Journal of Neurological Sciences 152 Suppl.

1 (1997) S43S48

Fasciculations: what do we know of their signicance?

Joy Desai*, Michael Swash
Department of Neurology, The Royal London Hospital, London E1 1 BB, UK

Abstract Fasciculations are observed in patients with neurogenic disorders and in healthy individuals. Depending on the associated clinical symptoms and signs, they may signify the presence of a variety of disorders of the lower motor neuron. Divergent and occasionally conicting opinions prevail regarding the aetiology, pathogenesis, clinical signicance, neurophysiological characteristics and the physiological site of origin of fasciculations. In this review we examine the published literature and attempt to clarify these issues. 1997 Elsevier Science B.V. Keywords: Fasciculations; Drugs; Central neural inuences; Neurophysiological experiments; Ionic gradients; Amyotrophic lateral sclerosis

1. Introduction Fasciculations are visible, spontaneously discharging motor units that may be observed both in disease and in
Table 1 Fasciculation potentials in various disorders (a) Normal individuals Spontaneous (occasional) Following exercise Benign fasciculations (persistent) (b) Lower motor neuron disorders Amyotrophic lateral sclerosis (ALS / MND) Radiculopathy Multifocal motor neuropathy Peripheral neuropathy (acquired, inammatory) Entrapment neuropathy Spinal muscular atrophy Radiation plexopathy Syringomyelia Creutzfeldt-Jakob disease (c) Metabolic disorders Thyrotoxicosis Tetany After anticholinesterase drugs After anaesthetic muscle relaxants

health. When recorded with a concentric needle electrode examination of muscles, they are called fasciculation potentials (AAEE, 1987). Fibrillations, positive sharp waves, complex high-frequency discharges and myotonic discharges are other spontaneous discharges observed on concentric needle electromyography. All of these types of spontaneous electrical activity may be neurophysiological features of many peripheral neuromuscular disorders. However, unlike the others, fasciculations are never observed in myopathic disorders. Fasciculations may be observed in a number of conditions (Table 1). The exact physiological site of origin of fasciculation potentials is not well established. Published literature suggests that fasciculations may be generated from within different discrete components of the lower motor neuron. However, it has also been implied that central neural mechanisms may modulate fasciculations. In this review we will examine the published evidence and attempt to clarify the conicting opinions that prevail regarding their origin, clinical interpretation and signicance.

2. Clinical associations Fasciculations have been observed in normal healthy individuals. On the other hand they are a characteristic feature of various diseases such as motor neuron disease

*Corresponding author. Tel.: 144 171 377 7472; fax: 144 171 377 7008. 0022-510X / 97 / $17.00 1997 Elsevier Science B.V. All rights reserved. PII S0022-510X( 97 )00243-8

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(ALS / MND), radiculopathy, peripheral neuropathy, tetany, thyrotoxicosis, anticholinesterase drug overdose, etc. (Sindermann et al., 1973; Raudino, 1991). Many of these disorders are neurogenic. Fasciculations are not characteristic of myopathic disorders. Trojaborg and Buchthal (1965) have attempted to distinguish benign from so called malignant fasciculations. They emphasised the ring rate as an important variable that distinguished the two, and suggested that fasciculations ring at a slow rate, about one every 34 s were observed in motor neuron disease, while in other relatively benign neurogenic conditions such as cervical spondylotic myelopathy, the ring rate was faster at about 1 Hz. However, Van der Heijden et al. (1994) studied the occurrence of fasciculations in 50 healthy volunteers aged 1825 years. They analysed the diurnal variations in frequency, the effects of cooling, and the morphology of fasciculation potentials. In some subjects they found considerable variation in the ring rate of fasciculations, especially in the small muscles of the foot, ranging from 100 to 3 / min. This work implies that physiological factors determine the marked uctuations in the ring rate of fasciculation potentials. It also questions the scientic validity of deducing either the aetiology or prognostic implications of fasciculations based on their ring rate alone. Abundant and widely distributed fasciculations are a hallmark of motor neuron disease (ALS / MND). Howard and Murray studied the topographic spread of fasciculations with multi-channel surface electrodes (using an EEG recording machine) in patients with motor neuron disease and other neurogenic disorders (Howard and Murray, 1992). They ultimately concluded that if fasciculations are recorded in less than ve regions by their technique, the diagnosis of motor neuron disease (ALS / MND) should be reconsidered. However fasciculations are also prominent and frequent in spinal muscular atrophies, especially in Kennedys Syndrome (Olney et al., 1991) and in Type 1 SMA (mainly in the tongue). They are pronounced in the acute phase of poliomyelitis but are less frequent in limb muscles ravaged by old poliomyelitis (Russell, 1952; Buchthal and Houcke, 1944), although they may become frequent in these limbs after exercise. Fasciculations are a prominent feature (often accompanied by myokymia) in disorders characterised by conduction block, e.g. mutifocal motor neuropathy and radiation-induced plexopathy (Roth et al., 1986; Esteban and Traba, 1993). In fact, their prominence in the former condition may lead to this disorder being mistaken for motor neuron disease. Fasciculations also occur in cavitatory lesions of the spinal cord in which anterior horn cells are involved, such as syringomyelia, and are often seen in cervical spondylotic radiculopathy. They may be observed (perhaps less frequently) in both acute and chronic inammatory demyelinating neuropathies. This may be related to the fact that conduction block is a characteristic feature of these inammatory neuropathies. However, fasciculations are not a prominent feature of axonal peripheral neuropathies,

