
==== Front
Ann Med
Ann Med
Annals of Medicine
0785-3890
1365-2060
Taylor & Francis

39233624
10.1080/07853890.2024.2398199
2398199
Version of Record
Review Article
Neurology
From suspicion to diagnosis: exploration strategy for suspected amyotrophic lateral sclerosis
M. Garnier et al.
Garnier Maëlle a
Camdessanché Jean-Philippe b
Cassereau Julien ac
https://orcid.org/0000-0003-1745-8299
Codron Philippe acd
a CRMR SLA, CHU d’Angers, Angers, France
b CRC SLA, CHU de Saint-Etienne, Saint-Etienne, France
c Inserm U1083-CNRS 6015, SFR ICAT, Université d’Angers, Angers, France
d Neurobiologie et Neuropathologie, CHU d’Angers, Angers, France
CONTACT Philippe CODRON codron.ph@outlook.com Service de neurologie, CHU d’Angers, 4 rue Larrey, 49933 Angers, France.
5 9 2024
2024
5 9 2024
56 1 23981995 2 2024
21 3 2024
10 5 2024
KnowledgeWorks Global Ltd.4 9 2024
published online in a building issue4 9 2024
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
2024
The Author(s)
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

Abstract

The diagnosis of amyotrophic lateral sclerosis (ALS) is based on evidence of upper and lower motor neuron degeneration in the bulbar, cervical, thoracic, and lumbar regions in a patient with progressive motor weakness, in the absence of differential diagnosis. Despite these well-defined criteria, ALS can be difficult to diagnose, given the wide variety of clinical phenotypes. Indeed, the central or peripheral location of the disease varies with a spectrum ranging from predominantly central to exclusively peripheral, symptoms can be extensive or limited to the limbs, bulbar area or respiratory muscles, and the duration of the disease may range from a few months to several decades. In the absence of a specific test, the diagnostic strategy relies on clinical, electrophysiological, biological and radiological investigations to confirm the disease and exclude ALS mimics. The main challenge is to establish a diagnosis based on robust clinical and paraclinical evidence without delaying treatment initiation by increasing the number of additional tests. This approach requires a thorough knowledge of the phenotypes of ALS and its main differential diagnoses.

KEY MESSAGES

The diagnosis of amyotrophic lateral sclerosis (ALS) is based on progressive degeneration of upper and lower motor neurons.

ALS can be difficult to diagnose due to the wide range of clinical phenotypes (central/peripheral location, symptom distribution, disease duration).

A thorough diagnostic strategy including clinical, electrophysiological, biological and radiological investigations is essential to confirm ALS and exclude differential diagnoses.

Keywords

Amyotrophic lateral sclerosis
ALS mimics
Gold Coast criteria
The author(s) reported there is no funding associated with the work featured in this article.
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pmcIntroduction

Amyotrophic lateral sclerosis (ALS), also known as Charcot’s disease, is a neurodegenerative disease affecting the upper motor neurons (UMN) in the cerebral cortex and the lower motor neurons (LMN) in the brainstem and the spinal cord. In Europe, the incidence of the disease is estimated at 2.5/100,000 (4 new cases per day) [1,2]. In 90% of cases, ALS is sporadic, with no known cause to date. Cumulative lifetime environmental exposures, known as the exposome, and genetic susceptibility are increasingly recognized as playing a role in the development and progression of ALS. Air pollution, neurotoxic pesticides, head and spinal injuries, electric shock, smoking, military service and physical activity are considered potential risk factors for ALS [3,4]. In 10% of cases, the disease is caused by the transmission of a pathogenic gene mutation. The average age of onset of ALS is around 65 years [2,5]. Patients affected by the disease develop a progressively worsening diffuse motor impairment leading to muscle weakness in the upper and lower limbs, and/or difficulty speaking and swallowing, and/or restrictive respiratory failure. Median survival is approximately 3 years from symptom onset [1,2]. The only drug treatment available in France to slow the progression of the disease is riluzole, which reduces the 1-year mortality rate by one third and prolongs life without a tracheostomy [6,7]. A multidisciplinary functional approach is also essential (non-invasive ventilation, enteral nutrition, physiotherapy, speech therapy, psychological support, analgesia), to improve survival and quality of life for patients [8].

