Maurik,* Hessel Franssen,† Daniel W. Millin,* Edgar J. G. Peters,‡ and Moshe Kon*
Purpose: To investigate the influence of nerve decompression at potential entrapment sites in the lower extremity in painful diabetic polyneuropathy on nerve conduction study variables. Methods: Forty-two patients with painful diabetic polyneuropathy were included in this prospective randomized controlled trial. Preoperative nerve conduction studies were performed bilaterally. Each patient underwent unilateral surgical decompression of the tibial nerve and common, superficial, and deep peroneal nerves. The contralateral side was used as a control: within-patient comparison. One year postoperatively, the nerve conduction studies were repeated. Univariate paired sample T-tests and a multivariate analysis of variance were performed to compare data. Results: In univariate analysis of the peroneal nerve, the distal compound muscle action potential amplitude measured at the extensor digitorum brevis muscle of the intervention legs decreased significantly, as did the area drop measured at the extensor digitorum brevis muscle of the control legs. The distal motor latency measured at the extensor digitorum brevis muscle of the intervention legs increased significantly, as did the distal compound muscle action potential amplitude measured at the anterior tibial muscle of the control legs. For the tibial nerve, the distal compound muscle action potential duration decreased significantly in the control legs. The multivariate analysis showed no significance overall. Conclusions: Decompression of nerves of the lower extremity in patients with painful diabetic polyneuropathy has no beneficial effect on nerve conduction study variables 12 months after surgery. Key Words: Painful diabetic polyneuropathy, Surgical decompression, Nerve conduction studies, Dellon procedure, Lower extremity.
elucidated, metabolic changes and microvascular damage may cause neurodegenerative changes. Treatment focusing on stabilizing glucose levels unfortunately cannot prevent progression. In 1991, Dellon suggested that the altered metabolic state makes nerves more prone to compression at certain anatomic spaces (Dellon and Mackinnon, 1991). Since 1992, several studies reported the effects of nerve decompression on visual analog scale (VAS) or on late complications such as ulceration and amputations. Reports on the effects of nerve decompression showed promising results for relief of pain and restoration of sensorimotor function, but these investigations lacked a prospective randomized design (Aszmann et al., 2000; Aszmann et al., 2004; Caffee, 2000; Chaudhry et al., 2008; Dellon, 1992; Ducic et al., 2004; Karagoz et al., 2008; Knobloch et al., 2012; Valdivia et al., 2005; Valdivia Valdivia et al., 2013; Wieman and Patel, 1995; Zhang et al., 2013). The present report on nerve conduction study (NCS) findings is part of our randomized controlled study on effects of nerve decompression surgery in patients with painful DPN. The Lower Extremity Nerve entrapment Study (LENS) is a randomized controlled study, performed at the University Medical Center Utrecht. Outcomes included pain, sensory deficits, quality of life, nerve ultrasound, and electromyogram results (Macaré van Maurik et al., 2013, 2014). The aim of this randomized controlled study was to investigate the effect of nerve decompression surgery on NCS results in patients with painful DPN.
(J Clin Neurophysiol 2015;32: 247–250)
D
iabetic polyneuropathy (DPN) is a common complication of diabetes mellitus and is an ever-increasing health and economic issue in the Western world (Driver et al., 2010). It is characterized by numbness, pain, itching, and a burning sensation in a symmetric stocking–glove distribution. Although the etiology is not fully
From the Departments of *Plastic Surgery and †Neurology, University Medical Center Utrecht, Utrecht, the Netherlands; and ‡Department of Internal Medicine, VU University Medical Center, Amsterdam, the Netherlands. Supported by a grant (grant number: 1001-016) from NutsOhra, Amsterdam, the Netherlands, foundation for financial support in healthcare research. H. Franssen reports grants received from the Prinses Beatrix Spierfonds (grant number: W.OR14-07) and honoraria from Baxter. J. F. M. M. v. Maurik, H. Franssen, and D. W. Millin wrote the article, researched data, contributed to the discussion, and reviewed/edited the article. M. Kon and R. P. A. E. reviewed/edited the article. J. F. M. M. M. v. Maurik and R. P. A. E. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Address correspondence and reprint requests to Joanne F. M. Macaré van Maurik, MD, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands; e-mail: j.f.m. [email protected]. Copyright Ó 2015 by the American Clinical Neurophysiology Society
ISSN: 0736-0258/15/3203-0247
METHODS Patients Forty-two patients with painful diabetic neuropathy, assessed by Diabetic Neuropathy Symptom score and Diabetic Neuropathy Examination, were included in the Lower Extremity Nerve entrapment Study (LENS), a randomized controlled study (Meijer et al., 2000, 2002). The study with Dutch Trial Registry number NTR 2344 was conducted according to the principles of the Declaration of Helsinki and in accordance with the Dutch Medical Research Involving Human Subjects Act and was approved by the local medical ethical committee. All patients provided written informed consent. Inclusion criteria were age between 18 and 90 years, a positive Tinel sign of the tibial nerve and deep common peroneal nerve, Ankle–Brachial Index between 0.8 and 1.15 with palpable peripheral pulsations of the posterior tibial artery and dorsal pedal artery, a toe brachial index of $ 0.7 (to minimize the risk for postoperative wound complications), and patients had to understand written and spoken instructions. Exclusion criteria were body mass index .35 kg/m2, poor medical condition unsuitable for surgery, ankle fractures in the
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patient history, amputations proximal to the Lisfranc joint; active foot ulcers, satisfactory effect of pain medication (VAS, 0–1), and other causes for polyneuropathy than diabetes mellitus.
velocity or sensory conduction velocity, and 25% for segmental CMAP changes reflecting conduction block or temporal dispersion) (Van den Berg-Vos et al., 2002).
