Neurophysiological testing in the diagnosis of amyotrophic lateral sclerosis

David Burke

doi:10.4103/nsn.nsn_199_21

Neurophysiological testing in the diagnosis of amyotrophic lateral sclerosis

David Burke
Department of Neurology, Royal Prince Alfred Hospital, University of Sydney, Sydney, N.S.W, Australia

Correspondence Address:
David Burke
Department of Neurology, Royal Prince Alfred Hospital, University of Sydney, Sydney, N.S.W
Australia

Neurophysiological testing plays a very important role in the diagnosis of amyotrophic lateral sclerosis (known in the British world as motor neuron disease). As specified in the Awaji criteria, electromyography is critical for defining the neurogenic changes due to involvement of the lower motor neuron (LMN), and it can do so for muscles that are not involved clinically or are so only minimally. Demonstrating LMN involvement can be enhanced by the judicious use of neuromuscular ultrasound and imaging, particularly whole-body magnetic resonance imaging. There is a gap with involvement of the upper motor neuron (UMN), with promising procedures yet to be adopted widely. Reflex function can be used to demonstrate hyperreflexia and sometimes that paresis is at least partly of UMN origin. Protocols using transcranial magnetic stimulation can demonstrate enhanced excitability of interneuronal circuits in motor cortex and thereby pathology involving the UMN. The motivation behind studies using these and other techniques is to be able to make the diagnosis before the disease has spread significantly from its site of onset, when the clinical deficit is still minor.

Keywords: Amyotrophic lateral sclerosis, electromyography, transcranial magnetic stimulation

How to cite this article:
Burke D. Neurophysiological testing in the diagnosis of amyotrophic lateral sclerosis. Neurol Sci Neurophysiol 2022;39:1-7

How to cite this URL:
Burke D. Neurophysiological testing in the diagnosis of amyotrophic lateral sclerosis. Neurol Sci Neurophysiol [serial online] 2022 [cited 2023 Jun 4];39:1-7. Available from: http://www.nsnjournal.org/text.asp?2022/39/1/1/342365

Introduction

The disease, amyotrophic lateral sclerosis, ALS (also known as motor neuron disease), typically involves degeneration of motor pathways, involving both the upper motor neuron (UMN) in cerebral cortex and the lower motor neuron (LMN) in the brainstem and spinal cord. Increasingly, however, it is being appreciated that ALS may involve more than motor neuron degeneration – some patients develop cognitive and behavioral changes, even overt frontotemporal dementia, sensory abnormalities which are usually subclinical and autonomic changes. Nevertheless, the motor changes are the cardinal manifestations, without which the diagnosis cannot be made. This review will focus on how neurophysiological testing can assist the diagnosis. It will not consider the value of quantitative/semi-quantitative techniques (such as motor unit number estimates) that can be used to follow disease progress and the response to therapy.

The onset of ALS is insidious and there may be a relatively long period of minor symptoms that are too readily dismissed before the true diagnosis becomes apparent. The baseball star Lou Gehrig is a case in point: his batting average decreased in the year before ALS was diagnosed (career average 0.340; year before diagnosis 0.295, the first time in >10 years that his average was under 0.3). The initial symptoms were nonspecific: “I tired mid-season. I don't know why, but I just couldn't get going again.” (https://en.wikipedia.org/wiki/Lou_Gehrig). Studies in another neurogenerative disease, Parkinson's disease, suggest that, at the onset of the first symptoms, 30% of the neurons in the substantia nigra have been lost,^[1] and that at least 50% and possibly as much as 60%–70% are lost before a significant deficit develops. This is likely to be the case in ALS, and it means that by the time that a diagnosis of definite ALS can be made using the original El Escorial criteria,^[2] most neurons will already be committed to the disease process, if they are not already dead. Early diagnosis is becoming an increasingly important issue because new drugs are being developed and trialed and existing drugs are being “re-purposed” (Kiernan et al., 2021), and it is important to test them on patients who do not have such advanced disease that nothing will help.^[33] With this motivation, a consensus meeting was held on the Gold Coast in Australia to define what was truly necessary for diagnosis, resulting in the “Gold Coast criteria.”^[3]

To put advances in diagnostic testing into perspective, it is important to highlight some features of the original and revised El Escorial criteria.^[2],[4] They were based on clinical features and were originally designed to reflect the certainty of diagnosis of ALS: Definite, Probable, Possible, and Suspected [Table 1]. The revised criteria introduced “laboratory-supported probable ALS” and dropped “suspected ALS,” in a move to incorporate the use of electromyography (EMG). However, a diagnosis of definite ALS still required the involvement of bulbar muscles and two spinal regions. Many patients died with ALS without ever fulfilling those criteria. Not surprisingly, diagnostic specificity of the El Escorial criteria was high, but the sensitivity was low.

