Educational scope notice: This is a study note for medical students, not medical advice, diagnosis, or treatment guidance. Clinical management should follow local protocols and current guidelines.
Diagnosing ALS is a clinical exercise. There is no single positive test that confirms the disease. Instead, the diagnosis rests on demonstrating combined upper and lower motor neuron degeneration across body regions while excluding mimics. Average diagnostic delay in Europe and North America is about one year, often because patients are first referred to orthopaedic or other non-neurological services.
The five elements of clinical examination
Each body region is assessed for:
- Muscle bulk — wasted (LMN) or preserved (UMN).
- Strength — whether weakness is present and how severe it is.
- Muscle tone — increased and spastic (UMN) or decreased and flaccid (LMN).
- Deep tendon reflexes — brisk (UMN) or diminished or absent (LMN).
- Abnormal reflexes — Babinski sign present (UMN) or absent (LMN).
UMN versus LMN signs
The distinction between UMN and LMN patterns is central to every neurological examination, but in ALS the key finding is that both patterns coexist in the same body segment.
| Feature | Upper motor neuron | Lower motor neuron |
|---|---|---|
| Muscle bulk | Maintained | Lost (atrophy) |
| Strength | Slightly decreased | Markedly reduced |
| Tone | Increased (spasticity) | Decreased (flaccidity) |
| Reflexes | Heightened (hyperreflexia) | Diminished or absent |
| Abnormal reflexes | Present (Babinski) | Absent |
In a pure muscle disease, reflexes are diminished or absent because the reflex arc is disrupted. Finding preserved or brisk reflexes in an atrophied, weak limb is therefore a red flag for combined UMN and LMN involvement, the diagnostic hallmark of ALS. A pure neuropathy would eliminate reflexes, and a pure myopathy would not produce hyperreflexia.
How diagnostic criteria evolved
Criteria have moved toward earlier recognition, balancing sensitivity against the risk of misdiagnosis.
- El Escorial criteria. The original criteria required clinical UMN and LMN signs in several body regions (bulbar, cervical, thoracic, lumbosacral) for definite ALS. They were category-based and trial-oriented.
- Awaji-Shima criteria. This revision gave EMG findings the same weight as clinical examination: EMG-demonstrated subclinical LMN involvement in additional regions counts toward the diagnostic total, permitting earlier diagnosis and treatment.
- Gold Coast criteria. The most recent simplification treats UMN and LMN signs in a single segment as sufficient to support the diagnosis. The rationale is that avoiding unacceptable diagnostic delay matters more than the small accompanying risk of overdiagnosis.
Neurophysiology: EMG and nerve conduction studies
EMG patterns
Electromyography uses a needle electrode to record muscle electrical activity at rest, during voluntary contraction, and with increasing effort. The pattern distinguishes neurogenic from myopathic processes.
| Condition | At rest (insertion) | Voluntary contraction | Recruitment |
|---|---|---|---|
| Normal | Brief signals, then silence | Orderly action potentials | Full recruitment |
| LMN lesion | Fibrillation and positive sharp waves (unstable membrane) | Large, irregular potentials as surviving neurons adopt abandoned fibres | Reduced, fast firing rate |
| UMN lesion | Silence (membrane unaffected) | Fewer activated motor units | Reduced, slow firing |
| Myopathy | Silence | Reduced amplitude from muscle fibre damage | Full recruitment, low amplitude |
In ALS, LMN and UMN patterns often overlap, and the observed pattern reflects whichever system dominates in the tested muscle. EMG is not fully sensitive and is operator-dependent. Over-reliance on EMG in UMN-predominant or bulbar presentations causes avoidable delay.
Nerve conduction studies
Nerve conduction is typically normal in ALS because the disease primarily affects the motor neuron cell body rather than the myelin sheath. Assessment therefore requires normal sensory conduction, normal motor conduction (with the caveat that velocity may fall slightly when the compound motor action potential amplitude is low), and absence of persistent conduction blocks or diffuse demyelinating features. Significant conduction slowing or conduction blocks should prompt consideration of mimics, particularly chronic inflammatory demyelinating polyneuropathy, which is treatable.
