1. STS TREATMENTS REVERSE NERVE
CONDUCTION LOSS AND LOSS OF PROTECTIVE
SENSATION IN PATIENTS WITH DIABETES TYPE 2
Deborah Carver, M.D. (1)
Jose Gaurdiola, Ph.D. (2)
Marian Hendricks, D.O. (3)
Donald Rhodes, D.P.M., F.A.C.F.A.S. (4)
Glenda Sue Roefer, D.O., C.D.E. (5)
(1) Neurology Clinic of Central Texas, New Braunfels, Texas
(2) Texas A&M University Corpus Christi, Department of Computing and
Mathematical Sciences, Corpus Christi, Texas
(3) Coastal Bend Chronic Pain Center, Corpus Christi, Texas
(4) Coastal Bend Chronic Pain Center, Corpus Christi, Texas
(5) Thomas Spann Clinic, Corpus Christi, Texas
OBJECTIVE— To determine if Sympathetic Therapy System treatment can reverse
Loss of Protective Sensation (LOPS), reverse decreased nerve conduction, and decrease
subjective neuropathy symptoms in patients with diabetes mellitus type 2.
RESEARCH DESIGN AND METHODS—19 patients suffering from diabetes
type 2 received sympathetic therapy system treatments (Dynatron STS, Dynatronics
Corporation, Salt Lake City, Utah). Sympathetic therapy is designed to stimulate the
production of neuropeptides utilizing electric current. Twelve men and seven women,
ranging in age from 25 to 88 years old, with an average age of 54 years old were treated
utilizing twice daily treatments for one month followed by once daily treatments for the
duration of the six month study. Each participant filled in questionnaires, while in the
clinic, and rated their symptoms on a VAS scale of 0 to10. Nerve conduction velocity
studies (NCV) and Vibration Perception Threshold testing (VPT) were performed prior to
the study, at 90 and 180 days. In addition, the VPT testing was also performed at 30 and
RESULTS—Both Vibration Perception Threshold (VPT) and Nerve Conduction
Velocity (NCV) showed statistically significant improvement. In addition, the
participants’ rating of their symptoms mirrored the objective testing. NCV studies
showed an overall improvement of 43% at 90 days and 47% improvement at 180 days.
NCV studies showed that 23% of the nonresponsive nerves became responsive by day
180. Specifically, 3% of the nonresponsive sural nerves and 42% of the nonresponsive
peroneal nerves became responsive. NCV testing showed that 47% of the nerves tested
had improvement by 180 days. This included 40% of the sural nerves and 53% of the
peroneal nerves. At the beginning of the study, 11% of the 190 sites tested had a normal
VPT testing. At 180 days, 44% of the 190 sites tested had a normal VPT testing. At the
beginning of the study VPT testing showed that 73% of the 190 sites had a LOPS (Loss
of Protective Sensation). At day 180, VPT testing showed that only 39% of the 190 sites
tested had LOPS. In addition, at day 180, VPT testing showed that 91% of the 190 sites
had improved, compared to the beginning of the study. Analysis showed that there was a
statistically significant improvement in the VPT results even after only one month of
treatment (p <.001, Friedman test). This statistical improvement remained throughout the
six-month study. The participants reported moderate to severe foot and ankle symptoms
including pain, tingling, and numbness before the study. However, these symptoms were
reported as markedly improved within month one of treatment.
CONCLUSIONS—STS therapy effectively improved VPT (LOPS) and NCV
deficits, as well as, the subjective neuropathic symptoms in the patients with diabetes
type 2 seen in this pilot study. This pilot study demonstrates the need for follow up
studies involving more patients and sham treatments for better evaluation of this
According to the American Diabetes Association, there are over 20.8 million children and
adults in the United States, or approximately 7% of the population, who have diabetes. In
addition, the U.S. spends over $132 billion a year on diabetes -- $13,242 on each patient
with diabetes, compared with $2,560 per person for people who do not have diabetes --
measured in the direct and indirect costs of emergency room visits, expensive and
extended hospitalizations, disability insurance costs, absenteeism and lost worker
productivity. In addition, more than 5.5 million Americans have been diagnosed with
diabetic peripheral neuropathies. This process is progressive and can lead to increased
risk of injury, infection, Charcot joints, and amputation. South Texas, with its high
Hispanic population has a very high incidence of amputations. Diabetic peripheral
neuropathy is a common complication associated with diabetes. It increases with both age
and duration of diabetes, and is present in more than 50% of Type 2 diabetic patients
aged over 60 years. (1)
Testing for diabetic peripheral neuropathies is recommended on a regular basis such as
monofilament testing at office visits. Routine neurological examinations such as light
touch and pinprick sensation, though commonly used to test for neuropathies, have been
found to be less sensitive to diagnose diabetic neuropathy than Vibration Perception
Threshold testing (VPT). A recent study of diabetic type 2 patients showed that the VPT
was elevated in 65% of the patients with sensory complaints but also in 20% of the
patients without sensory complaints. (2)
In the past, there have not been effective treatments for this disease process, and the
largely unsatisfactory results reported for the pharmacological treatment of diabetic
neuropathy has spurred the search for alternative therapies. (3)
In 2003, the long-term complications of diabetic peripheral neuropathy experienced by
2.4 million people in the U.S. with reduced vibration detection were estimated to cost all