Procedure
Statistical Analysis
Patients were operated on one leg, using the other leg as a within-patient control. A web-based randomization program was used to choose the leg receiving intervention. According to the procedure described by Dellon (Dellon, 1992), the following nerves were decompressed: (1) tibial nerve and its calcaneal, medial plantar, and lateral plantar branches at the medial ankle site, (2) common peroneal nerve at the level of the fibular head, (3) superficial peroneal nerve at the level of the lower leg, 10 to 14 cm above the lateral malleolus, and (4) deep peroneal nerve at the level of the first web. All nerve decompressions were performed by the same surgeon (J.F.M.M. v.M.) with the patient in supine position under general anesthesia; a tourniquet was placed around the upper leg. After the operation, a compression bandage was applied around the lower leg, and patients were instructed to mobilize unburdened for 2.5 weeks. Preoperatively and 12 months postoperatively, the pain was evaluated with VAS.
Nerve conduction studies variables of preoperative and postoperative intervention and control legs were compared using paired samples t-test. To compare the change in NCS outcomes for the intervention and control legs after the operation, we created D values for both legs. The D values were calculated by subtracting the postoperative values from the preoperative values within the intervention and control legs, respectively. The difference in D values between the intervention legs and the control legs were then calculated to obtain paired samples. Using a multivariate analysis of variance, these data were then analyzed to look for significant differences between the intervention legs and the control legs. Differences were considered significant when P # 0.05. Data analysis was performed with statistical software (IBM SPSS Statistics, version 21.0; IBM Corp, Armonk, NY).
NCS Protocol Nerve conduction studies were performed on the operated leg (intervention leg) and nonoperated leg (control leg), using a Viking Select EMG apparatus. Preoperatively and 12 months postoperatively, NCS were performed by three specially trained and skilled technicians using a specially designed protocol. To ensure reproducibility between the first and second NCS, stimulation and recording sites were marked and photographed from a standard angle, and distances between stimulation electrodes and between distal stimulation and recording electrodes were noted; furthermore, each patient was investigated by the same technician for both NCS. Before NCS, both legs were warmed in water at 378C during 30 minutes; during NCS, the legs were kept warm under an infrared heater set at 378C (Franssen and Wieneke, 1994). Motor NCS were performed in the (1) deep peroneal nerve (recording: extensor digitorum brevis muscle, stimulation: between malleoli, 3 cm distal to the fibular head, and 5 cm proximal to the fibular head), (2) deep peroneal nerve (recording: anterior tibial muscle, stimulation: 3 cm distal and 5 cm proximal to the fibular head), (3) tibial nerve (recording: abductor hallucis muscle, stimulation: behind the medial malleolus and proximal to the site of decompression, and popliteal fossa). Per nerve, we analyzed amplitude, area, and duration of the negative compound muscle action potential (CMAP) part and distal motor latency. Per nerve segment, we analyzed motor nerve conduction velocity per segment, and segmental area drop calculated as ([distal area 2 proximal area] 100%)/distal area. Sensory NCS was performed for the superficial peroneal nerve (recording: one-third of the distance from the lateral malleolus toward the medial malleolus, stimulation: 12 cm more proximally on the lateral aspect of the lower leg). We analyzed amplitude of the sensory nerve action potential and sensory conduction velocity. Sensory nerve action potentials were averaged until they were clearly distinguishable from baseline. Nerve conduction studies of the intervention leg and control leg were simultaneously performed before and after surgery. For individual patients, a change between the first and second NCS was considered meaningful if it exceeded intraobserver variability as established in a previous study (1.5 mV for distal CMAPs, 5 mV for sensory nerve action potentials, 5 m/s for motor nerve conduction 248
RESULTS Of the 42 patients who were initially included, one was lost to follow-up and another patient died from an unrelated cause before the end of the study. The remaining 40 patients were investigated in this study. Of these 40 patients, 2 had an infection of the wound at the ankle site; both of them were treated with antibiotics, and one of them was readmitted to the hospital. A third patient had to be reoperated for a hematoma due to the use of anticoagulants. The mean Diabetic Neuropathy Examination and Diabetic Neuropathy Symptom scores were 8 and 4, respectively. At baseline, VAS was 6.1 (95% confidence interval, 5.5–6.7) for both the intervention and control legs, and mean HbA1c was 57.3 mmol/mol. Baseline characteristics are summarized in Table 1. One year after operation, VAS had significantly decreased in both the intervention and control legs to 3.5 (95% confidence interval, 2.5–4.4) and 5.3 (95% confidence interval, 4.4–6.2 [P , 0.001]), respectively (Macaré van Maurik et al., 2014). Mean HbA1c was 59.5 mmol/mol (95% confidence interval, 54.6–64.6). Nerve conduction study outcomes between the intervention and control legs are summarized in Table 2.
TABLE 1.
n (Either in percentage or SD)
Variable Male (%) Female (%) Age, mean years (6SD) BMI, mean kg/m2 (6SD) Diabetes mellitus Type 1 Type 2 Duration of DM, mean years (6SD) HbA1c, mean mmol/mol (6SD) Surgical decompression Right leg (%) Left leg (%)
Participants, N ¼ 40 26 14 61.2 29.3
(65) (35) (610.96) (64.27)
10 30 19.5 57.3
(25) (75) (612.2) (613.8)
18 (45) 22 (55)
BMI, body mass index.