probably a reection of their distinct pathogenesis, as compared to the demyelinating neuropathies. Fasciculations are therefore a clinical feature of diseases which pathologically affect distinct and discrete components of the motor neuron from the anterior horn cell to the myelinated nerve bre. The physiological basis of their occurrence in normal individuals is not clear, but a theory based on ephaptic transmission has been proposed (Trontelj and Janko, 1993).

3. Fasciculations, drugs and central neural inuences Several authors have observed that cholinomimetic drugs induce fasciculations in normal persons and perhaps more readily so in those with lower motor neuron dysfunction (Russel et al., 1938; De Jong and Simons, 1942; Odom et al., 1943; Standaert and Riker, 1967; Patel and Swami, 1969). Langley and Kato (1915) demonstrated, in rabbit experiments, that parenterally administered physostigmine induced muscular twitches which were abolished by curarisation. The twitches failed to appear in denervated muscle after Wallerian degeneration had taken place. Twenty-ve years later, in cat experiments, the anterior and posterior L5S1 roots were sectioned near the spinal cord by Masland and Wigton (1940). Parenterally administered neostigmine resulted in muscle fasciculations accompanied by electrical discharges in the anterior roots distal to the section site. It was demonstrated that these discharges were conducted antidromically from a distal origin in the motor nerves. Small doses of curare, insufcient to block neuromuscular transmission, completely abolished both the fasciculations and the antidromic discharges. Around the same time it was shown by Russel et al. (1938), in human experiments, that peripheral nerve block did not alter the frequency of neostigmine-induced fasciculations both in normal individuals and in progressive muscular atrophy. Forster and Alpers (1944) administered nonparalysing doses of curare to patients with motor neuron disease (ALS / MND) and found that this abolished both spontaneous as well as neostigmine-induced fasciculations. More recently these ndings were conrmed by Conradi et al. (1982), using pancuronium, in two patients with ALS / MND. Fasciculations induced by neostigmine are the result of the initial random depolarisation of unmyelinated nerve terminals (Sprouse et al., 1985). When this depolarisation is of sufcient magnitude and duration, current ows retrogradely from this region and action potentials may be generated at the distal node of Ranvier. Repetitive ring ensues if the current ow is maintained for a sufcient time and the threshold of the distal node is reached. Transmission of these neural events to the muscle results in fasciculations (Baker and Stanec, 1987). These fasciculations resemble motor unit potentials in their morphology (Conradi et al., 1982). Inhalational anaesthetics, such as isourane, depress the depolarisation of the end-plate at

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the neuromuscular junction. Isourane has been found to inhibit muscle fasciculations caused by succinylcholine in children (Baker and Stanec, 1987; Randell et al., 1993). These experimental observations support a distal origin for fasciculations, probably within the distal axonal arborisation. However, alfentanil inhibits muscle fasciculations caused by suxamethonium (Yli-Hankala et al., 1992). Alfentanil is an opioid receptor agonist that inuences opiate receptors within the central nervous system. Romano (1996) reported a reduction in frequency of fasciculation discharges in patients with ALS during treatment with gabapentin. The exact mode of action of this drug, used in the treatment of chronic complex partial seizures, is not known though it is believed to increase the activity of the enzyme g-aminobutyric acid in the central nervous system. Mills (1995) reported that fasciculations could be evoked by cortical magnetic stimulation in three of 33 patients with motor neuron disease. He postulated that cortical stimulation may have generated a large synchronous excitatory post-synaptic potential that was capable of driving a motor neuron in order to produce a fasciculation potential, thus implying a proximal rather than a distal origin for some fasciculation potentials in this disease. It is possible, therefore, that central neural mechanisms do modulate fasciculations, as was suggested many years ago by Denny-Brown and Pennybacker (1938).

