Article Text

PDF

Review
Fasciculation in amyotrophic lateral sclerosis: origin and pathophysiological relevance
  1. Mamede de Carvalho1,2,
  2. Matthew C Kiernan3,
  3. Michael Swash2,4
  1. 1 Department of Neurosciences and Mental Health, Hospital de Santa Maria-CHLN, Lisbon, Portugal
  2. 2 Institute of Physiology-IMM, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
  3. 3 Bushell Chair of Neurology, Sydney Medical School, University of Sydney, Brain & Mind Centre, University of Sydney, Sydney, NSW, Australia
  4. 4 Department of Neurology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  1. Correspondence to Professor Mamede de Carvalho, Institute of Physiology-IMM, Faculty of Medicine, University of Lisbon, Portugal, 1649-028, Lisbon, Portugal; mamedemg{at}mail.telepac.pt

Abstract

This review considers the origin and significance of fasciculations in neurological practice, with an emphasis on fasciculations in amyotrophic lateral sclerosis (ALS), and in benign fasciculation syndromes. Fasciculation represents a brief spontaneous contraction that affects a small number of muscle fibres, causing a flicker of movement under the skin. While an understanding of the role of fasciculation in ALS remains incomplete, fasciculations derive from ectopic activity generated in the motor system. A proximal origin seems likely to contribute to the generation of fasciculation in the early stages of ALS, while distal sites of origin become more prominent later in the disease, associated with distal motor axonal sprouting as part of the reinnervation response that develops secondary to loss of motor neurons. Fasciculations are distinct from the recurrent trains of axonal firing described in neuromyotonia. Fasciculation without weakness, muscle atrophy or increased tendon reflexes suggests a benign fasciculation syndrome, even when of sudden onset. Regardless of origin, fasciculations often present as the initial abnormality in ALS, an early harbinger of dysfunction and aberrant firing of motor neurons.

  • amyotrophic lateral sclerosis
  • benign fasciculations
  • fasciculations
  • hyperexcitability
  • motor neuron disease

Statistics from Altmetric.com

Introduction

Although their origin remains a source of debate, fasciculations are a very obvious phenomenon in amyotrophic lateral sclerosis (ALS). These apparently random, spontaneous twitching of muscle fibres are enough to trigger anxiety in the healthiest of people and send them scurrying to Dr Google. But when manifested in the presence of concomitant muscle wasting, fasciculations take on more complex considerations.

Fasciculations may appear irregular both in terms of firing pattern and muscle involvement, although intensive technological investigation and mathematical modelling suggests a more ordered development. In the case of ALS, while fasciculations are an almost inevitable accompaniment of the disease, the role of fasciculations in disease pathogenesis remains to be determined. Similarly, in a disease defined by involvement of the upper and lower motor neuron, with or without fronto-temporal dementia, determination of how, whether and when fasciculations may arise in the upper or lower motor neuron compartments or, indeed, arise simultaneously in both, may prove critical in understanding the underlying disease process.

In the case of the motor axon, fasciculations may arise from both proximal and distal segments and, separately, from within the motor neuron itself (figure 1). Fasciculations have also been identified as linked to cortical hyperexcitability in ALS, with elegant descriptions of synchrony of discharges suggestive of a common synaptic input arising from the corticospinal tract. Perhaps, at a simple level, the hyperexcitability that drives the development of fasciculation may be generated peripherally as a result of membrane instability in motor axons as well as in lower motor neurons that are intrinsically hyperexcitable. There is evidence, in addition, that fasciculations may be recruited by a hyperexcitable corticospinal system. The apparent contrast between these two compartments of the human nervous system will form the crux of this review, which will explore the origins and pathogenic significance of fasciculations in ALS. We will further consider that fasciculations may occur in many disease states other than ALS, and indeed in healthy subjects, where their origin and significance remain somewhat mysterious.

