Our experience of reinnervation of sole in diabetic sensorimotor polyneuropathy: A chance to change the natural history of disease

Abstract

Diabetic sensorimotor polyneuropathy (DSPN) is the commonest form of neuropathy which leads to insensate sole, diabetic foot ulcers (DFU) and its complications. We share our experience in recovery of sensation in the sole after prophylactic surgery such as nerve decompression (ND) or sensory neurotization by nerve transfer (NT) in patients having Diabetic sensorimotor polyneuropathy DSPN. 32 patients (46 feet) were selected for either nerve decompression or sensory neurotization depending upon presence or absence of Tinel’s sign at tarsal tunnel. At 6 month post-operatively perception of touch and pain recovered in all feet; temperature and pressure perception recovered in ∼95% feet; average vibration perception threshold returned to normal range and 2-Point Discrimination came down significantly. There were no ulcers or amputation in operated limbs during follow up period of 6 months. Prophylactic surgery in the form of ND and NT can be offered with minimal complications which significantly improve sensations in the sole in selected cases of DSPN. These have the potential to improve the quality of life of patient and change the natural course of disease.

1. Introduction

Global diabetes prevalence in 2019 was estimated to be 9.3% (463 million people), and rising to 10.2% (578 million) by 2030.¹ India contributes a major part of this global burden as the number of people with diabetes has increased from 26·0 million in 1990 to 65·0 million in 2016.² Almost half of the long term diabetic patients suffer from Diabetic sensorimotor polyneuropathy (DSPN) and one in every five patient of DSPN develops a Diabetic foot ulcer (DFU) with a recurrence rate of almost 100% by 10 years.^3,4 Once DSPN sets in, it is considered an irreversible progressive process leading to foot ulcers and its consequence finally leading to amputation.⁵ Surgery is frequently required to treat diabetic foot infections/ulcerations and gangrene as emergency procedure; however, surgery as a prophylactic measure for DSPN has not been well established.

DSPN is defined as “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes.“⁶ DSPN is essentially a clinical diagnosis and minimum of two abnormalities (i.e., abnormal symptoms and signs) should be present for its diagnosis.⁷ It is the most common neurological complication of diabetes with a length-dependent degeneration and predominant involvement of small myelinated and unmyelinated axons leading to dissociated symmetrical sensory loss in a stocking distribution.⁸ It mainly affects the lower limb and posterior tibial and common peroneal are the most commonly affected nerves.⁹ Ankle reflexes are usually absent. In most cases electrophysiology is abnormal which simply confirms the presence of a neuropathy but does not indicate the underlying cause. DSPN leads to frequent infections, foot ulcerations, amputations and other sequelae which impair the quality of life and lead to substantial financial burden on the healthcare system.^{10, 11, 12} Clinicians have little to offer to these patients except optimal glycemic control.

In this article we reappraise the scientific basis and our experience of reinnervation of sole in DSPN with Nerve decompression (ND)¹³ and our technique of sensory nerve transfer (NT; saphenous Nerve to sensory fascicles of posterior tibial nerve) at the level of ankle.

2. Material and methods

This prospective interventional study was conducted in a tertiary hospital in central India over a period of five years (January 2015–December 2019). Before commencing the study institutional ethics committee approval and written/informed consent from all patients were taken. 60 patients with DSPN who complained of tingling, numbness and burning pain in feet were screened in diabetic clinic. 28 patients were excluded because of associated Osteomyelitis (n = 4), active cellulitis (n = 3), major gangrene (n = 3), normal sensation (n = 5) and refusal for surgery (n = 13). 32 patients (46 feet) with loss of sensations on sole were selected for surgical treatment of DSPN. 13 patients (Age28-70 years, average 35.57 years; 7 Males, 6 Females; 22 feet) who had positive Tinel’s sign at tarsal tunnel underwent nerve decompression. None of these patients had presence of Tinel’s sign at head of fibula or dorsum of foot and there were no sensory symptoms in the territory of common and deep peroneal nerves. 19 patients (Age45-65 years, average 54.17 years; 11 Males, 8 Females; 24 feet) who had absent Tinel’s sign at tarsal tunnel underwent nerve transfer (saphenous nerve to sensory fascicles of posterior tibial nerve). (Figure- 1).

Fig. 1.

CONSORT diagram.

In ND group 2 patients after intervention were further excluded as one patient died on 3rd PO day due to myocardial infarction and 1 patient was lost to follow-up at 3 months. Two patients in NT group were further excluded as 1 patient died postoperatively due to diabetic ketoacidosis and in 1 patient saphenous nerve was found to be fibrotic and encased in the scar tissue. 18 contralateral feet (ND = 4, NT = 14) were not operated. In ND group 4 contralateral feet were not operated due to presence of normal sensations while in NT group 14 contralateral feet were not operated due to presence of major gangrene (4 feet) osteomyelitis (4 feet), presence of normal sensation (5 feet) and below knee amputation (1 foot).

