Peroneal Motor Nerve Conduction Velocity Research Articles

Serum lipoprotein (a) in type 1 diabetic children and adolescents: relationships with HbA1c and subclinical complications.

In a population of 106 young type I diabetic patients, we evaluated whether a relationship exists between lipoprotein (Lp)(a) or apolipoproteins and the degree of metabolic control (HbA1c, fructosamine) or the subclinical complications. The patients were subdivided according to puberty and to the presence or not of subclinical complications (no complications [n = 32]; retinopathy at fluorescein angiography [n = 28]; neuropathy diagnosed by reduced peroneal motor nerve conduction velocity [n = 30]; nephropathy determined by presence of micro-albuminuria [n = 15]. Lp(a) concentrations were not significantly increased in the whole group of diabetic patients. There was no difference between girls and boys, nor between the prepubertal children and the others. There were no significant correlations between the markers of metabolic control and Lp(a). Nevertheless, if the diabetic patients were divided into two groups according to the levels of HbA1c (<7.6 or > or = 6% Hb), Lp(a) tends to be higher in the poorly controlled, but not to any significant degree. On the other hand, significant increases of total cholesterol, triglycerides, low density lipoprotein cholesterol and apolipoprotein B levels were observed in poorly controlled patients. Lp(a) concentrations were significantly lower in patients with subclinical neuropathy or nephropathy than in patients without these complications, but not in patients with retinopathy versus no retinopathy. These results are confirmed by categorical analysis (i.e. Lp(a) < or = 30 vs > 30 mg/dl). Lp(a) levels are not significantly increased in poorly controlled insulin-dependent diabetes mellitus patients. High controlled insulin-dependent diabetes mellitus patients. High levels of Lp(a), in young diabetic patients, are not markers for subclinical complications (retinopathy, neuropathy and nephropathy). On the contrary, low Lp(a) levels were found in subjects with subclinical neuropathy or nephropathy.

Longitudinal studies of the duplication form of Charcot-Marie-Tooth polyneuropathy.

This study presents a longitudinal comparison of motor nerve conduction velocities (MCVs) in patients with Charcot-Marie-Tooth type 1A with proven duplication of a segment of chromosome 17p11.2p12. Results were compared for 8 CMT1A duplication patients from one family whose MCV measurements were taken 22 years apart (1967 and 1989). Measurements from a total of seven median motor and five peroneal motor MCVs were compared. Median MCVs showed a slight reduction that averaged 2.2 m/s, and peroneal MCVs showed an average decrease of 3.0 m/s. In addition, mild objective increase in limb weakness was seen in only 1 of 8 patients and subjective symptoms of gradual worsening of leg strength were noted in half the patients over the same period. In this study of a small group of CMT1A patients with proven segmental duplication of chromosome 17p11.2p12, the motor conduction velocities and clinical motor exam did not change significantly over 22 years.

Longitudinal studies of the duplication form of Charcot‐Marie‐Tooth polyneuropathy

This study presents a longitudinal comparison of motor nerve conduction velocities (MCVs) in patients with Charcot-Marie-Tooth type 1A with proven duplication of a segment of chromosome 17p11.2p12. Results were compared for 8 CMT1A duplication patients from one family whose MCV measurements were taken 22 years apart (1967 and 1989). Measurements from a total of seven median motor and five peroneal motor MCVs were compared. Median MCVs showed a slight reduction that averaged 2.2 m/s, and peroneal MCVs showed an average decrease of 3.0 m/s. In addition, mild objective increase in limb weakness was seen in only 1 of 8 patients and subjective symptoms of gradual worsening of leg strength were noted in half the patients over the same period. In this study of a small group of CMT1A patients with proven segmental duplication of chromosome 17p11.2p12, the motor conduction velocities and clinical motor exam did not change significantly over 22 years. © 1996 John Wiley & Sons, Inc.

970 An evaluation of the neurotoxicity of a phase I dose finding study of docetaxel (D) in combination with vinorelbin (V)