Figure 1

Potential generators of fasciculation across compartments of the human nervous system. Corticospinal and propriospinal drive represent upper motor neuron activation of an anterior horn cell (AHC). Modulation of output from the AHC occurs via Renshaw cell collateral inhibition, and also by input from interneurons and propriospinal neurons and by afferents from muscle spindles and tendon organs (Group la, Group lb and Group ll afferents). In amyotrophic lateral sclerosis (ALS), there is functional abnormality in the upper motor neuron (UMN) and in the AHC that develops over time, leading to axonal degeneration (and attempted regeneration), with loss of the terminal innervation of muscle fibres, causing weakness. Hyperexcitability of the UMN pathway may drive surviving AHCs in the lower motor neuron (LMN) towards hyperexcitability, leading to fasciculation; that is, spontaneous firing in the LMN pathway. These fasciculations may arise in the AHC early in ALS, and in the terminal arborisation when there is regeneration after muscle fibre denervation, especially later in the disease. Spontaneous motor unit activity also occurs at an axonal level in autoimmune and metabolic channelopathies and states of ionic imbalance. Benign fasciculation disorder (BFS), with or without cramp, represents a distal LMN excitability of uncertain biochemical causation.

Historical perspective

Involuntary ‘fibrillar twitching’ or ‘flickering’ of limb muscles and the tongue, seen through skin and mucous membrane, was first described in the disorder now recognised as ALS more than 150 years ago.1 It was an early clinical observation that fasciculation precedes other symptoms.2 Even in the 19th century ‘fibrillar twitching’ was understood as a sign of a denervating, rather than a myopathic disorder, and Charcot emphasised its importance in the diagnosis of ALS.3

The modern term ‘fasciculation’ was introduced by Denny-Brown and Pennybacker in their seminal 1938 paper4 to describe electromyographic (EMG) evidence that these involuntary twitches were due to spontaneous contraction of muscle fascicles, originating from motor unit depolarisation. They reserved the term fibrillation for small diphasic electrical potentials originating from denervated single muscle fibres. Nonetheless, in clinical practice, fasciculation of the tongue is sometimes still referred to as ‘fibrillation’, a terminology that refers to the early 19th-century descriptions. However, even in the tongue it is improbable that fibrillating single muscle fibre activity can be visualised, given the small size of individual muscle fibres.

Origin of fasciculation

Fasciculations are characteristic of ALS.1–5 They are important in diagnosis of the disease and have been incorporated in formal diagnostic criteria.6 Real-time ultrasound imaging has revealed the dramatic extent of fasciculation in ALS.7 Fasciculations were at first thought always to originate in the lower motor neuron, near the soma of motor neurons.4 However, Norris noted that fasciculations could sometimes be recorded synchronously in muscles innervated by the same myotome, but by different motor nerves, suggesting that some fasciculations may have a supranuclear or perhaps even a cortical origin.8 It should be recognised, nonetheless, that in LMN disorders, slight contraction of a muscle in one limb can be associated with simultaneous contraction of a muscle in the opposite limb.9 In support for a central origin, reduction in the frequency of fasciculation (although not complete suppression) may develop following spinal anaesthesia, indicating a central origin or at least influence that may promote the generation of fasciculations.10 Furthermore, in ALS, some fasciculations can be driven by cortical stimulation.11 These observations suggest central modulation or, alternatively, that a distal axonal generator can be over-ridden by more proximally generated neuronal activity. To clarify these possibilities, collision and F-wave techniques have been used to determine the origin of fasciculations, with mixed findings, leading to conclusions that fasciculations can arise both in distal and proximal parts of the lower motor neuron (LMN).12–15

Apart from any central influence, the origin of fasciculations is dependent on the functional state of the LMN (figure 1). In ALS, complex unstable fasciculations arise in abnormal, reinnervated, surviving motor units, most likely from a generator site located in distal axonal branches.16 Complex and unstable fasciculations tend to be found predominantly in weak, wasted muscles and have longer interdischarge intervals (IDIs), as compared with less complex, more stable fasciculations.17 These features may in turn suggest a more proximal origin for fasciculations recorded in mildly denervated muscles, consistent with the observation that 77% of all stable fasciculations could be voluntarily activated, as opposed to 12% of the more complex and unstable fasciculations found in weak atrophic muscles, which have a greater fibre density and jitter compared with stronger muscles.16