Diagnostic challenges and issues

ALS may be difficult to diagnose, given the wide variety of clinical phenotypes and the fear of missing a curable differential diagnosis. The main challenge is therefore to establish a diagnosis based on robust clinical and paraclinical evidence, without delaying the diagnosis announcement and the initiation of treatment by increasing the number of sometimes expensive additional tests. The diagnosis of ALS is based on the combination of evidence of central and peripheral motor neuron damage, progressive involvement of the bulbar, cervical, thoracic, and lumbar areas, and the absence of a differential diagnosis to explain the symptoms. These elements are included in the Gold Coast diagnostic criteria published in 2019 [9] (Table 1), which progressively replace the revised El Escorial [10] and Awaji-shima [11] criteria. These new criteria are less restrictive and replace the degrees of certainty (possible, probable, definite ALS) with a positive or negative diagnosis, which is clearer for both patients and physicians. The first 3 steps of the diagnosis should be clinical, electrophysiological, and paraclinical, with the aim of both supporting the diagnosis of ALS and ruling out pathologies – especially curable ones – that may mimic the disease. This approach therefore requires a thorough knowledge of the phenotypes of ALS and its main differential diagnoses.

Table 1. Gold Coast diagnostic criteria for ALS [9].

Progressive motor impairment documented by history or repeated clinical assessment, preceded by normal motor function, AND	
Presence of upper and lower motor neuron dysfunction in at least 1 body regiona (in the same body region if only one is involved) OR lower motor neuron dysfunction in at least 2 body regions, AND	
Investigations excluding other disease processes	
a Bulbar, cervical, thoracic, and lumbosacral.

Clinical phenotypes of ALS

There is considerable clinical variability among ALS patients [12,13] (Figure 1), although they share a common neuropathological profile with neuronal degeneration and hyperphosphorylated TDP-43 inclusions in neurons and glial cells [14,15]. This clinical heterogeneity has several aspects. First, the central or peripheral location of the disease may vary, with a spectrum ranging from exclusively central disease, known as Primary Lateral Sclerosis (PLS), to purely peripheral forms, known as Progressive Muscular Atrophy (PMA). Furthermore, the topography of the muscle weakness may vary from patient to another and, at least at the onset of the disease, the symptoms may be limited to the limbs, the bulbar level, or even the respiratory level only. The oculomotor and sphincter systems are however usually spared. Nearly half of patients have cognitive or psychobehavioural impairment, and 10–15% of cases fulfill criteria for frontotemporal lobar degeneration (FTLD) [16]. In addition, 30% to 60% of patients may present with hypermetabolic syndrome, defined as an increased resting energy consumption leading to weight loss and accelerated decline in motor function and survival [17,18]. Finally, the duration of the disease varies from patient to patient, ranging from a few months to several decades [19].

Figure 1. Clinical phenotypes of ALS (initial presentation). ALS: amyotrophic lateral sclerosis, LMN: lower motor neuron, UMN: upper motor neuron.

Main differential diagnoses

The European Federation of Neurological Associations (EFNA) listed 77 differential diagnoses for ALS [20]. The main are grouped according to their mechanism of pathogenicity in Table 2.

Table 2. Main differential diagnoses of ALS.

Central nervous system lesions Brain lesion

Degenerative cervical myelopathy

Other lesions of the spinal cord with radicular involvement

Hirayama’s Disease

	
Autoimmune diseases of the peripheral nervous system Multifocal motor neuropathy

Chronic inflammatory demyelinating polyneuropathy

	
Infectious diseases HIV infection, West Nile virus, Lyme disease, Syphilis

Post-polio syndrome

	
Metabolic and toxic diseases Dysthyroidism

Hyperparathyroidism

Vitamin B12 deficiency

Lead poisoning

	
Genetic diseases Hereditary spastic paraplegia

Adrenomyeloneuropathy

Spinal muscular atrophy (type III or type IV)

Hereditary neuropathy with motor expression

X-linked spinal and bulbar muscular atrophy (Kennedy’s disease)

GM2 gangliosidosis

Alexander disease

Brown-Vialetto-Van-Laere disease

	
Cancer-related disorders Paraneoplastic syndrome

Postradiation myeloradiculopathy

	
Muscular pathologies and neuromuscular junction disorders Myopathy

Inclusion body myositis

Autoimmune myasthenia gravis

	
Peripheral nerve hyperexcitability disorder Cramp fasciculation syndrome

	

These pathologies partly guide the investigations to be performed when a patient presents with symptoms suggestive of the disease, with three main steps: clinical, electrophysiological and paraclinical (biological and radiological) investigations.