D, belonging to the taxoid class of anticancer agents, enhances microtubule assembly and inhibits the depolymerization of tubulin. The cytotoxic activity of V is through inhibition of the microtubule assembly. D and V have both shown clinical activity in advanced breast cancer as single agent. Additionally, therapeutic synergism has been observed in preclinical studies when the two drugs are combined simultaneously. Thus, a phase I study of a combination of these 2 drugs commenced in patients with metastatic breast cancer. However, as D. and V. induce mild neurotoxicity, neurological effects of this combination were evaluated. Neurological function at baseline, during (every 2 cycles and at the end of the study), and following treatment, in 13 metastatic breast cancer patients treated with docetaxel (60–85 mg/m2) and vinorelbine (20–22.5 mg/m2—D1–D5), none of them treated with vinca-alcaloids and/or CDDP, were prospectively evaluated. Deep tendon reflexes decrease was the most frequent abnormal finding, which occurred in 10 patients (77%). Mild, temporary and reversible grade 1 asymptomatic paresthesia were seen in 4 patients (31%). Pin sensibility, vibration sensation and muscular strength were always normal. Median and peroneal motor nerve conduction velocities, as well as median sensitive nerve conduction velocity, remained in the normal ranges. Peripheral neurotoxicity induced by the docetaxel-vinorelbine combination therapy appears to be mild (grade 1 according to NCI toxicity criteria).

Restoring lower limb blood flow improves conduction velocity in diabetic patients

Human diabetic peripheral neuropathy is believed to have, at least in part, a microvascular basis. This study was designed to examine the effects of restoration of arterial blood supply on peripheral nerve function in six non-insulin-dependent diabetic patients with peripheral occlusive vascular disease. In the revascularised legs, transcutaneous oxygen increased from a median 37.5 (28.5-45.7 interquartile range) mmHg to 55.5 (53.5-62.5) mmHg, p = 0.036, mean increase 20.2 (14.8-25.6, 95% confidence intervals(CI) mmHg. This was accompanied by a significant improvement in peroneal motor nerve conduction velocity from 31.7 (26.5-36.3) m/s to 33.5 (32.9-39.4) m/s, p = 0.04, mean increase 4.7 (1.7-7.7, 95% CI) m/s. There was no significant change in transcutaneous oxygen or peroneal nerve motor conduction velocity in the contralateral control limbs. This improvement in conduction velocity with improved tissue oxygenation suggests that studies of agents which might indirectly bring about improvements in microvascular blood flow should be urgently considered.

Thermal threshold determination in alcoholic polyneuropathy: an improvement of diagnosis

Reports on the incidence of alcoholic polyneuropathies are variable depending on diagnostic tools. In this study, 50 chronic alcoholics with positive MALT (Munich Alcoholism Test) and greater than seven years history of excessive alcohol abuse were examined neurologically. Tibial and peroneal motor and sural nerve conduction velocities (NCV) were studied. Warm and cold perception was evaluated in the area behind the internal malleolus using a Somedic-Thermotest. Thresholds were determined by the method of limits. The effect of a slow, medium and fast temperature change rate on thermal perception was tested. Thirty-eight patients (76%) showed signs of neuropathy. Thermal perception was more often abnormal (62%) than NCV (42%) and clinical examination (56%). A medium temperature change rate of 2.0-2.5 degrees C/s was the most sensitive index of small fiber neuropathy. Thermal threshold measurement proved to be a reliable, sensitive and easy to perform method that should become standard in the examination of polyneuropathies.

Central motor conduction time in children and adolescents with insulin-dependent diabetes mellitus (IDDM)

Measurement of central motor conduction time (CMCT) after percutaneous magnetic stimulation of the brain is an electrophysiological method that may discover subclinical impairment of central nervous system (CNS). In order to detect an impairment of CNS, we measured CMCT right (R) and left (L) after percutaneous stimulation of the brain in 34 patients affected by insulin-dependent diabetes mellitus (IDDM) (16 males and 18 females), aged 16.4 ± 4.1 years (7.3–23.2 years), with duration of disease 7.6 ± 4.9 years ( 7 12–16 years), and HbA 1c annual mean 7.41 ± 1.1% (n.v. 5.14 ± 0.84%). Twenty-three sex- and age-matched healthy subjects served as controls. In our IDDM patients we observed a delay of CMCT R ( P < 0.0005) and L ( P < 0.0005) as compared to controls. No correlation was found between CMCT (R and L) and chronologic age, duration of disease, peroneal motor nerve conduction velocity. No association was observed between CMCT (R and L) and HLA antigens. On the basis of IDDM duration, patients were divided into 2 groups (G): G I (9 pts) with IDDM < 2 years and G II (25 pts) with IDDM > 5 years, 12 of them with precocious signs of one or more microangiopathic complications. No difference in CMCT (R and L) was observed between the 2 groups and between G I and controls; G II patients had a longer delay of CMCT R ( P < 0.0001) and L ( P < 0.0001) than controls. In G II patients, a positive correlation between CMCT R and HbA 1c of the 5 years before the test ( P < 0.025) was also observed. In the 12 of G II patients with precocious retinopathy and/or nephropathy, a positive correlation was found between CMCT R and HbA 1c levels over the 5 years ( P = 0.005) before the test. Our results show a delay in CMCT, related with the degree of metabolic control in patients with longstanding IDDM and/or microangiopathic complications.