U.S. health care payers approximately $14.7 billion over the next 10 years. (4) Peripheral
neuropathy (or diabetic polyneuropathy) can present as a loss of sensation that can lead to
neuropathic ulcers, and it is a leading cause of amputation. (5)(6)
It has been found that compliance with a preventative foot care program reduces the
incidence of foot ulceration in individuals with reduced vibration detection. (7) In
addition, identification and treatment of individuals with reduced vibration detection that
resulted in improved or normalized vibration perception would reduce the risk of
ulceration and amputation. This could save up to $11.8 billion and save 333,000 life-
years over the next 10 years. (8) The treatment of diabetic foot ulcerations and
amputation is time-consuming and expensive. Treatment aimed at improving peripheral
neuropathy, reversing or preventing loss of protective sensation (LOPS), and avoidance
of ulcerations and amputations could potentially save valuable resources and improve
health outcomes. (9)
In a study published in 2002, treatments utilizing the Dynatronic STS system were shown
to successfully decrease the objective signs and subjective symptoms of peripheral
neuropathy patients. During that study, daily skin temperatures were obtained from the
palmar surface of the thumbs and the plantar surface of the bilateral hallux. The study
demonstrated that there was a partial or complete normalization of the actual skin
temperature and the skin temperature gradient, left to right. Two patients in that study
had diabetes, and both of these patients had improvement in nerve conduction velocity by
the end of one month of hourly STS treatments. (10)
Interestingly since then, two different studies have shown that, if elevated temperature
differences between contralateral sites can be kept below 4 degrees Fahrenheit, plantar
ulcerations in diabetic feet can be markedly reduced. Although this was not specifically
addressed in this particular study, it will be addressed in an upcoming study to show that
this treatment will cause normalization of temperature differences and decreased LOPS.
RESEARCH DESIGN AND METHODS
This investigation employed a single-case experimental design. The subjects received the
treatment and would, therefore, be considered a single group or a time-series design (13)
Study participants were recruited from the South Texas area.
This study was comprised of 19 patients with Diabetes Mellitus type 2. Patients with
pacemakers (due to the contraindication for electrical stimulation) or amputated limbs
(due to the treatment requiring all four extremities to attach electrodes) were excluded
from this study. During each visit to the clinic, the patients filled in questionnaires and
rated their symptoms on a visual analog scale (VAS) of 0 to10. Nerve conduction
velocity studies (NCV) and Vibration Perception Threshold testing (VPT) were
performed prior to the study, at 90 and 180 days. In addition, the VPT testing was
performed at 30 and 60 days. Five different sites of each foot were tested for VPT.
These included the plantar aspect of the head of the hallux proximal phalanx head, the
plantar aspect of the 1st and 5th metatarsal heads, the medial malleolus, and the lateral
malleolus. Nerve conduction velocity studies were performed on the sural and peroneal
The patients were evaluated and received STS treatments every day in the clinic for the
first thirty days and once per week thereafter for 180 days. In addition, the participants
administered STS treatments to themselves at home each evening after 7 P.M. When the
patients were seen in the clinic, their unit’s hour meter was checked to insure that the
patient had utilized the unit for the previous night or week’s treatments. STS treatments
are two simultaneous interferential treatments at a low carrier frequency, which allows
longer beat duration than standard interferential treatments. The electrode leads are
color-coded with the red and white leads utilizing an 1850 Hertz carrier frequency, with
the yellow and black leads utilizing a 2850 Hertz carrier frequency. In this study, the
beat frequency of both pairs was set to ramp up and down between 8 and 12 beats per
second. The treatment was administered utilizing 8 TENS-type self-adherent electrodes.
All of the electrodes utilized for the lower body treatments were “Optimizer” electrodes
(magnetic electrodes from Alan Neuromedical Technologies) while only the red and
white electrodes utilized for the upper body utilized the “Optimizer” electrodes. Patients
completed pain grids, while in the clinic, depicting the area of worst pain, and secondary
areas of pain. The electrode pad placement protocols were selected on the basis of the
location of the worst pain of that day. If the patient had no area(s) of pain, a generalized
upper and/or lower body STS protocol was administered, which had been designed for
diabetes. All of these protocols were based upon acupuncture points, dermatomes,
thermatomes, and nerve roots. Each treatment included forty minutes of treatment given
through the lower extremities and forty minutes of treatment given through the upper
Only 17 of the participants received NCV testing at day 0 and 180. One of those
participants did not receive NCV testing at day 90. All 19 participants received VPT
testing at day 0, 30, 60, 90, and 180.
Percentage of Patient Testing Sites with Normal VPT compared to
Abnormal VPT (Markedly increased risk of amputation)
Normal (<15) Day 0 Abnormal (>25) Normal (<15) Day 180 Abnormal (>25)
Percentage of nerve sites with normal VPT (<15V.)
