Frequency-modulated electromagnetic neural stimulation (FREMS) as a treatment for symptomatic diabetic neuropathy: results from a double-blind, randomised, multicentre, long-term, placebo-controlled clinical trial.

AIMS/HYPOTHESIS: The aim was to evaluate the efficacy and safety of transcutaneous frequency-modulated electromagnetic neural stimulation (frequency rhythmic electrical modulation system, FREMS) as a treatment for symptomatic peripheral neuropathy in patients with diabetes mellitus. METHODS: This was a double-blind, randomised, multicentre, parallel-group study of three series, each of ten treatment sessions of FREMS or placebo administered within 3 weeks, 3 months apart, with an overall follow-up of about 51 weeks. The primary endpoint was the change in nerve conduction velocity (NCV) of deep peroneal, tibial and sural nerves. Secondary endpoints included the effects of treatment on pain, tactile, thermal and vibration sensations. Patients eligible to participate were aged 18-75 years with diabetes for ≥ 1 year, HbA(1c) <11.0% (97 mmol/mol), with symptomatic diabetic polyneuropathy at the lower extremities (i.e. abnormal amplitude, latency or NCV of either tibial, deep peroneal or sural nerve, but with an evocable potential and measurable NCV of the sural nerve), a Michigan Diabetes Neuropathy Score ≥ 7 and on a stable dose of medications for diabetic neuropathy in the month prior to enrolment. Data were collected in an outpatient setting. Participants were allocated to the FREMS or placebo arm (1:1 ratio) according to a sequence generated by a computer random number generator, without block or stratification factors. Investigators digitised patients' date of birth and site number into an interactive voice recording system to obtain the assigned treatment. Participants, investigators conducting the trial, or people assessing the outcomes were blinded to group assignment. RESULTS: Patients (n = 110) with symptomatic neuropathy were randomised to FREMS (n = 54) or placebo (n = 56). In the intention-to-treat population (50 FREMS, 51 placebo), changes in NCV of the three examined nerves were not different between FREMS and placebo (deep peroneal [means ± SE]: 0.74 ± 0.71 vs 0.06 ± 1.38 m/s; tibial: 2.08 ± 0.84 vs 0.61 ± 0.43 m/s; and sural: 0.80 ± 1.08 vs -0.91 ± 1.13 m/s; FREMS vs placebo, respectively). FREMS induced a significant reduction in day and night pain as measured by a visual analogue scale immediately after each treatment session, although this beneficial effect was no longer measurable 3 months after treatment. Compared with the placebo group, in the FREMS group the cold sensation threshold was significantly improved, while non-significant differences were observed in the vibration and warm sensation thresholds. No relevant side effects were recorded during the study. CONCLUSIONS/INTERPRETATION: FREMS proved to be a safe treatment for symptomatic diabetic neuropathy, with immediate, although transient, reduction in pain, and no effect on NCV. TRIAL REGISTRATION: ClinicalTrials.gov NCT01628627. FUNDING: The clinical trial was sponsored by Lorenz Biotech (Medolla, Italy), lately Lorenz Lifetech (Ozzano dell'Emilia, Italy).

Recommendations for the use of cardiovascular tests in diagnosing diabetic autonomic neuropathy.

Despite its prevalence, clinical and prognostic impact, diabetic autonomic neuropathy, is widely under-diagnosed. The need for training and expertise to perform the cardiovascular tests (usually the task of diabetologists) is one possible reason. The availability of computer-assisted systems has allowed a wider diffusion of testing, but has also highlighted the need for an adequate knowledge of physiopathological backgrounds for their correct application and interpretation. The recommendations presented here were developed by the Neuropathy Study Group of the Italian Society of Diabetology and then endorsed by the Italian Association for the Study of Neurovegetative System, to promote the widespread adoption of good clinical practice in diabetic cardiovascular autonomic testing by outlining main evidence-based aspects, i.e. which tests, how to perform them, adequate interpretation of the results and their diagnostic use, confounding conditions that can impact on tests reliability. Therefore, these recommendations include the essential aspects of the physiopathological substrate of the tests, the controversial points in their analysis, their diagnostic characteristics, as well as safety. Detailed information is given on the physiological (age, weight, body position, resting heart rate and blood pressure, respiratory pattern, exercise, meals, acute blood glucose changes) and pathophysiological confounding factors, with emphasis on the effects of drugs. Instructions on how to perform the tests and interpret their results are also considered together with indications of candidate patients and periodicity of testing. A patient instruction sheet on why and how to perform the tests is included. Finally, the specific requirements for computerized systems to perform and evaluate cardiovascular tests are provided.

Rigiscan evaluation of specific nervous impairment in patients with diabetes and erectile disorders.