Studies of complex fasciculations have determined that double fasciculations occurred in two band intervals, 4–10 ms, related to an abnormal supernormal period in distal axonal branches, and 30–50 ms, indicating a common generator at a more proximal origin.17 High-density surface EMG recording has confirmed this finding of two typical IDI interval sets of fasciculations in ALS; 4–5 ms and approximately 70 ms. Approximately 80% of fasciculations recorded in ALS with this technique were in the shorter IDI band, perhaps suggesting an origin in distal axon branches,18 although others have criticised this interpretation, suggesting that short IDIs do not rule out a more proximal origin.19 A technique using double EMG needle recordings from two different motor units has revealed that, early in the disease, many fasciculations have a proximal origin.20 However, this double recording technique technique does not allow verification of Norris’ observations that suggested a spinal contribution (or perhaps a relay centre) for at least some fasciculations in ALS.

In ALS, fasciculations are often the first and only abnormality recorded in muscles as yet seemingly unaffected by the disease, at least without evidence of dysfunction involving the lower motor neuron. These early fasciculations are typically of simple morphology (figure 2A). They may precede other features of ALS by many months. In follow-up studies, both voluntarily generated motor unit potential (MUPs) and spontaneous fasciculations become more complex, showing increased jitter and blocking of components of these complex units,2 consistent with ongoing reinnervation as a compensatory process during motor neurodegeneration (figure 2B). However, compensatory reinnervation is insufficient to keep pace with the ongoing motor pathway destruction in the disease.

Early reduction of the motor threshold, most pronounced in ALS patients with profuse fasciculations, preserved muscle bulk and hyper-reflexia, has suggested a cortical origin for some fasciculations.21 Indeed, cortical motor hyperexcitability is a very early feature of ALS, even developing before the disease becomes clinically and symptomatically evident.22 Fasciculations that appear early in the course of the disease have the same morphology as the first recruited motor units (figure 2A), a finding consistent with increased excitability within LMNs, at anterior horn cell level,22 which probably also occurs in more affected neurons. This observation is confirmed by the increased frequency of fasciculation potentials observed following peripheral sensory nerve stimulation.23 Prolific fasciculation potentials recorded during an EMG examination appear to be a poor prognostic factor,24 25 implying hyperexcitability of the peripheral motor system.26 The infrequent fasciculations found in primary lateral sclerosis (PLS) fire at a much lower frequency.25 In PLS, neurodegeneration is restricted to the upper motor neuron, and survival is much longer. In progressive muscular atrophy, a disorder that pathologically resembles classical Charcot ALS, fasciculations are prominent although survival is variable.

Figure 2

(A) Fasciculation potentials of stable, simple morphology, recorded from an early affected muscle in an ALS patient. The origin of such potentials is probably in the proximal motor axon or in the anterior horn cell. (B) A polyphasic, unstable fasciculation potential, possibly originating from distal motor axonal spouts following reinnervation. There are eight consecutive discharges representing firing of the same motor unit.

Abnormal behaviour of the axonal membrane and constituent ion channels has been identified in motor nerves in patients with ALS by threshold tracking techniques which have revealed changes indicative of increased persistent Na+ channel conduction and reduction in K+ currents.21 Follow-up studies show increasing K+ channel dysfunction in motor axons, but in longitudinal studies, K+ channel dysfunction was greater in patients with ALS with relatively stable CMAP amplitudes, suggesting that this change could be a compensatory mechanism.27 Both decreased K+ conductance and increased persistent Na+ conductance contribute to instability of the axonal membrane, resulting in the development of ectopic activity. Computer modelling suggested that reducing voltage-dependent potassium conductance caused axon instability, a possible mechanism for induction of fasciculation potentials.28 Studies in the superoxide dismutase oxygen 1 (SOD1) animal model of ALS suggest that at an early phase motor axons enter a state of membrane depolarisation but, later in the disease, axonal degeneration causes more complex changes in axonal excitability.29 In addition to suggesting further therapeutic targets in ALS, reduction in axonal K+ conductance decreases a hyperpolarising tendency while an increase in persistent Na+ conductance increases depolarising drive.30 In ALS the prognosis is determined, at least in part, by the advent of an increasing persistent axonal sodium current, as detected in threshold tracking studies.26