Day 0 Day 30 Day 60 Day 180
Distal Motor Latency Motor NCV AMP. CMAP
normal <= 5.8 m/sec normal > 43 m/sec normal > 2.3
Right Peroneal Nerve Right Peroneal Nerve Right Peroneal Nerve
Day 0 Day 90 Day 180 Day 0 Day 90 Day 180 Day 0 Day 90 Day 180
Nonresponsive 4/17=24% 1/16=6% 1/17=6% 4/17=24% 1/16=6% 2/17=12% 4/17=24% 1/16=6% 2/17=12%
IMPROVED 0- 90 DAYS 7/16 =44% 11/16=69% 11/16=69%
IMPROVED 0-180 DAYS 9/17= 53% 10/17=59% 9/17=53%
Responsive 75% 75% 75% 50% 75% 50%
Distal Sensory Latency Sensory NCV AMP. SNAP
normal < 3.2 m/sec normal > 40 m/sec normal > 10
Right Sural Nerve Right Sural Nerve Right Sural Nerve
Day 0 Day 90 Day 180 Day 0 Day 90 Day 180 Day 0 Day 90 Day 180
Nonresponsive 7/17=41% 8/16=50% 7/17=41% 7/17=41% 8/16=47% 7/17=41% 7/17=41% 8/16=50% 7/17=41%
IMPROVED 0- 90 DAYS 5/16=31% 3/16=19% 7/16=44%
IMPROVED 0-180 DAYS 6/17=35% 5/17 = 29% 8/17=47%
Nonresponsive to Responsive <6%> 0% <6%> 0% <6%> 0%
Distal Motor Latency Motor NCV AMP. CMAP
normal < 5.8 m/sec normal > 43 m/sec normal > 2.3
Left Peroneal Nerve Left Peroneal Nerve Left Peroneal Nerve
Day 0 Day 90 Day 180 Day 0 Day 90 Day 180 Day 0 Day 90 Day 180
Nonresponsive 4/17=24% 2/16=13% 3/17=18% 4/17=24% 2/16=13% 3/17=18% 4/17=24% 2/16=13% 3/17=18%
IMPROVED 0- 90 DAYS 6/16=38% 8/16=50% 10/16=63%
IMPROVED 0-180 DAYS 6/17=35% 10/17=62% 9/17=53%
Nonresponsive to Responsive 50% 25% 50% 25% 50% 25%
Distal Sensory Latency Sensory NCV AMP. SNAP
normal < 3.2 normal > 40 m/sec normal > 10
Left Sural Nerve Left Sural Nerve Left Sural Nerve
Day 0 Day 90 Day 180 Day 0 Day 90 Day 180 Day 0 Day 90 Day 180
Nonresponsive 7/17=41% 8/16=50% 6/17=35% 7/17=41% 8/16=50% 6/17=35% 7/17=41% 8/16=50% 6/17=35%
IMPROVED 0- 90 DAYS 3/16=19% 4/16=25% 7/16=44%
IMPROVED 0-180 DAYS 6/17=35% 8/17=47% 8/17=47%
Nonresponsive to Responsive <6%> 6% <6%> 6% <6%> 6%
Nerve Conduction Velocity Studies
0 to 90 days
Nonresponsive to Responsive Nerves
0 to 180 days
Nonresponsive to Responsive
VPT Improvement Day 0 to Day 180
0-15 16-25 26-91 >91 0-25 >25
% of 19 Pts Day 0 11% 16% 64% 9% 27% 73%
% of 19 Pts Day 30 28% 26% 42% 4% 54% 46%
% of 19 Pts Day 60 38% 19% 41% 2% 57% 43%
% of 19 Pts Day 90 43% 21% 34% 2% 64% 36%
% of 19 Pts Day 180 44% 16% 35% 4% 61% 39%
Better Worse Same
% of 19 Pts Day 0
% of 19 Pts Day 30 81% 14% 5%
% of 19 Pts Day 60 91% 8% 1%
% of 19 Pts Day 90 88% 10% 2%
% of 19 Pts Day 180 91% 8% 1%
PATIENT SYMPTOM VAS (0-10)
Day 0 Day 30 Day 60 Day 90 Day 180
Burning 2.1 0.5 0.8 0.9 0.7
Pain 4.1 1.2 1.4 1.1 1.2
Numbness 3.1 1.6 1.2 1.1 2.0
Tingling 3.9 1.1 0.8 0.5 0.5
Discoloration 1.1 0.5 0.4 0.3 0.3
Swelling 2.1 0.4 0.4 0.1 0.6
Aching 3.2 1.1 0.6 1.2 1.1
Itching 0.8 0.2 0.5 0.5 0.5
Stiffness 2.0 0.9 0.7 0.6 0.9
Ankles Sx 3.2 1.1 0.8 1.2 0.8
AVERAGE VAS 2.6 0.9 0.8 0.8 0.8
PERCENTAGES OF PATIENTS WHO WERE SYMPTOM FREE
Semmes-Weinstein monofilament testing was not utilized due to the possible problems
with reproducibility and lack of quantification. In addition, when mono-filament testing
has been compared to VPT >25V, it was found that a significant number of patients were
identified at risk with VPT had been not been identified by the mono-filament testing.