Table 1: Original El-Escorial criteria for the diagnosis of amyotrophic lateral sclerosis

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Lower Motor Neuron Involvement: Electromyography

As noted above, the diagnosis of ALS has long rested on clinical criteria, which may be supplemented by the demonstration of consistent neurophysiological abnormalities. The Awaji Criteria addressed the EMG evidence of LMN involvement,^[5] and their validation in subsequent trials has confirmed that diagnosis is possible earlier than would occur if the original or revised El Escorial criteria were followed. Nevertheless, in a large multicenter study of 399 patients with suspected ALS, Johnsen et al.^[6] wrote that “Revised El Escorial and Awaji criteria are complex and might require training for use” and “Inter-rater agreement was generally low both for rEEC [revised El Escorial Criteria] and AC [Awaji Criteria]”. In the Awaji criteria:

EMG findings were afforded the same weight as a physical examination, and electrophysiological evidence for chronic neurogenic change was considered equivalent to clinical evidence. To an experienced electromyographer, it is amazing that objective evidence of abnormality was previously not given the weight of clinical evidence, given that weakness requires significant loss of function to be demonstrable and that EMG can define subclinical neurogenic changes (fibrillation and positive sharp waves, fasciculation, neuropathic motor units)
The type of EMG data that can indicate ALS was expanded. Fasciculation is a major feature of ALS but had been neglected been neglected in previous diagnostic criteria, presumably because of the emphasis on clinical features. Benign fasciculation is very common and it may be impossible to identify this on clinical examination alone. However, on EMG, instability of the fasciculation potential was considered an important finding differentiating the ectopic discharge in ALS from fasciculation in otherwise healthy subjects. In the Awaji criteria, fasciculation potentials were considered equivalent to fibrillation potentials and positive sharp waves in identifying denervation. An example is given in [Figure 1] – a raster display of consecutive fasciculation potentials in tibialis anterior (TA). The following should be noted: (i) multiple motor units are spontaneously active in the same recording site; (ii) the increased duration of some motor unit action potentials (MUAPs), sometimes >20 ms; (iii) the complexity of some MUAPs; (iv) instability of components of the MUAP when the unit discharges spontaneously again. The down-going arrows indicate an unstable component in a relatively simple MUAP (#1a, b, c); the upgoing arrows indicate three unstable components when that discharge is aligned to the fasciculation potential from the same MUAP (#2a, b), two traces earlier.

Figure 1: Fasciculation in left tibialis anterior of a patient clinically suspected of suffering from ALS. Ten consecutive fasciculation discharges, with unit #1 discharging three times (downward arrows, 1a, b, c) and unit #2 discharging twice (2a,b; upward arrows in 2b). Note the duration of the MUAPs, their complexity and the variability of the arrowed components. Male patient aged 49, with chronic partial denervation and fasciculation in multiple muscles, and H reflexes at rest in right and left tibialis anterior and left extensor carpi radialis

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As an aside, it is important to wait some time to detect infrequent fasciculation: Observation for up to 90 s may be required to detect fasciculation.^[7] In ALS, voluntarily activated MUAPs are also commonly unstable reflecting sprouting of the motor axons and the relative immaturity of the reinnervation. Here, it should be noted that the pathological motor units usually seen on EMG in the patient with ALS are the surviving motor units, not those most affected (which are dead), and that the neuropathic changes result from the motor unit retaining the ability to sprout and take on denervated muscle fibers. In other words, the neurogenic changes which are the focus of electromyographers do not imply that the studied units are diseased.

The Awaji criteria were not “evidence-based”: They were experience-based, and they addressed only LMN abnormalities. They have improved the sensitivity but not the specificity of the diagnosis, which was already high using the older criteria, partly because patients were diagnosed later in the disease. Subsequent studies have shown that the sensitivity was less than it might have been because the Awaji Criteria omitted the laboratory-supported category.^[8],[9] There was greater sensitivity particularly for bulbar-onset disease. Interestingly, it has been reported that: “Inclusion of possible as a positive finding enhanced sensitivity of both criteria, while maintaining specificity,”^[8] an indication that even these criteria are quite strict.