Regenerating motor end plates are more sensitive to acetylcholine released in synaptic clefts, as shown in neurogenic disorders by fasciculations induced by small doses of parenteral neostigmine.31 The efferent impulse from a motor neuron is generated at the initial segment of the nerve fibre (the axon hillock) where the threshold (the inverse of electrical excitability) of the neuronal membrane is lowest. Neuronal firing occurs in response to a change in membrane charge caused by the summated, graded excitatory postsynaptic potentials (EPSPs) at dendritic synapses with the cell body. EPSPs develop from the opening of ligand-gated channels by glutamate, released from presynaptic terminals, a major excitatory neurotransmitter that leads to hypopolarisation, making spontaneous neuronal firing more likely. Glutamate is present in increased concentration in the neuropil in ALS. Neuronal inhibition is induced by glycine, an inhibitory transmitter released from presynaptic terminals that triggers a chloride current, causing transient neuronal membrane hyperpolarisation. Inhibition also occurs by depolarisation of the primary afferent (Group Ia) terminal through the action of gamma-amino butyric acid, an inhibitory transmitter present in that spindle afferent system. The resultant change in the gain of the motoneuron, a consequence of some of these effects, can induce a persistent inward current and a plateau potential, long outlasting the inducing neuronal activity, increasing the probability that the neuron will discharge. Motor axons innervating muscles have different properties according to their discharge rates. Fasciculation is more likely to arise in larger, faster conducting motor axons since these are more excitable and have greater hyperpolarisation-activated cyclic nucleotide-gated channel (HCN) activity.32 HCN activity is associated with a prolonged after-hyperpolarisation potential, a potential dependent on a calcium-activated potassium channel.32

Fasciculations therefore have complex biophysical origins, and these are different in motor neuronal cell bodies and motor axons. In ALS, there is evidence that fasciculations are induced in cell bodies early in the disease and in distal axons later, when there is well-developed reinnervation with distal axonal sprouting (figure 2B). Neuromyotonia, a form of repetitive, spontaneous, motor axonal discharge, probably develops from biophysical abnormalities in voltage-activated slow K+ channels in motor axons, sometimes associated with specific antibody blockade.33 Better understanding of the factors favouring ectopic impulse generation would lead to more effective management, for example, by specific sodium-channel blocking drugs, antiglutamatergic drugs, or perhaps, magnesium supplements.

Clinical correlates of fasciculation

Although fasciculations occur in healthy people, in particular in foot muscles and gastrocnemius,34 such fasciculations are infrequently symptomatic. Awareness of fasciculations often raises concern about the possibility of motor neuron disease, especially in the modern era, in which, access to the Internet reinforces this possible association (http://www.aboutbfs.com). This concern is inevitably frequent among physicians or other workers in healthcare systems, and has been termed fasciculation anxiety syndrome.35 It is an important disease marker only when associated with other neurological symptoms and signs, particularly weakness. For example, diffuse fasciculations and weak wasted muscles suggest ALS, but fasciculations without motor system abnormality are likely to be benign.

