Mechanosensitivity during lower extremity neurodynamic testing is diminished in individuals with Type 2 Diabetes Mellitus and peripheral neuropathy: a cross sectional study

Diabetes mellitus (DM) is a group of metabolic disorders that are characterized by hyperglycemia [1]. The Center for Disease Control (CDC) estimated the mean prevalence of DM in the United States (US) in 2005 was 7.0% [2]. Type 2 diabetes mellitus (T2DM) is the most common form of diabetes and is estimated to represent 90-95% of those in the US with diabetes [2]. In 2002, the total estimated direct and indirect costs of DM medical care in the US was $132 billion [3].

Chronic hyperglycemia has adverse metabolic and vascular consequences for the peripheral nervous system [1, 4]. Distal symmetrical polyneuropathy (DSP) is the most common neural consequence of hyperglycemia and is present in 30%-60% of people with T2DM depending on the methodology for assessment [1, 5, 6]. DSP presents as distal, symmetrical sensory alterations that begin in the feet and progress into the legs and hands [1, 5‐8]. Multiple types of sensation are affected in DSP including vibration sense [9, 10], light touch sensation [6, 8], position sense [5, 8], temperature discrimination [5, 7, 8], as well as diminished ankle reflexes [5‐8]. Pain can also be present [1, 5‐8]. Motor loss is usually minor or sub-clinical until advanced stages of the disease [1, 5‐7]. The severity of DSP is related to the duration and severity of hyperglycemia [6, 7].

Clinical neurodynamic tests are procedures designed to assess the mechanosensitivity of the nervous system through sequential limb movements [11‐14]. Multiple studies have examined the response of neural structures in the lower extremity to a straight leg raise test (SLR) in people with healthy nervous systems [12, 13, 15‐17]. In these studies, ankle dorsiflexion is most commonly used to "sensitize" the SLR test by adding longitudinal loads to the sciatic and tibial nerves. No study to date has examined the mechanosensitivity of peripheral nerves to the elongation and compression associated with limb movement in people with T2DM. In fact, most studies examining neurodynamic testing specifically exclude people with T2DM [12, 14, 18‐20]. Since T2DM and DSP have been shown to affect multi-modal sensory, reflex and motor systems in the distal lower extremities [1, 5‐8], we expected to find a similar reduction in peripheral nerve mechanosensitivity. The objective of this study was to determine the unique effects of T2DM and DSP severity on peripheral nerve mechanosensitivity in the lower extremity to enhance our understanding of appropriate activity guidelines and physical assessment considerations for people with T2DM. We present the unique impacts of T2DM and DSP on range of motion changes, muscle activity, and symptoms during SLR neurodynamic testing.

This cross sectional study included 43 people with T2DM recruited from local medical and academic facilities. Sample size was based on power calculations for a multiple linear regression model with 5 predictor variables, alpha = 0.05, power of 0.8, and an effect size = 0.35. Exclusion criteria included low back or leg pain lasting >3 consecutive days in the past 6 months, complex regional pain syndrome, lumbar spine surgeries, chemical dependence or alcohol abuse, a history of sciatica or trauma to the nerves of the lower extremity, or chemotherapy in the past year. Participants had to meet flexibility requirements of isolated hip flexion ≥90°, full knee extension, ankle dorsiflexion ≥0° and plantar flexion ≥30°. Institutional review boards at UCSF, SFSU and the General Clinical Research Center's Advisory Committee at UCSF approved the study and assured compliance with the ethical treatment of human subjects. Written informed consent was obtained from subjects prior to testing. All subjects attended a single clinical assessment session. One examiner (BB) performed all physical examinations.

The sample of people with T2DM (n = 43) consisted of 21 females and 22 males with an average age of 56.3 ± 11.1 (range 21-75) years. Demographic information and clinical examinations of signs of neuropathy included VPT, MNSIc, and MDNS are provided in Table 1. Vibration perception thresholds (VPT) repeated measures reliability (ICC) was 0.97 (95% CI, 0.96, 0.98). Mean MNSIc scores of 3.9 ± 2.4 exceeded the ≥2 cutoff for identifying DSP [31], and mean MDNS of 13.8 ± 8.7 exceeded the >6 cutoff for identifying DSP [22]. Subgroup analysis showed that MDNS scores extended over the range of severity of DSP (p < 0.001). Specifically, those individuals with signs of severe DSP had the highest scores on the MDNS (22.4 ± 8.3) compared to individuals with no signs of DSP (4.6 ± 5.0, p < 0.001), individuals with signs of mild DSP (8.8 ± 4.4, p < 0.001) and individuals with signs of moderate DSP (16.5 ± 5.8, p = 0.023).

