Integrity Of Autonomic Nervous System Research Articles

Composite autonomic severity scoring in spinocerebellar ataxia type 1 and 2

ObjectivesThe aim of the present study was to evaluate the integrity of autonomic nervous system in spinocerebellar ataxia (SCA) type 1 and 2 patients using battery of autonomic function tests and their comprehensive scoring using composite autonomic severity score (CASS). Material and methodsBattery of autonomic function test comprising of cardiovascular (baroreflex dependent and non-baroreflex dependent) and sudomotor functions were assessed in age and gender-matched SCA1 (n = 31), SCA2 (n = 40) patients along with healthy controls (n = 40). To assess the grade of autonomic abnormalities, the composite autonomic severity score (CASS) was computed using the results of the standard autonomic function tests. ResultsWe found reduction in baroreflex dependent autonomic reactivity parameters predominantly a significant fall of systolic blood pressure (<0.001) and lower 30:15 ratio (<0.001) during head up tilt in both the SCA1 and SCA2 as compared to controls. On sudomotor assessment, distal leg latency of sweat response was prolonged in SCA1 than SCA2 patients. Moderate generalized autonomic failure was commonly found amongst SCA1 (80.65%) and SCA2 (85%) patients. Severe autonomic failure was found to be more in SCA1 (6.45%) than SCA2 (2.50%) patients. ConclusionsCardiovascular autonomic function assessment in SCA1 and SCA2 patients revealed a significant impairment in the baroreflex loop integrity. Severity scoring using CASS suggests the existence of moderate autonomic failure in majority of both SCA1 and SCA2 patients.

Heart rate variability as an indicator of COVID-19 induced myocardial injury: a retrospective cohort study

BackgroundHeart rate variability (HRV) is a valuable indicator of autonomic nervous system integrity and can be a prognostic tool of COVID-19 induced myocardial affection. This study aimed to compare HRV indices between patients who developed myocardial injury and those without myocardial injury in COVID-19 patients who were admitted to intensive care unit (ICU).MethodsIn this retrospective study, the data from 238 COVID-19 adult patients who were admitted to ICU from April 2020 to June 2021 were collected. The patients were assigned to myocardial injury and non-myocardial injury groups. The main collected data were R-R intervals, standard deviation of NN intervals (SDANN) and the root mean square of successive differences between normal heartbeats (RMSSD) that were measured daily during the first five days of ICU admission.ResultsThe R-R intervals, the SDANN and the RMSSD were significantly shorter in the myocardial injury group than the non-myocardial group at the first, t second, third, fourth and the fifth days of ICU admission. There were no significant differences between the myocardial injury and the non-myocardial injury groups with regard the number of patients who needed mechanical ventilation, ICU length of stay and the number of ICU deaths.ConclusionsFrom the results of this retrospective study, we concluded that the indices of HRV were greatly affected in COVID-19 patients who developed myocardial injury.

Pupil light reflex in Parkinson’s disease patients with and without freezing of gait symptoms

PURPOSE:Freezing of gait (FOG) is considered as a motor disorder that affects some Parkinson’s disease (PD) patients; however, sensory systems may also be involved in FOG. The pupil light reflex (PLR) is a reliable measure of the autonomic nervous system. Different dilation and constriction pupil parameters may be used to investigate the integrity of the autonomic nervous system in PD patients with and without FOG symptoms. This study aimed to look at the integrity of autonomic nervous system and to investigate the nonmotor functions mediated by the cholinergic system in Parkinson’s patients with and without FOG symptoms.METHODS:Constriction and dilation pupil light reflexes were measured by using a handheld pupillometer. Twenty-two patients with FOG symptoms, 25 patients without FOG symptoms, and 25 aged-matched healthy controls participated in this study.RESULTS:The results showed that most of the constriction parameters and dilation latency of both patient groups differed significantly from healthy controls. FOG patients showed larger pupil size under light condition and larger deficits in constriction latency than nonFOG patients. Both the groups of PD patients had longer dilation latencies than healthy controls.CONCLUSION:This study suggests that the cholinergic autonomic nervous system is affected in PD patients more than the adrenergic system. FOG patients had larger impairments in nondopaminergic mediated functions such as pupil light reflexes, which suggests that FOG patients have greater impairment in functions that involve cholinergic neurotransmitters.