Nerve conduction velocity testing is widely accepted as a methodology for determining
peripheral neuropathies by testing hypoesthesia of A-beta neurons. There is strong
correlation between NCV and VPT testing, and research has shown that these tests can
predict foot ulceration and death in diabetes. (17)(18)(19)(20)(21)(22) After the NCV
testing at day 90 and particularly after the NCV at day 180, virtually all of the
participants complained that the testing was painful. No participant complained of the
pain caused by the NCV testing before the study started.
Vibration perception sensitively reflects disturbances in the function of fast adapting
mechanoreceptors and of thick myelinated sensory nerve fibers. Both are commonly
affected in diabetes. VPT measurements using a bioesthesiometer have been
demonstrated to be reproducible under different levels of blood glucose, at different
hours of the day, ambient temperature, and skin temperature. It has been shown that
increased disease duration leads to significantly higher VPT readings in diabetic patients.
Also it has been shown that VPT has a significantly higher specificity than neuropathy
score. (23)(24) (25)(26)(27)
It has been demonstrated that VPT shows twice the prevalence of abnormality compared
with clinical examination or clinical evidence of neuropathy. (28)(29) VPT has been
shown to be a good predictor of the long-term complications of diabetic peripheral
neuropathy. It has been shown that patients with a VPT<15V. have had a cumulative
incidence of foot ulceration of 2.9% compared with 19.8% in patients with a VPT>25V.
The average individual with reduced vibration detection (>25V.) is estimated to incur
approximately five times more direct medical costs for foot ulcer and amputations than an
average individual with normal VPT (<15 V.). (30)(31) While some clinics only test the
great toe for sensitivity and specificity for VPT to determine LOPS, other studies have
shown that there is a great variability between testing sites. In addition, studies have
shown that variability between sites was significantly greater in the diabetics than the
nondiabetic subjects. (32)(33)(34)(35)
The results of the VPT testing were analyzed utilizing the Friedman test and computed
using the statistical package SPSS. The null hypothesis was rejected at p <.001.
Therefore, it was found that a statistically significant difference was apparent. The
Wilcoxon signed rank test with the Bonferroni adjustment was also used to evaluate the
VPT data. The improvement was found to be significant at the 0.002 level.
It has been shown by numerous investigators, that a reduction or impaired blood flow and
the resultant endoneurial hypoxia are important factors underlying nerve conduction
deficits. Studies have demonstrated that there is a good correlation between the degree of
microangiopathy and measures of neuropathic severity in diabetics. It has also been
shown that with a return of more normal blood flow, there is a normalization of nerve
Other researchers have shown that revascularization surgery and hyperbaric oxygenation
significantly increased the transcutaneous oxygen tension and the oxygen tension in
ischemic tissues. However, no differences were noticed in the vibration perception
threshold, NCV or Semmes-Weinstein monofilament measurements. (41)(42)(43)(44)
It has been observed that the cAMP level in diabetic nerves is decreased and that the
decrease in nerve conduction is proportional to the reduction in cAMP. It has been
shown that cAMP content may play an important role in the development of diabetic
neuropathy by modulating Na+, K+, and ATPase activity in the peripheral nerves. It has
been shown that electrical stimulation of nerves can increase nerve blood flow and nerve
conduction and significantly increased intracellular cAMP, which allows peripheral nerve
regeneration. (46)(47) In addition, it has been shown that these treatments can normalize
nerve transmission and increase circulation to the nerves. It has been shown that this is
due to the release of Calcitonin gene-related peptide (CGRP) and Vasoactive Intestinal
Polypeptide (VIP). (48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)
In this pilot study, five different sites of each foot were tested. These included the plantar
aspect of the head of the hallux proximal phalanx head, the plantar aspect of the 1st and 5th
metatarsal heads, the medial malleolus, and the lateral malleolus. It was found that there
was a great variation between testing sites, which matches previous results cited. There
was a marked improvement in the VPT scores through the study and there was a 400%
increase in the testing sites rated as “normal” (VPT <15) when the 180-day scores were
compared to day 0. When the testing sites which were considered to have LOPS (VPT
>25) at day 0 were compared to results on day 180, 47% of those sites were no longer
considered to have LOPS. Earlier in this article, there was an estimate given that the
long-term complications of diabetic peripheral neuropathy experienced by the 2.4 million
people in the U.S. with reduced vibration detection will cost all U.S. health care payers
approximately $14.7 billion over the next 10 years. If all the patients with LOPS
received therapy with comparable results to this study, it would be estimated savings of
In this study, there was a marked improvement in NCV, particularly in the peroneal
nerves. Many of the nonresponsive nerves became responsive with treatment and, since
diabetic neuropathies continue to worsen with time, even maintenance of NCV would be
The participants evaluated their symptoms throughout the study and rated them on a scale
of 0-10. At the beginning of the study, the overall VAS was 2.6. Beginning at 30 days
and extending through the end of the 180-day study, the VAS was less than 1.0. The
average pain in the feet was rated at 4.1 but had reduced to 1.2 at 30 days and continued
at approximately that level throughout the study. The best improvement was in the
reported average tingling, which was 3.9 at the beginning of the study and had dropped to
0.5 by 90 days and remained there for the rest of the study. In actuality, all of the
participants’ symptoms markedly improved and remained improved for the remainder of
the study. As is apparent in tables 4 and 5, a significant number of the participants
became symptom free, even as early as 30 days into the study. All of these symptoms
decreased in severity throughout the study, with the exception of ankle symptoms. While
the ankle symptoms decreased from day 0 through day 60, they were increased by day
90. In all probability, this was due to the markedly increased activity of the participants
as the study progressed and the participants felt better. The ankle symptoms did decrease
by the end of the study. The percentage of patients who did not have pain or tingling in
their feet increased from 26% to 58% and from 37% to 63% respectively. Table 6
compares patients’ perception of pain and tingling in their feet with the objective findings
of VPT and NCV. As can be seen from this table, there was a good correlation between
the decreased patients’ symptom VAS scores and improved VPT findings, as well as,
VPT improvements and NCV improvements.