Correlations between assessment tools and demographic data are presented in Table 1. The three clinical measurement tools used to identify signs of DSP (VPT, MDNS, MNSIc) were highly correlated (>0.70 correlation coefficient). The strongest such correlations were between MDNS and MNSIc (0.82, p < 0.0005) and between MDNS and VPT-AVG (0.76, p < 0.0005). Subgroups correlated with age (0.59, p < 0.001), MDNS score (0.74, p < 0.001), MNSIc score (0.69, p < 0.001). Age had a high correlation with VPT-AVG (0.57, p < 0.0005) but did not correlate with maximal hip flexion ROM at P2 for PF/SLR (-0.14, p = 0.370).

The clinical questionnaires for symptoms related to neuropathy (MNSIq) and activity level (Modified Baecke questionnaire) are presented in Table 1. Further analysis revealed that there were no differences between MNSIq scores amongst subgroups (p = 0.480). The Modified Baecke questionnaire work, sports and leisure subscales and the total score did not vary amongst subgroups (p = 0.659, p = 0.347, p = 0.516, p = 0.324, respectively). From the BPI-SF, the reported average pain rating (Q5) was 3.0 ± 2.6 on a 0-10 point scale. The reported pain "right now" (Q6) was 1.9 ± 2.2 on a 0-10 point scale. Subgroup analysis revealed that there was no difference in Q5 ratings (p = 0.894) or Q6 ratings (p = 0.762) between subgroups.

We found that mechanosensitivity in the lower extremity is present in people with T2DM when evaluated through clinical neurodynamic testing. However, many of the outcome measures utilized in neurodynamic testing, including changes in hip flexion range of motion with addition of ankle dorsiflexion, symptom location and muscle activity, differed in people with T2DM when compared with previous findings in people without T2DM. Importantly, some of the signs and symptoms that present with the sensitizing maneuver of ankle dorsiflexion were not present in individuals with T2DM with signs of severe neuropathy.

The magnitude of impact that the addition of ankle dorsiflexion has on hip flexion range of motion during SLR testing may reflect the state of mechanosensitivity of the neural structures being tested. Mechanosensitivity is a normal protective response to the stresses applied to nerves during limb movement. Thus, it is reasonable to expect hip flexion range of motion to be reduced when a SLR is performed with the ankle in a position of dorsiflexion. The addition of dorsiflexion has been shown to induce longitudinal gliding and increased strain in the lower extremity posterior neural structures, providing a "sensitized" version of the SLR [32‐34]. In previous studies of healthy individuals, the addition of dorsiflexion to the SLR resulted in between 5.5° and 10.1° reduction in SLR angle depending on the test endpoint [12, 16]. In people with T2DM we found that the addition of ankle dorsiflexion caused a normal 4° reduction in hip flexion range of motion when tested to P1, but only a 5° reduction when tested to P2. This represents a statistically significant 50% reduction in the effect of dorsiflexion on hip flexion range of motion in people with T2DM compared to people without T2DM when tested to P2 (p = 0.039) [12]. Moreover, in individuals with T2DM and severe DSP the addition of dorsiflexion did not alter hip flexion range of motion at P1 or P2. This represents statistically significant 90% reductions in the effect of dorsiflexion on hip flexion in people with T2DM with severe DSP when tested to P2 compared to people without T2DM (p = 0.001) [12]. The diminished response to the "sensitized" SLR in people with T2DM and severe DSP may reflect a reduced protective response to neural loading during limb movements due to a diminished mechanosensitivity of the lower extremity nervous system.

A comparison to findings in healthy controls in a previous study demonstrates that our sample of people with T2DM had reduced general flexibility during SLR [12]. Specifically, during the SLR with the least load on the nervous system (PF/SLR), people with T2DM had 54.3° ± 21.5° of hip flexion ROM, significantly less than the 67.6° ± 22.1° documented in the same test in healthy individuals without T2DM (p = 0.027) [12]. These findings are in agreement with studies that have documented reduced range of motion in both ankle and hip joints in people with T2DM compared to healthy individuals without DM [35‐37]. To our knowledge, our study is the first to document a reduction in available hip range of motion during SLR testing in people with T2DM. Further studies are warranted to examine the mechanisms behind proximal mobility changes in people with T2DM.

The absence of triggered muscle activation found in the present study in people with T2DM is drastically different from that found previously in healthy individuals without T2DM. In the present study we found only the tibialis anterior became activated during the DF/SLR as defined by a 1.5× increase over resting EMG activity. In comparison, a previous study of healthy individuals without T2DM found muscle activation using this same threshold criteria during the PF/SLR in the rectus femoris at P1 and in the soleus, medial gastrocnemius, tibialis anterior, vastus medialis, rectus femoris, biceps femoris, and gluteus maximus at P2 [12]. This study also found activation of the soleus, tibialis anterior, vastus medialis, and semitendinosis muscles during DF/SLR at P1 and the soleus, medial gastrocnemius, tibialis anterior, vastus medialis, rectus femoris, and semitendinosis at P2 [12]. People with T2DM did not exhibit the co-contraction of anterior and posterior limb muscles that was evident in healthy controls at P1 in the sensitized DF/SLR.

