The Impact of Bariatric Surgery on Neuropathic Pain and on Objective Markers of Neuropathy

Background: Obesity (BMI ≥ 30 kg/m 2 ) is associated with T2 diabetes (40-fold relative risk) and cardiovascular complications. Bariatric surgery is becoming a treatment of choice in obese individuals because of the multiple benefits associated with significant weight loss leading to an improved quality of life and decreased morbidity and mortality, which far out weighs the cost of surgery. A major metabolic benefit is the remission from T2 diabetes as a consequence of alterations in gut hormone signaling and weight loss. Indeed cost-effectiveness analyses have led NICE to recommend that all patients with a BMI ≥ 35 kg/m 2 with T2 diabetes should be considered for bariatric surgery. In relation to the impact on macro vascular complications there is a significant reduction in MI and stroke in long term follow up studies, which translates to reduced mortality. For the microvascular complications of diabetes, studies are limited but have primarily focused on retinopathy and nephropathy after bariatric surgery. Despite the fact that neuropathy (nerve damage) can lead to pain and foot ulceration with amputation together with increased mortality from autonomic neuropathy, few studies have objectively assessed the impact of bariatric surgery on neuropathy. However, there are concerns that neuropathy could worsen following bariatric surgery due to nutritional deficiencies [1] and indeed there are case-reports of acute Guillain-Barre like demyelinating [2] and motor axonal [3, 4] neuropathy following bariatric surgery. The term post bariatric surgery neuropathic pain has also been coined with a reported prevalence of 33% following bariatric surgery [5]. However, a more recent study has shown complete resolution of neuropathic symptoms with an improvement in the neuropathy disability score [6]. Whereas a recent case-control study has showed no improvement in nerve conduction velocity [7]. Given the potential benefits and indeed harm following bariatric surgery there is a need for a systematic quantitative assessment of neuropathy to define true rates of remission or worsening. Aims: Systematically define the baseline prevalence of neuropathic pain and neuropathy and the outcomes following bariatric surgery on neuropathic pain and objective markers of somatic and autonomic neuropathy in obese subjects with and without T2 diabetes, 6 and 12 months after surgery. Methods: This is a prospective, randomized, single center trial assessing the effect of gastric bypass surgery. The subjects in the study were recruited from Salford Royal NHS Foundation Trust, UK and the study was performed at the Wellcome Trust Clinical Research Facility/NIHR, Manchester, UK from 3 September 2013 until 30 July 2015. We estimated that the minimum sample required to detect a significant difference in peripheral autonomic (Neuropad response) and sensory nerve morphology using the novel imaging technique of corneal confocal microscopy (CCM) to quantify corneal nerve fibre length (CNFL) over 12 months was 52 and 46 subjects, respectively with a power of 80%. Exclusion criteria included history of neuropathy due to non-diabetic cause and corneal trauma or surgery. Painful neuropathy was defined using a composite score of the McGill questionnaire with either a positive neuropathic symptom profile (NSP) or diabetic neuropathy symptom (DNS). The objective end-points for remission from neuropathy were: 1) >15 nerve branches/mm 2 in corneal nerve branch density (CNBD) and >15 mm/mm 2 in corneal nerve fibre length (CNFL), 2) for autonomic neuropathy >90% on the Neuropad response, and 3) for sensory neuropathy, < 2 on the neuropathic disability score (NDS) and < 15 Volts for vibration perception threshold (VPT). The Local Research Ethics committee approved this study and all subjects gave informed consent to take part in the study. The research adhered to the tenets of the declaration of Helsinki. Results: Of 106 subjects recruited, 40 refused and 23 are awaiting follow-up assessments. We have analysed 43 subjects with an average age of 52.2 ± 2.1 years. Baseline BMI was 50.6 ± 2.8 kg/m 2 and was significantly reduced to 38.2 ± 1.4 kg/m 2 (P < 0.0001) and 35.8 ± 1.7 kg/m 2 (P < 0.0001) at 6 and 12 months, respectively. 