Absence of fetal heart rate cycling on the intrapartum cardiotocograph (CTG) is associated with intrapartum pyrexia and lower Apgar scores

Background Cycling consists of alternating periods of reduced and normal fetal heart variability, reflecting changes in fetal behavioral states. Occurrence of active and quiet sleep cycles is considered to be a hallmark of fetal autonomic nervous system integrity, demonstrating healthy interaction between the parasympathetic and sympathetic nervous systems. Cycling is an overlooked feature in most international cardiotocography (CTG) guidelines. The authors tested the hypothesis that fetuses showing no cycling in the intrapartum period have poorer outcomes. Aim To investigate whether the absence of cycling at the commencement of intrapartum fetal monitoring is associated with poorer neonatal outcomes (umbilical arterial cord pH, Apgar scores and neonatal unit admission). Methods Analysis of a database of sequentially acquired intrapartum CTG traces from a single center. Only cases of singleton pregnancies over 36 weeks gestation in cephalic presentation with recorded umbilical artery cord pH were considered. Neonatal outcomes were assessed based on umbilical cord artery pH, Apgar ≤7 at 5 min and unexpected admission to the neonatal unit. Intrapartum pyrexia, presence of meconium-stained amniotic fluid and mode of delivery were also recorded. Results A total of 684 cases were analyzed. Absence of cycling from the beginning of the intrapartum CTG recording was noted in 5% of cases. Cases with no cycling were more likely to have maternal pyrexia (≥37.8 °C) (p = .006) and Apgars ≤7 at 5 min (p = .04). There was an association between increasing baseline fetal heart rate and the proportion of cases with no cycling. There was no significant difference between the two groups with regard to the mode of delivery or umbilical cord arterial pH <7.05 (p = .53). Conclusion Absence of cycling is associated with intrapartum maternal pyrexia and fetuses with the absence of cycling are more likely to have poorer perinatal outcomes measured by Apgar ≤ 7 at 5 min, despite no association with fetal acidosis. Results from this research were presented at the XXVI European Congress of Perinatal Medicine in September 2018.

Heart rate variability evaluation in the assessment of cardiac autonomic neuropathy in patients with type 2 diabetes

