Acetylcholine receptor protein. Neuromuscular transmission in immunized rabbits.

Rabbits injected with purified acetylcholine (ACh) receptor protein produce antibodies against the receptor and develop generalized muscle weakness. The compound muscle action potentials show a decremental fall in amplitude with repetitive nerve stimulation. Both the weakness and the decrement is counteracted by reversible cholinesterase inhibitors. Intracellular recordings from muscle endplates show that the amplitude of the miniature end-plate potentials is considerably reduced. A reduced binding of neurotoxin to muscles from immunized rabbits was observed. Nerve impulses release a normal number of ACh packages (quanta) from the motor nerve terminals. The muscle weakness in immunized rabbits thus has the same features as the muscle weakness in myasthenia gravis and may be a good animal model of myasthenia gravis.

Treatment of Lambert-Eaton syndrome: 3,4-diaminopyridine and pyridostigmine.

We used a new drug, 3,4-diaminopyridine, to treat five patients with the Lambert-Eaton syndrome, one with a carcinoma and four cryptogenic. The effects of intravenous, oral, and rectal administration were evaluated clinically and electrophysiologically after single doses and during continuous treatment for up to 21 months. 3,4-Diaminopyridine effectively ameliorated the neuromuscular and autonomic nervous system disorders without severe side effects. Anticholinesterase drugs strongly potentiated the benefit of 3,4-diaminopyridine.

Effects of 4-aminopyridine on neuromuscular transmission.

4-Aminopyridine (4-AP) powerfully increases transmitter release from motor nerve terminals of rat and frog skeletal muscle in response to single nerve impulses. The drug also enhances transmitter release during repetitive nerve activity but, at D-tubocurarine-blocked endplates, only the first impulses cause increased transmitter release at stimulation frequencies at or above 50 Hz. At magnesium- and botulinum-poisoned endplates, 4-AP potentiates transmitter release at every stimulus during tetanic nerve stimulation and restores neuromuscular transmission. Spontaneous transmitter release in the rat is not affected by the drug, but at some frog endplates miniature endplate potential (mepp) frequency increases. The drug has no post-synaptic action, as evidenced by its lack of effect on amplitude or time course of mepps. Decreasing the temperature from 37 to 15 degrees C does not abolish the effect of 4-AP on neuromuscular transmission. In the presence of 4-AP, single nerve impulses produce repetitive spontaneous activity in the nerve terminal of the frog nerve-muscle preparation. Experiments on the mode of action of 4-AP suggest that the drug increases transmitter release by enhancing the influx of calcium ions during depolarization of the nerve terminal.

Botulinum toxin and 4-aminoquinoline induce a similar abnormal type of spontaneous quantal transmitter release at the rat neuromuscular junction.

Intracellular recordings from botulinum toxin type A (BoTx)-poisoned extensor digitorum longus muscles from adult rats have shown that the toxin initially reduced the frequency of miniature endplate potentials (m.e.p.ps) to about 1/200 of normal. After a few days the m.e.p.p. frequency rose and was subsequently maintained at a level of about 1/3 of that at normal endplates. Depolarization of the nerve terminals with 20-30 mM KCl-Ringer initially failed to affect the frequency of m.e.p.ps and later caused only a 2-3--fold increase in their frequency. The temperature dependence of m.e.p.p. frequency at BoTx-poisoned endplates had a Q10 of about 12 compared to 2-3 for normal junctions. The time to peak of a population of m.e.p.ps at Botx-poisoned junctions was prolonged as compared to normal and fast- and slow-rising m.e.p.ps originated within the same post-synaptic membrane field area. M.e.p.ps in BoTx-poisoned muscles resembled the m.e.p.ps which 4-aminoquinoline (4-AQ) has been shown to induce in normal muscle, and we therefore examined and compared these two release processes for acetylcholine. Procedures known to markedly affect m.e.p.p. frequency at normal junctions, such as nerve terminal depolarization or changes in extra- and intracellular Ca2+ concentrations, failed to affect m.e.p.p. frequency in BoTx-poisoned muscles and similarly the frequency of m.e.p.ps induced by 4-AQ in normal muscle. Tonicity changes in the extracellular medium altered m.e.p.p. frequency in both the experimental conditions, but in a direction opposite to that at normal junctions. The temperature dependence of the frequency of 4-AQ-induced m.e.p.ps was similar to that of m.e.p.ps at BoTx-poisoned junctions. It is concluded that BoTx poisoning induces an abnormal type of spontaneous quantal transmitter release, characterized by being insensitive to nerve terminal depolarization and to transmembrane Ca2+ fluxes. This transmitter release has characteristics similar to that previously described for the release induced, at normal junctions, by 4-AQ.