Clinical examination

The clinical examination is the first step in the diagnostic work-up. Motor, bulbar, and respiratory signs must be examined in detail, each time trying to identify elements associated with UMN and LMN involvement (Table 3). It is also important to look for non-motor signs, which may be part of the disease (dysexecutive syndrome, behavioral impairment, weight loss) or in opposition to it (sensory loss, oculomotor paralysis, vesicosphincter signs). Lastly, particular importance should be attached to establish a family tree that spans at least three generations and includes all antecedents in the family, looking specifically for relatives with motor neuron disease, cognitive disorders, or psychiatric symptoms, and family tree censorships. The risk factors for ALS mentioned above should also be investigated.

Table 3. Clinical signs of upper motor neuron (UMN) and lower motor neuron (LMN) impairment that should be evaluated during the clinical examination of a patient suspected of having ALS.

UMN impairment in the limbs and trunk Diffused and polykinetic osteotendinous reflexes

Preserved osteotendinous reflexes in a region with LMN impairment

Hoffman sign, Babinski sign

Clavicle reflex

Pyramidal hypertonia (spasticity)

Ankle clonus, patellar clonus

	
LMN impairment in the limbs and trunk Muscle weakness

Cramps

Muscle atrophy

Fasciculations

Osteotendinous reflexes reduced or absent

	
UMN impairment in the bulbar region Dysphonia, Dysarthria, Dysphagia

Jaw clonus

Buccofacial apraxia

Hyperactive or repeating jaw jerk reflex

Spasmodic laughing and crying 

	
LMN impairment in the bulbar region Dysphonia, Dysarthria, Dysphagia

Tongue fasciculations

Tongue atrophy

Salivary stasis

Velar hypotonia

	
Respiratory impairment Dyspnea, tachypnea, orthopnea

Use of the accessory respiratory muscles

Clinical signs of hypercapnia (headache, asterixis, hypercrinia)

	

Electrophysiology exploration

Electroneuromyography (ENMG) is the key test for the detection of LMN involvement and the specification of its topography [21]. In this disease, there is usually no change in either motor or sensory nerve conduction. The amplitude of motor potentials may be reduced, reflecting axonal loss, and pseudo-blocks may be observed in case of rapid motor neuron loss. Detection records and accurately defines LMN damage. Abnormal resting activity (fasciculation potentials, fibrillation potentials, positive slow waves) and neurogenic recruitment (motor unit potentials of increased duration and/or amplitude) indicate active and chronic denervation. A region is considered affected if denervation is recorded in two muscles innervated by different roots and nerves for the cervical and lumbar regions, and in one muscle for the bulbar and thoracic regions [9]. These criteria therefore require a systematic exploration of all four anatomical regions, without limiting the examination to clinically affected areas. A standardized protocol for the electrophysiological examination of a patient suspected of having ALS was proposed in 2022 by Lenglet and Camdessanché [21] (Table 4).

Table 4. Gold Coast criteria for lower motor neuron (LMN) impairment on electroneuromyogram (EMNG) [9] and proposed protocol for investigating a patient suspected of having ALS [21].

Gold Coast criteria for LMN dysfunction on EMNG Evidence of chronic neurogenic change, defined by large motor unit potentials of increased duration and/or increased amplitude (with polyphasia), and motor unit instability regarded as supportive but not obligatory evidence, AND

Evidence of ongoing denervation, including fibrillation potentials or positive sharp waves, or fasciculation potentials.

In TWO limb muscles innervated by different roots and nerves, or ONE bulbar muscle, or ONE thoracic muscle

	
ENMG exploration protocol proposed by Lenglet and Camdessanché
Nerve conduction studies (sensory and muscle action potentials)Median, ulnar (to Erb’s point if necessary), fibular and tibial nerves, in addition to nerves in the affected areas.

First interosseus dorsalis and abductor digiti minimi used to study ulnar nerve conduction.

Myography Lower limbs: tibialis anterior and vastus lateralis

Upper limbs: interosseus dorsalis and deltoidus or biceps brachii

Thoracic region: rectus abdominis or paraspinatus dorsalis

Bulbar region : sternocleidomastoideus, genioglossus, trapezius superior

And additional muscles depending on the clinical presentation

Repetitive nerve stimulationIn the case of proximal upper limb deficits, isolated bulbar involvement or in the absence denervation: radial nerve/anconeus, spinal nerve/trapezius superior, V-XII nerves/submental triangle on both sides.