Differences in peripheral and autonomic nerve function measurements in painful and painless neuropathy. A clinical study.

To examine the differences in peripheral and autonomic nerve function measurements between diabetic patients without neuropathy (group 1, n = 38, mean age 50.9, range 29-71 years), with painless neuropathy (group 2, n = 32, mean age 49.2, range 30-71 years), and with painful neuropathy (group 3, n = 52, mean age 51.5, range 28-73 years). The evaluation of neuropathy was based on clinical symptoms, signs, and quantitative sensory testing, including current perception threshold (CPT) with a neurometer and electrophysiology. The Neuropathy Symptom Score and the Neuropathy Disability Score were higher in patients with painful neuropathy compared with patients with painless neuropathy (6.8 +/- 2.7 vs. 0.5 +/- 0.8 [mean +/- SD], P < 0.0001, and 12.5 +/- 6.2 vs. 8.6 +/- 6.8, P < 0.01, respectively). In contrast, no differences were found in the quantitative sensory testing, including CPT measurements, the electrophysiological measurements, and the autonomic nerve system function tests in the two groups. Significant differences were found in all the above measurements when groups 2 and 3 were compared with diabetic patients without neuropathy (group 1). When all diabetic patients were considered as one group, significant correlations were found between CPT and the other peripheral nerve function assessments. In particular, peroneal nerve motor conduction velocity correlated with CPT at 2 kHz (r = -0.48, P < 0.001) and vibration perception threshold (r = -0.50, P < 0.001). We conclude that no difference could be found in the function of small and large nerve fibers between painful and painless diabetic neuropathy using conventional tests currently used. The CPT evaluation failed to quantify painful symptoms, but it compared favorably with other quantitative sensory tests in quantifying peripheral neuropathy.

A Study of Peripheral Diabetic Neuropathy. The Application of Age‐Related Reference Values

The standardization of methodology and the provision of age-related reference values have been addressed for the design of and interpretation of data from a multicentre neuropathy trial. Age-related reference values were generated from 120 healthy volunteers. Vibration perception thresholds (VPT) deteriorated significantly with age (p less than 0.001). Patients were selected on the basis of age-related abnormal VPT and peroneal motor nerve conduction velocity. They were assessed at the beginning and end of a placebo run-in period (baseline data). The coefficients of variation (CV%) for VPT at the medial malleolus (16.81 per cent, n = 316) and great toe (19.23 per cent, n = 313) were lower compared to results in healthy volunteers (29.7 per cent and 20.8 per cent, respectively, n = 49). The CV% for expiratory:inspiratory (E:I) ratio (4.82 per cent, n = 215), Valsalva manoeuvre (10.84 per cent, n = 249) and 30:15 ratio (7.73 per cent, n = 292) from patients corresponded to those recorded in volunteers (7.6 per cent, n = 45 11.0 per cent, n = 49 9.5 per cent, n = 48, respectively). Most patient values for VPT at the great toe fell beyond the 95 centile line for volunteers. E:I ratio for volunteers showed a more variable relationship with age, although patient values appeared to be located below the 5 centile line for volunteer data.

Neurophysiological study of the effect of combined kidney and pancreas transplantation on diabetic neuropathy: a 2-year follow-up evaluation

Previous study have reported a significant improvement of peripheral neuropathy following combined pancreas and kidney transplantation attributed to improvement of blood glucose control by some authors and to elimination of uraemia by others. To asses the specific role of uraemia and hyperglycaemia in neuropathy, 16 diabetic uraemic patients with combined pancreas and kidney transplantation were compared to 9 diabetic patients with a renal graft only. Neurophysiological studies of peripheral neuropathy included ulnar and deep peroneal nerve motor conduction velocity, median and sural nerve sensory conduction velocity were performed at baseline and 1 and 2 years after transplantation. One year after transplantation mean nerve conduction velocity significantly improved in both groups. However, changes were statistically significant in the kidney-pancreas group only. At the 2 year follow-up nerve conduction velocity had increased further in the pancreas-kidney group only. These data suggest that improvement of nerve conduction velocity following pancreas and kidney transplantation is predominantly due to the long-term euglycaemic state.