Antagonism of the paralysis produced by botulinum toxin in the rat. The effects of tetraethylammonium, guanidine and 4-aminopyridine.

The injection of botulinum toxin type A into the hind-leg of adult rats causes complete paralysis of the leg lasting for several weeks. In the extensor digitorum longus (EDL) muscle transmitter release is reduced to a level of less than 1% of normal. Tetraethylammonium (TEA) and guanidine in concentrations of about 3 mM restore, in EDL muslces in vitro, neuromuscular transmission to about the normal level, provided that the external calcium concentration is 4 mM or higher. 4-Aminopyridine (4-AP) has similar restorative effect but is about 20-30 times more potent. Unlike TEA and guanidine, 4-AP is effective when the ambient calcium concentration is 2 mM; this drug is therefore also active in vivo. The intravenous injection of 4-AP (5 mg/kg body weight) restores neuromuscular transmission from complete paralysis by botulinum toxin to a normal level as shown by the recording of almost normal twitch and tetanic tensions in the EDL muscle. In rats paralysed by a lethal dose of botulinum toxin, the intraperitoneal administration of 4-AP restores general motor activity, the effect lasting 1-2 hours. A study of the effects of these drugs on spontaneous and evoked transmitter release suggests that all three compounds increase the level of free calcium inside the nerve terminals. In botulinum poisoning the transmitter release mechanism appears to be intact, but a reduced sensitivity to calcium has been shown (Cull-Candy et al. 1976), and this could explain why the drugs restore evoked transmitter release in botulinum poisoning.

Effects of 4-aminopyridine on statistical parameters of transmitter release at the neuromuscular junction.

4-Aminopyridine (4-AP) potentiates transmitter release from motor nerve terminals by increasing the quantum content (m) of endplate potentials. Estimates of the binomial parameters of transmitter release shows that 4-AP enhances m by increasing n and not p.

An extrapyramidal choreiform syndrome caused by amphetamine addiction.

Four cases are described to demonstrate the extrapyramidal clinical syndrome sometimes appearing in chronic amphetamine users. The symptoms are dominated by choreiform or athetoid movements, ataxia and disturbances of gait. The syndrome develops during amphetamine abuse and may be observed also during abstinence. The symptoms usually disappear within a week when the drug is discontinued, but may remain for years.

Clinical signs of temporomandibular joint internal derangement in adults. An epidemiologic study.

This study investigated the frequency and distribution of clinical signs of temporomandibular joint (TMJ) internal derangement in an adult non-TMJ patient population. Four hundred three persons who participated in an epidemiologic investigation were examined for clinical signs of TMJ internal derangement by four examiners who followed a standardized form. Clinical signs of internal derangement were found in 76 persons (19%). Twenty-nine persons (7%) had reciprocal clicking and 47 (12%) had a history of clicking replaced by limitation of mouth opening with deviation to the affected side. Reciprocal clicking was associated with TMJ pain during mouth opening and with limitation of jaw movement. A history of clicking replaced by limitation of mouth opening with deviation to the affected side was associated with pain during mouth opening, limitation of opening, and palpatory tenderness of the TMJ. The study indicates that clinical signs of TMJ internal derangement are present in nearly one fifth of non-TMJ patients. Those with clinical signs of internal derangement frequently also have subjective symptoms but they have not sought treatment for these symptoms.

No short-term difference in outcome after temporomandibular joint arthrography alone or with immediate lavage.

Thirty-three patients with an arthrographically documented anterior disk displacement without reduction were randomly assigned to be treated with upper joint space lavage or to serve as controls in an 8-week clinical trial. Pain was evaluated by the patients on a visual analog scale at rest and after chewing gum. The clinical examination followed a standardized protocol. Improvements in pain and mouth opening were found in both the lavage and control group after 8 weeks, but there were no statistically significant differences between the treatment and control groups. It was concluded that upper joint space lavage after arthrography seems to be ineffective to decrease pain and to increase mouth opening in patients with anterior disk displacement without reduction.

