Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that selectively affects upper motor neurons (UMN) and lower motor neurons (LMN) in the spinal cord, brainstem, and cerebral cortex. It presents with muscle weakness, atrophy, fasciculations, dysarthria, and dysphagia, ultimately leading to respiratory failure and death.
The incidence is approximately 2–3 per 100,000 person-years in individuals aged 15 years and older, with similar rates reported in Europe 7). Prevalence is highest in white males aged 60 years and older. Men have a 1.2–1.5 times higher risk than women. The mean age of onset is 62 years for sporadic ALS (peak: 58–63 years) 4) and significantly younger at 47–52 years for familial ALS 4).
ALS is clinically classified into four subtypes.
Ophthalmic findings can appear at any stage of ALS, but the oculomotor, trochlear, and abducens nuclei that innervate the extraocular muscles are usually spared until very late in the disease. However, involvement of brainstem networks responsible for fixation control, smooth pursuit, and saccades leads to various eye movement abnormalities. Changes in the anterior visual pathway (retina and optic tract) have also been reported, making neuro-ophthalmic evaluation an important aspect of ALS management.
Extraocular motor neurons tend to be preserved until late stages, but square-wave jerks, impaired smooth pursuit, and saccadic abnormalities can be observed relatively early. Involvement of the anterior visual pathway has also been reported, such as changes in the inner nuclear layer of the retina detectable by OCT in patients with C9orf72 mutations.
Initial symptoms of ALS can appear in any part of the body.
Fixation Abnormalities
Square-wave jerks: Brief horizontal conjugate saccades (<2°) that occur during fixation. They are thought to be caused by dysfunction of the cerebellar vermis or omnipause neurons. They are also seen in other diseases such as Parkinson’s disease, PSP, cerebellar ataxia, and MS.
Saccadic hypometria: Saccades that undershoot the target.
Abnormal Smooth Pursuit Eye Movements
Cogwheeling: Smooth pursuit is interrupted, becoming jerky like a cogwheel.
Saccadic dysmetria: Accompanied by hypometric or hypermetric corrective saccades.
In bulbar-onset ALS, abnormal smooth pursuit and saccadic dysmetria are more common than in spinal-onset ALS.
Downbeat nystagmus: Reported as a characteristic finding of FEWDON-MND. As of 2025, 14 cases of FEWDON-MND have been reported, with a median age of onset of 24.5 years (IQR 18.5–36.8 years) and a female predominance (M:F = 4:10)2). The course is slowly progressive, and respiratory impairment is rare.
In addition, oculomotor disturbances have been reported in 4 of 21 cases in a review of ALS with chorea8).
Involvement of the anterior visual pathway (retina and optic tract) in the ALS disease process has been reported.
Square-wave jerks are brief horizontal conjugate saccades (<2°) that occur during fixation, where the eyes momentarily deviate and then quickly return. They are thought to be caused by dysfunction of the cerebellar vermis or omnipause neurons (saccade-suppressing neurons). Patients are rarely aware of them, but they can cause fixation instability.
A case of ALS with MT-ND6 gene mutation (m.14484T>C) has been reported, where a young-onset (age 36) ALS coexisted with LHON (Leber hereditary optic neuropathy)-related mutation4). Mitochondrial DNA deletions have been shown to be more frequent in sporadic ALS patients than in healthy controls4).
Familial ALS accounts for about 5–10% of all ALS cases, caused by gene mutations such as SOD1 and C9orf72, with an onset age of 47–52 years, which is younger than sporadic ALS (62 years). The remaining 90–95% are sporadic ALS, thought to involve environmental factors and complex causes, but details remain unclear.
ALS is primarily a clinical diagnosis. No specific biomarkers are currently established, and excluding other diseases is important.
| Criteria name | Summary |
|---|---|
| El Escorial criteria | Progressive UMN+LMN signs in one region, or LMN signs in two or more regions. Exclusion of other diseases required. |
| Awaji criteria | Revised version of El Escorial criteria. Emphasis on EMG findings. |
| Gold Coast criteria | Latest diagnostic criteria. Enables more comprehensive diagnosis4) |
Electromyography (EMG) is the most important ancillary test in ALS diagnosis.