Fasciculation versus myokymia
- Fasciculation — quick, localised, irregular twitches visible under the skin that do not move the limb. Fasciculations reflect LMN denervation and are characteristic of ALS.
- Myokymia — persistent, rhythmic rippling within the same muscle segment. Myokymia is generally non-specific and often relates to stress, fatigue, or physiological factors.
Neurofilaments: the NfL biomarker
Neurofilaments are structural components of the axonal cytoskeleton, released into cerebrospinal fluid and blood when motor neurons degenerate. Of the three chains (light, medium, heavy), neurofilament light chain (NfL) is the most clinically developed diagnostic biomarker. Single-molecule array (Simoa) technology, which counts individual protein molecules, makes these minute blood concentrations measurable.
- Reported cut-off. NfL above approximately 62 pg/ml, measured in cerebrospinal fluid or serum with Simoa technology, has been reported to distinguish ALS from controls and mimics with useful accuracy. Cut-offs are assay- and laboratory-dependent.
- Prodromal rise. In carriers of pathogenic ALS mutations, NfL rises before symptom onset, over months to a few years depending on the cohort and assay, indicating that the biological process starts before symptoms appear.
- Limited specificity. NfL also rises after trauma, in multiple sclerosis, and in some parkinsonian disorders, so it cannot screen the general population. Its value lies in the ALS clinic, where it helps separate true ALS from mimics.
Neuroimaging
MRI in ALS primarily excludes mimics rather than confirming the diagnosis. Some findings support it: corticospinal tract hyperintensity on T2-weighted images (particularly in the posterior limb of the internal capsule), precentral gyrus signal change, and frontotemporal atrophy in patients with ALS–FTD overlap. Reported frequencies vary widely across studies, so these are clues rather than criteria. Transcranial magnetic stimulation can demonstrate corticospinal dysfunction but is not part of formal diagnostic guidelines for lack of standardised evidence.
Cognitive screening: the Edinburgh scale
Traditional neuropsychological testing takes hours and depends on motor function, which ALS impairs. The Edinburgh Cognitive ALS Screen (ECAS) was designed for this situation. It takes 15–20 minutes, minimises the effect of physical disability through interchangeable subtests, and assesses executive function (the most commonly impaired domain in ALS), language, and memory. Screening matters because roughly half of ALS patients show cognitive or behavioural change and about 10% develop frontotemporal dementia. Executive dysfunction has been associated with shorter survival.
Differential diagnosis
Spondylotic myelopathy
The most frequent and critical differential in older patients. A cervical disc protrusion can compress the anterior horn (LMN signs in the arms) and the lateral corticospinal tract (UMN signs in the legs), mimicking ALS. The distinguishing feature is that spondylotic myelopathy produces nothing above the lesion level: no bulbar or cranial nerve signs. ALS commonly spreads above the initial level. Checking for bulbar involvement before cervical spine surgery is essential.
Inclusion body myositis and polymyositis
Both cause progressive weakness but lack UMN signs. Muscle biopsy separates them: inclusion body myositis shows rimmed vacuoles with inflammatory infiltrates, while polymyositis shows endomysial cytotoxic T-cell infiltrates.
Kennedy disease (spinal and bulbar muscular atrophy)
An X-linked CAG trinucleotide expansion in the androgen receptor gene affecting older males, and an important mimic: about 2% of sporadic cases labelled as ALS in one series (roughly 1 in 50), with small single-digit percentages across series. Distinguishing features are LMN signs only with no UMN involvement, systemic androgen-insensitivity features such as gynaecomastia and infertility progressing to testicular atrophy, and confirmation by genetic testing.
Evidence anchors
- NICE. Motor neurone disease: assessment and management (NG42): https://www.nice.org.uk/guidance/ng42
- Geevasinga N et al. Diagnosing ALS: the Gold Coast criteria and the role of EMG (2022, open access): https://pmc.ncbi.nlm.nih.gov/articles/PMC9120398/
- NINDS. Amyotrophic lateral sclerosis: https://www.ninds.nih.gov/health-information/disorders/amyotrophic-lateral-sclerosis-als