Copyright Ó 2015 by the American Clinical Neurophysiology Society
Journal of Clinical Neurophysiology Volume 32, Number 3, June 2015
TABLE 2.
NCS Results After Nerve Decompression in DPN
NCS Results Intervention Legs Preoperative (6SD)
Peroneal nerve
Tibial nerve
Extensor digitorum brevis muscle Distal CMAP amplitude, mV Distal CMAP duration, milliseconds Distal motor latency, milliseconds Motor conduction velocity: lower leg, m/s Motor conduction velocity: fibular head, m/s Area drop: lower leg, % Area drop: fibular head, % Tibialis anterior muscle Distal CMAP amplitude, mV Motor conduction velocity, m/s Superficial peroneal nerve SNAP amplitude, mV Sensory conduction velocity, m/s Distal CMAP amplitude, mV Distal CMAP duration, milliseconds Distal motor latency, milliseconds Motor conduction velocity, m/s Area drop, %
Postoperative (6SD)
Control Legs P*
Preoperative (6SD)
(1.8) (1.3) (1.2) (8) (10) (15) (12)
† NS ‡ NS NS NS NS
3.4 4.5 4.1 37 42 11 5
5.0 (1.5) 54 (13)
4.9 (1.4) 54 (14)
NS NS
3.0 23 4.7 4.8 4.3 36 13
2.3 19 4.1 5.0 4.5 37 16
NS NS NS NS NS NS NS
3.1 4.9 4.3 38 41 12 4
(2.6) (1.5) (1.1) (9) (10) (14) (7)
(4.9) (21) (4.0) (1.7) (1.4) (13) (16)
2.1 4.9 4.7 37 41 9 6
(4.5) (21) (3.9) (1.5) (1.4) (10) (18)
(2.7) (1.6) (1.4) (12) (18) (11) (11)
Postoperative (6SD) (2.4) (1.7) (1.3) (10) (15) (8) (12)
NS NS NS NS NS § NS
4.8 (1.5) 53 (12)
5.2 (1.3) 54 (10)
§ NS
3.7 22 4.3 5.1 4.3 36 13
2.6 21 4.1 4.6 4.1 35 12
NS NS NS § NS NS NS
(5.0) (20) (3.7) (1.6) (1.3) (12) (12)
2.9 4.6 4.4 37 43 6 7
P*
(3.5) (21) (3.6) (1.8) (1.6) (13) (12)
NB: when comparing intervention and control legs, the post-operative distal CMAP amplitude measured at the EDB was found to be significant (P # 0.01). *Measured using paired sample t-test. †P # 0.001. ‡P # 0.01. §P # 0.05. CMAP, compound muscle action potential; EDB, extensor digitorum brevis muscle; NS, no significance, P . 0.05; NCS, nerve conduction study; SNAP, sensory nerve action potential.
At baseline, the intervention legs did not differ from the control legs. For the univariate analysis, paired sample t-tests were performed for each individual parameter. For the peroneal nerve, distal CMAP amplitude measured at the extensor digitorum brevis muscle of the intervention legs decreased significantly. The distal motor latency measured at the extensor digitorum brevis muscle of the intervention legs increased significantly. The area drop in the lower leg measured at the extensor digitorum brevis muscle of the control legs decreased significantly. The distal CMAP amplitude measured at the anterior tibial muscle of the control legs increased significantly. When comparing intervention and control legs, the postoperative distal CMAP amplitude was significantly higher in the control legs. For the tibial nerve, the distal CMAP duration decreased significantly in the control legs. To analyze the overall effect of decompression, a multivariate analysis of variance was performed on all variables; no significant difference in NCS outcome was noted between the intervention and control legs (P ¼ 0.120). Univariate analysis results were therefore redundant.