IntroductionHeart rate variability (HRV) is a respected measure used in the assessment of cardiac autonomic neuropathy (CAN) and it can serve as an independent prognostic indicator of sudden arrhythmic death risk. Despite the importance of early detection, the diagnosis of CAN is often made too late, especially in diabetics. Besides the long subclinical phase of CAN, reasons for this include great diversification of employed diagnostic methods and absence of universally accepted normal values; the latter applies mostly in HRV evaluated using short-term spectral analysis (SAHRV). AimThe aim of this cross-sectional study involving patients with type 2 diabetes was to summarize the real potential of using a testing method for CAN diagnosis by short-term SAHRV, including an autonomic load imposed during an orthoclinostatic test (Supine1–Standing–Supine2, short 5-min recordings). Three different normative approaches to the postprocessing analysis of acquired data described by different authors were employed.Secondary aim of the study was to assess the benefit of rate-controlled breathing. The next aim was to compare the HRV data measured with the selected clinical and laboratory indices in patient examined. Materials and methodsThe study included 43 patients with type 2 diabetes (12 women, 31 men, mean age 51.1±10.7 y) and no history of manifest CAN or serious cardiovascular illness, except uncomplicated hypertension. Using a diagnostic system DiANS PF8 with telemetric transfer of ECG and respiratory rate, series of reflex tests according to Ewing and SAHRV (Fourier tachogram analysis, window 256) during autonomic load imposed by Supine1–Standing–Supine2 test (SSS test) and during 5min of rate-controlled, non-deepened breathing (PB, 12cycles/min) were performed. Acquired spectral indices were analyzed and compared with normatives of 3 authors using the same recording algorithm, SSS test, but different data postprocessing analysis. These were (1) so called “functional age” of autonomic nervous system (ANS), (2) assessment of CAN severity according to age-stratified medians and percentiles, (3) assessment of CAN severity according to cumulative spectral power during the entire test (cumLFHF). ResultsAccording to the total Ewing score (ETS), 11.6% patients were categorized as CAN-free (ETS=0), 32.6% were diagnosed with possible CAN (ETS=1), and 55.8% labeled with manifest CAN (ETS=2–3). Moderate correlation between ETS and individual SAHRV parameters following orthoclinostasis (test SSS) in Supine2 position was described [ms2]: TP (total power, f=0.02–0.5Hz): r=−0.4, p<0.006; LF component (low frequency, 0.05–0.15Hz): r=−0.31, p<0.04; HF component (high frequency, 0.15–0.5Hz): r=−0.45, p<0.003) and the same applied to rate-controlled breathing PB (TP, [ms2]: r=−0.56, p<0.0001; LF: r=−0.38, p<0.018; HF: r=−0.52, p<0.001). Moderate correlation was also found between ETS and HRV assessment using a complex indicator – “functional age of ANS” (r=0.37, p<0.015), ETS and cumLFHF [ms2, lnms2]: r=−0.46, p<0.002). In most patients, significant difference between functional age of ANS and calendar age was confirmed (mean 21.8±12.9 y, median 23.5 years, p<0.0001). An attempt to assess the severity CAN using age-stratified medians and percentiles of TP, LF, HF, and LF/HF was not successful.As for SAHRV and clinical indices (anthropometric, echocardiographic, QTc, laboratory), moderate correlation between the glycated hemoglobin on one side and basic SAHRV indices (TP, LF, HF, LF/HF), functional age of ANS and cumLFHF on the other side was prominent (r=0.36–0.53, p<0.0004 to p<0.02). ConclusionAssessment of CAN using evaluation of HRV can optimally be performed (and simply realized in clinical practice) using SAHRV based on short ECG recordings during autonomic load imposed by orthoclinostatic test (Supine1–Standing–Supine2) and on postprocessing data analysis using complex indicator called “functional age of ANS”. In the detailed evaluation of sympathovagal balance, it complements the screening assessment with cardiovascular reflex tests (Ewing's battery). Besides the orthoclinostatic load, pronounced vagal provocation using rate-controlled, non-deepened breathing (12cycles/min) represents a recommended facultative load option increasing the yield of the SAHRV method.The detection and assessment of CAN severity while applying the cumulative indicator of HRV (cumLFHF) showed a good discrimination power in the frontline screening for CAN, albeit without the possibility to distinguish between the sympathetic and vagal branch of ANS.Presented cross-sectional study in type 2 diabetes mellitus demonstrated a significant autonomic dysfunction in majority patients examined, independently of diabetes duration. It supports the recommendation to assess the ANS integrity in type 2 diabetes already at diagnosis, within the initial staging of the illness. The severity of CAN correlates well with metabolic control of diabetes as evaluated by glycated hemoglobin.

EFFECT OF AN EARLY NEUROCOGNITIVE REHABILITATION ON AUTONOMIC NERVOUS SYSTEM IN CRITICALLY ILL PATIENTS

Recent clinical and electrophysiological studies reveal a high incidence of autonomic nervous system (ANS) dysfunction in patients treated in ICU [1]. ANS disturbances may produce diverse and unexpected consequences. For instance, critically ill patients are at risk of neurocognitive impairments that may persist after hospital discharge. Among various pathophysiological mechanisms proposed, ANS dysfunction leading cholinergic deficiency seems one of the most viable to explain the development of long-term sequelae. Heart rate variability (HRV) has been related to the activity of the prefrontal cortex [2] hence, prefrontal activation could help to strengthen the autonomic nervous system integrity. We are interested in assessing the improvement of the ANS dysfunction through neural circuits' activation. Thus, we propose a novel therapy that could allow the reinforcing of ANS through an early neurocognitive intervention targeted to improve prefrontal activation.

Autonomic testing of women with interstitial cystitis/bladder pain syndrome.