A multicentre trial of the aldose-reductase inhibitor, tolrestat, in patients with symptomatic diabetic neuropathy

The effects of the aldose-reductase inhibitor, tolrestat, on chronic symptomatic diabetic sensorimotor neuropathy were studied during a placebo-controlled, randomised, 52-week multicentre trial. Of the four tolrestat doses investigated, only the highest dose group, 200 mg once daily, showed subjective and objective benefit over baseline and placebo, and further analyses are confined to this group (n = 112) and placebo (n = 107). Painful and paraesthetic symptoms were analysed separately: improvement in paraesthetic symptoms were seen at one year (p = 0.04), though painful symptoms improved on both placebo and active therapies. Significant improvement in both tibial and peroneal motor nerve conduction velocities were seen at 52 weeks. Tolrestat 200 mg once daily was significantly better than placebo in producing concordant improvements in both motor nerve conduction velocities and paraesthetic symptom scores at 24 weeks (p = 0.01), 42 weeks (p = 0.01) and 52 weeks (p = 0.02). Long-term benefit [concordant improvement at 24 weeks maintained until 52 weeks] was seen in 28% of treated patients compared to 5% on placebo (p = 0.001). It is concluded that some sustained improvement in symptomatic diabetic neuropathy may be obtained following aldose-reductase inhibition with tolrestat 200 mg once daily.

The Effect of γ‐Linolenic Acid on Human Diabetic Peripheral Neuropathy: A Double‐blind Placebo‐controlled Trial

Twenty-two patients with distal diabetic polyneuropathy confirmed both clinically and by objective nerve function studies, completed a double-blind, placebo-controlled study to assess the effect of dietary supplementation with gamma-linolenic acid on their neuropathy. Patients received either 360 mg gamma-linolenic acid (12 patients) or indistinguishable placebo capsules (10 patients) for 6 months. All patients were assessed at the beginning and end of the study period by neuropathy symptom and sign scoring, motor and sensory nerve conduction studies, and thermal threshold measurements. When compared with the placebo group, patients on gamma-linolenic acid showed statistically significant improvement in neuropathy symptom scores (p less than 0.001), median nerve motor conduction velocity (p less than 0.01) and compound muscle action potential amplitude (p less than 0.01), peroneal nerve motor conduction velocity (p less than 0.05) and compound muscle action potential amplitude (p less than 0.05), median (p less than 0.01) and sural (p less than 0.001) sensory nerve action potential amplitude and ankle heat threshold (p less than 0.001) and cold threshold (p less than 0.01) values. gamma-Linolenic acid therapy might have a useful role in the prevention and treatment of distal diabetic polyneuropathy.

X-LINKED DOMINANT HEREDITARY MOTOR AND SENSORY NEUROPATHY

Modern techniques have defined the hereditary motor and sensory neuropathies (HMSN) as a genetically heterogeneous group of disorders. This includes a rare variant with X-linked dominant inheritance. We have traced this disorder through 6 generations of a large Canadian kindred; neurological and electrophysiological examinations were performed in 57 family members and nerve biopsies were studied in 2 affected males, early and late in the disease; 42/83 family members were affected. No male-to-male transmission was encountered in 19 sons of affected fathers, whereas all their daughters expressed the disease. Linkage was shown to the DNA loci DXYS1 Z max = 2.87 at theta max = 0.06 and to PGK1 Z max = 1.51 at theta max = 0 (Beckett et al., 1986). The typical clinical features are onset in early childhood, pes cavus, atrophy and weakness of peroneal muscles and intrinsic hand muscles, and sensory abnormalities. Males were severely affected, whereas females had mild or subclinical disease. Electrophysiological observations indicated a substantial loss of distal motor and sensory nerve fibres. Evoked compound muscle action potentials in extensor digitorum brevis were absent or severely reduced in 42% of cases and the peroneal motor nerve conduction velocity was mildly reduced to a mean 36.5 +/- 7.4 m.s-1. Sural sensory nerve action potentials were absent or severely reduced in 75% of those affected. Nerve biopsies showed loss of myelinated and unmyelinated nerve fibres, regenerative sprouting and secondary demyelination. The findings indicate that this distinct variant of HMSN is the result of primary axonal degeneration.

Abnormal Foot Pressures Alone May not Cause Ulceration

Both rheumatoid arthritis and diabetes have been associated with the development of abnormally high pressures under the feet, and ulceration has been considered to be a problem in both conditions. In order to examine further the relationship between high foot pressure, neurological abnormalities, and ulceration, we have studied two groups of patients: (a) 38 diabetic patients and (b) 37 patients with rheumatoid arthritis who had similar clinical abnormalities of the feet. Thirty-two percent of diabetic patients had a history of plantar ulceration compared with none of the rheumatoid group (p less than 0.01). However, the diabetic group had considerably more severe neuropathy (peroneal nerve motor conduction velocity 35.4 +/- 4.8 m s-1 vs 44.4 +/- 5.2 m s-1 (mean +/- SD), p less than 0.001; vibration perception threshold 33.5 +/- 13.4 vs 16.9 +/- 10.9, p less than 0.001), with a similar frequency of elevated plantar pressures (51% vs 61%, NS). These data emphasize the importance of the loss of sensory awareness in the pathogenesis of diabetic foot ulceration, and suggest that high pressure alone is not a direct cause of ulceration.