DISCUSSION As part of the LENS study, we investigated the influence on NCS variables of nerve decompression at potential entrapment sites of lower extremity nerves in painful diabetic neuropathy. Copyright Ó 2015 by the American Clinical Neurophysiology Society
Using multivariate tests, our results showed no significant change between intervention legs and control legs. Other, nonrandomized studies showed VAS decrease after decompression of lower extremity nerves in patients with painful DPN, suggesting direct nerve compression, an etiological factor for painful DPN. Contrary to results in these previous studies, our results suggested that nerve decompression had no influence on NCS variables (Dellon, 1992; Zhang et al., 2013). These findings correspond with the results of an ultrasound study of the tibial nerves in which we showed that decompression of the tarsal tunnel did not influence the cross-sectional area of the tibial nerve (Macaré van Maurik et al., 2013). Because the study could not be blinded accurately, a sham procedure was initially discussed but was rejected on ethical grounds. However, a strict NCS protocol was used to help keep bias at a minimum. The results of our study revealed several albeit small differences in NCS variables when using univariate paired sample t-test analysis. However, when using a multivariate analysis of variance, no significance was observed. Although the postoperative worsening in some NCS variables in our study is likely to be clinically irrelevant, the decline in peroneal nerve CMAP amplitude suggests that the nerve itself might even be adversely affected by the surgical decompression. The improvement in VAS after decompression seems to be attributable to other factors than to those measurable with NCS or ultrasound (Macaré van Maurik et al., 2013). With NCS, large myelinated axons are tested, while the function of small nonmyelinated fibers have to be examined physically; for example 249
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Quantitative Sensory Testing might be a useful tool for detection of small fiber threshold alterations for thermal pain and sensation in future studies to surgical decompression (Rolke et al., 2006). It would also be interesting to investigate (micro)vascular alterations after surgical decompression in this population. The significant improvement in VAS scores of both the intervention and the control legs could be attributed to a phenomenon where the operated leg influenced the control leg; this can also be observed in posttraumatic neuropathic pains (Arguis et al., 2008; Fitzgerald, 1982; Huang and Yu, 2010; Jancalek, 2011). The absolute difference in VAS scores of the intervention and control legs remained significant. Also, a possible placebo effect as the cause of the subjective pain relief cannot be ruled out. Other studies on the effect of nerve decompression on NCS variables in DPN showed beneficial effects. A prospective cohort study of 560 patients with DPN found significant improvement in nerve conduction velocity of the posterior tibial and common peroneal and superficial peroneal nerves (Zhang et al., 2013). Other variables such as distal motor latency, CMAP amplitude, CMAP duration, or sensory nerve action potential amplitude were not reported. Furthermore, nerves were cooled to 308C in a water bath, thereby decreasing motor nerve conduction velocity, sensory conduction velocity, and increasing distal motor latency (Franssen and Wieneke, 1994). For these reasons, our NCS results cannot be compared with that study. Another prospective cohort study included 60 patients with both diabetes mellitus type 1 and type 2 (Dellon, 1992). Improvement in unspecified electrodiagnostic tests was found in 68% of patients, and no change in 30% of patients. Only excellent, good, fair, and poor results were described but no results for NCS variables. Both upper and lower limb nerves were investigated, but the study was not stratified accordingly (Dellon 1992). The study described better results after decompression of nerves in the upper extremities than in lower extremity nerves, possibly related to the higher conduction velocity in upper limb nerves (Wanatabe et al., 2010; Bromberg and Albers, 1993). In conclusion, decompression of lower extremity nerves in patients with painful DPN has no effect on NCS variables 12 months after surgery. ACKNOWLEDGMENTS Statistical analysis: D. W. Millin, Department of Plastic Surgery, University Medical Center Utrecht, Utrecht, the Netherlands, in association with M. J. C. Eijkemans, Associate Professor Biostatics and Research Support, Julius Center, Utrecht, the Netherlands. The authors thank J. L. de Kleijn for background data collection. Trial Registry Number: NTR 2344 (Nederlands Trial Register, www. trialregister.nl). REFERENCES Arguis MJ, Perez J, Martínez G, et al. Contralateral neuropathic pain following a surgical model of unilateral nerve Injury in Rats. Reg Anesth Pain Med 2008;33:211–216. Aszmann O, Tassler PL, Dellon AL. Changing the natural history of diabetic neuropathy: incidence of ulcer/amputation in the contralateral limb of patients with a unilateral nerve decompression procedure. Ann Plast Surg 2004;53:517–522.
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Aszmann OC, Kress KM, Dellon AL. Results of decompression of peripheral nerves in diabetics: a prospective, blinded study. Plast Reconstr Surg 2000;106:816–822. Bromberg MB, Albers JW. Patterns of sensory nerve conduction abnormalities in demyelinating and axonal peripheral nerve disorders. Muscle Nerve 1993;16:262–266. Caffee HHH. Treatment of diabetic neuropathy by decompression of the posterior tibial nerve. Plast Reconstr Surg 2000;106:813–815. Chaudhry V, Russell J, Belzberg A. Decompressive surgery of lower limbs for symmetrical diabetic peripheral neuropathy. Cochrane Database Syst Rev 2008;16:CD006152. Dellon AL, Mackinnon SE. Chronic nerve compression model for the double crush hypothesis. Ann Plast Surg 1991;26:259–264. Dellon AL. Treatment of symptomatic diabetic neuropathy by surgical decompression of multiple peripheral nerves. Plast Reconstr Surg 1992;89:689–697. Driver VR, Fabbi M, Lavery LA, Gibbons G. The costs of diabetic foot: the economic case for the limb salvage team. J Vasc Surg 2010;52(3 Suppl):17S–22S. Ducic I, Short KW, Dellon AL. Relationship between loss of pedal sensibility, balance, and falls in patients with peripheral neuropathy. Ann Plast Surg 2004;52:535–540. Fitzgerald M. The contralateral input to the dorsal