PurposeInterstitial cystitis/bladder pain syndrome (IC/BPS) is characterized by urinary urgency, frequency, nocturia, pain worse as the bladder fills and improved after emptying. These features might suggest abnormal autonomic bladder control mechanisms. We compared the structural integrity of the autonomic nervous system (ANS) in IC/BPS and control subjects.MethodsIRB-approved study at University Hospitals Case Medical Center, Cleveland, OH to evaluate the structural integrity of the ANS in adult females. Testing included cardiovascular response to deep breathing, Valsalva maneuver, 30 min head up tilt, and sudomotor test.ResultsDifferences in ANS integrity for IC/BPS subjects and controls were determined by modified Composite Autonomic Severity Score (CASS) that includes sudomotor, adrenergic and cardiovascular indices. Baseline heart rate (HR) and HRs from each of three 10 min upright segments of a tilt test were compared and trend analyses performed using t tests. Healthy and IC/BPS subjects were demographically similar. The two groups did not differ in modified-CASS scores but elevated average peak heart rate was evident during baseline (supine; p = 0.057) for IC/BPS subjects prior to a tilt test. Difference at baseline was maintained at each interval during the tilt, with nearly identical slopes across intervals. The preliminary nature of this report denotes a small sample size and important differences may not be detected.ConclusionsThe findings show no structural ANS abnormalities in IC/BPS subjects. Higher baseline HR supports the concept of functional rather than structural change in the ANS, such as abnormality of sympathetic/parasympathetic balance that will require further evaluation.

Pupillary behavior in relation to wavelength and age.

Pupil light reflex can be used as a non-invasive ocular predictor of cephalic autonomic nervous system integrity. Spectral sensitivity of the pupil's response to light has, for some time, been an interesting issue. It has generally, however, only been investigated with the use of white light and studies with monochromatic wavelengths are scarce. This study investigates the effects of wavelength and age within three parameters of the pupil light reflex (amplitude of response, latency, and velocity of constriction) in a large sample of younger and older adults (N = 97), in mesopic conditions. Subjects were exposed to a single light stimulus at four different wavelengths: white (5600°K), blue (450 nm), green (510 nm), and red (600 nm). Data was analyzed appropriately, and, when applicable, using the General Linear Model (GLM), Randomized Complete Block Design (RCBD), Student's t-test and/or ANCOVA. Across all subjects, pupillary response to light had the greatest amplitude and shortest latency in white and green light conditions. In regards to age, older subjects (46–78 years) showed an increased latency in white light and decreased velocity of constriction in green light compared to younger subjects (18–45 years old). This study provides data patterns on parameters of wavelength-dependent pupil reflexes to light in adults and it contributes to the large body of pupillometric research. It is hoped that this study will add to the overall evaluation of cephalic autonomic nervous system integrity.

GLP-1: What is known, new and controversial in 2010?

Over the past 2 years, more than 1300 manuscripts have been published on glucagon-like peptide-1 (GLP-1) and yet, what do we know about it for sure? The European Club for the Study of GLP-1 (EuCSGLP-1) has debated the latest controversies concerning GLP-1, including both fundamental and clinical aspects, and concluded that the control of glucose metabolism by GLP-1 requires paracrine activation of the enteric nervous system to regulate numerous physiological functions. This involves—but is not limited to—the endocrine pancreas, liver, cardiovascular system, gastric-emptying and the brain. For this reason, the role of GLP-1 as an endocrine hormone has come under question. As systemic concentration of the peptide was not thought to be relevant to its physiological action, it was proposed that dipeptidyl peptidase-4 (DPP4) inhibitors would involve the control of enteric, rather than circulating, DPP4 activity to effectively regulate glycaemia. In any case, the concomitant insulinotropic and glucagonostatic roles of GLP-1 were believed to be of equal importance to glucose control. Another important question was related to the role of GLP-1 on beta cell apoptosis, regeneration and differentiation in type 2 diabetic patients. Although evidence in vitro showed that GLP-1 controls these functions, such effects remain elusive in humans in vivo. Nevertheless, the consensus was that GLP-1 could control glucose responsiveness, one of the first impaired physiological functions at the onset of diabetes. The therapeutic efficiency of GLP-1 would be related to the initial restoration of glucose competence, while an increase of beta cell mass has not yet been demonstrated. From a clinical and fundamental point of view, it was concluded that, at the onset of diabetes, an initial triggering of GLP-1 secretion—by metformin coupled with a DPP4 inhibitor—would help to activate the gut–peripheral axis and, hence, restore adequate regulation of glycaemia. GLP-1 analogues would certainly be helpful in association with long-acting insulin (albeit off-label) in patients with impaired beta cells and GLP-1 secretory potential. However, a reliable and routine feasible test to systematically assess dynamic insulin secretion is essential. More important, factors that influence therapeutic response, such as compliance and lifestyle, as well as pharmacokinetics and dosing, disease duration, age, gender, ethnicity, patients’ clinical characteristics, autonomic nervous system integrity and genotype characteristics also need to be considered. A few innovative perspectives have been debated, such as the recently discovered cardiovascular protective effects of the native GLP-1 peptide and its degradation product GLP-1 9-36, as well as the neuroprotection offered by GLP-1. Although still considered speculative, these perspectives remain hopeful and promising.