4. Fasciculations in healthy individuals While the experiments reviewed above analysed the characteristics of fasciculation potentials in disease, others have scrutinized their neurophysiological variations in health. Collier (1980) studied 45 gynaecological patients and found that all voluntary muscles do not respond to suxamethonium in the same way. The biceps muscle seemed most sensitive, fasciculating in almost every individual, while the triceps did so only in 60%. The pectoral muscles seemed the most impervious to the stimulatory effects of suxamethonium and did not fasciculate in any of these 45 patients. A theory to account for these variations, based on the variable distribution of red and white muscle bres in the muscles throughout the body was proposed. This has not been tested and as yet there remains no data as to whether fasciculation potentials are more likely to occur in Type 1 or Type 2 motor units.

5. Experimental and neurophysiological clues to the origin of fasciculations During electromyographic studies of fasciculations, Denny-Brown and Pennybacker (1938) found that some fasciculations could be activated by voluntary effort. They therefore believed that fasciculations arose from over-

excited diseased anterior horn cells. However, they noted that these were impervious to spinal inhibition by active contraction of an antagonist muscle. Hence, they postulated a central excitatory state that was resistant to spinal synaptic modulatory inuences. Synchronous fasciculations were recorded from different parts of the same muscle in patients with anterior horn cell disease by Buchthal and Houcke (1944), leading them to believe that some central excitatory inuences modulated the neurophysiological manifestations of fasciculations. Norris (1965) also reported synchronous fasciculations in two different muscles on opposite sides of the body in patients with ALS / MND and other motor neuron disorders, adding credibility to the above observations. The above observations led these early investigators to believe that fasciculations arose from a proximal site along the diseased motor neuron. However, Montagna et al. (1987) studied the frequency, morphology and distribution of fasciculations during wakefulness and compared them to those during different stages of sleep in 10 patients with motor neuron disease. They did not nd any signicant changes and concluded that fasciculations, in ALS, are not modied during sleepinduced decrease in central nervous system excitability. Nerve section experiments were performed by Forster et al. (1946) in two patients. Fasciculations were found to persist immediately after nerve section only to disappear after 2 weeks when Wallerian degeneration had occurred. In one experiment, daily recordings were performed and fasciculations were noted to transiently increase in frequency on the second and third day after nerve section, only to rapidly decline in frequency after 1 week. The effects of spinal anaesthesia and nerve block on the intensity of fasciculations in patients with ALS have been studied by many investigators (Russel et al., 1938; De Jong and Simons, 1942; Odom et al., 1943; Swank and Price, 1943; Forster and Alpers, 1944; Denny-Brown, 1949). Many of them reported that these procedures had no inuence on the frequency of fasciculations. However, Swank and Price (1943) found that spinal anaesthesia reduced the number of fasciculations in two patients by 5065%; while peripheral nerve block resulted in variable effects. Denny-Brown (1949) found that peripheral nerve block reduced the ring rate of fasciculations but did not abolish them, prompting him to conclude that fasciculations could originate at any site, all along the motor axon. In the early 1980s the novel electrophysiological method of collision was used to study the physiological site of origin of fasciculations. Fasciculation potentials were recorded by concentric needle EMG in a distal muscle. Each fasciculation potential was used to trigger a stimulating electrode at a proximal site on the motor nerve, either at the knee or the elbow. If the orthodromic impulse triggered by the electrical stimulus initiated by a fasciculation potential were to meet the antidromic impulse of the fasciculation itself, a collision would occur. The impulse would be blocked and no M-wave would be recorded. This