Distal fasciculations occur in neuropathies, especially multifocal motor neuropathy36 and also in chronic inflammatory demyelinating polyneuropathy (CIDP) but only rarely in diabetic neuropathy or Charcot-Marie-Tooth disease. Focal demyelination in peripheral motor or sensory axons can lead to increased axonal excitability and ectopic firing, and fasciculations may develop after peripheral compressive nerve injury or traumatic motor root lesions.37 Sometimes focal fasciculations follow radiation injury to cervical plexus38 or to the spinal cord as part of a slowly progressive LMN syndrome.39 Fasciculations are prominent in chronic lower motor neuron disorders such as postpolio syndrome,40 spinal muscular atrophy, especially bulbo-facial fasciculation in Kennedy’s disease.41 In the latter disorder, EMG recordings have shown that fasciculation potentials occur at a much slower rate than in ALS and tend not to be complex in type.41 Fasciculations occur in partially denervated upper limb muscles in cervical spondylotic myelopathy, and in cervical spondylosis they have also been described in leg muscles, a feature suggesting coincidental lumbar spondylosis or perhaps an associated UMN influence.42 Acquired metabolic disorders may also be associated with fasciculations, as in thyrotoxicosis,43 hypocalcaemia44 and hypomagnesaemia.45 Cholinergic hyperactivity at motor end plates secondary to organophosphate poisoning causes widespread fasciculations.46 Neurotoxic envenomisation, due to certain spider, snake and scorpion bites causes fasciculations as paralysis develops.47 Finally, fasciculation can also result from high caffeine intake, unaccustomed exercise48 and drugs with serotoninergic49 or cholinergic activity (pyridostigmine),31 or depolarising paralytic agents, for example, succinylcholine used in surgical anaesthesia.50 Sparse distal fasciculations were reported in 2 of 70 patients with inclusion body myositis, but this appears exceptionally uncommon.51

Methods for detecting fasciculations

Fasciculations are typically identified by clinical observation in muscles at rest, that is, superficial parts of muscles, such as deltoids, biceps brachii, triceps and thenar eminence in the upper limbs or in quadriceps and calf muscles in the lower limbs. The tongue is a particularly suitable muscle for clinical detection of fasciculations since its mucous epithelium is thin; indeed, bilateral fasciculation of the tongue is highly suspicious of a diagnosis of ALS.5 Patients can sometimes feel the movement of an affected muscle during fasciculations or they or their partners may observe the abnormal involuntary muscular movement. Fasciculatory contraction of a muscle is a different phenomenon, closely associated with chronic reinnervation such that contractions of large reinnervated motor units can be seen through the mucous membrane of the tongue or the skin overlying a limb muscle during a movement. Sometimes cramps accompany fasciculations during voluntary movements, both in ALS and in the benign cramp-fasciculation syndrome.52

The conventional EMG method for fasciculation detection requires recording with a concentric needle EMG electrode from several locations, each for at least 90 s to be sure that fasciculations are or are not present.53 Fasciculation potentials should be searched for in several upper limb and lower limb muscles and also, when clinically relevant, in the genioglossus, although in the latter it is difficult to achieve full relaxation during needle EMG examination. The trapezius muscle has been recommended as the most informative muscle for detecting fasciculations in possible ALS.54 Surface electrodes, placed at multiple recording sites, have also been used.25 55 High-density surface EMG, which provides simultaneous information about many different motor units is particularly suitable for long recordings.48 Ultrasound imaging can directly visualise fasciculations in resting muscle7 including tongue and other muscles such as biceps brachii which are accessible to the ultrasound probe.56 These studies reveal near simultaneous contraction of several fascicles, suggesting that many neighbouring motor units are often recruited into fasciculatory activity. In contrast, concentric needle EMG electrodes, which are designed for recording from a few motor units in focal areas of muscle, do not reveal the full extent of fasciculation. Ultrasound imaging may be the most sensitive method for fasciculation potential (FP) detection,57 since the full depth of a muscle can be examined. However, ultrasound studies do not allow analysis of the morphology or firing characteristics of the motor units involved. 