Clinical and subclinical autonomic dysfunction in chronic inflammatory demyelinating polyradiculoneuropathy

Autonomic neuropathy, although common in Guillain-Barré syndrome, is considered rare in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and has not been systematically investigated in that disorder. The present study was aimed at determining the prevalence of autonomic dysfunction and investigating the integrity of autonomic nervous system (ANS) reflexes in CIDP. We studied 17 patients with idiopathic CIDP and 20 healthy controls. Six quantitative autonomic function tests (AFTs) were used: Valsalva ratio, 30/15 ratio, and inspiration-expiration difference for parasympathetic function; and tilt test, handgrip test, and sympathetic skin response for sympathetic function. Eleven patients had symptoms of autonomic dysfunction. AFTs were abnormal in 13 patients. Parasympathetic and sympathetic systems were affected with equal frequency. The tilt test was abnormal most frequently, followed by the 30/15 ratio. Three patients developed postural hypotension with loss of consciousness during the tilt test. Abnormality of AFTs did not correlate with the presence of dysautonomic symptoms; duration, severity, and clinical course of the disease; or with age or gender of patients. Our study suggests a higher frequency of clinical and subclinical involvement of the ANS in CIDP than previously estimated. Dysautonomic symptoms are frequent but are mild. However, upon prolonged passive standing, autonomic failure can lead to loss of consciousness. The subclinical involvement of the ANS affects mainly the sympathetic vasomotor and parasympathetic cardiovascular fibers.

Splanchnic erythrocyte content decreases during hemodialysis: A new compensatory mechanism for hypovolemia

Splanchnic and splenic erythrocyte volumes decrease during postural changes and exercise to help maintain central blood volume and cardiac output. The contribution of this compensatory mechanism to hemodynamic stability during dialysis has not been studied, however. In 8 ESRD patients, age 51.0 +/- 4.5 years old, we measured changes in the splanchnic/splenic erythrocyte volume during dialysis by tagging the patients' erythrocytes with technetium and following abdominal radioactivity over time. Splanchnic radioactivity decreased to 90.2 +/- 3.8% (mean +/- SEM) of the baseline value after 2 hr of accelerated fluid removal (3.7 +/- 0.4 liters) during dialysis (DUF), while it remained relatively unchanged after two hours of dialysis without fluid removal (DD) [106.5 +/- 2.3%, P (DUF vs. DD) = 0.03]. Splenic radioactivity decreased to 89.2 +/- 5.0% of the initial value during DUF versus 103 +/- 3.8% during DD, but the decrease was noted only during the last 30 minutes of DUF and did not attain statistical significance. Autonomic nervous system integrity was measured by the spontaneous variation of the R-R interval during deep respiration (E/I ratio) and by the Valsalva ratio. The mean E/I and Valsalva ratios in the eight patients were 1.13 +/- 0.03 (+/-SEM) and 1.42 +/- 0.1 respectively, suggesting reasonably adequate autonomic nervous system functioning. The results suggest that contraction of the splanchnic, and possibly the splenic, vascular beds occurs during fluid removal associated with hemodialysis. The resultant addition of erythrocytes to the circulation may help maintain central blood volume and cardiac output.