horn of the spinal cord in the decerebrate spinal rat. Brain Res 1982;236:275–287. Franssen H, Wieneke GH. Nerve conduction and temperature: necessary warming time. Muscle Nerve 1994;17:336–344. Huang D, Yu B. The mirror-image pain: an unclered phenomenon and its possible mechanism. Neurosci Biobehav Rev 2010;34:528–532. Jancalek R. Signaling mechanisms in mirror image pain pathogenesis. Ann Neurosci 2011;18:123–127. Karagoz H, Yuksel F, Ulkur E, Celikoz B. Early and late results of nerve decompression procedures in diabetic neuropathy: a series from Turkiye. J Reconstr Microsurg 2008;24:95–101. Knobloch K, Gohritz G, Vogt PM. Surgical decompression of the lower leg in painful diabetic polyneuropathy. Oper Orthop Traumatol 2012;24:74–79. Macaré van Maurik JFM, Schouten MEL, Katen IT, et al. Ultrasound findings after surgical decompression of the tarsal tunnel in patients with painful diabetic polyneuropathy: a prospective, randomised, study. Diabetes Care 2013;37:767–772. Macaré van Maurik JFM, van Hal M, van Eijk RPA, et al. Value of surgical decompression of compressed nerves in the lower extremity in patients with painful diabetic neuropathy. A randomized controlled trial. Plast Reconstr Surg 2014;134:325–332. doi: 10.1097/PRS.0000000000000369. Meijer JW, van Sonderen E, Blaauwwiekel EE, et al. Diabetic neuropathy examination: a hierarchical scoring system to diagnose distal polyneuropathy in diabetes. Diabetes Care 2000;23:750–753. Meijer JWG, Smit AJ, Sonderen EV, et al. Symptom scoring systems to diagnose distal polyneuropathy in diabetes: the Diabetic Neuropathy Symptom score. Diabet Med 2002;19:962–965. Rolke R, Baron R, Maier C, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain 2006;123:231–243. Valdivia JMV, Dellon AL, Weinand ME, Maloney CT Jr. Surgical treatment of peripheral neuropathy: outcomes from 100 consecutive decompressions. J Am Podiatr Med Assoc 2005;95:451–454. Valdivia Valdivia JM, Weinand M, Maloney CT, et al. Surgical treatment of superimposed, lower extremity, peripheral nerve entrapments with diabetic and idiopathic neuropathy. Ann Plast Surg 2013;70:675–679. Van den Berg-Vos RM, Franssen H, Wokke JH, Van den Berg LH. Multifocal motor neuropathy: long-term clinical and electrophysiological assessment of intravenous immunoglobulin maintenance treatment. Brain J Neurol 2002;125(Pt 8):1875–1886. Watanabe T, Ito H, Sekine A, et al. Sonographic evaluation of the peripheral nerve in diabetic patients the relationship between nerve conduction studies, echo intensity, and cross-sectional area. J Ultrasound Med 2010;29:697–708. Wieman TJ, Patel VG. Treatment of hyperesthetic neuropathic pain in diabetics. Decompression of the tarsal tunnel. Ann Surg 1995;221:660–664; discussion 664–5. Zhang W, Zhong W, Yang M, et al. Evaluation of the clinical efficacy of multiple lower-extremity nerve decompression in diabetic peripheral neuropathy. Br J Neurosurg 2013;27:795–799.
Copyright Ó 2015 by the American Clinical Neurophysiology Society
Nerve Conduction Studies After Decompression in Painful Diabetic Polyneuropathy Joanne F. M. Macaré van Maurik,* Hessel Franssen,† Daniel W. Millin,* Edgar J. G. Peters,‡ and Moshe Kon*
Purpose: To investigate the influence of nerve decompression at potential entrapment sites in the lower extremity in painful diabetic polyneuropathy on nerve conduction study variables. Methods: Forty-two patients with painful diabetic polyneuropathy were included in this prospective randomized controlled trial. Preoperative nerve conduction studies were performed bilaterally. Each patient underwent unilateral surgical decompression of the tibial nerve and common, superficial, and deep peroneal nerves. The contralateral side was used as a control: within-patient comparison. One year postoperatively, the nerve conduction studies were repeated. Univariate paired sample T-tests and a multivariate analysis of variance were performed to compare data. Results: In univariate analysis of the peroneal nerve, the distal compound muscle action potential amplitude measured at the extensor digitorum brevis muscle of the intervention legs decreased significantly, as did the area drop measured at the extensor digitorum brevis muscle of the control legs. The distal motor latency measured at the extensor digitorum brevis muscle of the intervention legs increased significantly, as did the distal compound muscle action potential amplitude measured at the anterior tibial muscle of the control legs. For the tibial nerve, the distal compound muscle action potential duration decreased significantly in the control legs. The multivariate analysis showed no significance overall. Conclusions: Decompression of nerves of the lower extremity in patients with painful diabetic polyneuropathy has no beneficial effect on nerve conduction study variables 12 months after surgery. Key Words: Painful diabetic polyneuropathy, Surgical decompression, Nerve conduction studies, Dellon procedure, Lower extremity.
elucidated, metabolic changes and microvascular damage may cause neurodegenerative changes. Treatment focusing on stabilizing glucose levels unfortunately cannot prevent progression. In 1991, Dellon suggested that the altered metabolic state makes nerves more prone to compression at certain anatomic spaces (Dellon and Mackinnon, 1991). Since 1992, several studies reported the effects of nerve decompression on visual analog scale (VAS) or on late complications such as ulceration and amputations. Reports on the effects of nerve decompression showed promising results for relief of pain and restoration of sensorimotor function, but these investigations lacked a prospective randomized design (Aszmann et al., 2000; Aszmann et al., 2004; Caffee, 2000; Chaudhry et al., 2008; Dellon, 1992; Ducic et al., 2004; Karagoz et al., 2008; Knobloch et al., 2012; Valdivia et al., 2005; Valdivia Valdivia et al., 2013; Wieman and Patel, 1995; Zhang et al., 2013). The present report on nerve conduction study (NCS) findings is part of our randomized controlled study on effects of nerve decompression surgery in patients with painful DPN. The Lower Extremity Nerve entrapment Study (LENS) is a randomized controlled study, performed at the University Medical Center Utrecht. Outcomes included pain, sensory deficits, quality of life, nerve ultrasound, and electromyogram results (Macaré van Maurik et al., 2013, 2014). The aim of this randomized controlled study was to investigate the effect of nerve decompression surgery on NCS results in patients with painful DPN.