In the electrodiagnosis of FEWDON-MND, a characteristic finding is reduced CMAP amplitude of the radial nerve, and needle electromyography shows chronic motor axon loss (large amplitude, long duration MUAP, reduced recruitment) in all cases. Active denervation (PSW, fibrillation) is rare to mild 2).
It is important to differentiate ALS from the following diseases.
There is currently no curative treatment for ALS. The goals of management are to slow functional decline, relieve symptoms, and maintain quality of life.
The main disease-modifying drugs are listed below.
| Drug Name | Mechanism | Effect |
|---|---|---|
| Riluzole | Glutamate release inhibition | Approximately 3-month survival extension |
| Edaravone | Free radical scavenging and oxidative stress reduction | Slowing of functional decline |
The standard dose of riluzole is 50 mg twice daily (bid)1).
A multidisciplinary team approach is essential for comprehensive management of ALS.
Survival time is typically 2 to 5 years after diagnosis. The 5-year survival rate is reported to be about 20%, the 10-year survival rate about 10%, and survival beyond 20 years about 5%. Poor prognostic factors include bulbar-onset type, older age at onset, and early respiratory muscle impairment. FEWDON-MND progresses slowly, respiratory impairment is rare, and it has a better prognosis than ALS 2).
There is currently no curative treatment. Riluzole is the only established disease-modifying drug, reported to extend survival by about 3 months. Edaravone has been shown to slow functional decline. New therapeutic agents, such as antisense oligonucleotides for SOD1 mutations, are in the research and development stage see 7. Latest research and future prospects: Research stage reports.
Nuclear export of RNA-binding proteins (such as TDP-43 and FUS) and formation of cytoplasmic inclusions are major pathologies of ALS. FUS mutations have been reported in ALS-MS combined cases1). In C9orf72 mutations, both loss of function and toxic gain of function (formation of RNA foci and production of dipeptide repeat proteins) contribute to the pathology.
Wu et al. (2025) reported a young-onset ALS patient (36-year-old female) with an MT-ND6 gene mutation (m.14484T>C) 4). Muscle biopsy revealed fascicular atrophy in approximately 30–50% of muscle fibers, and electron microscopy confirmed mitochondrial proliferation and swelling. This suggests that dysfunction of mitochondrial respiratory chain complex I may be involved in the pathogenesis of ALS.
Extraocular motor neurons (oculomotor, trochlear, and abducens nuclei) are usually preserved until the late stages of the disease. The following mechanisms are hypothesized to cause ocular motor abnormalities.
Rajagopalan & Pioro (2024) demonstrated different gray matter degeneration patterns between ALS-foveal retinal thickness+ group (with corticospinal tract T2 hyperintensity) and ALS-foveal retinal thickness- group using multifractal analysis 9). In the ALS-foveal retinal thickness+ group, MF degeneration pattern in the frontal lobe was prominent, while in the ALS-foveal retinal thickness- group, degeneration at the cortical (neuronopathy) or spinal (distal axonopathy) level was suggested. Conventional VBM and cortical thickness analysis did not detect significant differences.
In ALS patients, disruption of the blood-brain barrier (BBB) and blood-spinal cord barrier has been observed, along with accumulation of immunoglobulin G in the spinal cord parenchyma. It has been reported that BBB disruption may trigger the onset of NMOSD 5). As a mechanism of ALS and MS comorbidity, a cascade involving coexistence of degenerative and inflammatory processes, leading to reactive oxygen species and nitric oxide production, and subsequently cell death and apoptosis, has been proposed 1). It has also been suggested that the HLA-B*18:01A antigen may be involved in activating both neuroinflammation and neurodegeneration 1).