All known diabetics with DSPN and good physical condition with sufficient lower extremity blood supply demonstrated either by a palpable pulses, an ankle/brachial index >0.70 and normal doppler studies, previous minor amputation/ulcerations were included in the study. Patients with poor general condition, major amputation/gangrenous of foot, history of ankle fractures or amputations proximal to the tarso-metatarsal joint, presence of osteomyelitis, were excluded from the study. All patients had Type II diabetes. The average duration of diabetes was 10 years (range = 5–16 years) and average duration of neuropathic symptoms was 1 year (range = 6–18 months). All patients were shifted to insulin from oral hypoglycemic agents for peri-operative period for the control of diabetes. None of the patient had ulcer at the time of presentation in cases of ND while 7 patients had ulcers in NT group. None of the patient presented with painful neuropathy.

Preoperatively X-ray of the foot was done to look for osteomyelitis, ultrasound of tarsal tunnel to rule out space occupying lesions and Arterial Doppler study of lower extremity to rule out ischemia. Sensory tests were performed on the sole in the territory of lateral plantar, medial plantar and calcaneal nerves. For the details of sensory tests readers can refer article by Agarwal et al.¹⁴ Sensory assessment was graded by British Medical Research Council (MRC) scoring system (range = S0–S4). Patients required nerve transfer Nerve conduction velocity (NCV) of femoral nerve was done to confirm intact sensory supply of saphenous nerve. The conduction velocity of 41.7±3.4 m/s and amplitude of 9 mV in saphenous nerve was considered adequate.

After undergoing all preliminary investigations, patients were taken up for nerve decompression or nerve transfer at tarsal tunnel. Post-operatively the advancement of a Tinel’ sign was checked periodically and sensory assessment was done at 3 and 6 months in all three territories of sole. Sensory recovery was graded according to MRC scoring system. Ulcer healing was assessed by two independent surgeons at 3 months and at 6 months.

The primary outcome was recovery of sensations on the sole while secondary outcome was healing of plantar ulceration.

2.1. Procedure

Procedure for nerve decompression and nerve transfer was described elsewhere. (Fig. 2, Fig. 3) For the details readers can refer article by Agarwal et al.^{14, 15}.

Fig. 2.

Showing Tarsal tunnel release.

Fig. 3.

Showing SN to PTN transfer.

3. Results

32 patients (46 feet) underwent sensory reinnervation of sole (13 patients, 22 feet, ND group, 19 patient, 24 feet, NT group). Preoperative evaluation showed touch was absent in 91.30% of patients. 73.91% patients had loss of pain perception, 68.84% had loss of temperature perception and 63.04% had loss of pressure sensation. The VPT was average 37.24V in all patients. 2-PD was average 35.6 mm and MRC scale was S0 was in 27 feet and S1 was in 19 feet. At 3 month 28 patients (38 feet) were available for follow up. Touch and temperature recovered in 82.45%. Pain recovered in 85.08%. Perception of pressure recovered in 84.21%. VPT improved to average 28.37V and 2-PD reduced to average 30.50 mm in all feet. MRC scale improved to S₂ in9 feet and S₃ in 2 in9 feet. At 6 month 25 patients (36 feet) were available for follow-up. Perception of touch, pain recovered in all three territories of feet in all patients. Temperature perception recovered in 92.59% feet and pressure perception recovered in 97.59% feet. VPT returned to normal range (20.57V) and 2-PD came down to average 25.75 mm.MRC scale improved to S2 in 2 feet, S₃ in 5 feet and S3+ in 29 feet (Table 1).

Table 1.

Showing sensory parameters preoperatively, 3 and 6 months postoperatively.

Sensory assessment	PREOP			POST OP 3 MONTHS			POST OP 6 MONTHS
	32 Patients (46 feet)			28 patients (38 feet)			25 patients (36 feet)
	MP	LP	CAL	MP	LP	CAL	MP	LP	CAL
Touch	Absent in 40	Absent in 43	Absent in 43	Present in 31	Present in 27	Present in 36	Present in36	Present in36	Present in36
Pain	Absent in 34	Absent in 31	Absent in 37	Present in 33	Present in 28	Present in 36	Present in36	Present in36	Present in36
Temperature Hot/Cold	Absent in 31	Absent in 32	Absent in 32	Present in 33	Present in 24	Present in37	Present in 35	Present in 34	Present in 31
Pressure	Absent in 27	Absent in 28	Absent in 32	32	27	37	Present in 35	Present in 35	Present in 35
Vibration	37.24V			28.37V			20.57V
2PD	35.6 mm			30.50 mm			25.75 mm
MRC Scale	S0-27 Feet S1-19 Feet			S2-9 Feet S3-29 Feet			S2-2 Feet S3-5 Feet S3+ 29 Feet
Ulcer	Present in 7 feet			Present in all 7 but size reduction by 50–70%			Healed in all cases

MP = Median planter nerve territory.

LP = Lateral planter nerve territory.

Cal = Calcaneal nerve territory.

2PD = 2 point discrimination.

∗ = Average of all feet.

There were no ulcers, recurrent cellulitis or amputation in operated limb during follow up period of 6 months. Complications included delayed wound healing in 6 patients (6 feet) which required dressings only. Immediately after the procedure, a small zone of paresthaesia was observed over the medial dorsum of the foot; due to loss of SN innervation. This zone gradually narrowed and disappeared over a period of six months.