(J Clin Neurophysiol 2015;32: 247–250)
D
iabetic polyneuropathy (DPN) is a common complication of diabetes mellitus and is an ever-increasing health and economic issue in the Western world (Driver et al., 2010). It is characterized by numbness, pain, itching, and a burning sensation in a symmetric stocking–glove distribution. Although the etiology is not fully
From the Departments of *Plastic Surgery and †Neurology, University Medical Center Utrecht, Utrecht, the Netherlands; and ‡Department of Internal Medicine, VU University Medical Center, Amsterdam, the Netherlands. Supported by a grant (grant number: 1001-016) from NutsOhra, Amsterdam, the Netherlands, foundation for financial support in healthcare research. H. Franssen reports grants received from the Prinses Beatrix Spierfonds (grant number: W.OR14-07) and honoraria from Baxter. J. F. M. M. v. Maurik, H. Franssen, and D. W. Millin wrote the article, researched data, contributed to the discussion, and reviewed/edited the article. M. Kon and R. P. A. E. reviewed/edited the article. J. F. M. M. M. v. Maurik and R. P. A. E. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Address correspondence and reprint requests to Joanne F. M. Macaré van Maurik, MD, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands; e-mail: j.f.m. [email protected]. Copyright Ó 2015 by the American Clinical Neurophysiology Society
ISSN: 0736-0258/15/3203-0247
METHODS Patients Forty-two patients with painful diabetic neuropathy, assessed by Diabetic Neuropathy Symptom score and Diabetic Neuropathy Examination, were included in the Lower Extremity Nerve entrapment Study (LENS), a randomized controlled study (Meijer et al., 2000, 2002). The study with Dutch Trial Registry number NTR 2344 was conducted according to the principles of the Declaration of Helsinki and in accordance with the Dutch Medical Research Involving Human Subjects Act and was approved by the local medical ethical committee. All patients provided written informed consent. Inclusion criteria were age between 18 and 90 years, a positive Tinel sign of the tibial nerve and deep common peroneal nerve, Ankle–Brachial Index between 0.8 and 1.15 with palpable peripheral pulsations of the posterior tibial artery and dorsal pedal artery, a toe brachial index of $ 0.7 (to minimize the risk for postoperative wound complications), and patients had to understand written and spoken instructions. Exclusion criteria were body mass index .35 kg/m2, poor medical condition unsuitable for surgery, ankle fractures in the
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patient history, amputations proximal to the Lisfranc joint; active foot ulcers, satisfactory effect of pain medication (VAS, 0–1), and other causes for polyneuropathy than diabetes mellitus.
velocity or sensory conduction velocity, and 25% for segmental CMAP changes reflecting conduction block or temporal dispersion) (Van den Berg-Vos et al., 2002).
Procedure
Statistical Analysis
Patients were operated on one leg, using the other leg as a within-patient control. A web-based randomization program was used to choose the leg receiving intervention. According to the procedure described by Dellon (Dellon, 1992), the following nerves were decompressed: (1) tibial nerve and its calcaneal, medial plantar, and lateral plantar branches at the medial ankle site, (2) common peroneal nerve at the level of the fibular head, (3) superficial peroneal nerve at the level of the lower leg, 10 to 14 cm above the lateral malleolus, and (4) deep peroneal nerve at the level of the first web. All nerve decompressions were performed by the same surgeon (J.F.M.M. v.M.) with the patient in supine position under general anesthesia; a tourniquet was placed around the upper leg. After the operation, a compression bandage was applied around the lower leg, and patients were instructed to mobilize unburdened for 2.5 weeks. Preoperatively and 12 months postoperatively, the pain was evaluated with VAS.
Nerve conduction studies variables of preoperative and postoperative intervention and control legs were compared using paired samples t-test. To compare the change in NCS outcomes for the intervention and control legs after the operation, we created D values for both legs. The D values were calculated by subtracting the postoperative values from the preoperative values within the intervention and control legs, respectively. The difference in D values between the intervention legs and the control legs were then calculated to obtain paired samples. Using a multivariate analysis of variance, these data were then analyzed to look for significant differences between the intervention legs and the control legs. Differences were considered significant when P # 0.05. Data analysis was performed with statistical software (IBM SPSS Statistics, version 21.0; IBM Corp, Armonk, NY).
