Exercise and Neuropathy (Chad’s Review)

I’m intending to make this blog a review of pertinent research on exercise and neuropathy and making comments with regards to my thoughts and how it affects my current treatment programs for neuropathy. I’ll be updating and adding studies to it as they come out (thus far there aren’t many) or as I locate them, with the most recent research being on top.


Exercise increases cutaneous nerve density in diabetic patients without neuropathy. Singleton JR, Marcus RL, Jackson JE, K Lessard M1, Graham TE, Smith AG. Ann Clin Transl Neurol. 2014 Oct;1(10):844-9

“Exercisers increased IENFD at both ankle and proximal thigh, while controls showed a small decline in IENFD at both sites.”

“While other neuropathy measures were not significantly different between groups at 12 months there was a trend toward slower progression of UENS and other neuropathy measures in the exercise group.”

“Together, these results support the concept that distal nerve fiber injury may occur in patients with diabetes prior to neuropathy symptom onset, and that cutaneous axons can regenerate in response to metabolic improvement.”

“IENFD specifically evaluates distal unmyelinated axons and thus does not directly assess large myelinated fibers. However, IENFD is correlated to large fiber surrogates, including NCS, among patients with diabetic neuropathy.”

My comments

IENDF means “intraepidermal nerve fiber density” which is the number of nerve fibers in the skin, which is lessened in those with neuropathy and those about to get neuropathy.

The exercise program was a year long. Aerobic exercise ramped up from a supervised 30 min per week at 65% of max heart rate (MHR) and progressed to 50 minutes at 85% MHR by week 7. They also lifted weights, doing 2-3 sets of 12 reps. They were given a non-described home exercise program consisting of both aerobic and strength training in addition to the supervised exercise. The subjects also received nutritional counseling.

Unlike to the below (Kluding 2012) study this one was able to show distal (at the ankle) nerve regrowth. However it’s impossible to tell if that’s because the treatment program was longer (a year vs 10 weeks) or if it was because of non-described dietary interventions, or because the subjects had nerve fiber damage that hadn’t yet progressed to the point of neuropathy. Still it’s great news that diet and exercise can reverse peripheral nerve damage.


The effect of exercise on neuropathic symptoms, nerve function, and cutaneous innervation in people with diabetic peripheral neuropathy. Kluding PM, Pasnoor M, Singh R, Jernigan S, Farmer K, Rucker J, Sharma NK, Wright DE. J Diabetes Complications. 2012 Sep-Oct;26(5):424-9.

“Significant reductions in pain (-18.1±35.5 mm on a 100 mm scale, P=.05), neuropathic symptoms (-1.24±1.8 on MNSI, P=.01), and increased intraepidermal nerve fiber branching (+0.11±0.15 branch nodes/fiber, P=.008) from a proximal skin biopsy were noted following the intervention.”

“This is the first study to describe improvements in neuropathic and cutaneous nerve fiber branching following supervised exercise in people with diabetic peripheral neuropathy. These findings are particularly promising given the short duration of the intervention, but need to be validated by comparison with a control group in future studies.”

“Significant improvements were observed following exercise in the number of branches per fiber in the proximal biopsy site, although no significant improvements were noted in the distal IENF measures or proximal IENF density. This may reflect less extensive damage in proximal nerve fibers, or earlier response of these fibers to exercise-induced plasticity in a 10-week intervention. Although the change in IENF density was not statistically significant, the observed increase in this measure is consistent with modest 30% increase in IENF density following 1 year of lifestyle intervention (Smith et al. 2006).”

My comments:

The exercise program was 10 weeks long starting with 2 days per week of cardio (on various machines) 30 minutes per day at 50% VO2R (reserve aerobic capacity) and progressed to 50 minutes two days per week at 70% V02R. Strength training started with 1 set of 10 reps 1 day per week and progressed to 1 set of 20 reps a set 2 days per week. The strength training exercises were crunches, bicep curls, chest press, lat pulls, leg extensions, seated leg curls, seated rows, shoulder presses, squats, and tricep presses.