Improvement in neuromuscular transmission in myasthenia gravis by 3,4-diaminopyridine.

3,4-Diaminopyridine (3,4-DAP), a potent potentiator of action potential evoked release of acetylcholine from presynaptic terminals in the neuromuscular junction was given i.v. and p.o. to two patients with myasthenia gravis. Effects were monitored electrophysiologically by repetitive nerve stimulation and by standardized clinical testing. Administration of 8 mg and 9 mg 3,4-DAP i.v. produced a clear improvement in the neuromuscular transmission after approximately 20 min. When 3,4-DAP was given p.o. 24 mg was shown to be effective. At a dosage of 18-24 mg p.o. 3,4-DAP significantly potentiated the effect of the cholinesterase inhibitor pyridostigmine at an optimal dose. The maximal effect of 3,4-DAP p.o. was obtained after 2.5-3 h. No significant CNS side-effects were found which is in contrast to those reported for 4-aminopyridine. The results suggest that 3,4-DAP may be useful as an addition to the conventional treatment with cholinesterase inhibitors when immunosuppressive treatment is considered contraindicated or when it has not yet reached its full effect.

Effects of 4-aminopyridine in myasthenia gravis.

A new drug, 4-aminopyridine, was prepared for use in humans and tested by repeated injections in six patients with myasthenia gravis. The drug caused improvement of muscle strength and neuromuscular transmission as demonstrated by clinical observations and repetitive electrical nerve stimulation. The drug was effective in cases without any other treatment as well as in cases undergoing treatment with anticholinesterases. It is concluded that 4-aminopyridine may be of value as a supplementary drug in the treatment of myasthenia gravis.

4-aminopyridine--a new drug tested in the treatment of Eaton-Lambert syndrome.

A 67 year old man with the myasthenic syndrome associated with small cell bronchogenic carcinoma was treated with a new drug, 4-aminopyridine. The muscle weakness showed marked improvement and electrophysiological examinations demonstrated restoration of neuromuscular transmission.

Long-term follow-up after occlusal treatment to correct abnormal temporomandibular joint disk position.

Fifteen patients with temporomandibular joint disk displacement in whom a normal condyle-disk relationship could be established were treated with occlusal changes to maintain the disk in a recaptured position. Occlusal changes were achieved by prosthodontics in 11 patients and by orthodontics in four patients. Follow-up after about 3 years showed that joint function was improved, intensity of pain was reduced, and joint and muscle tenderness were less frequent than before treatment. Intermittent locking, use of analgesics, sleep disturbances, and absence from work because of temporomandibular joint symptoms were also less frequent. Radiographic examination performed in 11 patients at follow-up demonstrated anteroinferior condylar position in the majority of the patients, but only minor hard tissue changes. Arthrography showed the disk to be in a correct position relative to the condyle in 82% (9 of 11) of the patients. These results suggest that permanent change of the occlusion with the objective of eliminating abnormal disk position may be effective treatment for disk displacement when conventional methods of treatment have failed to alleviate the symptoms. The extent of dental treatment needed to maintain the disk in a correct position should, however, be considered relative to the severity of the symptoms.

Temporomandibular joint disk displacement: arthrographic and tomographic follow-up after 6 months' treatment with disk-repositioning onlays.

Eighteen patients with an arthrographic diagnosis of temporomandibular joint disk displacement with reduction were treated with disk-repositioning onlays for 6 months. Arthrograms and tomograms were obtained before and after treatment. The arthrographic examination after treatment showed that the disk remained in the superior position in twelve but was again displaced in six patients. Three of the patients with disk displacement manifested no clinical signs, such as clicking or locking; two showed signs of locking; and one had reciprocal clicking. The patients with clicking or locking had more symptoms than the other patients. A retrospective analysis of the pretreatment arthrograms suggested that there could have been a medial component to the disk displacement in four of the six patients in whom the disk became displaced again during treatment. Medial disk displacement were not seen in the patients with a successful treatment outcome. This study suggests that recurrence of symptoms during treatment with disk-repositioning onlays is frequently associated with recurrent disk displacement. The study further suggests that medial displacement of the disk is more difficult to treat.