4. Discussion

The role of emergent and curative surgeries (debridement, drainage of abscesses, coverage for open wounds or bone/joint resection for osteomyelitis, and amputations) is well accepted by patients.^16,17 However, patients are reluctant for elective or prophylactic surgery for established neuropathy. The choice of surgical procedure depends upon presence/absence of Tinel’s sign at the tarsal tunnel. If the Tinel’s sign is present than ND is performed and if Tinel’s sign is absent NT can be performed (Fig. 1). A positive Tinel’s sign has 92% positive predictive value for diabetic neuropathy¹⁸ as it represents signals from these mechanically sensitive axonal sprouts at the sites of chronic nerve compression.¹⁹ The rationale for nerve decompression is that in diabetes nerve’s volume increases due to increased water content and inflammatory reactions within the nerve (first crush). This lead to compression when the nerve passes through fibro-osseous tunnels (second crush) which decrease in blood flow and anterograde axoplasmic transport leading to demyelination and axonal atrophy resulting in paresthesia, tingling and numbness clinically.²⁰ ND relieves the compression of nerve and increases the blood flow and anterograde axoplasmic flow which transports the lipoproteins necessary for rebuilding the nerves.²¹ Dellon first proposed peripheral nerve decompression in the tarsal tunnel to treat DSPN with improvement of the symptoms, normalization of Tinel’s sign and nerve conduction studies.⁶ Since than many studies have confirmed the efficacy of nerve decompression.^{22, 23, 24, 25, 26, 27} However; the critics are skeptical of the benefits of surgical treatment for a metabolic disease, and even more so as large number of patients show immediate and bilateral pain relief after unilateral surgery.^{28, 29, 30} However, nerve entrapment co-exists with DSPN in 30% cases³¹ and relief of contralateral symptoms in unilateral ND is explained by the release of immunomodulatory cytokines which get transported via blood and affect contralateral peripheral nerves and mirror image theory of pain pathway.^{32, 33, 34}

In advanced compression, axonal atrophy and loss of two-point discrimination, Tinel sign is often negative because no further regeneration is occurring.³⁵ We hypothesized that these patients are not suitable for ND and required fresh source of axons and therefore can benefit by NT. Our previous report of successful reinnervation of sole in Hansen Disease by nerve transfer encouraged us to use same concept in DSPN.³⁶ The rationale for nerve transfer is based on the fact that there are no differences in all aspects of nerve regeneration related to diabetes as compared to healthy nerves, and more importantly, nerve morphometry remains preserved in DSPN.^{37, 38, 39, 40, 41} Sensory end organs are resistant to degeneration and retain the potential for re-innervation for longer period as compared to motor neurotization.⁴² Although earlier experimental works suggested that nerve regeneration in DSPN is impaired because of microangiopathy leading to hypoxia of nerves, endoneurial fibrosis resulting in an unfavorable environment for nerve regeneration⁴³ however; many experimental and clinical studies have since refuted this concept.^{42, 43, 44} Saphenous nerve is suitable for sensory neurotization of sole as it is a pure sensory nerve close to the target, expandable, good sensory axon density (n = 3782; at the distal thigh level) and rarely gets involved in DSNP.^45,46 However; commonly seen mismatch between donor and recipient nerves does not lead to a problem because only 20% of axons are enough to regain the lost functions and each axon can increase up to five times the amount of fibers it innervates.^47,48 Additionally, there is lots of intercommunication between the fascicles of Posterior Tibial Nerve (PTN) which leads to innervation of whole feet. SN sacrifice leads to minimal sensory loss, on the dorsum of foot which shrinks with progression of time.

The pattern of sensory recovery after ND and NT was similar; first touch and pain followed by pressure and vibration; while 2 PD was last to recover. The sensation was regained first in the calcaneal nerve territory followed by medial plantar nerve then lateral plantar territory; and sensation of great toe was last to recover.

Limitations of our observations include absence of patients with painful neuropathy, and lack of assessment of nerve function in terms of morphology and electrophysiology. Our studies are not randomized control trials; however, Evidence-based medicine is not restricted to randomized trials and meta-analyses; it involves having the best external evidence that can answer a clinical question and provide its solution.

It is well known that anesthesia of sole is the reason for ulcerations and risk of future lower extremity amputations. Moreover; all phases of wound healing are impaired in denervated tissue. Therefore, we believe that natural history of diabetic foot can be changed by re-innervating the sole as rightly mentioned by Dellon: ‘It is a cause for optimism in diabetic neuropathy’.⁴⁹

5. Conclusion

Prophylactic surgery in the form of ND and NT are simple operations with minimal complications, which can significantly improve sensations in the sole in selected cases of DSPN. These can prevent further complications like DFUs, recurrent cellulitis and amputations and have the potential to improve the quality of life of patients and change the natural course of disease.

Author’s contribution

Prof. Pawan Agarwal- Conceptualization; Formal analysis; Investigation; Methodology; Writing - original draft; Writing - review & editing.

Prof. Dhananjaya Sharma- Formal analysis; Investigation; Methodology; review & editing.

Declaration of competing interest

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.