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would be the case if fasciculations arose distally. Fasciculations arising proximal to the site of the stimulating electrode would obviously cause no such collision and a normal M-wave would be recorded. With this technique, Wettstein (1979) reported that 15 of 25 recorded fasciculations arose proximal to the knee or elbow, two arose distally and eight arose at multiple sites. However, Roth (1971), who devised this technique, had found that nine of 12 fasciculations arose at far distal sites. He, therefore, re-evaluated the method in a study of 100 fasciculation potentials (Roth, 1982). He was able to identify aws in Wettsteins technique including the presence of a signicant delay between the onset of a fasciculation and the triggering of the stimulating electrode. From among the 100 fasciculations he studied, he could identify a distal origin in 80. In a second study, Roth (1984) compared fasciculation potentials with the F-responses evoked by the distally derived fasciculations themselves. This study included patients with lower motor neuron disorders and normal subjects. He found that the shape of the fasciculatory F-response never varied, whereas the shape of the fasciculation potential sometimes varied quite markedly. However the shape of the fasciculation potential was never identical to its F-response. Comparison of the latencies of the fasciculation-evoked F-responses with standard F-responses and M-responses in the same muscle further suggested that fasciculations arose from a very distal axonal site in 97% of normal persons and in 89% of patients with neurogenic disorders. These observations therefore suggested that most fasciculations arose from the distal arborization of the motor axon. Conradi et al. (1982) studied the congurations of fasciculations and voluntary motor unit potentials in 10 ALS / MND patients. The recording was congured in a manner such that only one motor unit could be activated by maximum voluntary activation of the EDB muscle. They noted that the shapes of motor unit potentials evoked by volition or by nerve stimulation varied only slightly, whereas the shapes of fasciculation potentials often varied markedly. However, most fasciculation potentials seemed to be composed of elements of the voluntary motor unit potentials and some were even identiable as fragments of these motor unit potentials. These observations also pointed towards an origin of fasciculations within the terminal arborization of the motor axon. Janko et al. (1989) studied 152 fasciculating motor units in 17 patients with motor neuron disease (ALS / MND) using SFEMG. They noted abnormal jitter, intermittent blocking and increased bre density in a majority of these units. They concluded that these abnormalities reected degrees of collateral sprouting and the functional immaturity of new axonal twigs and motor end-plates. They correlated the discharge rate of fasciculations with the extent and recency of distal collateral sprouting. Their

ndings corroborated the conclusions of Stalberg and Trontelj who had found similar features of neuromuscular instability upon studying fasciculation potentials with SFEMG. Guiloff and Modarres-Sadeghi (1992) analysed 200 voluntarily activated motor units and 211 fasciculations from the biceps of 10 patients with motor neuron disease (ALS / MND) using Macro-EMG. They found that fasciculations had a higher mean bre density than voluntary units, but similar macro amplitude and area. Fasciculations which could be voluntarily activated represented 10% of the total fasciculations recorded and had macro parameters and mean number of components in the SF-EMG readings similar to those of voluntarily activated non-fasciculating units in the same abnormal muscles. They concluded that for these 10% of fasciculations the site of origin was near or above the point of axonal branching. They felt that the other recorded fasciculation potentials which could not be voluntarily activated may have arisen from a number of different sites along the nerve. They postulated that in MND/ALS, proximal and distal sites of origin of fasciculation potentials may coexist. Carvalho and Swash (1997) studied fasciculation potentials in patients with ALS / MND, benign fasciculations and other neurogenic diseases. They compared their bre density, jitter and stability and their voluntary recruitability. Motor units were analysed using CNEMG, SFEMG and Macro-EMG. Amongst the various groups muscles were matched for strength and then sampled for these neurophysiological variables. They found that, in early ALS / MND, fasciculation potentials were stable, easily recruitable and had only slightly increased jitter and bre density, whereas in late ALS / MND the fasciculation potentials were less stable, poorly recruitable and had signicantly increased jitter and bre density. They concluded that in early ALS / MND fasciculations may arise from a proximal generator site, and in late ALS / MND from a more distal axonal site. Swank and Price (1943) had suggested that a distal site was usual in the slowly progressive type of neuronopathy but that proximal sites were more common in a rapidly progressive disorder. It is possible that, in ALS / MND, the site of origin of fasciculations is variable and can change during the progressive course of the disease. This could explain the seemingly variable results of the previous attempts at locating the site of origin of fasciculations, both in clinical as well as in experimental studies.

6. Changes in ionic concentrations and the genesis of fasciculations Fasciculations are often observed in disorders characterised by persistent conduction block in the peripheral nerves. In a study of 14 patients with peripheral neuropathies or plexopathies associated with conduction block,