In reviewing this study's results, it could be hypothesized that improved circulation to the
nerves resulted in the improvement in the diabetic peripheral neuropathy patients. The
hypothesis for this study is that the STS treatments are effective due to a combination of
the following aspects of the treatments: low frequency electrical current passing through
long sections of nerves, production of cyclic adenosine monophosphate, electrode pad
placement (including acupuncture points), the choice of the peripheral nerves being
stimulated so that there is a cross-over effect in the CNS, leakage of action potentials
from the nerves being stimulated into nerves entering the sympathetic ganglia, the
quadrilateral location of stimulation, creation of action potentials through sympathetic
nerves in the peripheral nerves being stimulated, production of ACTH, production of
dynorphins, enkephalins or beta-endorphins, creation of action potentials through
sympathetic nerves in the peripheral nerves being stimulated which enter the sympathetic
ganglia directly, local analgesia resulting in a decrease of substance P; and/or the
production of melatonin and circulation altering neuropeptides such as vasoactive
intestinal polypeptide (VIP) and calcitonin gene-related peptide (CGRP).
In addition, utilizing this therapy to relieve painful areas in the participants’ bodies
diminished the amount of substance P and, therefore, would increase nerve oxygenation
due to increased effectiveness of CGRP. (66)
Further studies of this technology need to be performed. These future studies should
include controls and greater number of participants. In addition, if it can be demonstrated
that this therapy was effective due to the increase in neuropeptides such as CGRP and
VIP, further studies will need to be performed to demonstrate its effectiveness in treating
the underlying biochemical pathologies of related diseases such as Parkinson’s Disease.
This small pilot study showed the effectiveness of this treatment for symptomatic and
objective improvement of the peripheral neuropathies in patients with diabetes type 2.
Finally, all of medicine revolves around the patient’s perception of their health.
Therefore, the most important improvement for the participants was shown in their rating
of their symptoms rather than the improvement in the objective testing. 84% of the study
participants stated that they felt better or much better after one week of treatment and
more than 90% felt better or much better after 30 days of treatment and throughout the
rest of the study.
(1) Young MJ, Boulton AJ, MacLeod AF, Williams DR, Sonksen PH. “A multicentre
study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital
clinic population.” Diabetologia. 1993 Feb; 36(2):150-4.)
(2) van der Naalt J, Fidler V, Oosterhuis HJ. “Vibration perception threshold, complaints
and sensory examination in diabetic patients.” Acta Neurol Scand. 1991 May; 83(5)
(3) Bosi E, Conti M, Vermigli C, Cazzetta G, Peretti E, Cordoni MC, Galimberti G,
Scionti L. “Effectiveness of frequency-modulated electromagnetic neural stimulation in
the treatment of painful diabetic neuropathy.” Diabetologia. 2005 May; 48(5):817-23.
Epub 2005 Apr 15.)
(4) Gordois A, Scuffham P, Shearer A, Oglesby A: “The health care costs of peripheral
neuropathy for people with diabetes in the U.S.” Diabetes Care 26:1790–1795, 2003.
Young MJ, Breddy JL, Veves A, Boulton AJ.
(5) Poncelet AN: Diabetic polyneuropathy: risk factors, patterns of presentation,
diagnosis, and treatment (Review). Geriatrics 58:16–18, 24–25, 30, 2003.
(6) Vileikyte L, Rubin RR, Leventhal H: Psychological aspects of diabetic neuropathic
foot complications: an overview. Diabetes Metab Res Rev 20 (Suppl. 1):S13–S18, 2004.
(7) MJ Young, JL Breddy, A Veves, and AJ Boulton. “The prediction of diabetic
neuropathic foot ulceration using vibration perception thresholds: a prospective study.”
Diabetes Care 17:557–560, 1994.
(8) Arran Shearer, MSc, Paul Scuffham, PHD1, Adam Gordois, MSC1 and Alan Oglesby,
MPH. “Predicted Costs and Outcomes From Reduced Vibration Detection in People
With Diabetes in the U.S. Diabetes Care 26:2305-2310, 2003.