The effect of ulinastatin on reduced nerve conduction velocity and blood pressure.

Application of a pneumatic tourniquet in orthopedic surgery is sometimes followed by hypotension and paralysis. Seventy-five patients scheduled for knee joint surgery were examined to evaluate the effects of ulinastatin on changes in blood pressure, venous pH and motor nerve conduction by pneumatic tourniquet application above the knee joint. In fifty-five of the patients, the femoral vein of the operating side was cannulated with a catheter to obtain venous blood samples before and after tourniquet application. 300,000 Unit of ulinastatin (UST) was administered intravenously before inflation of the tourniquet in 10 patients. In the other sixteen patients, the motor nerve conduction velocity (MNCV) of the peroneal nerve was measured before inflation and after release of the tourniquet. In the UST-free group, the reduced blood pressure and pH persisted for more than 15 min, while in the UST-treated group, the reduced blood pressure returned to the normal leven in 15 min. In the control group, femoral venous P(O)(2) continued to increase after 10 min, but that in the UST-treated group returned to the normal range. Tourniquet application significantly reduced peroneal MNCV. Pre-and post-treatment with UST significantly lessened the reduction of MNCV induced by the tourniquet. It is concluded that UST may have protective and therapeutic effects on ischemic nerve injury, induced by the application of a turniquet.

The Effect of Metoclopramide Treatment on Diabetic Cystoparesis

To the Editor. —Metoclopramide hydrochloride is now commonly used to treat diabetic gastroparesis.1,2However, the effect of metoclopramide therapy on another important complication, diabetic cystoparesis,3has not been established. We recently observed, serendipitously, the effect on asymptomatic diabetic cystoparesis of metoclopramide given for the treatment of symptomatic diabetic gastroparesis. Report of a Case. —A 62-year-old man with nonketotic diabetes who has required insulin injections since 1968 had peripheral neuropathy with a peroneal motor nerve conduction velocity of 35.1 m/s (normal, ≥42 m/s). He had gastrointestinal tract symptoms of nausea and postprandial fullness. An upper gastrointestinal tract series showed marked gastric retention of barium that was indicative of gastroparesis. He had been impotent for ten years and had a history of nocturia but denied having current urinary symptoms. A residual urine volume determined by a standard radionuclide technique revealed 1019 mL of residual urine in the bladder. He was

Peripheral nerve function in relation to quality of metabolic control in diabetes.

It has been proposed that increased polyol pathway activity resulting from hyperglycaemia induces neuropathy in diabetic patients. Recently, it has been demonstrated that erythrocyte sorbitol content is a reflection of polyol pathway activity in nerve. In the present study the relationship of erythrocyte sorbitol and glycosylated haemoglobin (HbA1) levels to peripheral nerve functions were investigated in 62 diabetic patients. Peroneal and median motor nerve conduction velocities, H-M intervals of the Hoffmann reflex, thermal discrimination thresholds and vibratory perception thresholds, either singly or in combination, were not significantly correlated with erythrocyte sorbitol or HbA1 levels. These findings show that a single measurement of erythrocyte sorbitol or HbA1 content cannot predict impairment of nerve function in diabetic subjects.

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.

Increased nerve conduction in diabetics after a year of improved glucoregulation

We studied median, ulnar and peroneal motor nerve conduction velocity (NCV) and median sensory action potential (SAP) latency and amplitude in 18 insulin-dependent diabetic patients who were begun on a continuous subcutaneous insulin infusion (CSII) program. With institution of this therapy, significant decreases in mean blood glucose and glycosylated hemoglobin occurred. After 12 months of CSII treatment, median, peroneal, and ulnar motor NCVs all increased significantly. The average NCV increase was 2.5 m/s. Median SAP amplitude and latency did not significantly change. In a second group of 12 diabetic patients with the same mean age and comparable initial NCV and SAP measures, no significant changes in motor NCVs or SAPs occurred after 12 months of conventional insulin treatment. These results indicated the need for further long-term studies of the role of strict glucose control in the prevention of diabetic neuropathy.

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.