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Roth et al. (1986) found that the frequency of fasciculations was greater when there was more marked conduction block, and was greatest in nerves with complete block. Resolution of the conduction block resulted in the cessation of fasciculations a few months later. They suggested two possible explanations for fasciculations in nerves exhibiting conduction blocks. The nerves might be hyperexcitable due to a fall in resting membrane potential in the axons distal to the conduction block, giving rise to ephaptic responses and thus generating fasciculations. Alternatively, the production of collateral sprouts in the terminal arborisation of the damaged nerve bres could be the site of origin for fasciculations since newly sprouted nerve endings are more sensitive to acetylcholine. Simpson and Thomaides (1988a) studied the relationship of fasciculations to focal loss of nerve accommodation in peripheral neuropathies. Their thoughts on the genesis of fasciculations mirrored those of Roth et al. (1986). They proposed that a localised loss of accommodation in motor nerve bres triggered repetitive ring of neurons, giving rise to fasciculations. Poor accommodation and increased sensitivity to acetylcholine are recognised properties of growth cones of peripheral axons. They believed that local sites of low accommodation represented nodal sprouts with growth cones in extra-muscular and intra-muscular parts of peripheral motor axons, a result of reinnervation. Similarly, in amyotrophic lateral sclerosis (ALS / MND) they found an association between focal extramuscular sites of defective accommodation of motor nerves and the presence of fasciculations (Simpson and Thomaides, 1988b). However they reported that the focal points of low accommodation showed no special predilection to be distal or proximal. Sprouse et al. (1985) studied the effect of adrenalectomy on neostigmine-induced fasciculations, in rat experiments. They found that in adrenalectomised animals, neostigmineinduced fasciculations were reduced in frequency and intensity. Restoration of neostigmine responsiveness was attained by dietary restriction of potassium. Thus, they highlighted the dramatic effect of ionic uctuations, especially the role of potassium, on fasciculations. Bostock et al. (1995) have proposed that fasciculations in ALS / MND may arise in the internodal component of the peripheral motor axon, as a result of accumulation of extra-cellular potassium and an inward potassium current when the membrane is hyperpolarised relative to the equilibrium potential for potassium. A similar mechanism has been proposed for the pathogenesis of post-ischaemic fasciculations. The inhibition of neostigmine-induced fasciculations by calcium channel blocking agents (in rat experiments) has been a remarkable nding (Raines et al., 1989). Perhaps a calcium-mediated current participates in the generation of repetitive potentials at the presynaptic motor nerve terminals. All these observations suggest that changes in the

conduction properties of ionic channels (e.g. potassium, calcium) and uctuations in the ionic gradients along the membranes of motor axons profoundly inuence the origin and pathogenesis of fasciculations.

7. Conclusions A diversity of systemic factors modulate fasciculations in disease and health. Fasciculations are a characteristic feature of many disorders of the lower motor neuron. Their clinical signicance should be interpreted in the light of the company they keep, i.e. whether they are accompanied by weakness, wasting, sensory disturbances, sphincter dysfunction, etc. When unaccompanied by any other symptom or sign of neurological dysfunction, they are likely to be benign. Neurophysiologically, fasciculations are often considered to be evidence of active denervation and are lumped together with brillations and positive sharp waves under the rubric of spontaneous activity. However, in neurogenic disorders fasciculations are more likely to be a manifestation of motor axonal instability, probably a reection of recent reinnervation and collateral sprouting, rather than an effect of denervation. At a molecular level this could be correlated with changes in potassium and calcium channel conductance and axonal membrane ionic gradients. The exact link between these two observations is not clear. In neurogenic diseases, this link may be the presence of focal areas of low accommodation at the sites of growth cones and nodal sprouts within the axon, a consequence of ongoing reinnervation. On the other hand, benign fasciculations could result from the ephaptic transmission of currents along motor axons, perhaps due to altered ionic gradients across the axonal membranes. Alternatively, ephaptic transmission could be the consequence of dysfunctional potassium ion channels within structurally normal motor axons. In most peripheral neuromuscular disorders, published evidence points towards a distal site of origin of fasciculations, within the terminal arborisation of the motor axon. However, this may not necessarily be true for fasciculations in amyotrophic lateral sclerosis (ALS / MND). Fasciculations are a hallmark of the widespread involvement of motor neurons in the spinal cord in motor neuron disease (ALS / MND). That fasciculations could be driven in certain circumstances by cortical excitatory postsynaptic volleys is a fascinating novel concept. The possibility that multiple and changing sites of origin could exist especially in patients with ALS / MND has been recently proposed and this deserves further consideration. The relationship of multiple and changing sites of origin to either the severity or the rapidity of progression of ALS / MND is not clear at present. Similarly, the ontogeny and temporal prole of changes in the characteristics of fasciculations during the progression of ALS / MND is