(9)Calle-Pascual AL, Durán A, Benedi A, Calvo MI, Charro A, Diaz JA, Calle JR, Gil E,
Maranes JP, Cabezas-Cerrato J. “A preventative foot care programme for people with
diabetes with different stages of neuropathy.” Diabetes Res Clin Pract 57:111–117,
(10) Guido E. “Effects of Sympathetic Therapy on Chronic Pain in Peripheral
Neuropathy Subjects”. American Journal of Pain Management 2002 Jan; 12(1):31-34.
(11) Lavery LA, Higgins KR,Lanctot DR, Constantiniides, GP, Zamorano RG,
Armstrong DG, Athanasiou KA, and Agrawal CM. “Home Monitoring of Foot Skin
Temperatures to Prevent Ulceration”, Diabetes Care 27:2642-2647, November 2004.
(12) Lavery LA, Higgins KR,Lanctot DR, Constantiniides, GP, Zamorano RG,
Armstrong DG, Athanasiou KA, and Agrawal CM.Preventing Diabetic Foot Ulcer
Recurrence in High-Risk Patients”, Diabetes Care 30:14-20, January 2007.
(13) Glass GV, 1988. Quasi-experiments: The case of interrupted times series. In R.M.
Jaeger (Ed.), Complimentary methods for research in education (pp.445-464).
Washington, D.C.: American Educational Research Association.
(14) McGill M, Molyneaux L, Spencer R, Heng LF, Yue DK. “Possible sources of
discrepancies in the use of the Semmes-Weinstein monofilament. Impact on prevalence
of insensate foot and workload requirements.” Diabetes Care. 1999 Apr; 22(4):598-602.
(15) Gin H, Rigalleau V, Baillet L, Rabemanantsoa C. “Comparison between
monofilament, tuning fork and vibration perception tests for screening patients at risk of
foot complication.” Diabetes Metab. 2002 Dec;28(6 Pt 1):457-61.
(16) Resnick HE, Vinik AI, Schwartz AV, Leveille SG, Brancati FL, Balfour J, Guralnik
JM. “Independent effects of peripheral nerve dysfunction on lower-extremity physical
function in old age: the Women's Health and Aging Study.” Diabetes Care. 2000
(17) Veves A, Malik RA, Lye RH, Masson EA, Sharma AK, Schady W, Boulton AJ.
“The relationship between sural nerve morphometric findings and measures of peripheral
nerve function in mild diabetic neuropathy.” Diabet Med. 1991 Dec;8(10):917-21.
(18) Shun CT, Chang YC, Wu HP, Hsieh SC, Lin WM, Lin YH, Tai TY, Hsieh ST.
“Skin denervation in type 2 diabetes: correlations with diabetic duration and functional
impairments.” Brain. 2004 Dec;127(Pt 12):E20; author reply E21.
(19) Vinik AI, Bril V, Litchy WJ, Price KL, Bastyr EJ 3rd; MBBQ Study Group. Sural
sensory action potential identifies diabetic peripheral neuropathy responders to therapy.”
Muscle Nerve. 2005 Nov;32(5):619-25.
(20) Carrington AL, Shaw JE, Van Schie CH, Abbott CA, Vileikyte L, Boulton AJ.
“Can motor nerve conduction velocity predict foot problems in diabetic subjects over a 6-
year outcome period?” Diabetes Care. 2002 Nov;25(11):2010-5.
(21) Tchen PH, Chiu HC, Fu CC. “Vibratory perception threshold in diabetic
neuropathy.” J Formos Med Assoc. 1990 Jan;89(1):23-9.
(22) Ohnishi A, Yamamoto T, Murai Y, Ikeda M, Sugimoto H, Miyoshi T. “[Correlation
between vibratory detection threshold and conduction study of sural nerve in diabetic
patients].” J UOEH. 1989 Dec 1;11(4):425-8.
(23) Armstrong DG, Lavery LA, Vela SA, Quebedeaux TL, Fleischli JG. “Choosing a
practical screening instrument to identify patients at risk for diabetic foot ulceration.”
Arch Intern Med. 1998 Feb 9;158(3):289-92.
(24) Damci T, Osar Z, Beyhan S, Ilkova H, Ozyazar M, Gorpe U, Bagriacik N. “Does
instantaneous blood glucose affect vibration perception threshold measurement using
biothesiometer?” Diabetes Res Clin Pract. 1999 Oct;46(1):19-22.
(25) Tjon-A-Tsien AM, van Dijk JG, van der Velde EA, Kamzoul BA, Lemkes HH.
“Determinants of vibration perception thresholds in IDDM and NIDDM patients.”
Diabetes Res Clin Pract. 1995 Mar;27(3):211-9.
(26) Ribera RL, Valls J, Gonzalez-Clemente JM, Vidal J, Manzanares JM, Esmatjes E.
“[Measurement of vibratory threshold in the diagnosis of diabetic neuropathy].” Rev
Clin Esp. 1994 Oct;194(10):901-5.
(27) Claus D, Carvalho VP, Neundorfer B, Blaise JF. “[Perception of vibration. Normal
findings and methodologic aspects].” Nervenarzt. 1988 Mar;59(3):138-42.