Our sample of individuals with T2DM had much higher resting muscle activity in comparison to previously reported healthy individuals without T2DM [12]. It is possible that this apparent higher resting muscle activity is a MVC calculation artifact due to a reduction in contraction effort during MVC procedures either due to true strength deficits or to the presence of resting symptoms. Since resting activity is converted into a %MVC, the values of muscle activity at rest would be higher if the effort during MVC testing was reduced because of the presence of pain. The authors speculate that reduced muscle output during MVC testing due to resting symptoms, contributed to the findings of higher resting activity in our study when expressed as %MVC. One possible explanation for the activation of the tibialis anterior is related to the START position for this DF/SLR test which included fixation in a customized brace. Since the increase in tibialis anterior activity was triggered during dorsiflexion positioning and then remained stable during SLR to P1 or P2, we hypothesize that the brace itself provided pressure or proprioceptive feedback to the participant that created a responsive increase in muscle tone in the tibialis anterior. Further investigation is necessary to elucidate if this finding is clinically important and to understand why this was not observed in the posterior leg musculature.

Reliance solely on muscle activity measures for decisive conclusions for mechanosensitivity is not reasonable due to the high variability of this type of measurement. Some individuals had no muscle activation during SLR testing at P1 and P2, which is consistent with previous study findings [38, 39]. In our present study, 12.2% of the people with T2DM had no muscle activity at P2 during PF/SLR compared to 10.0% of healthy individuals without T2DM in our previous study [12]. Comparisons during DF/SLR showed that 14.6% of the people with T2DM had no muscle activity at P2 compared to 5.0% of healthy individuals without T2DM in our previous study [12].

Symptom quality, intensity and distribution differed in people with T2DM when compared to healthy individuals without T2DM [12]. At the START position, people with T2DM frequently reported symptoms associated with neurogenic sources, such as numbness and tingling, which were not present in healthy individuals. During limb movement, people with T2DM reported pain (>20% at P1 and >30% at P2) more frequently than healthy individuals (≤10%). Furthermore, the subgroup of people with signs of severe DSP reported symptoms associated with neurogenic sources, such as numbness and tingling 55.6% of the time and pain 33.3% of the time during SLR testing. The intensity of symptoms reported in people with T2DM during DF/SLR and PF/SLR tests was 0.3 points higher on a 0-10 point numeric pain rating scale at P1. Although this is statistically significant it does not represent a clinically meaningful difference between tests [40]. People with T2DM reported more symptoms at the START position than those without T2DM. The percentage of people with T2DM with symptoms in the START position during PF/SLR testing was 41.9% and during DF/SLR was 51.2%. In comparison, the percentage of healthy individuals without T2DM with symptoms in the START position was 15.0% during PF/SLR and 25.0% during DF/SLR. Lastly, in contrast to healthy controls, people with T2DM reported symptoms on the dorsal and plantar surfaces of bilateral feet in the START position (16-30%) [12]. In healthy individuals without T2DM, frequency of symptoms in the posterior hip was at most 10% compared to 27.9% in people with T2DM, with the most dramatic difference occurring at P2.

In the subgroup of individuals with T2DM and severe DSP we found symptoms and clinical examination signs that were consistent with recent findings examining pain presentation phenotypes in neuropathic pain conditions [41]. Scholz et al. determined eight specific patterns of signs and symptoms of which they found people with DSP presented with three of these patterns [41]. These three patterns had multiple characteristics in common that relate to our findings, including ongoing pain, dysesthesia (primarily tingling and numbness), reduced response to monofilament, pinprick and vibration testing and the absence of a response to passive movement evoked pain and an absent response to straight leg raise testing [41]. These characteristics match the cluster of symptoms and physical signs identified in our study sample, particularly those with signs of severe DSP.

A mechanism that would explain the reduction of mechanosensitivity seen in people with T2DM and DSP has yet to be established. A recent study documented an altered ratio of mechanoresponsive to mechanoinsensitive C-fibers in people with diabetes and mild DSP in the common fibular nerve at the knee level [42]. It was found that the ratio of 2:1 mechanoresponsive:mechanoinsensitive C-fibers in healthy controls without DM or neuropathy was reversed to 1:2 in subjects with DM and mild DSP. The shift appeared to occur simultaneously with a general reduction of C-fibers. The authors concluded that changes in small fiber health associated with DSP leads to an impairment of mechanoresponsive nocioceptors. Although the ratio of mechanoresponsive to mechanoinsensitive C-fibers is unknown in our population of individuals with T2DM and DSP, altered microneurographic findings would be consistent with the decrease in mechanosensitivity during the SLR tests that we found in this population.