Benign fasciculation and cramp fasciculation syndromes

Across a range of nerve hyperexcitability syndromes, benign fasciculation syndrome (BFS) presents with persistent fasciculation, without other neurological abnormality (box 1). Although benign fasciculations are very common in leg muscles,34 other muscles are also commonly affected23 48 without progression or neurological causation (box 1). The phenomenon is often intermittent but may continue for months or years. Benign fasciculations are often more prominent after exercise, and less obvious after a period of rest, and diurnal variation in frequency and firing rate may be noted.58 Fasciculations may also be precipitated and aggravated through mood-related changes, particularly anxiety, presumably through hyperventilation and alterations in central excitability. Electromyographic analysis (figure 2) typically confirms that the fasciculations in BFS are simple in form without evidence of reinnervation and without impulse blocking within the fasciculation potential itself3 (figure 2). BFS may commence relatively abruptly, although without any associated illness. Axonal excitability was studied in a carefully defined group of 20 subjects with benign fasciculations, not on medication, using the threshold tracking technique.59 The results, analysed with mathematical modelling, were best explained by depolarisation of the voltage dependency of HCN channels in motor axons, causing increased inward rectification, although polarisation parameters of the resting membrane potential were not changed. It was suggested that HCN channels had a functional role during the rhythmic discharge associated with a voluntary contraction. It was also noted in this study that in BFS motor unit discharge rates were higher than controls during maximal voluntary effort, implying disturbance of the firing rate–force relationship, caused by an abnormality in orderly recruitment.

The firing frequency of benign fasciculations has been reported to be faster than the fasciculations observed in motor neuron disease,60 although Mills confirmed this only in advanced ALS.17 Unlike ALS, in which fasciculations often originate from several different, closely related motor units, benign fasciculations generally originate from a single hyperexcitable motor unit, without increased complexity (figures 1 and 2). The origin of this ectopic activity is most frequently proximal to the distal axonal branching point.2 19 An ultrasound study of benign fasciculations has confirmed a predominant but not exclusive lower limb distribution,34 with a possible slight increase in fasciculations in lower limb muscles after exercise,48 61 not found in studies of a hand muscle.23 Furthermore, the firing frequency of fasciculations in BFS has been shown to vary at different times in the day.58 BFS probably represents a spectrum of disordered LMN function (figure 1). The key difference between fasciculations associated with BFS, unlike ALS, is that in BFS muscle strength, tone and tendon reflexes are all normal. However, fasciculation potentials in concentric needle EMG recordings in the very early stages of ALS may be of normal morphology, as is usual but not invariable in BFS,17 rather than the more characteristic complex morphology usually associated with fasciculation potentials in established ALS.2 60 62

Box 1

Causes of fasciculation

Motor neuron disease and its variants

Spinal muscular atrophy and Kennedy syndrome

SCA 3 (Machado-Joseph disease)

Postpolio syndrome

Herpes Virus one infection

Neuropathies

  • Multifocal motor neuropathy with conduction block

  • Chronic inflammatory demyelinating polyneuropathy

  • Other Immune-related neuropathies (eg, IgM1- related)

  • Charcot–Marie–Tooth syndromes

  • Nerve entrapment syndromes and nerve injuries

Motor root and plexus lesions

  • Inflammatory

  • Radiation plexopathy

Spinal cord disorders

  • Syringomyelia

  • Cervical spondylosis with cord compression

  • Radiation myelopathy

  • Viral myelitis for example, herpes zoster, rabies

Metabolic disease

  • Hypocalcaemia

  • Hyperthyroidism

  • Hypomagnesaemia

Hyperexcitability of peripheral motor axons

  • Benign fasciculation syndrome

  • Cramp-fasciculation syndrome

  • Post-exercise fasciculation

Drug-related fasciculation

  • Caffeine, cholinergic drugs, amphetamines, antihistamines, serotonin compounds, salbutamol, benzodiazepine withdrawal

  • Organophosphate insecticide poisoning

Envenomisation: bites by snakes, funnel-web spider, or scorpion

Pharmacological cholinergic block in anaesthetic practice

Related autoimmune disorders

  • Anti-voltage-gated potassium channels (VGKC) immune disease (encephalopathy with peripheral axonal disorder)

