Heredopathia atactica polyneuritiformis: Refsum's disease.

Seven patients with Heredopathia Atactica Polyneuritiformis are described. There were 3 groups of clinical characteristics: first, congenital abnormalities such as skeletal deformities, unrelated to phytanic acid levels; second, signs and symptoms such as retinitis pigmentosa which come on slowly and are not directly related to the plasma phytanic acid level; third, lesions such as the neuropathy, rash and cardiac arrhythmias which can change quickly and are linked to the plasma phytanic acid level. Exacerbations of the signs in the third group are precipitated by a low calorie intake and mobilisation of phytanic acid from the adipose tissue. Poor vision is due not only to retinitis but also to small pupils which fail to dilate in the dark. The use of plasma exchange is discussed. With good dietary supervision it is possible to produce a considerable clinical recovery for the neuropathy.

The spatial distribution of excitability and membrane current in normal and demyelinated mammalian nerve fibres.

Thresholds to electrical stimulation have been recorded, concurrently with the membrane currents of conducted impulses, at many positions along undissected single fibres in rat spinal roots. In normal myelinated fibres, distinct threshold minima invariably coincided with sites of inward current generation, and were therefore identified as nodes of Ranvier. Between nodes, the thresholds rose by an order of magnitude. At normal nodes, the charge thresholds were linearly related to stimulus duration, as predicted by computer simulations of a model myelinated fibre (Bostock, 1983). The strength-duration time constants averaged 64.9 +/- 8.3 microseconds (mean +/- S.D.) at 37 degrees C, and had a Q10 of 1/1.39. They were relatively insensitive to changes in inter-electrode distance, or to partial anaesthetization with tetrodotoxin. In fibres treated with diphtheria toxin 6-8 days previously, to induce paranodal or segmental demyelination, threshold minima were found both at nodes and in internodal regions generating inward membrane current. In these fibres strength-duration curves were of the same general form as at normal nodes, but with strength-duration time constants increased at widened nodes (up to 350 microseconds) and at excitable internodes (600-725 microseconds). Comparison with the computer model indicated that these changes were most likely due to exposure of axon membrane with a time constant much longer than that of the normal nodal membrane. In none of the demyelinated fibres examined have we found any evidence of hyperexcitability.

Sequential EEG findings and symptoms in partial seizures of temporal lobe origin.

45 cases of partial seizures of temporal lobe origin undergoing sequential EEG investigation first with routine and then methohexitone activated EEG, 31 supplemented by sphenoidal electrodes, are reported. Methohexitone activated foci from temporal lobes which had previously not displayed temporal spike or sharp wave discharges in 15 (33.3%) cases. In 11 (24.4%) this was the first evidence of the focus in 15 (33.3%) cases. In 11 (24.8%) this was the first evidence of the focus in either temporal lobe and in 4 (8.9%) the focus was contralateral to one already seen in routine EEG. In 3 (6.7%) cases the sphenoidal electrodes were essential for demonstrating the focus. Methohexitone evoked temporal spikes or sharp waves irrespective of the nature of the initial routine EEG which was either normal, had non "epileptic" temporal abnormalities or abnormalities outside the temporal region. 2 X 2 chi 2 tests, comparing the frequency with which a particular symptom was accompanied by an EEG in a sequence with temporal discharges, showed that only in the case of evolution to generalised tonic/clonic seizures (secondary generalization) was the association statistically significant: chi 2 4.28, P less than 0.025. Similar testing of length of history and frequency of attacks against the frequency with which temporal discharges occurred failed to establish a statistically significant association.

The effects of 4-aminopyridine and tetraethylammonium ions on normal and demyelinated mammalian nerve fibres.

