To evaluate the effects of the aldose reductase inhibitor Ponalrestat (Statil) on diabetic autonomic neuropathy, a double-blind placebo controlled trial was carried out on a group of 34 diabetic patients with documented cardiac autonomic neuropathy. After a 4-week, placebo run-in period, patients were randomised for treatment with 600 mg Statil or placebo for another 24 weeks. Moreover, the reliability of the autonomic nerve function tests was investigated by comparing the results at onset and at week 4. Fifteen patients treated with Statil and 12 with placebo completed the study. Neither symptom scores nor cardiovascular reflexes, pupil reflexes and skin vasomotor reflexes improved after Statil therapy, which led us to conclude that Statil is not effective in the treatment of diabetic autonomic neuropathy. Reliability coefficients for cardiovascular reflexes and pupil reflex showed high values, ranging from 60% to 80%. Therefore these methods are recommended in future therapy trials.

In 22 patients with clinically definite multiple sclerosis (MS) who were without visual symptoms and had a visual acuity of at least 1.0 in both eyes at the time of measurement, the following tests were performed to detect subclinical lesions in the visual system: visual evoked potential (VEP), contrast sensitivity test (CS), flight of colours test (FOC), colour vision test (Ishihara plates) (CV) and the pupillary light reflex (PLR). VEP was abnormal in 81.8%, CS in 72.7%, FOC in 36.4%, CV in 31.8%, and PLR in 52.3% of the patients. VEP and CS together were most sensitive: combining these techniques subclinical lesions of the visual system were detected in 90.9% (20/22) of these asymptomatic patients.

In 46 patients with definite multiple sclerosis (MS) the direct and indirect pupillary light reflex latency (PLRL) and visual evoked potential (VEP) latency of the P100 were measured for each eye separately. The PLRL was measured at both photopic and scotopic illuminance level, using an infrared light reflection technique (IRIS). On average the PLRL increased at the scotopic illuminance level as compared with the photopic (P < 0.0001). An abnormal VEP was found in 80.4% of the patients, while 26.1% and 29.7% had an abnormal direct PLRL at photopic and scotopic illuminance level respectively.No correlations were found between PLRL and VEP or visual acuity.In MS patients with unilateral optic signs (optic neuritis or slowly progressive visual failure) a relative prolonged PLRL could be demonstrated in the symptomatic eye as compared to the asymptomatic eye.Based on formulae to quantitate relative afferent and efferent impairments of the pupillary pathway, it is demonstrated that prolonged PLRL measurements mainly reflect the nerve conduction in the efferent pupillary pathway.

In 42 diabetic patients the relationship between the latency of the pupillary light reflex and the pattern reversal visual evoked potential (P100) was examined. Fifty-five percent of diabetic patients had pupillary light reflex latencies above the normal range. In 19% the visual evoked potentials were prolonged when compared to the normal range. Latencies of pupillary light reflexes and VEPs showed no correlation. There was a minimal correlation between the presence of retinopathy and prolongation of both the pupillary light reflex and the visual evoked response latency (kappa coefficients respectively: 0.31, P less than 0.01 and 0.36, P less than 0.02). The presence of an increased pupillary light reflex latency was positively correlated with a reduced respiratory sinus arrhythmia (kappa coefficient: 0.58, P less than 0.0001). Increased VEP latencies showed no correlation with signs of cardiovascular autonomic neuropathy. We conclude that the afferent optic pathway can be affected in diabetic patients. However, prolongation of pupillary light reflex latency in diabetic patients is primarily due to an efferent pupillary defect and represents parasympathetic dysfunction.

In this study blood pressure (BP) and heart rate (HR) responses to standing and HR responses to deep breathing were assessed in 34 patients with clinically definite multiple sclerosis (MS) and 63 healthy subjects. Normal ranges, which were clearly age related for both HR responses, were obtained. The BP response to standing was abnormal in 13% of the MS patients, these patients demonstrating significant postural hypotension. The HR response to standing was abnormal in 28% of the MS patients, with a normal initial increase in heart rate and a significantly reduced reflex bradycardia. On deep breathing 36% of MS patients showed abnormal HR changes. The resting HR did not differ between both groups. Abnormalities of one or more tests were found in 53% of the MS patients. No relationship was found between abnormal cardiovascular autonomic responses and the symptoms, duration, severity and progression of the disease. Based on clinical and magnetic resonance imaging findings no indications were found for localisation of the autonomic disturbances in the brainstem. It is suggested that at least a part of the cardiovascular autonomic lesions in MS is located outside the brainstem, i.e. in supramedullary reflex pathways or in the spinal cord.

We have investigated the relations between respiration (RA), respiratory sinus arrhythmia (RSA) and respiratory related waves in arterial blood pressure (RBPV) during forced breathing. We used simple harmonic stimulus response techniques to estimate the gain factors and phases between RA, RSA and RBPV at one distinct frequency (0.1 Hz) in healthy subjects and in patients with manifest symptoms of diabetic neuropathy. Results in the diabetic subjects were used to dissect the direct mechanical links between RA and RBPV from the effects of RSA on RBPV. Our results show that in diabetic neuropathy RSA diminishes, whereas RBPV remains unchanged. We concluded that RSA, during deep breathing, originates from RBPV.