  • Neuromyotonia

Inclusion body myositis

A variant of BFS, cramp-fasciculation syndrome, is associated with pain, exercise intolerance, subjective fatigue and anxiety, as well as spontaneous cramp at rest and on exertion and fasciculation at rest.63 This condition typically occurs in young men. In young women intermittent distal tingling may be an associated feature (the terms ‘latent tetany’, ‘cryptotetany’ and ‘spasmophilia’ have also been used to describe this clinical picture). In some patients, an association with mild hypomagnesaemia has been identified.64 In these patients, fasciculations and paraesthesiae may be induced following 10 min of cuff-induced upper limb ischaemia followed by hyperventilation.65 After this test, protocol myokymic discharges (figure 3) and fasciculations become more prominent, as identified by EMG. Studies of muscle twitching, cramps and paraesthesiae with ectopic activity induced by hyperventilation or ischaemia, identified differential behaviour between sensory and motor fibres, in that sensory fibres were more likely to develop ectopic activity. These differences between sensory and motor nerve fibres in peripheral nerves appeared to relate to selective effects of hyperventilation on ‘threshold channels’ in the axons. The latter were considered analogous to persistent sodium channels active at resting membrane potential but expressed more in sensory than in motor axons. Separate studies in cramp identified bistability in the motor neuronal membrane as the likely trigger.52 Specifically, when the membrane was stable above threshold, that is, hyperpolarised at rest, spontaneous depolarisation may occur leading to motor neuronal discharges at 8–12 Hz, causing the clinical phenomena of myokymia and fasciculation. Progression to cramp may occur from ephaptic transmission to adjacent muscle fibres or recruitment of additional motor neurons. This motor neuronal activity can be suppressed by vibratory stimulation of Ia afferents and also by electrical stimulation of the motor axons.52 Fasciculation may occur associated with this motor neuronal bistability when the resting membrane potential is at a higher than normal level.

Figure 3

Myokymic discharges recorded in an upper limb muscle after ischaemic release following 10 min cuff inflation. There are clusters of motor unit discharges originating from axonal sites following the ischaemic period. This abnormality is associated with the ‘spasmophilia syndrome’, associated with axonal hyperexcitability ascribed to hypomagnesaemia (see text).

Cramps, occurring as a sole manifestation, tend to become more frequent in older people, often in the context of statin therapy; they are rare in upper limbs of healthy subjects without metabolic imbalance. Cramps may also develop during high-rate repetitive nerve stimulation.66 Benign fasciculations and cramp-fasciculation syndrome can be regarded as part of a larger spectrum of disease that also incorporates acquired auto-immune neuromyotonia.67 Indeed, antibodies to the voltage-gated potassium channel complex have been identified in 32% of patients with cramp-fasciculation syndrome,68 including leucine-rich glioma-inactivated-1 antibodies in a small, tested subset of patients. In a minority of patients, fasciculations and cramps may be associated with a non-progressive motor neuron disease syndrome with chronic neurogenic changes on EMG and increased creatine kinase (CK).69 These syndromes typically do not progress to motor neuron disease.70 However, exceptionally rarely, progression or cramp-fasciculation syndrome to ALS has been reported.71

All that fasciculate are not ALS

Prominent fasciculations and muscle atrophy, with predominant upper extremity involvement and brisk reflexes36 may cause multifocal motor neuropathy (MMN) to be misdiagnosed as ALS.72 Although focal conduction block in motor nerves suggests the diagnosis of MMN, it is sometimes difficult to detect, either because it is absent or very proximal. Neurophysiological evidence of chronic reinnervation within distinct nerve territories is important in differentiating MMN from slowly progressive ALS, and ultrasound can be useful to detect focal nerve enlargement. Systematic studies of the distribution and frequency of fasciculations in motor neuropathies, for example, by using ultrasound as a detection methodology, are lacking.

Axonal excitability studies have demonstrated a different pattern of abnormality in patients with MMN as compared with those with ALS. Distal to the site of conduction block in MMN there are changes indicative of axonal hyperpolarisation, including increased threshold change in threshold electrotonus (both depolarising and hyperpolarising) and prominently increased superexcitability.73 These abnormalities were normalised by application of depolarising current, suggesting that there was membrane hyperpolarisation. The development of hyperpolarisation distal to the site of conduction block implies blockade of Na+/K+ pump activity at the lesion site, leading to intracellular accumulation of Na+ (figure 1). As the excess Na+ ions diffuse along the axon, the axon pump distal to the block tends to overcompensate in an attempt to correct the ionic imbalance. Overactivity of the pump therefore leads to a net hyperpolarisation in membrane potential due to the discrepancy in K+ and Na+ transport ratios. Accordingly, areas of depolarisation and hyperpolarisation surround the site of conduction block along the axon. This pattern of excitability change differentiates MMN from ALS.