NCS Protocol Nerve conduction studies were performed on the operated leg (intervention leg) and nonoperated leg (control leg), using a Viking Select EMG apparatus. Preoperatively and 12 months postoperatively, NCS were performed by three specially trained and skilled technicians using a specially designed protocol. To ensure reproducibility between the first and second NCS, stimulation and recording sites were marked and photographed from a standard angle, and distances between stimulation electrodes and between distal stimulation and recording electrodes were noted; furthermore, each patient was investigated by the same technician for both NCS. Before NCS, both legs were warmed in water at 378C during 30 minutes; during NCS, the legs were kept warm under an infrared heater set at 378C (Franssen and Wieneke, 1994). Motor NCS were performed in the (1) deep peroneal nerve (recording: extensor digitorum brevis muscle, stimulation: between malleoli, 3 cm distal to the fibular head, and 5 cm proximal to the fibular head), (2) deep peroneal nerve (recording: anterior tibial muscle, stimulation: 3 cm distal and 5 cm proximal to the fibular head), (3) tibial nerve (recording: abductor hallucis muscle, stimulation: behind the medial malleolus and proximal to the site of decompression, and popliteal fossa). Per nerve, we analyzed amplitude, area, and duration of the negative compound muscle action potential (CMAP) part and distal motor latency. Per nerve segment, we analyzed motor nerve conduction velocity per segment, and segmental area drop calculated as ([distal area 2 proximal area] 100%)/distal area. Sensory NCS was performed for the superficial peroneal nerve (recording: one-third of the distance from the lateral malleolus toward the medial malleolus, stimulation: 12 cm more proximally on the lateral aspect of the lower leg). We analyzed amplitude of the sensory nerve action potential and sensory conduction velocity. Sensory nerve action potentials were averaged until they were clearly distinguishable from baseline. Nerve conduction studies of the intervention leg and control leg were simultaneously performed before and after surgery. For individual patients, a change between the first and second NCS was considered meaningful if it exceeded intraobserver variability as established in a previous study (1.5 mV for distal CMAPs, 5 mV for sensory nerve action potentials, 5 m/s for motor nerve conduction 248
RESULTS Of the 42 patients who were initially included, one was lost to follow-up and another patient died from an unrelated cause before the end of the study. The remaining 40 patients were investigated in this study. Of these 40 patients, 2 had an infection of the wound at the ankle site; both of them were treated with antibiotics, and one of them was readmitted to the hospital. A third patient had to be reoperated for a hematoma due to the use of anticoagulants. The mean Diabetic Neuropathy Examination and Diabetic Neuropathy Symptom scores were 8 and 4, respectively. At baseline, VAS was 6.1 (95% confidence interval, 5.5–6.7) for both the intervention and control legs, and mean HbA1c was 57.3 mmol/mol. Baseline characteristics are summarized in Table 1. One year after operation, VAS had significantly decreased in both the intervention and control legs to 3.5 (95% confidence interval, 2.5–4.4) and 5.3 (95% confidence interval, 4.4–6.2 [P , 0.001]), respectively (Macaré van Maurik et al., 2014). Mean HbA1c was 59.5 mmol/mol (95% confidence interval, 54.6–64.6). Nerve conduction study outcomes between the intervention and control legs are summarized in Table 2.
TABLE 1.
n (Either in percentage or SD)
Variable Male (%) Female (%) Age, mean years (6SD) BMI, mean kg/m2 (6SD) Diabetes mellitus Type 1 Type 2 Duration of DM, mean years (6SD) HbA1c, mean mmol/mol (6SD) Surgical decompression Right leg (%) Left leg (%)
Participants, N ¼ 40 26 14 61.2 29.3
(65) (35) (610.96) (64.27)
10 30 19.5 57.3
(25) (75) (612.2) (613.8)
18 (45) 22 (55)
BMI, body mass index.
Copyright Ó 2015 by the American Clinical Neurophysiology Society
Journal of Clinical Neurophysiology Volume 32, Number 3, June 2015
TABLE 2.
NCS Results After Nerve Decompression in DPN
NCS Results Intervention Legs Preoperative (6SD)
Peroneal nerve
Tibial nerve
Extensor digitorum brevis muscle Distal CMAP amplitude, mV Distal CMAP duration, milliseconds Distal motor latency, milliseconds Motor conduction velocity: lower leg, m/s Motor conduction velocity: fibular head, m/s Area drop: lower leg, % Area drop: fibular head, % Tibialis anterior muscle Distal CMAP amplitude, mV Motor conduction velocity, m/s Superficial peroneal nerve SNAP amplitude, mV Sensory conduction velocity, m/s Distal CMAP amplitude, mV Distal CMAP duration, milliseconds Distal motor latency, milliseconds Motor conduction velocity, m/s Area drop, %
Postoperative (6SD)
Control Legs P*
Preoperative (6SD)
(1.8) (1.3) (1.2) (8) (10) (15) (12)
† NS ‡ NS NS NS NS
3.4 4.5 4.1 37 42 11 5
5.0 (1.5) 54 (13)
4.9 (1.4) 54 (14)
NS NS
3.0 23 4.7 4.8 4.3 36 13
2.3 19 4.1 5.0 4.5 37 16
NS NS NS NS NS NS NS
3.1 4.9 4.3 38 41 12 4
(2.6) (1.5) (1.1) (9) (10) (14) (7)
(4.9) (21) (4.0) (1.7) (1.4) (13) (16)
2.1 4.9 4.7 37 41 9 6
(4.5) (21) (3.9) (1.5) (1.4) (10) (18)
(2.7) (1.6) (1.4) (12) (18) (11) (11)
Postoperative (6SD) (2.4) (1.7) (1.3) (10) (15) (8) (12)
NS NS NS NS NS § NS
4.8 (1.5) 53 (12)
5.2 (1.3) 54 (10)
§ NS
3.7 22 4.3 5.1 4.3 36 13
2.6 21 4.1 4.6 4.1 35 12
NS NS NS § NS NS NS
(5.0) (20) (3.7) (1.6) (1.3) (12) (12)
2.9 4.6 4.4 37 43 6 7
P*
(3.5) (21) (3.6) (1.8) (1.6) (13) (12)
NB: when comparing intervention and control legs, the post-operative distal CMAP amplitude measured at the EDB was found to be significant (P # 0.01). *Measured using paired sample t-test. †P # 0.001. ‡P # 0.01. §P # 0.05. CMAP, compound muscle action potential; EDB, extensor digitorum brevis muscle; NS, no significance, P . 0.05; NCS, nerve conduction study; SNAP, sensory nerve action potential.
