Four patients are described who developed sensorimotor neuropathy while being treated with simvastatin and had complete or partial resolution of clinical abnormalities after withdrawal of treatment. In one case onset was within days of commencing treatment, but in two cases symptoms did not develop for two years. The electrophysiological and pathological features of the neuropathy were those of axonal degeneration. Clinical evidence of proximal and distal weakness and muscle fasciculations and persistent abnormalities of sensory conduction after recovery suggest the possibility of toxic damage to anterior horn cells and dorsal root ganglia. Thirty eight other cases with symptoms suggestive of peripheral neuropathy have been reported to the Australian Adverse Drug Reactions Advisory Committee, 22 of whom recovered after cessation of treatment; in five cases there was recurrence after re-exposure to the drug. Simvastatin should be considered among the causes of peripheral neuropathy, and the drug should be withdrawn if patients receiving it develop muscle weakness or sensory disturbances. (7 Neurol Neurosurg Psychiatry 1995;58:625-628)

Steiness (1959) observed that diabetic subjects whose lower limbs were rendered ischaemic with a pneumatic cuff around the thigh were able to perceive a vibratory stimulus applied to the toes for longer periods than non-diabetics. In some diabetic subjects the threshold remained almost unchanged during a 30 minute period of experimental ischaemia. Steiness (1961a, b) showed that it was not possible to increase the time of perception of the stimulus in normal subjects by inducing hyperglycaemia in them, that the abnormal condition in diabetics was reversible, and that it bore some relationship to the state of control of the diabetes. This resistance of the peripheral nerves of diabetic subjects to ischaemia has been confirmed by Castaigne, Cathala, Dry, and Mastropaolo (1966). Gregersen (1968) studied the effects of limb ischaemia on vibration perception threshold, tactile sensation, pain, heat-induced pain sensation, and motor nerve conduction velocity in healthy and diabetic subjects. His results show that vibration perception, motor nerve conduction velocity, and tactile sensation are relativelyunaffected by ischaemia in the diabetic subjects, in contrast to that observed in the normal subjects. The sensations of heat and heat-induced pain, however, remained unchanged during the ischaemia in the diabetics as well as in the control group. Seneviratne and Peiris (1968b) have shown that the evoked sensory nerve action potential of the median nerve of diabetic subjects is resistant to ischaemia produced by vascular occlusion of the upper limb by pneumatic cuff compression. These evoked potentials, in contrast to those of normal subjects, showed a relative constancy of their amplitudes, durations, and latencies during a 30 minute period of complete vascular occlusion. These changes could be demonstrated in all the diabetic subjects studied irrespective of whether or not they had evidence of a neuropathy. None of their diabetic subjects experienced ischaemic or post-ischaemic paraesthesiae, which were a very constant feature of the early ischaemic and postischaemic phases in the control group.It was postulated that these differences in the behaviour of the nerves of diabetic subjects may have been due to the fact that the metabolites released from the tissues of the diabetic during vascular occlusion were essentially different from those produced by the tissues of normal subjects under similar conditions. Alternatively, there may have been no essential difference between the metabolites produced by the normal and diabetic subjects, the relative resistance of the diabetic nerve being due to its ability to maintain its activity under ischaemic conditions. The experiments described in this paper were designed to study the effects of hypoxia on the excitability of isolated peripheral nerve. METHODSExperimental diabetes was produced in 6-month-old male rats weighing between 100 to 150 g by a modification of the method described by Klebanoff and Greenbaum (1954). A single dose of alloxan monohydrate (BDH) of 150 mg/kg b...