Other methods for diagnosing lower motor neuron involvement: Imaging and ultrasound

Imaging of muscles can confirm neurogenic atrophy but not its cause, does not do so with greater sensitivity than EMG, and may not do so with greater sensitivity than clinical examination. Whole-body imaging can reveal widespread denervation, and sequential studies can reveal how rapidly it is progressing (Jenkins et al., 2018), but these studies may be more relevant to established disease than to defining the earliest possible changes.^[32] Fasciculation can be defined well by ultrasound, and this is useful with deep muscles and particularly with the tongue and other bulbar muscles,^{[10],[11],[12]} and there may be changes in echogenicity of nerve and muscle reflecting neurogenic atrophy. Patients commonly have difficulty relaxing bulbar muscles during needle EMG, but relaxation is essential for the identification of the ectopic discharge of fasciculation. For detecting fasciculation in limb muscles, ultrasound may offer little advantage over surface EMG recordings from a number of muscles simultaneously:^[13] With neither technique can the pathological features of the fasciculation potential be defined (see above). It is not clear whether changes in nerve and muscle echogenicity develop sufficiently early to be useful in the early diagnosis of ALS.

In the Awaji report, it was commented: “Methods for detection of upper motor neuron abnormality appear sensitive but require further study, particularly regarding their value when clinical signs of upper motor neuron lesion are uncertain.” That may have been so in 2008.

Upper Motor Neuron Involvement: Hyperreflexia and Weakness

If the H reflex can be recorded in a relaxed patient for a muscle that normally has no demonstrable H reflex unless potentiated by a voluntary contraction:

The patient is hyperreflexic for that reflex arc.

If there are LMN findings on EMG for that muscle:

There is putative evidence of UMN and LMN abnormalities for a single muscle.

If the reflex is obtainable at rest (or during contraction) at normal latency for age and height:

There is no demonstrable proximal lesion affecting sensory or motor axons.

The methodology that I have adopted has been detailed elsewhere.^[14] [Figure 2] illustrates the findings for TA of a patient suspected of suffering ALS. In patients being seen for neurophysiological evidence of ALS, I test TA, abductor pollicis brevis and extensor carpi radialis (ECR) bilaterally. I do not usually test soleus, quadriceps, or flexor carpi radialis because H reflexes can be obtained reliably at rest from these muscles and demonstrating that the reflex is preserved would not establish hyperreflexia. It should be noted that ~10% of healthy subjects the H reflex can be obtained in ECR.

Figure 2: H reflex recorded at rest from tibialis anterior of a patient clinically suspected of suffering from ALS. The stimulus intensity was increased for the successive sweeps, accounting for the growth of the M wave. Stimulus rate once/3 s to deep peroneal branch of common peroneal nerve. The H reflex is larger in the first two trials than the M wave. The presence of a H reflex at rest is putative evidence of hyperreflexia. The patient was a different patient from Fig. 1, but also had LMN changes on EMG - i.e., upper and lower motor neuron abnormalities for the same muscle

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It is common to see patients with a footdrop and denervation in TA. The question may then arise whether the weakness is all of LMN origin. A useful ploy is to encourage a maximal voluntary contraction of TA, recording surface EMG of TA, and to deliver a noxious stimulus to the sole of the foot during the maximal effort. A significant increase in EMG and greater dorsiflexion in response to the reflex input provides some evidence for an UMN contribution to the weakness.

Upper Motor Neuron Involvement: Corticospinal Abnormalities

The intensity of the transcranial magnetic stimulus required to produce a motor evoked potential (the “threshold” for the MEP) is commonly assumed to be a measure of the excitability of the motor cortex (Rossini et al., 2016). Mills^[15] found “no evidence of a phase of increased corticomotor hyperexcitability at any stage of disease.” However, Vucic and Kiernan^[16] reported enhanced excitability early in the disease using threshold-tracking TMS, and subsequently, it was found that resting motor threshold was significantly lower in those ALS patients with frontotemporal dementia.^[17] Measures of central motor conduction are normal or only mildly abnormal in ALS,^[15] any changes presumably reflecting the size of the corticomotoneuronal units that have degenerated.