26/43 (60%) of subjects had T2 diabetes before surgery. Based on normalization of HbA1c the remission rate from diabetes was 81% 12 months after surgery. Baseline HbA1c in 26 subjects with T2 diabetes was 7.4 ± 0.3% and was significantly reduced to 5.9 ± 0.2% (P = 0.0007) and 5.6 ± 0.1% (P < 0.0001) at 6 and 12 months, respectively. Hypertension (Systolic BP >120 mmHg) was identified in 37/43 (86%) of subjects pre-surgery. The remission rate from hypertension was 57%, 12 months after bariatric surgery. The average starting systolic blood pressure in these subjects was 130.3 ± 2.7 mmHg and was significantly reduced to 120.8 ± 3.13 (P = 0.03) and 114.4 ± 5.49 (P = 0.008) at 6 and 12 months, respectively. The prevalence of sensory neuropathy assessed using the Neuropathy Disability Score (NDS) in 41 subjects was 34% pre-surgery and the remission rate was 50%, 12 months after surgery. Baseline NDS was 2.0 ± 0.4, indicative of minimal neuropathy but was significantly improved to 0.89 ± 0.4 (P = 0.05) at 12 months. Vibration perception threshold was 13.6 ± 1.25 V and showed no improvement (12.6 ± 1.46 V, P = 0.58) 12 months after surgery. The prevalence of neuropathic pain in 36 subjects was 39% pre-surgery and a complete recovery was observed in 71% and 93% of patients at 6 and 12 months, respectively. Likewise, 45% of the 22 subjects with T2 diabetes had neuropathic pain at baseline and 70% and 90% had no painful neuropathy at 6 and 12 months, respectively. The prevalence of peripheral autonomic dysfunction assessed using Neuropad in 24 subjects was 57% pre-surgery and the remission rate was 69% 12 months after surgery. The Neuropad response at baseline was 77.95 ± 5.1% and improved significantly (91.3 ± 3.86%, P = 0.04) 12 months after surgery. Corneal confocal microscopy showed a significant increase in corneal nerve fibre length in the 26 subjects with diabetes from a mean of 14.2 ± 0.7 mm/mm 2 to 16.7 ± 1.04 mm/mm 2 (P = 0.049) and an increase in corneal nerve branch density (32.8 ± 3.35 no./mm 2 to 43.2 ± 4.49 no./mm 2 (P = 0.068). However, there was no change in corneal nerve fibre length or branch density in 17 subjects without T2 diabetes 12 months after surgery. Conclusion: Our study shows a high prevalence of diabetes; hypertension, neuropathic pain and neuropathy assessed using objective measures of somatic and autonomic neuropathy in obese people. Bariatric surgery results in significant weight loss, and improved glycemic control and blood pressure, with a reduction in the prevalence of painful neuropathy and improvement in autonomic and in particular small fibre neuropathy assessed using corneal confocal microscopy. Morbid obesity is common (-30%) in the Qatari population and bariatric surgery is an increasingly performed procedure. Contrary to previous data showing a worsening of both neuropathic symptoms and deficits, our data show significant weight loss with an improvement in glycaemic control and blood pressure which improves neuropathy and therefore provide a strong rationale for undertaking bariatric surgery and reducing disabilities to reach the goals of VISION 2020-Qatar. References 1. Thaisetthawatkul, P., et al., A controlled study of peripheral neuropathy after bariatric surgery. Neurology, 2004. 63(8): p. 1462-70. 2. Ishaque, N., et al., Guillain-Barre syndrome (demyelinating) six weeks after bariatric surgery: A case report and literature review. Obes Res Clin Pract, 2015. 9(4): p. 416-9. 3. Landais, A., Neurological complications of bariatric surgery. Obes Surg, 2014. 24(10): p. 1800-7. 4. Landais, A.F., Rare neurologic complication of bariatric surgery: acute motor axonal neuropathy (AMAN), a severe motor axonal form of the Guillain Barre syndrome. Surg Obes Relat Dis, 2014. 10(6): p. e85-7. 5. Kattalai Kailasam, V., et al., Postbariatric surgery neuropathic pain (PBSNP): case report, literature review, and treatment options. Pain Med, 2015. 16(2): p. 374-82. 6. Muller-Stich, B.P., et al., Gastric bypass leads to improvement of diabetic neuropathy independent of glucose normalization-results of a prospective cohort study (DiaSurg 1 study). Ann Surg, 2013. 258(5): p. 760-5; discussion 765-6. 7. Miras, A.D., et al., Type 2 diabetes mellitus and microvascular complications 1 year after Roux-en-Y gastric bypass: a case-control study. Diabetologia, 2015. 58(7): p. 1443-7.

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