(28) Maser RE, Nielsen VK, Bass EB, Manjoo Q, Dorman JS, Kelsey SF, Becker DJ,
Orchard TJ. “Measuring diabetic neuropathy. Assessment and comparison of clinical
examination and quantitative sensory testing.” Diabetes Care. 1989 Apr; 12(4):270-5.
(29) McKillop GM, Jamal GA, Kesson CM. “Vibration perception thresholds in 279
diabetic patients.” Scott Med J. 1988 Oct;33(5):334-5.
(30) Young MJ, Breddy JL, Veves A, Boulton AJ. “The prediction of diabetic
neuropathic foot ulceration using vibration perception thresholds. A prospective study.”
Diabetes Care. 1994 Jun; 17(6):557-60.
(31) Rahman M, Griffin SJ, Rathmann W, Wareham NJ. “How should peripheral
neuropathy be assessed in people with diabetes in primary care? A population-based
comparison of four measures.” Diabet Med. 2003 May;20(5):368-74.
(32) Armstrong DG, Hussain SK, Middleton J, Peters EJ, Wunderlich RP, Lavery LA.
“Vibration perception threshold: are multiple sites of testing superior to single site testing
on diabetic foot examination?” Ostomy Wound Manage. 1998 May;44(5):70-4, 76.
(33) Donaghue VM, Giurini JM, Rosenblum BI, Weissman PN, Veves A. “Variability in
function measurements of three sensory foot nerves in neuropathic diabetic patients.”
Diabetes Res Clin Pract. 1995 Jul;29(1):37-42.
(34) Abbott CA, Vileikyte L, Williamson S, Carrington AL, Boulton AJ. “Multicenter
study of the incidence of and predictive risk factors for diabetic neuropathic foot
ulceration.” Diabetes Care. 1998 Jul;21(7):1071-5.
(35) Williams G, Gill JS, Aber V, Mather HM. “Variability in vibration perception
threshold among sites: a potential source of error in biothesiometry.” Br Med J (Clin Res
Ed). 1988 Jan 23;296(6617):233-5.
(36) Cameron NE, Cotter MA, Low PA "Nerve blood flow in early experimental diabetes
in rats: relation to conduction deficits" Am J Physiol. 1991 Jul; 261(1 Pt 1): E1-8.
(37) Terata K, Coppey LJ, Davidson EP, Dunlap JA, Gutterman DD, Yorek MA
"Acetylcholine-induced arteriolar dilation is reduced in streptozotocin-induced diabetic
rats with motor nerve dysfunction" Br J Pharmacol. 1999 Oct; 128(3): 837-43.
(38) Malik RA, Tesfaye S, Thompson SD, Veves A, Sharma AK, Boulton AJ, Ward JD.
Endoneurial localisation of microvascular damage in human diabetic neuropathy.
Diabetologia. 1993 May;36(5):454-9.
(39) Malik RA, Veves A, Masson EA, Sharma AK, Ah-See AK, Schady W, Lye RH,
Boulton AJ. “Endoneurial capillary abnormalities in mild human diabetic neuropathy.” J
Neurol Neurosurg Psychiatry. 1992 Jul;55(7):557-61.
(40) Malik RA, Newrick PG, Sharma AK, Jennings A, Ah-See AK, Mayhew TM,
Jakubowski J, Boulton AJ, Ward JD. “Microangiopathy in human diabetic neuropathy:
relationship between capillary abnormalities and the severity of neuropathy.”
Diabetologia. 1989 Feb;32(2):92-102.
(41) Veves A, Donaghue VM, Sarnow MR, Giurini JM, Campbell DR, LoGerfo FW.
“The impact of reversal of hypoxia by revascularization on the peripheral nerve function
of diabetic patients.” Diabetologia. 1996 Mar;39(3):344-8.
(42) Aydin A, Ozden BC, Karamursel S, Solakoglu S, Aktas S, Erer M. “Effect of
hyperbaric oxygen therapy on nerve regeneration in early diabetes.” Microsurgery. 2004;
(43) Kennedy JM, Zochodne DW. “Impaired peripheral nerve regeneration in diabetes
mellitus.” J Peripher Nerv Syst. 2005 Jun;10(2):144-57.
(44) Polydefkis M, Hauer P, Sheth S, Sirdofsky M, Griffin JW, McArthur JC. “The time
course of epidermal nerve fibre regeneration: studies in normal controls and in people
with diabetes, with and without neuropathy.” Brain. 2004 Jul;127(Pt 7):1606-15. Epub
2004 May 5.
(45) Bradley JL, Thomas PK, King RH, Muddle JR, Ward JD, Tesfaye S, Boulton AJ,
Tsigos C, Young RJ. “Myelinated nerve fibre regeneration in diabetic sensory
polyneuropathy: correlation with type of diabetes.” Acta Neuropathol (Berl).
(45) Shun CT, Chang YC, Wu HP, Hsieh SC, Lin WM, Lin YH, Tai TY, Hsieh ST
“Skin denervation in type 2 diabetes: correlations with diabetic duration and functional
impairments.” Brain. 2004 Jul;127(Pt 7):1593-605. Epub 2004 May 5.
