https://ijmri.de/index.php/jmsi
volume 4, issue 2, 2025
509
DIAGNOSTIC CRITERIA FOR AMYOTROPHIC LATERAL SCLEROSIS
Abdukadirova D.T.,
Abdukadirov U.T.,
Xoshimjonov B.Sh
Andijan State Medical Insitute
Department of Neurology
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease
characterized by selective and combined degeneration of upper and lower motor neurons . The
incidence in worldwide ranges between 2–3 cases per 100,000 population per year, with a
prevalence of 1.1–8.2 per 100,000 population. In most cases, the disease onset occurs between
the ages of 55 and 70. Men have a slightly higher incidence rate than women [2, 5] .
Both sporadic and familial forms of ALS have been identified. Familial forms account for 5–
20% of all cases. These forms exhibit marked heterogeneity, not only in terms of inheritance
mechanisms and primary molecular defects but also in clinical manifestations, disease
progression, and prognosis . The etiology of most sporadic ALS cases remains unknown. Among
exogenous factors, the roles of metals (lead, mercury, selenium), pesticides, viruses, smoking,
dietary habits, history of electrical trauma, professional sports, injuries, and other factors have
been discussed . However, to date, no clear association between exposure to any single
exogenous factor and development of ALS. ALS is considered a multifactorial disease involving
a complex interplay of genetic, epigenetic, and environmental factors[1].
ALS is characterized by significant clinical heterogeneity. This variability includes age of onset,
initial localization part of nervous system, rate of progression, degree of upper and lower motor
neuron involvement, presence of non-motor clinical manifestations, and other features.
Advances in molecular biology, genetics, and neuroimaging emphasize the need to consider
ALS as a clinically and pathologically heterogeneous syndrome of neurodegenerative etiology,
encompassing both motor and non-motor manifestations with a broad spectrum of overlapping
phenotypic variants. This complexity explains the challenges in differential diagnosis, the
establishment of diagnostic criteria, and creating a unified disease classification. In most cases,
ALS clinically manifests with localized weakness and muscle atrophy in a limb or bulbar
musculature, accompanied by signs of corticospinal or corticonuclear pathway damage. The
combined degeneration of upper and lower motor neurons results in a mixed (spastic-atrophic)
paresis syndrome, which is considered almost pathognomonic for ALS. Based on the initial site
of involvement, the disease is categorized into spinal (including cervicothoracic, lumbosacral,
and cervical) and bulbar forms [4,8].
A hallmark of ALS is the sparing of motor neurons of the oculomotor nerve nuclei and Onuf
nucleus. Disease progression affects other levels of the cerebrospinal axis, leading to a clinical
presentation of total deafferentation syndrome in cases of prolonged survival. Most patients
ultimately succumb to bulbar and respiratory dysfunction or related complications.
In addition to the classic ALS variant (Charcot’s form), which involves the combined
degeneration of upper and lower motor neurons, several other variants have been described—
initially as distinct diseases—with isolated upper or lower motor neuron involvement.
Primary Lateral Sclerosis (PLS) is characterized by isolated upper motor neuron degeneration,
resulting in progressive spastic tetraparesis and pseudobulbar palsy. The hemiplegic form is
known as Mills’ syndrome.
https://ijmri.de/index.php/jmsi
volume 4, issue 2, 2025
510
Progressive Muscular Atrophy (PMA) involves isolated lower motor neuron degeneration. It
manifests as progressive flaccid paresis with muscle atrophy, fasciculations, and reduced or
absent tendon reflexes. Unlike spinal muscular atrophy, PMA typically presents with asymmetric
symptoms (especially at onset) and progresses more rapidly. The disease may begin with
proximal or distal limb muscle involvement, and in rare cases, bulbar dysfunction occurs [7].
Several forms are defined by localized pathology at onset and a lack of generalization for several
years (so-called localized forms), leading to distinct clinical phenotypes and relatively benign
disease courses:
Flail Arm Syndrome (FAS) (synonyms: scapulohumeral ALS, Vulpian-Bernhardt syndrome,
“floppy arm” syndrome, “man-in-the-barrel” syndrome, brachial amyotrophic diplegia) is
clinically characterized by predominantly proximal flaccid paraparesis in the arms without
generalization for at least one year. Some cases begin with asymmetric hand weakness but later
evolve into a classic phenotype with proximal and relatively symmetric flaccid paraparesis.
Flail Leg Syndrome (FLS) (synonyms: peroneal form, pseudopolyneuritic form, Marie-Patrikàs
disease) is characterized by isolated distal leg muscle weakness without generalization for at
least one year. Both flail arm syndrome and flail leg syndrome may exhibit mild upper motor
neuron signs (e.g., tendon hyperreflexia, Hoffmann’s or Babinski’s reflexes) but exclude
spasticity or clonus. Thus, they are classified as lower motor neuron-predominant forms.
Progressive Bulbar Palsy is typically the bulbar-onset form of ALS or, in rare cases, progressive
muscular atrophy. Some authors also recognize dropped head syndrome as a distinct phenotype,
marked by weakness in neck extensor muscles at onset.
The nosological independence of the described clinical variants has long been debated. In 1946,
W.R. Brain proposed the term “motor neuron disease” (MND) to unify ALS, progressive
muscular atrophy, primary lateral sclerosis, and progressive bulbar palsy into a single diagnostic
category. This term is used in the International Classification of Diseases, 10th Revision (ICD-
10), where rubric G12.2 (“Motor Neuron Disease”) includes ALS, progressive muscular atrophy,
primary lateral sclerosis, and progressive bulbar palsy [18].