None of the patients had increased neuropathic pain with the average reduction of pain being 18.1 points on a 100 mm scale. Converting that to common language, if you had neuropathy pain of 6/10 to start, after 10 weeks the pain was reduced about 2 points to a 4/10. Nerve fiber density was increased in the thigh but not at the ankle. So the good news is that the exercise seemed to help, but the bad news is that regarding neuron innervation it doesn’t sound like it helped as much lower down on the foot where it’s most needed.

The subjects had a an average BMI of 35 (obese) that wasn’t changed at all with the exercise. So probably diet in addition to the exercise would help with weight loss, and would also lessen foot pressure when standing and walking, and likely have positive effects on nerve health as well.


Lifestyle intervention for pre-diabetic neuropathy. Smith AG, Russell J, Feldman EL, Goldstein J, Peltier A, Smith S, Hamwi J, Pollari D, Bixby B, Howard J, Singleton JR. Diabetes Care. 2006 Jun;29(6):1294-9

Baseline distal IENFD was 0.9 +/- 1.2 fibers/mm and proximal IENFD was 4.8 +/- 2.3 fibers/mm. Baseline distal IENFD correlated with fasting glucose (P < 0.001) and OGTT (P < 0.01). After 1 year of treatment, there was a 0.3 +/- 1.1-fiber/mm improvement in distal IENFD and a 1.4 +/- 2.3-fiber/mm improvement in proximal IENFD (P < 0.004). The change in proximal IENFD correlated with decreased neuropathic pain (P < 0.05) and a change in sural sensory amplitude (P < 0.03).

These findings indicate that diet and exercise counseling for IGT results in cutaneous reinnervation and improved pain. Skin biopsy was the most sensitive measure of neuropathy change over 1 year. IENFD should be included as an end point in future neuropathy trials.

All subjects received individualized counseling with goals of reducing weight by 7% and increasing weekly exercise to 150 min. Dietary counseling occurred quarterly.

“However, subjects who had absent epidermal fibers and loss of the dermal nerve plexus were unlikely to experience significant reinnervation. However, some with absent epidermal but preserved dermal fibers did experience reinnervation. Only 31% of subjects noted improvement in distal IENFD. In contrast, 70% experienced reinnervation at the proximal biopsy site.”

My comments:

Details about the diet and exercise counseling or adherence were not given, but the combination was apparently effective enough that there was mild weight loss (decreasing BMI from 32.1 to 31) over the year they were studied. Also they were able to show distal (ankle) nerve reinnervation, though noted it seemed difficult to achieve than proximal (thigh) nerve regeneration, and they noted that there is maybe a threshold where peripheral nerves are too long gone to come back. That would indicate that early onset of diet and exercise interventions would be in the best interest of those with prediabetes.


My overall take home message

I expect that 20-30 minutes of exercise every day would do more than 50 minutes two days per week. The strength training programs if described didn’t sound too bad, but if I were trying to increase lower leg circulation I’d make sure to include calf raises. However, as much as I’m a fan of strength training, I don’t expect the weights are as important as the aerobic exercise for nerve reinnervation. I do expect the strength training to help with neuropathy related disabilities such as strength balance loss. Also it seems like optimal reinnervation takes a long time to achieve and it’s best started before it’s too late.

Also no biopsies were taken from the sole of the foot, and I don’t think there are any good conventional exercises that target the foot intrinsic muscles on the plantar surface of the foot. On the contrary electric muscle stimulation (EMS) contracts exactly the muscle that’s underneath the electrode. Plus EMS specifically lessens neuropathic pain, and with the parameters I use it does so nigh immediately. EMS might also be an ideal adjunct because those with type 2 diabetes aren’t known to be big exercisers and EMS can be done while watching TV. Still if I had type 2 diabetes my first priority would be REVERSING said diabetes, which research is indicating is possible. You just have to suffer HARD for eight weeks.

As always, if you have any comments, questions or need for clarifications, please don’t hesitate to ask.

Chad Reilly, Physical Therapist

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