At baseline, the intervention legs did not differ from the control legs. For the univariate analysis, paired sample t-tests were performed for each individual parameter. For the peroneal nerve, distal CMAP amplitude measured at the extensor digitorum brevis muscle of the intervention legs decreased significantly. The distal motor latency measured at the extensor digitorum brevis muscle of the intervention legs increased significantly. The area drop in the lower leg measured at the extensor digitorum brevis muscle of the control legs decreased significantly. The distal CMAP amplitude measured at the anterior tibial muscle of the control legs increased significantly. When comparing intervention and control legs, the postoperative distal CMAP amplitude was significantly higher in the control legs. For the tibial nerve, the distal CMAP duration decreased significantly in the control legs. To analyze the overall effect of decompression, a multivariate analysis of variance was performed on all variables; no significant difference in NCS outcome was noted between the intervention and control legs (P ¼ 0.120). Univariate analysis results were therefore redundant.
DISCUSSION As part of the LENS study, we investigated the influence on NCS variables of nerve decompression at potential entrapment sites of lower extremity nerves in painful diabetic neuropathy. Copyright Ó 2015 by the American Clinical Neurophysiology Society
Using multivariate tests, our results showed no significant change between intervention legs and control legs. Other, nonrandomized studies showed VAS decrease after decompression of lower extremity nerves in patients with painful DPN, suggesting direct nerve compression, an etiological factor for painful DPN. Contrary to results in these previous studies, our results suggested that nerve decompression had no influence on NCS variables (Dellon, 1992; Zhang et al., 2013). These findings correspond with the results of an ultrasound study of the tibial nerves in which we showed that decompression of the tarsal tunnel did not influence the cross-sectional area of the tibial nerve (Macaré van Maurik et al., 2013). Because the study could not be blinded accurately, a sham procedure was initially discussed but was rejected on ethical grounds. However, a strict NCS protocol was used to help keep bias at a minimum. The results of our study revealed several albeit small differences in NCS variables when using univariate paired sample t-test analysis. However, when using a multivariate analysis of variance, no significance was observed. Although the postoperative worsening in some NCS variables in our study is likely to be clinically irrelevant, the decline in peroneal nerve CMAP amplitude suggests that the nerve itself might even be adversely affected by the surgical decompression. The improvement in VAS after decompression seems to be attributable to other factors than to those measurable with NCS or ultrasound (Macaré van Maurik et al., 2013). With NCS, large myelinated axons are tested, while the function of small nonmyelinated fibers have to be examined physically; for example 249
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Quantitative Sensory Testing might be a useful tool for detection of small fiber threshold alterations for thermal pain and sensation in future studies to surgical decompression (Rolke et al., 2006). It would also be interesting to investigate (micro)vascular alterations after surgical decompression in this population. The significant improvement in VAS scores of both the intervention and the control legs could be attributed to a phenomenon where the operated leg influenced the control leg; this can also be observed in posttraumatic neuropathic pains (Arguis et al., 2008; Fitzgerald, 1982; Huang and Yu, 2010; Jancalek, 2011). The absolute difference in VAS scores of the intervention and control legs remained significant. Also, a possible placebo effect as the cause of the subjective pain relief cannot be ruled out. Other studies on the effect of nerve decompression on NCS variables in DPN showed beneficial effects. A prospective cohort study of 560 patients with DPN found significant improvement in nerve conduction velocity of the posterior tibial and common peroneal and superficial peroneal nerves (Zhang et al., 2013). Other variables such as distal motor latency, CMAP amplitude, CMAP duration, or sensory nerve action potential amplitude were not reported. Furthermore, nerves were cooled to 308C in a water bath, thereby decreasing motor nerve conduction velocity, sensory conduction velocity, and increasing distal motor latency (Franssen and Wieneke, 1994). For these reasons, our NCS results cannot be compared with that study. Another prospective cohort study included 60 patients with both diabetes mellitus type 1 and type 2 (Dellon, 1992). Improvement in unspecified electrodiagnostic tests was found in 68% of patients, and no change in 30% of patients. Only excellent, good, fair, and poor results were described but no results for NCS variables. Both upper and lower limb nerves were investigated, but the study was not stratified accordingly (Dellon 1992). The study described better results after decompression of nerves in the upper extremities than in lower extremity nerves, possibly related to the higher conduction velocity in upper limb nerves (Wanatabe et al., 2010; Bromberg and Albers, 1993). In conclusion, decompression of lower extremity nerves in patients with painful DPN has no effect on NCS variables 12 months after surgery. ACKNOWLEDGMENTS Statistical analysis: D. W. Millin, Department of Plastic Surgery, University Medical Center Utrecht, Utrecht, the Netherlands, in association with M. J. C. Eijkemans, Associate Professor Biostatics and Research Support, Julius Center, Utrecht, the Netherlands. The authors thank J. L. de Kleijn for background data collection. Trial Registry Number: NTR 2344 (Nederlands Trial Register, www. trialregister.nl). REFERENCES Arguis MJ, Perez J, Martínez G, et al. Contralateral neuropathic pain following a surgical model of unilateral nerve Injury in Rats. Reg Anesth Pain Med 2008;33:211–216. Aszmann O, Tassler PL, Dellon AL. Changing the natural history of diabetic neuropathy: incidence of ulcer/amputation in the contralateral limb of patients with a unilateral nerve decompression procedure. Ann Plast Surg 2004;53:517–522.
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