OBJECTIVE: A proposed new, minimally invasive, and painless method for studying impairment of the autonomic system of the penile region in type 2 diabetes patients. RESEARCH DESIGN AND METHODS: Thirteen subjects were selected from 150 patients with type 2 diabetes and erectile dysfunction who were studied in accordance with the National Institutes of Health consensus. The 13 subjects (group A), aged 55 +/- 8 years, had acceptable metabolic control (HbA1c, < 8%); no arterial or venous diseases or initial Peyronie's disease, as evaluated by penile Doppler ultrasonography and intracavernous prostaglandin E1 injection; and penile tumescence at the base (PTB) < 30 mm. Group B consisted of 13 control subjects with the same characteristics, including mean age (53.1 +/- 9 years), metabolic control (HbA1c, 7.3 +/- 0.7%), and duration of disease (8.3 +/- 0.7 years), but PTB was > 30 mm. Student's t test was used to evaluate differences in the results of autonomic cardiovascular tests, somatic tests (vibration perception threshold [VPT]), and diabetic neuropathy score (DNS) in both groups. The coefficient of variation of PTB was evaluated using the Rigiscan device (Dacomed, Minneapolis, MN), and Bayes' test was used to test sensitivity, specificity, and positive predictive values of the cardiovascular tests. RESULTS: Patients with PTB < 30 mm had significant (P < 0.05) impairment of parasympathetic tests (lying to standing, P < 0.02; standing to lying, P < 0.04; squat test, P < 0.03) compared with subjects with higher PTB values. No difference in DNS and VPT at the base and tip of the penis was found between the two groups. The variability of the test is 10% in normal subjects and 15% in both groups of patients. PTB sensitivity was 54%, specificity 89%, and positive predictive value 79%. CONCLUSIONS: In patients with diabetes and without vascular diseases, the PTB evaluated by Rigiscan is related to impairment of the autonomic nervous system. A PTB value < 30 mm may be considered a useful, noninvasive marker in studying parasympathetic damage of the penile region.

Early involvement of central nervous system in type I diabetic patients.

OBJECTIVE: To investigate whether the asymptomatic involvement of the central and peripheral nervous systems may be an early complication of diabetes. RESEARCH DESIGN AND METHODS: We studied early impairment of the central and peripheral nervous system pathways in 15 type I diabetic patients with good metabolic control and short disease duration and in 10 healthy control subjects using a set of neurophysiological tests. RESULTS: Results in diabetic subjects showed 1) impairment of motor (7% and somatosensory (13%) pathways of the central nervous system, 2) impairment of motor and sensory conduction velocities (40-60%), and 3) normal values of the vibration perception threshold and cardiovascular autonomic tests. CONCLUSIONS: The damage is more evident in peripheral sites where hyperglycemia and aldose reductase pathways are more active. Instead, several episodes of hypoglycemia, which occur in type I diabetic patients in good metabolic control, may cause alterations of brain nervous cells.

Evaluation of the vagal-sympathetic interaction in diabetics with autonomic neuropathy through power spectrum density analysis of the heart rate. A critical revision of the natural history of diabetic autonomic neuropathy is possible.

In this paper we apply spectral analysis methods to heart rate variability to assess the autonomic nervous system activity in normal subjects and in patients affected by different degrees of diabetic autonomic neuropathy. The current opinion, based on different clinical tests, is that parasympathetic impairment occurs earlier in autonomic dysfunctions. However, the use of power spectrum density analysis based on a single parameter (heart rate) suggests a simultaneous involvement of parasympathetic and sympathetic pathways leading to the conclusion that perhaps the natural history of diabetic autonomic neuropathy should be substantially rewritten.

[Poisoning with ammonium tetraformiate--a substance used in silage formation]. / Een intoxicatie met ammoniumtetraformiaat--een hulpstof bij het inkuilen van veevoer.

The case is reported of a 23-year-old man, working in agriculture, who was exposed to the silage additive ammonium tetraformiate, a strong acid. While pumping the fluid some of the substance entered his mouth and was swallowed. He vomited and developed transient dyspnoea. On admission he appeared acidotic, with haemolysis and haemoglobinuria. Lesions on the soft palate and in the oesophagus were observed, and a pulmonary infiltrate developed. Information on the substance was initially not available. Labeling appeared incomplete and misleading. Optimal treatment was delayed.

Cellular retention on diagnostic contact lenses: an evaluation of current cleaning protocol.

AIMS: To compare cellular contamination of diagnostic contact lenses after two different cleaning methods. METHODS: Twenty-five used diagnostic contact lenses were cleaned by two different methods and the material retained on their contact surface examined for cells. Two diagnostic contact lenses were examined using electron microscopy and surface debris was subjected to x-ray photoelectron spectroscopy. RESULTS: Significantly more cells were present on used lenses compared with controls (P<0.001). There was no significant difference in total cell count between the lenses subjected to the two cleaning strategies but the lenses simply wiped clean retained marginally more nucleated cells than controls (P=0.039). Electron microscopy showed the majority of the debris on or close to the rim of the lens. X-ray photoelectron spectroscopy confirmed the presence of proteinaceous material. CONCLUSIONS: Regardless of cleaning method, significant cellular debris is retained on the surface of diagnostic contact lenses after use.