Inoue et al. (2025) described in detail the pathological features of familial ALS patients with the SOD1 p.L127S mutation and emphasized the importance of developing targeted therapies such as antisense oligonucleotides (ASOs) for SOD1 mutations 3). Early therapeutic intervention through early genetic diagnosis may be key to improving prognosis.
Theuriet et al. (2025) reported in detail the electrophysiological characteristics of 14 patients with FEWDON-MND 2). Although the pathophysiology remains unclear, a genetic cause is considered most likely, and tests for C9orf72, SOD1, and ALS panel genes were all negative. Mild elevation of CK levels (280–748 UI/L) was observed in all 3 cases, and recognition as a new disease entity is progressing.
Aljthalin et al. (2024) systematically reviewed 33 cases of ALS-MS comorbidity from 1986 to 2023 1). They pointed out that C9orf72 mutations may serve as a bridging factor between the two diseases, and that HLA-B*18:01A antigen may activate both neuroinflammation and neurodegeneration. Autonomic dysfunction is attracting attention as an independent predictor of ALS progression.
Wu et al. (2025) reported a detailed case of ALS coexisting with the LHON-related mitochondrial mutation (m.14484T>C), and also showed that a study of 700 European individuals found no significant association between mitochondrial DNA haplogroups and ALS 4). Research continues on the possibility that genes encoding mitochondrial proteins, such as CHCHD10 mutations, may be involved in the FTD-ALS spectrum.
Rajagopalan & Pioro (2024) showed that multifractal (MF) analysis of frontal gray matter could classify three groups—controls, ALS with foveal thickness+, and ALS with foveal thickness-—with 98% accuracy 9). MF indicators captured differences that conventional VBM or cortical thickness analysis could not detect, and their use as new biomarkers is expected.
Mentis et al. (2022) first identified the p.Q1369R mutation in the DYNC1H1 gene in ALS patients 7). DYNC1H1, which encodes cytoplasmic dynein heavy chain, is involved in retrograde axonal transport, neuronal migration, and protein recycling. They proposed that mutations increasing the stability of this protein may be involved in the ALS-FTD spectrum.
Aljthalin R, Alrfaei B, Hakami A, et al. Multiple sclerosis and amyotrophic lateral sclerosis: is there an association or a red flag? BMC Neurology. 2024;24:307.
Theuriet J, Campana-Salort E, Leonard-Louis S, et al. Electrophysiological Abnormalities in Finger Extension Weakness and Downbeat Nystagmus Motor Neuron Disease (FEWDON-MND): About 3 Cases and Review of the Literature. Muscle & Nerve. 2025;71:644-650.
Inoue K, Nishiyama A, Hikawa R, et al. Familial ALS With p.L127S (L126S) Variant of the Cu/Zn SOD1 Gene: Two Autopsy Cases and Literature Review. Neuropathology. 2025;45:e70028.
Wu JY, Huang YH, Hsiao CT, et al. Amyotrophic Lateral Sclerosis With Concurrent LHON-associated m.14484T>C Mutation. Rev. Neurol. 2025;80(11):44110.
Kim JY, Kim SM, Kim YJ, et al. Sporadic amyotrophic lateral sclerosis with seropositive neuromyelitis optica spectrum disorder: a case report. Medicine. 2021;100(22):e26065.
Zhao X, Yi J, Li H, et al. The G41D mutation in SOD1-related amyotrophic lateral sclerosis exhibits phenotypic heterogeneity. Medicine. 2022;101(8):e28961.
Mentis AF, Dardiotis E, Rikos D, et al. A novel variant in DYNC1H1 could contribute to human amyotrophic lateral sclerosis-frontotemporal dementia spectrum. Cold Spring Harb Mol Case Stud. 2022;8(3):a006096.
Zhang A, Sun X, Bai Q, et al. Coexisting amyotrophic lateral sclerosis and chorea: A case report and literature review. Medicine. 2022;101(47):e31752.
Rajagopalan V, Pioro EP. Differing patterns of cortical grey matter pathology identified by multifractal analysis in UMN-predominant ALS patients with and without MRI signal change. J Neurol Sci. 2024;459:122945.