The function of interneuronal circuits in the cerebral cortex has been a focus of much activity, particularly in Sydney, and it is now routine for patients in whom UMN signs are questionable or absent to be referred for a range of TMS studies, in particular the threshold for the MEP, paired-pulse studies of short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF), and the cortical silent period. These studies use threshold-tracking in which the intensity of the TMS is adjusted automatically by the computer to keep the MEP within a narrow target window. This technique has advantages over measuring the changes in amplitude (or area) of the MEP produced by a constant stimulus.^[18],[19] “Threshold-tracking measurements of SICI may be able to improve reproducibility, to shorten acquisition time and to reduce sample sizes for interventional studies compared with the conventional technique.”^[18] While comparisons of threshold tracking TMS and the conventional technique have confirmed the efficacy of both ways of measuring SICI, it has recently been shown that with threshold tracking, the reduction in SICI was greatest in patients with the fewest UMN signs, even before UMN signs have developed.^[20]

In ALS, whether sporadic or familial, it has been reported that SICI is reduced, ICF increased, and the cortical silent period shortened. These changes may occur before there is clinical evidence of involvement of the test limb, may be seen early in familial ALS, even before the first symptoms, and may be partially reversed by riluzole therapy.^[21] These changes are seen in ALS variants (flail arm syndrome; primary lateral sclerosis), but not in Kennedy's disease or other conditions that might be confused with ALS. The reduction in SICI has been found to be an adverse prognostic factor.^[22] These findings are supported by those of Tankisi et al.^[20] and reinforce the view that such studies have an important place in demonstrating UMN involvement in suspected ALS.

The Gold Coast Criteria

A goal in managing patients suspected of suffering from ALS should be to make the diagnosis before the disease has spread too far throughout the neuraxis.^[23],[24] ALS commonly starts in a single body region^[25],[26] and then spreads in a consistent pattern. The ideal situation would be for diagnose and treat the disease when only a single limb or even a single muscle group is involved, impractical though this may currently sound.

The Gold Coast criteria emanated from a consensus meeting held in 2019 to simplify the diagnostic criteria for ALS, with a focus on applicability to recruiting patients early in their disease process into clinical trials. Rather than tweaking deficient criteria yet again, it was resolved to start from scratch and rely on current experience. The following are extracts from the resulting report:^[3]

”The following statements summarize our current understanding of ALS.

Amyotrophic lateral sclerosis is a progressive disorder of the motor system

Clinically focal onset is most frequent, but a generalized symptom onset is also recognized
The motor disorder in ALS reflects both lower and UMN dysfunction, but it is recognized that UMN signs are not always clinically evident
Evidence of LMN dysfunction can be derived from clinical examination and/or from EMG
For the purpose of diagnosis, evidence of UMN dysfunction is currently derived from clinical examination
Supportive evidence of LMN dysfunction can be derived from ultrasound detection of fasciculations from multiple muscles.^[27] Supportive evidence of UMN dysfunction can be derived from transcranial magnetic stimulation studies of the central motor nervous system, magnetic resonance imaging (MRI), and neurofilament levels.^[28] It should be stressed that the current diagnosis does not require these studies.

Amyotrophic lateral sclerosis may include cognitive, behavioral and/or psychiatric abnormalities although these are not essential for diagnosis.

Based on the above understandings, the Gold Coast meeting was designed to produce a simplified set of criteria, spelt out in [Table 2]. They should be read in conjunction with the four footnotes which clarify the criteria.

Table 2: Gold coast criteria for diagnosis of amyotrophic lateral sclerosis

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Other Diagnostic Procedures to Demonstrate Umn Involvement

These have been addressed in a number of reviews, such as Swash et al.^[29] MRI tractography using diffusion tensor imaging can provide evidence of corticospinal degeneration, and this correlates with clinical and TMS studies of corticospinal involvement. However, at the moment, MRI techniques are not yet sufficiently sensitive to be of diagnostic value in individual patients. Neurofilaments may found in the CSF and blood of patients with ALS and other disorders,^[30] particularly those with UMN involvement, correlating with the intensity of the disease. Neuropsychological testing is of value if there is evidence of cognitive impairment or possibly ALS-FTD.^[31]

A common situation is the presentation of patients with clinically definite LMN signs but clinically uncertain or absent UMN signs. Here, abnormalities in tests of cerebral function, whether motor or not, become highly significant.

Conclusions

To maximize the chances that drug therapies can arrest the otherwise inevitable decline of the patient with ALS, the goal should be to have reasonable clinical certainty when the clinical feature are largely confined to one territory. As discussed above, neurophysiological testing can help.

Can we refine the EMG findings? We can use ultrasound to identify that fasciculation is widespread
Can we define hyperreflexia and UMN weakness? We may be able to demonstrate H reflexes for muscles that do not have H reflexes at rest, and we may be able to increase the strength of a paretic muscle reflexly
Can we demonstrate cerebral involvement? We can study single-shock TMS (CMCT) and double-shock TMS (SICI) and perhaps other cerebral processes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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Figures

[Figure 1], [Figure 2]

Tables

[Table 1], [Table 2]