In postpolio syndrome, fasciculations have been described in the majority of affected patients, associated with loss of endurance, limited ambulation, increased weakness with functional impairment and increased fatigue.74 Fasciculations in postpolio syndrome are usually more prominent after exercise and consist of large involuntary fascicular contractions, representing reinnervated motor units or groups of motor units.9 Fasciculations were a well-recognised feature in acute poliomyelitis, before onset of the paralytic phase of the illness. Ritchie Russell75 noted that in acute polio the slight involuntary contractions of muscular units closely resembled those seen in motor neuron disease’ and that ‘the appearance of this sign often indicates that paralysis will affect the muscles showing fasciculation within the next 24 hours’, an observation raising tempting speculations regarding fasciculation and motor neuron death in ALS. Thus, in acute poliomyelitis fasciculations were considered to originate from sick, infected lower motor neurons, whereas the complex fasciculations characteristic of postpolio syndrome probably originate in distal regenerated axonal branches innervating residual reinnervated motor units, sometimes associated with action tremor.9

In syringomyelia, fasciculations occur in affected muscles, therefore usually in a segmental distribution in upper limb muscles.76 Compressive root lesions cause pain and sensory symptoms with weakness and fasciculations. Most fasciculations in root lesions originate from distal axonal sprouts associated with reinnervation, but some (about 25%) have a more proximal origin, presumably at the point of compression of the motor root.37 Fasciculation is also a feature of isolated acute or subacute peripheral nerve compression syndromes,77 although in chronic nerve compression disorders such as carpal tunnel syndrome, fasciculations are rarely observed clinically.78 Because nerve compression causes focal demyelination, these discrepancies raise the probability that specific mechanisms, such as trauma-induced channelopathies in the nodal structures or ephaptic axonal activity at the site of compression–demyelination are important in this process.

Fasciculation, especially of the tongue, is prominent in type1 and type 2 spinal muscle atrophy, disorders in which survival is relatively short. Fasciculation in limb muscles and tongue can also be seen in patients with type 3 spinal muscular atrophy (SMA).

Fasciculations—an unresolved issue

When you have eliminated all which is impossible, then whatever remains, however improbable, must be the truth. (Arthur Conan Doyle, The Case-Book of Sherlock Holmes).

Fasciculations in ALS are associated with hyperexcitability of the peripheral motor axon, and the disease itself is associated with hyperexcitability in the central nervous system. At present, the extent of interplay between central and lower motor neuron excitability and fasciculations remains unresolved. It seems likely that repetitive fasciculation implies rapid progression, although the biophysical abnormalities underlying fasciculations in ALS remain incompletely understood. It is possible, for example, that rapid fasciculation may precipitate metabolic stress in affected motor neurons, thus hastening cell death.

Returning then to basic principles, ALS results from neurodegeneration in several compartments or systems in the nervous system. While there remain questions of primacy, if we simply accept that there exist proximal and distal factors in fasciculation, it remains conceivable that early in the disease, when fasciculations may appear as a primary manifestation, in the absence of muscle weakness, the processes linked to supraspinal excitability are dominant. Later, with progressive dysfunction of the lower motor neuron system, as muscles become weak and complex highly unstable motor units develop, ectopic activity is driven through peripheral motor axonal generators. Eventually, as corticospinal tract and peripheral motor axons degenerate, fasciculations (and cramp) become less prominent. Regardless of these suppositions, fasciculations are a major and characteristic feature of ALS, and consideration of their contribution to the pathophysiology of the disease seems critical to unravelling the complex jigsaw that is ALS.

References

View Abstract

Footnotes

  • Competing interests None declared.

  • Provenance and peer review Commissioned; externally peer reviewed.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.