Contribution of Vasopressin to Orthostatic Blood Pressure Maintenance in Essential Hypertension

Arginine vasopressin (AVP) has been found to participate in blood pressure maintenance especially when other pressor systems are endogenously or pharmacologically impaired. The purpose of this study was to assess the pressor contribution of AVP to orthostatic blood pressure maintenance in otherwise healthy patients with essential hypertension. Twenty-seven patients were grouped according to age (young n = 13, elderly n = 14) and race (white n = 13, black n = 14). Integrity of autonomic nervous system (ANS) was assessed by Valsalva's maneuver, cold pressor test and head-up tilt. AVP contribution to blood pressure was estimated by the fall in mean arterial pressure in response to IV injection of 0.5 mg of a V1 AVP inhibitor (AVPi). Elderly subjects were found to have a mild (subclinical) ANS impairment as indicated by absence of bradycardia in phase 4 of Valsalva's maneuver and hypotension without concurrent tachycardia during head up tilt. Depressor responses to AVPi while subjects were in the upright position, were greater in elderly and blacks (-15 +/- 11 mm Hg and -15 +/- 12 mm Hg, respectively, P < .05) than young and whites (-8 +/- 6 and -7 +/- 6 mm Hg, respectively, ns). The greater importance of the AVP component in the elderly may be at least partially explained by a mild ANS impairement, whereas hormonal characteristics of hypertension in blacks may explain greater AVPi induced fall in mean arterial pressure. Our data show that both age and race influence the response to AVPi.

Multiple peaks in human nerve action potentials: [formula omitted], E. Stålberg and F. Zarola (Dept. of Clin. Neurophysiology, University Hospital, Uppsala, Sweden)

Three clinical trials to evaluate the efficacy of the aldose reductase inhibitor sorbinil in improving or preventing diabetic neural function have either been completed or are currently in progress. In the first study from Seattle and Chicago, motor and sensory nerve conduction velocities (NCV) were evaluated in 39 insulin- and noninsulin-dependent, glycemic-stable diabetic patients in a randomized, double-blind, crossover trial. During the 9 weeks of treatment with 250 mg/d of sorbinil, there was a faster nerve conduction velocity of all 3 nerves tested when compared with the placebo period: peroneal motor NCV (+0.70 ± 0.24 m/s; x ± SEM; P < 0.008), median motor NCV (+0.66 ± 0.27 m/s; P < 0.005), and median sensory NCV (+1.16 ± 0.50 m/s; P < 0.035). Conduction velocity for all 3 nerves declined significantly within 3 weeks following cessation of the drug. These effects of sorbinil were unrelated to glycemic control, which was constant during the study. Although the effects of sorbinil in improving nerve conduction velocity were small, the findings suggest that the polyol-pathway activity contributes to slowed nerve conduction velocity in diabetics. The second study is a seven-center, double-blind, randomized, 12-month trial of 210 to 280 diabetic patients with clinical signs, symptoms, and objective measurements of neuropathy. The trial has a common-core protocol with end-point evaluations of scored neural signs, symptoms, and neural measurements. Two unique neural tests were designed and validated for use in this trial: thermal and tactile perception thresholds of the fingers and toes. Thresholds were determined using a two-alternative, forced-choice procedure on the Opticon Tactile Tester and Thermal Sensitivity Tester. Data analysis showed that there was no significant difference as a result of gender, dominant v nondominant side, age, digit temperature, room temperature, presence of heavy callouses, or technologists. In validation studies, diabetics without clinical evidence (history and examination) of diabetic neuropathy were not significantly different from normals, but diabetics with clinical evidence of diabetic neuropathy had elevated finger and toe thermal and tactile perception thresholds (all P < 0.001). There was no significant difference in the test results from normals from each of the seven centers. Thus, these tests were well suited for multicenter trials. Special protocols in each of the seven centers allowed for a broad spectrum of ancillary studies including the following: evaluation of autonomic nervous system integrity, white blood cell sorbitol and myo-inositol levels, impotence evaluation, single-fiber electromyography, sural nerve biopsy, and sensory evoked potentials. This trial is designed to address the question of whether sorbinil could improve diabetic neuropathy. Using the core protocol and the special studies for each center, a wide spectrum of neurologic end-points are evaluated in a bouble-blind fashion. The third protocol is a 12-center, double-blind, randomized, 212-year study of 600 to 720 diabetic patients with minimal or no diabetic complications. There is a common-core protocol with end-point measures of retinopathy, nephropathy, and neuropathy. This trial is unique in that (1) the placebo data adds valuable information into the natural history of diabetic complications, and (2) there is a unique collaborative arrangement between the national Institutes of Health and a pharmaceutical company, representing a first of its kind. This trial is designed to address the question of whether sorbinil could prevent diabetic complications (the primary end-point is retinopathy; the secondary end-points are nephropathy and neuropathy). In summary, these three trials are landmark trials representing advances in the basic pathophysiology of diabetic neuropathy, resulting in the development of new clinical tools and establishing a precedence for collaboration in important clinical trials.