	

Paraclinical tests

Systematic prescription of a standardized biological examination (Table 5) and a frontal chest X-ray is recommended by the EFNA to screen for the main differential diagnoses of ALS [20]. Brain and spinal MRI should also be organized to rule out lesions in the central nervous system. In patients with ALS, it is sometimes possible to observe a T2 hypersignal of the cortico-spinal tract, from the semi-oval centers to the brainstem, as well as a cortical atrophy predominant in the frontal regions.

Table 5. Paraclinical tests recommended by the EFNS for patients with suspected ALS [20].

Biology Ionogram, urea, creatinine

Fasting blood glucose, AST, ALT, LDH, albumin

Calcium, Thyroid-stimulating hormone, free T4, free T3 hormone assays

Haematological screen

Serum protein electrophoresis, serum immunoelectrophoresis

C-reactive protein

Vitamin B12 and folate

Creatine kinase

Serologies (Borrelia, viruses including HIV, syphilis)a

	
Radiology Chest X-ray

Brain and spinal cord MRI

	
a If exposed or risk of infection.

Diagnostic strategy

Several situations can be identified at the end of this initial clinical, electrical, biological, and radiological examination (Figure 2).

Figure 2. Diagnostic strategy for a patient with suspected ALS. AMN: adrenomyeloneuropathy, CIDP: chronic inflammatory demyelinating polyradiculoneuropathy, CNS: Central nervous system, CT CAP: CT scan chest abdomen pelvis, EMNG: electromyoneurography, HSP: hereditary spastic paraplegia, LMN: lower motor neuron, LP: lumbar puncture, MCV: motor nerve conduction velocity, MMN: multifocal motor neuropathy, SCV: sensory nerve conduction velocity, SD: syndrome, SMA: spinal muscular atrophy, UMN: upper motor neuron.

ALS mimic identified

In this case, clinical and paraclinical investigations should then be directed to the pathology causing the patient’s symptoms. Occasionally, MRI may reveal spinal cord injury with radicular involvement, especially in degenerative cervical myelopathy. This can complicate the diagnosis in a patient with purely motor symptoms. In this case, signs of LMN damage more diffuse than expected from the lesion and/or bulbar signs may point to ALS.

Gold Coast criteria fulfilled, UMN and LMN signs without atypia

The diagnosis of ALS can be announced to the patient. If the disease is in its early stages, or if two pathologies are evoked, a new EMNG at 3 or 6 months - depending on the rate of worsening - will help to be more conclusive.

Isolated UMN signs

If brain and spinal MRI exclude central nervous system lesion, the diagnosis of PLS or Mills syndrome can be made. Repeated clinical and eventually electrical evaluations must be performed to ensure that there is no delayed LMN impairment. In a young patient presenting with very progressive weakness predominantly in the lower limbs, hereditary spastic paraplegia or adrenoleukodystrophy may be investigated.

Isolated LMN signs

The absence of UMN damage may be confirmed by normal motor evoked potentials. In this case, the search for undetected blocks may motivate the repetition of EMNG and the use of high-voltage radicular stimulation techniques or triple stimulation in the hypothesis of multifocal motor neuropathy (MMN) or chronic dysimmune neuropathy [21]. In addition, anti-ganglioside antibodies testing, CSF analysis, plexus MRI, and trial treatment with intravenous immunoglobulins may be considered. In a young man presenting with asymmetric progressive pseudo-ulnar motor signs, a cervical MRI with dynamic flexion sequences can be performed to look for a compression of the anterior spinal cord with the posterior part of the vertebral bodies. This may be a sign of Hirayama’s disease. Finally, in the case of a young subject with very progressive motor symptoms and chronic signs on ENMG (giant motor unit potentials, electroclinical dissociation), four hypotheses can be investigated: spinal muscular atrophy (type III or type IV), hereditary distal motor neuropathy (BSCL2, HSPB1, HSPB8 and GARS genes in particular), Charcot-Marie-Tooth disease (CMT2) with motor predominance (MFN2 and MT-ATP6 genes in particular) and GM2 gangliosidosis. In the absence of elements suggestive of these conditions, and if two regions are affected, the diagnosis of PMA can be made according to the Gold Coast criteria.

Isolated bulbar signs

Special attention must be paid to the course of the mixed nerves on radiologic studies in the search for a lesion. Similarly, in the presence of atypical or fluctuating symptoms, repetitive nerve stimulation and anti-RACh and anti-MuSK antibodies testing will help to rule out autoimmune myasthenia, which can sometimes mimic bulbar ALS. It should be noted that decrements are sometimes observed in ALS, so their presence does not formally exclude the disease. Less frequently, Alexander disease (hereditary leukodystrophy caused by mutation of the GFAP gene) may be suspected if there is cervical cord atrophy on MRI, and Brown-Vialetto-Van-Laere disease in patients under 30 with hearing loss (mutation of the SLC52A2/A3 genes). In the absence of further evidence, the diagnosis of bulbar ALS with UMN and/or LMN impairment can be made.