(46) Cameron NE, Cotter MA, Robertson S "Chronic low frequency electrical activation
for one week corrects nerve conduction velocity deficits in rats with diabetes of three
months duration" Diabetologia. 1989 Oct; 32(10): 759-61.
(47) Cameron NE, Cotter MA, Robertson S, Maxfield EK "Nerve function in
experimental diabetes in rats: effects of electrical stimulation" Am J Physiol. 1993 Feb;
264(2 Pt 1):E161-6.
(48) Winter A "The use of Transcutaneous Electrical Stimulation (TNS) in the Treatment
of Multiple Sclerosis." Journal of Neurosurgical Nursing. J Neurosurg Nurs. 1976
(49) Brain SD, Tippins JR, Morris HR, MacIntyre I, Williams TJ "Potent Vasodilator
activity of calcitonin gene-related peptide in human skin" J Invest Dermatol. 1986 Oct;
(50) Kaada B, "Systemic sclerosis: successful treatment of ulcerations, pain, Raynaud's
phenomenon, calcinosis, and dysphagia by transcutaneous nerve stimulation." Acupunct
Electrother Res 1984; 9(1): 31-44.
(51) Kaada B."Vasodilation induced by transcutaneous nerve stimulation in peripheral
ischemia (Raynaud's phenomenon and diabetic polyneuropathy.” Eur Heart J 1982 Aug;
(52) Kaada B., Lygren I. "Lower plasma levels of some gastrointestinal peptides in
Raynaud's disease. Influence of transcutaneous nerve stimulation.” Gen Pharmacol 1985;
(53) Jager K, Muench R, Seifert H, Beglinger C, Bollinger A, Fischer JA "Calcitonin
gene-related peptide (CGRP) causes redistribution of blood flow in humans." Eur J Clin
Pharmacol. 1990; 39(5): 491-4.
(54) Knedlitschek G, Noszvai-Nagy M, Meyer-Waarden H, Schimmelpfeng J,
Weibezahn KF, Dertinger H. "Cyclic AMP response in cells exposed to electric fields of
different frequencies and intensities." Radiat Environ Biophys 1994; 33(2): 141-7.
(55) Sontag W, Dertinger H. "Response of cytosolic calcium, cyclic AMP, and cyclic
GMP in Dimethylsulfoxide-differentiated HL-60 cells to modulated low frequency
electric currents." Bioelectromagnetics 1998; 19(8): 452-8.
(56) O'Dorisio MS, Wood CL, Wenger GD, Vassalo LM. "Cyclic AMP-dependent
protein kinase in Molt 4b lymphoblasts: identification by photoaffinity labeling and
activation in intact cells by vasoactive intestinal polypeptide (VIP) and peptide histidine
isoleucine (PHI)." J Immunol 1985 Jun; 134(6): 4078-86.
(57) Yamamoto M, Sobue G, Li M, Mitsuma T, Kimata K, Yamada Y. "cAMP-
dependent differential regulation of extracellular matrix (ECM) gene expression in
cultured rat Schwann cells." Brain Res 1994 Aug 8; 653(1-2): 335-9.
(58) Calcutt NA, Mizisin AP, Yaksh TL. “Impaired induction of vasoactive intestinal
polypeptide after sciatic nerve injury in the streptozotocin-diabetic rat.” J Neurol Sci.
(59) Shindo H, Tawata M, Onaya T. "Reduction of cyclic AMP in the sciatic nerve of rats
made diabetic with streptozotocin and the mechanism involved." J Endocrinol 1993 Mar;
(60) Shindo H, Tawata M, Onaya T. “Reduction of cyclic AMP in the sciatic nerve of
rats made diabetic with streptozotocin and the mechanism involved.” J Endocrinol. 1993
(61) Shindo H, Tawata M, Aida K, Onaya T. “The role of cyclic adenosine 3',5'-
monophosphate and polyol metabolism in diabetic neuropathy.” J Clin Endocrinol
Metab. 1992 Feb;74(2):393-8.
(62) Shindo H, Tawata M, Onaya T. “Cyclic adenosine 3',5'-monophosphate enhances
sodium, potassium-adenosine triphosphatase activity in the sciatic nerve of
streptozotocin-induced diabetic rats.” Endocrinology. 1993 Feb;132(2):510-6.
(63) Lindberger M, Schroder HD, Schultzberg M, Kristensson K, Persson A, Ostman J,
Link H. " Nerve fibre studies in skin biopsies in peripheral neuropathies.
Immunohistochemical analysis of neuropeptides in diabetes mellitus." J Neurol Sci 1989
Nov; 93(2-3): 289-96.
(65) Rossi R, Johansson O."Cutaneous innervation and the role of neuronal peptides in
cutaneous inflammation: a minireview." Eur J Dermatol 1998 Jul-Aug;8(5): 299-306.
(66) Brain SD, Williams TJ. “Substance P regulates the vasodilator activity of
Calcitonin Gene-related Peptide”. Nature 1988 Sept 1; 335(6185): 73-5.