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J. Desai, M. Swash / Journal of Neurological Sciences 152 Suppl. 1 (1997) S43 S48 Norris, Jr. F.H., 1965. Synchronous fasciculation in motor neuron disease. Arch. Neurol. 13, 495500. Odom, G., Russel, C.K., McEachern, D., 1943. Studies of neuromuscular disorders: the myogram, blood cholinesterase and the effect of prostigmin in myasthenia gravis and progressive muscular atrophy. Brain 66, 117. Olney, R.K., Aminoff, M.J., So, Y.T., 1991. Clinical and electrodiagnostic features of X-linked recessive bulbo-spinal neuronopathy. Neurology 41, 825828. Patel, A.N., Swami, R.K., 1969. Muscle percussion and neostigmine test in the clinical evaluation of neuromuscular disorders. New Engl. J. Med. 281, 523526. Raines, A., Henderson, T.R., Dretchen, K.L., 1989. Effects of calcium channel blocking agents on neostigmine-induced fasciculations. Eur. J. Pharmacol. 173, 1117. Randell, T., Yli-Hankala, A., Lindgren, L., 1993. Isourane inhibits muscle fasciculations caused by succinylcholine in children. Acta Anaesthesiol. Scand. 37, 262264. Raudino, F., 1991. Fasciculations in peripheral neuropathies. Electromyogr. Clin. Neurophysiol. 3 (1), 5354. Romano, J.G., 1996. Reduction of fasciculations in patients with ALS with the use of gabapentin. Arch. Neurol. 53 (8), 716. Roth, G., 1971. Fasciculations dorigine peripherique. Electromyography 11, 413428. Roth, G., 1982. The origin of fasciculations. Ann. Neurol. 12, 542554. Roth, G., 1984. Fasciculations and their F-response. Localisation of their axonal origin. J. Neurol. Sci. 63 (3), 299306. Roth, G., Rohr, J., Majistris, M.R., Ochsner, F., 1986. Motor neuropathy with proximal multifocal persistent conduction block, fasciculations and myokimia. Evolution to tetraplegia. Eur. Neurol. 25 (6), 416423. Russel, C.K., Odom, G., McEachern, D., 1938. Physiological and chemical studies of neuromuscular disorders. Trans. Am. Neurol. Assoc. 64, 120124. Russell, W.R., 1952. Poliomyelitis. Edward Arnold, London, p. 84. Sindermann, F., Conrad, B., Jacobi, H.M., Prochazka, V.J., 1973. Unusual properties of repetitive fasciculations. EEG Clin. Neurophysiol. 35, 173179. Simpson, J.A., Thomaides, T., 1988a. Fasciculation and focal loss of accomodation in peripheral neuropathies. Acta Neurol. Scand. 77 (2), 133141. Simpson, J.A., Thomaides, T., 1988b. Local sites of low accommodation of peripheral motor axons and the pathogenesis of fasciculations in amyotrophic lateral sclerosis. Acta Neurol. Scand. 77 (2), 142147. Sprouse, J.S., Baker, T., Riker, Jr. W.F., 1985. Pharmacologic exitability of rat motor nerve endings: the effect of adrenalectomy on neostigmine induced fasciculations. J. Pharmacol. Exp. Ther. 235 (3), 864872. Standaert, F.G., Riker, Jr. W.G., 1967. The consequences of cholinergic drug actions on motor nerve terminals. Ann. NY Acad. Sci. 144, 517533. Swank, R.L., Price, J.C., 1943. Fascicular muscle twitchings in amyotrophic lateral sclerosis. Their origin. Arch. Neurol. Psychiatry 49, 2226. Trojaborg, W., Buchthal, F., 1965. Malignant and benign fasciculations. Acta Neurol. Scand. 41 (Suppl. 13), 251254. Trontelj, J.V., Janko, M., 1993. The pathophysiological mechanism of fasciculations in normal people. Zdrav Vestn. 62, 435439. Van der Heijden, A., Spaans, F., Reulen, J., 1994. Fasciculation potentials in foot and leg muscles of healthy young adults. Electroencephalogr. Clin. Neurophysiol. 93 (3), 163168. Wettstein, A., 1979. The origin of fasciculations in motor neuron disease. Ann. Neurol. 5, 295300. Yli-Hankala, A., Randell, T., Varpula, T., Lindgren, L., 1992. Alfentanil inhibits muscle fasciculations caused by suxamethonium in children and young adults. Acta Anaesthesiol. Scand. 36, 588591.

unknown. This has implications for the monitoring and assessment of progression of ALS / MND, especially during therapeutic trials since fasciculations are modulated by the actions of various drugs. It remains for future neurophysiological research to address these issues and further unravel the physiological implications of this characteristic clinical feature of ALS / MND.

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