Signs restricted to the respiratory function

This is a rare situation usually seen in patients admitted to a pulmonary department or intensive care unit for acute or subacute alveolar hypoventilation. The search for more diffuse motor neuron damage is essential in this situation. The diagnosis is based on the absence of other respiratory causes and the clinical course, in particular the development of motor or bulbar signs.

Rapid progression and associated non-motor signs

The rapid progression of symptoms, the presence of non-motor neurological signs (sensory, cerebellar, limbic), a generalized impairment, and paraclinical abnormalities (blood count, monoclonal gammapathy, pulmonary lesion) should prompt further investigations in search of a paraneoplastic origin that may lead to UMN and/or LMN impairment [22]. The most associated cancers are small cell lung cancer, breast adenocarcinoma, and hematologic malignancies (especially lymphoma). Investigations may be completed by a CSF analysis, thoraco-abdominal-pelvic CT scan or preferentially positron emission tomography, and anti-neuronal antibody testing.

Slow progression predominantly in the lower limbs, lingual atrophy and non-motor signs in a male

In a male, the presence of a marked lingual atrophy, peribuccal myokimia, gynecomastia, endocrine disorders, postural tremor, sensory signs, and sensory neuropathy on ENMG should raise the suspicion of X-linked spinal and bulbar muscular atrophy (Kennedy’s disease) due to the repetition of CAG triplets in exon-1 of the androgen receptor gene.

Frontotemporal spectrum disorder of ALS (ALS-FTSD)

As mentioned above, almost half of patients have cognitive dysfunction or behavioural changes, and the disease may begin with these symptoms. It is therefore essential to look for neuropsychological deficits in all ALS patients, especially those that are more specific to the disease: executive dysfunction (including deficits in social cognition), language impairment (dissociable from motor impairment) and behavioural changes (dissociable from pseudobulbar affect and depression, anxiety and sleep disturbance), in particular apathy. Reports from family members and carers are essential in this approach. The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) [23] or the ALS Cognitive Behavioural Screen (ALS-CBS) [24] are rapid assessment batteries for frontotemporal dysfunction that are recommended for all patients. If impaired, further neuropsychological assessment with specific and targeted tests should be undertaken. Four cognitive-behavioural phenotypes are defined by the revised Strong criteria [16], all grouped under the term “frontotemporal spectrum disorder of ALS” (ALS-FTSD): 1) ALS with cognitive impairment (ALSci): patients with executive dysfunction (including social cognition), language dysfunction, or combination of both. 2) ALS with behavioural impairment (ALSbi): patients with apathy and/or two or more other behavioural symptoms (including disinhibition, loss of sympathy and empathy, perseverative, stereotyped or compulsive behaviour, hyperorality/dietary change, loss of insight and psychotic symptoms). 3) ALS with combined cognitive and behavioural impairment (ALS-cbi): patients fulfilling criteria for both ALSci and ALSbi, but not for FTD. 4) ALS with frontotemporal dementia (ALS-FTD): patients with ALS who also have frontotemporal dementia.

Genetics of ALS

More than 30 pathogenic genes have been identified as responsible for ALS. Four of these genes account for more than 60% of familial ALS and 10% of sporadic ALS: C9orf72, SOD1, FUS and TARDBP [25,26]. The recent development of gene therapies led to systematic genetic analyses in France: any patient suffering from ALS, whether sporadic or familial, should benefit from a molecular biological study of the C9orf72 and SOD1 genes as soon as the disease is diagnosed [27]. Additional analysis (ALS Panel NGS) may be performed in cases of early onset (before age 40), slow or rapid progression, or if there is a suggestive family history. All samples should be sent to a reference laboratory. A dedicated consultation should then be organized to give the results to the patient in person.

Conclusion

The diagnosis of ALS must be based on robust clinical and paraclinical evidences. The identification of markers of the disease, such as neurofilament testing, diffusion tensor imaging techniques and omics approaches, is an active area of research. In the coming years, it should provide additional informations to help clinicians to diagnose the disease.

Authors contributions

MG and PC drafted the manuscript and the figures. JPC and JC revised the article for intellectual content. All authors approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data are available from the corresponding author upon reasonable request.
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