1. 4-Aminopyridine (4AP) and tetraethylammonium ions (TEA), which block voltage-dependent potassium channels in other nerve membranes, have been used to study nerve conduction in fibres of normal rat spinal roots and those demyelinated with diphtheria toxin. The pharmacological actions have been compared with those of temperature. 2. Both TEA and 4AP increased the amplitude and duration of the monophasically recorded compound action potentials of non-myelinated fibres in normal rat dorsal roots. Enhancement of the action potential amplitude by 4AP was maximal near 1 mM, and was not readily reversed by washing. At concentrations up to 50 mM the action of TEA was weaker and reversible. 3. In normal dorsal and ventral roots TEA (20 mM) and 4AP (5 mM) had only a mildly depressant action on the compound action potentials of myelinated fibres. Whereas the slight reduction in peak amplitude and increase in width was also found in a single fibres treated with TEA, none was discerned in single fibres exposed to 4AP over a wide temperature range. 4. It is concluded that voltage-dependent potassium channels occur in significant numbers in mammalian non-myelinated fibres, but not at nodes of Ranvier. 5. Spinal roots previously treated with diphtheria toxin to cause demyelination were studied by longitudinal current analysis. Fibres affected by diphtheria toxin had a late phase of outward current, either restricted to nodes or, in the case of continuous conduction, distributed along internodes, and this outward current was specifically blocked by 4AP. 6. Both 4AP and TEA increased the temperature at which conduction block occurred in most single demyelinated fibres, so that in some cases fibres blocked at physiological temperatures were enabled to conduct. 4AP was more potent than TEA, but less consistent in its effect. 7. It is concluded that potassium channels are present at widened nodes and in internodal axolemma exposed by demyelination. Their presence enables TEA and 4AP to overcome conduction block in some demyelinated nerve fibres.

Effects of 4-aminopyridine on normal and demyelinated mammalian nerve fibres.

We have previously demonstrated that a drug which prolongs action potentials can, like a reduction in temperature, overcome conduction failure in demyelinated nerve fibres. Although the particular substance then used, a scorpion venom, was not a suitable therapeutic agent, we suggested that other drugs, with similar but milder effects on the action potential, might be effective in the symptomatic treatment of multiple sclerosis. We now report some encouraging results obtained with 4-amino-pyridine (4AP), a substance which blocks the voltage-dependent potassium current in squid giant axons. The use of a potassium-blocking agent to prolong action potentials may seem surprising because we previously found tetraethylammonium chloride (TEA), another potassium blocker, ineffective on normal rat myelinated fibres, and two recent voltage-clamp studies have confirmed that mammalian nodes have few, if any, potassium channels. On the other hand, 4AP strongly potentiates transmitter release from the unmyelinated terminals of rat motor nerves, and the possibility arose that demyelinated axon membrane, which can conduct impulses continuously like an unmyelinated fibre, might further resemble its unmyelinated terminals by responding to 4AP. In testing this hypothesis, we have found that both TEA and 4AP prolong action potentials of demyelinated and unmyelinated fibres, and both facilitate conduction in fibres blocked by demyelination. 4AP is effective at lower concentrations, and is the more promising for clinical use, as it has already been used with beneficial effects in the treatment of Eaton-Lambert syndrome and myasthenia gravis.

Sensory conduction in medial plantar nerve: normal values, clinical applications, and a comparison with the sural and upper limb sensory nerve action potentials in peripheral neuropathy.

A method for recording the medial plantar sensory nerve action potential at the ankle with surface electrodes is described. Normal values in 69 control subjects are given and compared with the sural sensory nerve action potential in the same limb in the same subjects. Clinical applications were studied in 33 patients. The procedure may be applied in the diagnosis of L4-5 nerve plexus or root lesions, lesions of the sciatic, posterior tibial, and medial plantar nerves, and is a more sensitive test than other sensory nerve action potentials in the diagnosis of peripheral neuropathy.

The action of chlormadinone acetate (6-chloro-delta6-dehydro-17alpha-acetoxyprogesterone) upon experimentally induced ovulation in the rabbit.

1. The ovulation response to electrical stimulation of the median eminence, or to the intrapituitary infusion of median eminence extract, was observed in control rabbits and animals pre-treated with chlormadinone acetate.2. Chlormadinone acetate pre-treatment did not significantly reduce the proportion of rabbits ovulating in response to electrical stimulation. However, there was a significant reduction in the average number of ruptured follicles when compared with the animals in the control group.3. Chlormadinone acetate pre-treatment significantly reduced the proportion of animals ovulating in response to the intrapituitary infusion of median eminence extract as compared with the control series. However, there was no significant reduction in the average number of ruptured follicles (in those rabbits that ovulated) when compared with the control groups.4. Chlormadinone acetate pre-treatment produced no significant effect upon either the proportion of animals ovulating, or the average number of ruptured follicles, following I.V. injection of 50 mug LH.5. The conclusion drawn is that chlormadinone acetate blocks copulattion-induced ovulation in the rabbit by action at a site in the central nervous system located above the median eminence. The possible effects of chlormadinone acetate upon the secretion of FSH, the pituitary sensitivity to releasing factors and the ovarian sensitivity to LH are discussed.