When the limb of a normal subject is compressed by means of a sphygmomanometer cuff, placed on the upper arm and inflated to a pressure beyond the systolic blood pressure, a series of spontaneous sensations are felt in it during and after the release of the vascular occlusion. These sensations felt in the periphery, and collectively referred to as 'pins and needles', have attracted the attention of several investigators, including Lewis, Pickering and Rothschild (1931), Zotterman (1933), Kugelberg (1944Kugelberg ( , 1946, Weddell and Sinclair (1947), Merrington and Nathan (1949), Poole (1956a, b), andNathan (1958).The available evidence suggests that the impulses giving rise to ischaemic and post-ischaemic paraesthesiae arise in the sensory nerves of the limb. There is, however, no consensus of opinion concerning the mechanisms underlying the production of paraesthesiae, and the nature of the sensory nerve fibres involved. Weddell and Sinclair (1947) believed that the post-ischaemic paraesthesiae are due to the stimulation of peripheral nerve endings in the area in which they are felt, and that a greater proportion of the impulses thus aroused are conveyed in the afferent somatic fibres normally subserving the sensation of pain. Merrington and Nathan (1949), however, were of opinion that the nerve impulses felt as paraesthesiae arise in the nerve trunks recovering from the ischaemia, and not in the end organs, and that the fibres concerned are those normally serving the sensations of touch, pressure, and movement.The evidence suggests that the effect is primarily a vascular one. The ischaemic paraesthesiae are felt during a particular phase of the ischaemic process, while an adequate period of ischaemia must be followed by an adequate period of normal circulation before the nerve becomes the site of the postischaemic paraesthesiae. Kugelberg (1944Kugelberg ( , 1946 demonstrated an increase in the excitability of human motor nerves at a time when the postischaemic paraesthesiae were maximal, and showed that the spontaneous activity in these motor nerves arose when their excitability was raised to a critical value, and that the spontaneous activity ceased when the excitability fell below the critical level. Kugelberg and Cobb (1951) observed that the repetitive tendency and hyperexcitability of the motor nerves were greatly augmented by hyperventilation and hypocalcaemia, and b,lieved that this relationship to changes in the ionic environment of the nerve would explain the large range of variations in the reaction of normal subjects to ischaemic and post-ischaemic states. Nathan (1958) suggested that some Group A sensory nerve fibres may behave in a similar fashion -that after a few minutes of ischaemia they become sufficiently hyperexcitable for the fibres to fire off spontaneously, giving rise to the sensation of ischaemic paraesthesiae. A similar phase of hyperexcitability is believed to occur after the restoration of blood supply to the nerve, this phase lasting longer and being more intense than that occur...

SUMMARY Peripheral nerve function has been studied in 50 patients with chronic liver disease. An increase in the latency or a reduction in the response amplitude of the evoked sensory potential of the median nerve was detected in 34 of the 50 subjects. This was in striking contrast to the paucity of neurological signs and symptoms suggestive of peripheral nerve damage seen in these patients. There was no evidence to show that alcohol was responsible for the neuropathy. Abnormalities in the excitability changes of sensory nerve during ischaemia were detected in seven of the 16 subjects whose distal sensory latencies were within normal limits. A critical evaluation of the hypotheses which have been postulated to account for the increased resistance of peripheral nerve to inactivation by ischaemia has been made. It is concluded that an increase of the permeability of the periaxonal diffusion barrier to K offers the most acceptable explanation for this phenomenon.

A reduction of the conduction velocity in the motor nerves of diabetic patients has been shown by Mulder, Lambert, Bastron, and Sprague (1961), Skillman, Johnson, Hamwi, and Driskill (1961), and Lawrence and Locke (1961). They found evidence of slowing of the conduction velocity in patients who had evidence of a clinical neuropathy, and by statistical comparison demonstrated a reduced conduction velocity in some of their diabetic subjects who had no clinical evidence of a neuropathy. Downie and Newell (1961) and Gilliatt and Willison (1962) Poole (1956a) has shown that ischaemic and postischaemic paraesthesiae occur very constantly in healthy subjects between the ages of 12 to 60 years, when the circulation in the upper limb is restored after it has been occluded for a certain minimum duration. Poole (1956b) also showed that these paraesthesiae were absent or diminished in intensity or duration in subjects who had evidence of peripheral sensory nerve disease.In this study, excitability changes in relation to ischaemia in the sensory nerves of patients with diabetes mellitus have been investigated. We have in the accompanying paper (Seneviratne and Peiris, 1968) shown that there is a good correlation between these excitability changes and the times of onset and duration of ischaemic and post-ischaemic paraesthesiae. METHODSTwelve male subjects between the ages of 15 and 45, suffering from diabetes mellitus, were selected for this study. Diabetes mellitus was diagnosed according to the criteria recommended by WHO (1965).A careful clinical examination was carried out on all subjects in order to assess peripheral nerve function. All such examinations were done by one of us. A system of scoring was designed so that each positive symptom or sign from a list was allotted one point, the maximum possible score being 15 points. The following symptoms and signs were considered: pain in the legs, paraesthesiae in arms or legs, loss of sensation in the arms or legs, muscular weakness, sensory loss to pin-prick in the legs only, sensory loss to pin-prick in both legs and arms, loss of light touch, loss of vibration sense (a) at the ankle, (b) at the iliac crest, (c) at the wrist; calf tenderness, loss of ankle jerks, loss of other deep reflexes, muscle weakness on testing, and, lastly, wasting of muscles.Conventional electro-diagnostic tests of nerve function were done on all patients. A score of one point was allotted to each abnormality detected, so that maximum severity as judged by these means indicated three points.The measurements made for this purpose were the motor conduction in one external popliteal nerve, the latency of the sensory action potential at the wrist obtained by the method described (Seneviratne and Peiris, 1968), and the amplitude of this potential. The lowest values in normal subjects for these parameters were 35-6 m/sec (Thomas, Sears, and Gilliatt, 1959), 2-7 msec, and 66 uV respectively (Seneviratne and Peiris, 1968).When divided in this manner, the subjects studied could be assigned to two groups, ...