A 12-month randomized controlled study of the aldose reductase inhibitor ponalrestat in patients with chronic symptomatic diabetic neuropathy.

The effects of the aldose reductase inhibitor ponalrestat (600 mg day-1) on sensory, electrophysiological, and autonomic function were examined in 50 patients with chronic symptomatic, distal symmetrical diabetic neuropathy in a 52-week randomized, double-blind, parallel-group, placebo-controlled, single-centre study. In an endeavour to identify patients with a degree of neuropathy potentially amenable to pharmacological intervention, a minimum conduction velocity of 30 m s-1 was set for the peroneal motor nerve. At 52 weeks, no significant differences were observed between the ponalrestat and placebo groups in motor (ulnar, median, and peroneal) or sensory (ulnar and radial) nerve conduction velocities, vibration perception thresholds, adjectival symptom scores or tests of autonomic function (mean electrocardiographic R-R interval variability on deep breathing and orthostatic blood pressure response). Ponalrestat was clinically well tolerated and had no significant effect on glycaemic control. The lack of beneficial effects of ponalrestat may in part reflect the advanced stage of the neuropathic process in patients with established symptomatic disease, and the poor reproducibility of current neurophysiological techniques. Firmer knowledge of clinico-pathological correlates allied to improved non-invasive neurophysiological measurement techniques should facilitate the selection of patients for future therapeutic trials in diabetic neuropathy.

Selection of patients with symptomatic diabetic neuropathy for clinical trials.

Two hundred and fourteen patients with prima-facie evidence of symptomatic diabetic neuropathy were considered for inclusion in a clinical trial. Only 50 patients (24%) fulfilled all the clinical and electrophysiological criteria for entry. One hundred and nine patients (51%) were excluded on clinical grounds alone. Reasons for exclusion included the presence of alternative causes of neuropathy (15%), peripheral vascular disease (10%), proximal or asymmetrical neuropathies (11%), renal impairment (5%), nerve entrapment (4%), cerebrovascular disease (2%) and amputations (2%) with miscellaneous conditions accounting for the remaining 2%. Of the 105 patients who satisfied the clinical entry requirements another 55 patients (26%) were excluded by electrophysiological criteria. Peroneal motor nerve conduction velocity was unrecordable or unacceptably reduced (less than 30 m/s) in 42% of these patients, sensory nerve potentials were unrecordable in 8% and median nerve compression was evident in another 3%. The selection of cohorts for clinical trials in diabetic neuropathy involves careful consideration of clinical and electrophysiological features of the patients and exclusion of alternative causes of neuropathy.

Variability of three standard neurophysiological techniques in established symptomatic diabetic polyneuropathy.

The reproducibility of three standard neurophysiological techniques (motor and sensory nerve conduction velocities, vibration perception threshold and mean expiratory: inspiratory electrocardiographic R-R ratio) was determined from duplicate measurements approximately four weeks apart in 50 patients with chronic symptomatic diabetic polyneuropathy. There was no change in average glycaemic control (mean +/- SD) between the measurements (HbA1 10.7 +/- 2.0 vs. 10.4 +/- 2.1% at zero and four weeks respectively). While there were no significant differences in the mean values at zero and four weeks for any technique considerable intra-individual variability was observed in several measurements. Mean coefficients of variation (CV) for motor nerve conduction velocity ranged from 9.8% (ulnar nerve) to 10.7% (median) to 12.2% (peroneal nerve). Variability in sensory nerve conduction velocities (CVs 8.6, 8.7 and 14.7% for radial, ulnar and sural nerves respectively) was complicated by a high proportion of unrecordable action potentials. Duplicate action potentials were recordable from the sural nerve in only 15 (30%) patients. The highest intra-individual variability was observed in measurements of vibration perception threshold with CVs of 21.0% (thumb) and 18.0% (hallux). The apparently satisfactory CV of 3.6% for the cardiac E:I ratio test may represent an artefactually low degree of variability. Neurophysiological techniques in current use are characterized by technical limitations and intra-individual variability in patients with established diabetic neuropathy.

Neurological complications following liver transplantation.

17 (33%) of 52 patients who underwent 56 consecutive orthotopic liver transplants had serious neurological complications postoperatively. The commonest complication was fits, which occurred in 13 (25%) patients. 50% of patients had their onset of fits within the first week. In 3 patients the fits were associated with postoperative metabolic encephalopathy and fatal progressive neurological deterioration. In some patients the evidence implicating cyclosporin in the development of fits is strong. In others factors such as electrolyte disturbances, steroid treatment for graft rejection, and cerebral infarction may have contributed to the development of the fits. Phenytoin controlled the fits in 10 out of 13 patients. Other neurological complications included 1 case of central pontine myelinolysis, 1 of cerebral abscess, and 4 of non-encephalopathic psychosis.

Prediction of ifosfamide/mesna associated encephalopathy.

Ifosfamide and mesna were administered to 77 patients with advanced malignancies. Seven (9%) experienced a severe but reversible encephalopathy. In 56% of patients in whom EEG data was available, characteristic changes were seen with or without mild clinical toxicity. Discriminant analysis identified low serum albumin concentration, high serum creatinine concentration and the presence of pelvic disease as variables which predispose patients to the development of severe encephalopathy. A nomogram has been constructed which can be used to determine the probability that an individual patient may be given ifosfamide and mesna safely. This has important implications for the clinical use of a highly active chemotherapy regimen.

Isoflurane: effect on the encephalogram during carotid endarterectomy.

The effect of isoflurane on the electroencephalogram was studied in patients monitored during carotid endarterectomy. Increasing concentrations of this agent cause changes, but did not affect the ability to detect the onset of cerebral ischaemia consequent upon temporary occlusion of the internal carotid artery. At 1.0% and 1.5% concentration isoflurane caused significant decreases in mean arterial pressure which is undesirable in patients undergoing vascular surgery.

E.E.G. and personality factors in baby batterers.

Out of 35 parents who battered their children eight had an abnormal E.E.G. All of these were found to be psychopathic, of low intelligence, and to be persistent batterers. The presence of an abnormal E.E.G. strongly suggests that some baby batterers are more closely related to those who commit acts of violence and that taken as a whole they are not a homogenous group about whom it is safe to generalize. The possibility of a separate subgroup among baby batterers, therefore, needs close attention.