Increased pupillary light reflex latencies were found more often than a reduced darkness pupil size in diabetic patients with and without abnormal cardiovascular reflexes. This finding suggests that parasympathetic pupillary dysfunction precedes sympathetic pupillary denervation in diabetic autonomic neuropathy.

In 28 diabetic patients and 62 control subjects spectral analysis of spontaneous beat‐to‐beat RR interval variations was performed. The spectral analysis focused on the dominant frequency of the mid‐frequency band (0.04–0.12 Hz) or baro‐oscillatory phenomenon (BOP). Compared with control subjects the dominant frequency of the BOP (BOP frequency) in the diabetic patients was lower (p < 0.001), and the difference increased with age. The shift of the BOP frequency was positively correlated with the reduced variation in heart rate during deep breathing (r = 0.80, p < 0.001) in the diabetic patients. These findings indicate that determination of the BOP frequency is a useful method for assessing cardiovascular autonomic function, supplementary to the known cardiovascular reflex tests. Measurement of the BOP frequency has the advantage that no active patient co‐operation is required.

The efficacy and acceptability of multiple daily insulin injections (three preprandial injections of short‐acting insulin (NovoPen) plus once daily extended‐acting insulin) were compared with those of twice daily injections of short‐ and intermediate‐acting insulin. Sixteen Type 1 diabetic patients participated in a cross‐over study (6‐month treatment periods). Total areas under 24‐h plasma free insulin curves, assessed at the end of each study period, were not significantly different, but a greater area under this curve was found for the pen‐injector regimen from 1200 to 1600 h (150 ± 15 (SE) vs 106 ± 7 mU l−1 h, p < 0.01). Home blood glucose profiles showed significantly lower values with pen‐injector therapy after lunch (7.1 ± 0.6 vs 8.4 ± 0.4 mmol l−1, p = 0.05) and before and after dinner (6.4 ± 0.6 vs 8.8 ± 0.5 mmol l−1, p < 0.005, and 7.5 ± 0.7 vs 9.4 ± 1.1 mmol l−1, p < 0.05). Mean daily blood glucose concentration was also lower (7.1 ± 0.4 vs 8.2 ± 0.5 mmol l−1, p < 0.05). HbA1, fructosamine, hypoglycaemic reactions, and body weight were not significantly different. Thirteen patients decided to continue with pen‐injector therapy at the end of the study.

Debate about the lesion site in the Miller Fisher syndrome is still going on. We studied a patient with features of the Miller Fisher syndrome in whom arguments for both central and peripheral nervous system dysfunction were found.

Pupillary and cardiovascular autonomic functions were examined in 25 diabetic patients with and 25 diabetic patients without painful neuropathy. There were no significant differences between the groups with regard to age, duration of diabetes or glycaemic control. Vibratory perception, reflecting peripheral large fibre function, was more severely disturbed in the symptomatic group (P = 0.003). Thermal discrimination thresholds (TDTs), reflecting somatic small fibre function, were abnormal in all symptomatic patients and the difference between patients with and without symptoms was more pronounced (P less than 0.0001), than for large fibre function. The latency of the constriction reaction of the pupil (parasympathetic function) was prolonged in 17 symptomatic patients and in 6 patients without pain; it proved to be significantly more prolonged in the group with painful neuropathy (P = 0.001). Cardiovascular autonomic neuropathy was present in 29 patients, especially in patients with painful neuropathy (22 in the group with painful neuropathy, 7 in the group without pain). There was a significant correlation between results of TDT and respectively pupillary and cardiovascular autonomic function tests (kappa coeëfficient: 0.63 and 0.56, respectively, P less than 0.0001). We conclude that autonomic dysfunction is often present in patients with painful neuropathy. However, thermal sensory dysfunction is better correlated with the presence of symptoms than cardiovascular and pupillary autonomic dysfunction.

In 29 diabetic subjects with or without symptoms of diabetic peripheral and autonomic neuropathy, the association between the pupillary light reflex (the latency of the constriction of the pupil) and various sensory and motor neural measurements, duration of diabetes and quality of glycaemic control was evaluated. Compared with normal subjects the latency of the constriction reaction of the pupil was significantly prolonged in the group of diabetics (mean±SEM: 236.3±5.8 ms versus 210.5±3.7; P<0.001). Thermal discrimination thresholds were positively correlated with the latency of the constriction reaction of the pupil (r=0.43, P<0.025). Vibratory perception threshold, motor nerve conduction velocity of the peroneal nerve, H-M interval of the Hoffmann reflex and duration of diabetes were not correlated with the constriction latency, whereas glycaemic control showed a weak correlation. It is concluded that there may be a relationship between autonomic (parasympathetic) pupillary dysfunction and peripheral small nerve fibre dysfunction.