One major limitation of our study is the small sample size reducing the power to detect differences between variables with smaller effect sizes and diminishing the ability to extrapolate findings to larger populations. A potential covariate in our study is the impact of age on peripheral nerve health. We attempted to match our sample mean age to previous studies of peripheral nerve health in people with T2DM and studies of SLR neurodynamic testing to allow for valid comparisons. In our study we found no correlation between age and any hip flexion range of motion measure during SLR testing, in agreement with a previous study of age and hamstring length [43]. The average age of our study participants closely resembles larger studies including studies by Fedele et al. examining prevalence in 8757 people in Italy with T2DM (age = 55.8 ± 10.4) and by Rahman et al. examining multiple clinical measures of neuropathy (age = 63.0 ± 7.8) [10, 26]. In our study sex was not statistically associated with any hip flexion range of motion outcome measure, although a larger investigation with differing methodology found that women have greater hip range of motion during SLR testing [43].

An additional limitation is the difference of hip abduction range of motion at P2 during PF/SLR compared to DF/SLR which could have influenced the SLR outcome measures. The mean difference was less than 2° between the PF/SLR and DF/SLR and is not likely clinically significant but still represents a potential confounding variable that should be acknowledged in the interpretation of our study findings. Precisely controlled standardized procedures for clinical neurodynamic testing, as were utilized in this study, are warranted to minimize tester induced variability.

One characteristic difference between our present findings and that of SLR neurodynamic test findings in healthy individuals without T2DM is body mass index (BMI). The body mass index was larger in our sample of people with T2DM (32.8 ± 6.6 kg/m²) compared to healthy individuals without T2DM (25.9 ± 8.8 kg/m², p = 0.001) [12]. Mean weight in the people with T2DM was also greater in the present study (94.0 ± 18.3 kg) compared to the healthy individuals without T2DM (71.2 ± 24.8 kg, p < 0.001) [12]. Height was not different between these two study samples (p = 0.127) [12]. We did not find a correlation between BMI in people with T2DM and hip flexion range of motion during SLR. We did not measure nutritional deficits in our study such as vitamin B12 deficiencies which may be a potential confounding variable. Future studies should investigate neurodynamic testing in stratified BMI groups, BMI matched groups and vitamin B12 deficiencies to further explore the effects of body mass and nutritional status on mechanosensitivity of peripheral nerves.

Our study supports specific considerations for patient education and therapeutic exercise instructions. Alterations or avoidance of activities that involve cumulative loading of the nervous system via multiple joints should be considered in people with T2DM and signs of DSP. This could include avoiding movements into slumped postures with the feet elevated, altering specific activities of daily living such as forward bending to tie one's shoes, or avoiding specific movements or postures assumed during recreational activities such as yoga or Pilates. An understanding of the health of the nervous system including the ability to respond to and protect against over stretch should be incorporated into clinical decision making for physical examination, exercise prescription and patient education in people with T2DM. Although this study only examined passive limb positioning for short duration, it provides evidence to help support our clinical decisions related to protection of the peripheral nervous system in people with T2DM and DSP.

We have provided evidence that the normal protective responses to neural loading during neurodynamic testing may be diminished in people with T2DM particularly those with signs of severe DSP. Additionally, we found increased frequency of resting symptoms in people with T2DM and increased frequency of reported neurogenic related symptom qualities during SLR testing. We found the addition of ankle dorsiflexion does not induce the same degree of reduction of hip flexion range of motion and the same pattern of muscle protective guarding during SLR testing in people with T2DM. The findings of our study call into question the clinical decision of performing neurodynamic testing on people with signs of severe DSP. Without the ability to respond to the increases in neural loading associated with neurodynamic testing and sensitizing maneuvers, this population is at risk for injury from testing and the information gathered will be of limited use to the clinician. It is recommended that clinicians perform a simple screen of sensation such as vibration perception testing or the MDNS prior to considering the appropriateness of neurodynamic assessments.

When considering testing in people with T2DM, it is important to understand the global impact on mechanosensitivity due to the common distal symmetrical polyneuropathy associated with T2DM. When neurodynamic testing is deemed appropriate in this population, additional considerations are necessary for test interpretation in people with T2DM. It is paramount to clearly establish the person's resting symptoms prior to performing SLR testing. Symptoms that are normally associated with neurogenic sources may be present bilaterally at rest confounding SLR test interpretation in people with T2DM. Consideration of specific movement induced symptoms in addition to symptoms present at rest should assist the clinician interpret neurodynamic testing appropriately. Previous recommendations have included utilizing the onset of symptoms (P1) or the increase above resting symptoms as the end point of the SLR neurodynamic test [12, 44]. The findings of our study support using this same end point for SLR testing in people with T2DM to avoid potential harm of over stressing the nervous system [12].