Mild peripheral neuropathy prevents both leg muscular ischaemia and activation of exercise-induced coagulation in Type 2 diabetic patients with peripheral artery disease.

AIM: To study the influence of peripheral neuropathy on intermittent claudication in patients with Type 2 diabetes (T2DM). METHODS: Twenty-five patients with T2DM were grouped according to the ankle/brachial index (ABI): 10 with ABI > 0.9 without peripheral artery disease (PAD; group T2DM) and 15 with ABI < 0.9 with PAD (group T2DM + PAD). Twelve individuals without T2DM with PAD (group PAD without T2DM) were also enrolled. Tests for peripheral neuropathy were performed in all patients. ABI, rate pressure product, prothrombin fragments 1 + 2 (F1+2), thrombin-anti-thrombin complex (TAT), and d-dimer were measured before and after a treadmill test. During exercise both initial and absolute claudication distance and electrocardiogram readings were recorded. RESULTS: We found mild peripheral neuropathy in 20% of group T2DM and 46.7% of group T2DM + PAD (P < 0.01). After exercise, the rate pressure product increased in each group; ABI fell in T2DM + PAD (P < 0.0001) and in PAD without T2DM (P = 0.0005); the fall was greater in the latter group. Initial and absolute claudication distances were similar in PAD patients. In group T2DM + PAD, absolute claudication distance was longer in the subgroup without peripheral neuropathy (P < 0.05), whereas ABI and rate pressure products were similar. F1+2 values at rest were higher in group T2DM + PAD. After exercise, F1+2 values and TAT increased only in group PAD without T2DM. CONCLUSION: Only group PAD without T2DM experienced muscular ischaemia, whereas group T2DM + PAD did not. Mild peripheral neuropathy may have prevented them from reaching the point of muscular ischaemia during the treadmill test, because they stopped exercising with the early onset of pain. Reaching a false absolute claudication distance may induce ischaemic preconditioning. These findings suggest a possible protective role of mild peripheral neuropathy in T2DM patients with intermittent claudication, by preventing further activation of coagulation during treadmill testing.

Prolonged QT period in diabetic autonomic neuropathy: a possible role in sudden cardiac death?

Twenty four men with insulin dependent diabetes and different degrees of autonomic neuropathy were studied to establish the response of the QT interval to various heart rates. Nine men with autonomic neuropathy had a longer QT interval than 13 healthy individuals and 15 patients who had diabetes without, or with only mild, autonomic neuropathy. Those with autonomic neuropathy also had a proportionally greater lengthening of the QT interval for a given increase in RR interval. The results of this study suggest a basis for the finding that sudden death is more common in patients with diabetic autonomic neuropathy.

Heart rate spectral analysis for assessing autonomic regulation in diabetic patients.

Spectral analysis of the R-R variability signal has been used for assessing the autonomic regulation of heart rate in control subjects and in diabetic patients affected by autonomic neuropathy. Modifications of the parasympathetic-sympathetic balance following postural changes, as observed in normal subjects, were not significant in autonomic patients. In addition, the overall reduction of power occurring in diabetics at all frequencies indicates the impairment of both autonomic components.

Cigarette smoking is a risk factor for nephropathy and its progression in type 2 diabetes mellitus.

Cigarette smoking is a risk factor for diabetic nephropathy in Type 1 diabetes (T1DM); a few reports support this possibility in Type 2 diabetes (T2DM) as well. Since heterogeneity among populations could exist, we investigated the association of cigarette smoking and nephropathy, and progression of nephropathy in Italian T2DM patients. A retrospective study was conducted in 273 long-duration T2DM subjects with a 3-year follow-up in the out-patient clinic, and at least one access per year. Albumin excretion rate, serum creatinine, and a number of other parameters implicated in the development of diabetic renal disease were evaluated. Progression of nephropathy was defined as the passage from different stages of renal involvement (no renal derangement, microalbuminuria, proteinuric disease or severe nephropathy). At baseline, 13.2% of the subjects had microalbuminuria, and 3.7% proteinuric disease. Microalbuminuria and proteinuric disease were more frequent in actual smokers than in non- and former smokers (chi2=8.35; p=0.015). Progression of nephropathy was less common in non- and former smokers than in smokers (31 of 134, 23%, and 15 of 67, 22%, and 30 of 72, 42%, respectively; chi2=9.32;p=0.009). From logistic regression analysis, smoking (p=0.0012) emerged as the most important factor associated with progression of nephropathy, followed by packyears (p=0.011), HbA1c mean value at follow-up (p=0.024), and total cholesterol (p=0.038). In conclusion, cigarette smoking is a risk factor for progression of nephropathy also in Italian T2DM patients; reducing or quitting smoking should be part of the therapy or of the preventive measures in these patients and their relatives.