Clinical trials of sorbinil on nerve function

Three clinical trials to evaluate the efficacy of the aldose reductase inhibitor sorbinil in improving or preventing diabetic neural function have either been completed or are currently in progress. In the first study from Seattle and Chicago, motor and sensory nerve conduction velocities (NCV) were evaluated in 39 insulin- and noninsulin-dependent, glycemic-stable diabetic patients in a randomized, double-blind, crossover trial. During the 9 weeks of treatment with 250 mg/d of sorbinil, there was a faster nerve conduction velocity of all 3 nerves tested when compared with the placebo period: peroneal motor NCV (+0.70 ± 0.24 m/s; x ± SEM; P < 0.008), median motor NCV (+0.66 ± 0.27 m/s; P < 0.005), and median sensory NCV (+1.16 ± 0.50 m/s; P < 0.035). Conduction velocity for all 3 nerves declined significantly within 3 weeks following cessation of the drug. These effects of sorbinil were unrelated to glycemic control, which was constant during the study. Although the effects of sorbinil in improving nerve conduction velocity were small, the findings suggest that the polyol-pathway activity contributes to slowed nerve conduction velocity in diabetics. The second study is a seven-center, double-blind, randomized, 12-month trial of 210 to 280 diabetic patients with clinical signs, symptoms, and objective measurements of neuropathy. The trial has a common-core protocol with end-point evaluations of scored neural signs, symptoms, and neural measurements. Two unique neural tests were designed and validated for use in this trial: thermal and tactile perception thresholds of the fingers and toes. Thresholds were determined using a two-alternative, forced-choice procedure on the Opticon Tactile Tester and Thermal Sensitivity Tester. Data analysis showed that there was no significant difference as a result of gender, dominant v nondominant side, age, digit temperature, room temperature, presence of heavy callouses, or technologists. In validation studies, diabetics without clinical evidence (history and examination) of diabetic neuropathy were not significantly different from normals, but diabetics with clinical evidence of diabetic neuropathy had elevated finger and toe thermal and tactile perception thresholds (all P < 0.001). There was no significant difference in the test results from normals from each of the seven centers. Thus, these tests were well suited for multicenter trials. Special protocols in each of the seven centers allowed for a broad spectrum of ancillary studies including the following: evaluation of autonomic nervous system integrity, white blood cell sorbitol and myo-inositol levels, impotence evaluation, single-fiber electromyography, sural nerve biopsy, and sensory evoked potentials. This trial is designed to address the question of whether sorbinil could improve diabetic neuropathy. Using the core protocol and the special studies for each center, a wide spectrum of neurologic end-points are evaluated in a bouble-blind fashion. The third protocol is a 12-center, double-blind, randomized, 2 1 2 - year study of 600 to 720 diabetic patients with minimal or no diabetic complications. There is a common-core protocol with end-point measures of retinopathy, nephropathy, and neuropathy. This trial is unique in that (1) the placebo data adds valuable information into the natural history of diabetic complications, and (2) there is a unique collaborative arrangement between the national Institutes of Health and a pharmaceutical company, representing a first of its kind. This trial is designed to address the question of whether sorbinil could prevent diabetic complications (the primary end-point is retinopathy; the secondary end-points are nephropathy and neuropathy). In summary, these three trials are landmark trials representing advances in the basic pathophysiology of diabetic neuropathy, resulting in the development of new clinical tools and establishing a precedence for collaboration in important clinical trials.