To date, flail arm syndrome and flail leg syndrome have not been incorporated into ALS
classification systems and are typically regarded as distinct phenotypic variants in most studies
due to their more benign course compared to both classic ALS and progressive muscular atrophy.
When analyzing the clinical heterogeneity of ALS, it is essential to consider additional aspects
such as the presence of non-motor manifestations, age of disease onset, progression rate,
hereditary predisposition, and other factors. Notably, 10–15% of ALS patients exhibit cognitive
impairments that meet the diagnostic criteria for frontotemporal dementia (FTD).
Significant progress has been made in this field in recent years, particularly with the discovery of
genes such as C9orf72, mutations of which can lead to both ALS and FTD. Beyond cases of
combined ALS-FTD, there exists a spectrum of overlap phenotypes, including ALS with mild
cognitive impairment and frontotemporal dementia with subclinical motor neuron involvement.
Rarer cases describe ALS combined with extrapyramidal disorders (e.g., parkinsonism, chorea),
cerebellar ataxia, or sensory, oculomotor, and autonomic dysfunction. These findings, alongside
advances in ALS genetics and neuroimaging studies, strongly support the multisystem nature of
neurodegeneration in ALS [5]..
The "gold standard" for ALS diagnosis remains the revised El Escorial criteria, published in
2000. To diagnose ALS, the following criteria must be met:
Required Criteria:
1. Lower motor neuron (LMN) involvement confirmed clinically, electrophysiologically, or
pathomorphologically.
2. Upper motor neuron (UMN) involvement confirmed clinically.
3. Progressive symptom spread within one or more innervation regions during follow-up.
Exclusion Criteria:
https://ijmri.de/index.php/jmsi
volume 4, issue 2, 2025
511
1.Electrophysiological or pathological evidence of other diseases that could explain UMN and
LMN degeneration.
2.Neuroimaging findings that could account for the clinical or electrophysiological signs.
The diagnosis of ALS is established with varying degrees of certainty, depending on the number
of affected levels within the cerebrospinal axis.
In 2008, the Awaji criteria were introduced, retaining the core principles of the revised El
Escorial criteria while incorporating two key updates:
1. Electrophysiological evidence of LMN damage (via EMG) is considered equivalent in
diagnostic value to clinical LMN signs.
2. Fasciculation potentials, when observed alongside chronic denervation signs, are
recommended to be interpreted as equivalent to acute denervation signs.
The adoption of the Awaji criteria has increased the proportion of patients classified as
"definite/probable ALS" by 23% without compromising specificity [1].
Despite improvements in diagnostic criteria, ALS diagnosis remains a significant global
challenge. According to several large multinational studies, the time from symptom onset to
correct diagnosis ranges from 9 to 15 months, with 31–52% of cases being misdiagnosed at the
initial stage.A study by M. Kraemer et al. reported that 44% of ALS patients received incorrect
initial diagnoses, with the most common misdiagnoses being:
Vertebrogenic disorders (20.5%)
Neuropathies (13.6%)
Cerebrovascular diseases (7%)
Notably, 12% of misdiagnosed patients underwent unnecessary surgery, often for suspected
vertebrogenic pathology.
Similarly, S. Paganoni et al. (2014) found that the most frequent misdiagnoses were:
Neuropathies (28%)
Vertebrogenic disorders (18%)
Multiple studies emphasize the wide range of alternative diagnoses considered by neurologists
and general practitioners during initial evaluations, reflecting the marked clinical heterogeneity
of ALS at onset. This variability directs differential diagnostic efforts toward different pathways,
depending on:
Initial site of involvement
Predominance of upper or lower motor neuron signs
Progression rate
Other clinical factors
These challenges underscore the need for increased awareness, improved diagnostic tools, and
earlier recognition of ALS to minimize diagnostic delays and misclassification.
Diagnosis is particularly challenging in lower motor neuron (LMN)-predominant forms of ALS.
This difficulty arises because isolated LMN symptoms—such as weakness, muscle atrophy, and
fasciculations, without sensory deficits—overlap with numerous peripheral neuromotor
disorders.A study by L.C. Wijesekera et al. reported significant diagnostic delays for LMN-
predominant ALS variants:
Progressive muscular atrophy (PMA): 19.8 months
Flail arm syndrome (FAS): 24.8 months
Flail leg syndrome (FLS): 27.4 months
Classic ALS: 11.2–14.7 months
In FAS, 54.8% of patients receive incorrect initial diagnoses, with the most common
misdiagnoses being:
Multifocal motor neuropathy (MMN): 26%
Carpal tunnel syndrome: 17%
Spinal muscular atrophy: 17%
Cervical discogenic myelopathy: 17%
https://ijmri.de/index.php/jmsi
volume 4, issue 2, 2025
512
Conversely, progressive muscular atrophy (PMA) has a high false-positive diagnosis rate. J.
Visser et al. (2002) reported that 19% of patients initially diagnosed with PMA were later found
to have other conditions—exceeding the false-positive rate for ALS as a whole (7–10%).
The most common misdiagnoses for PMA include:
Multifocal motor neuropathy (MMN)
Chronic inflammatory demyelinating polyneuropathy (CIDP)
Crucially, many ALS-mimicking conditions presenting with isolated LMN signs are either
treatable or follow a more benign course. This underscores the importance of early and accurate
diagnosis in order to:
Avoid unnecessary delays in treatment
Differentiate ALS from other treatable neuromuscular disorders
Guide appropriate therapeutic interventions
Thus, the clinical heterogeneity of ALS, limitations of current diagnostic criteria, and low
sensitivity of clinical exams in detecting upper motor neuron (UMN) signs are key barriers to
timely diagnosis. These factors delay diagnosis and initiation of disease-modifying therapy, lead
to inclusion of late-stage patients in clinical trials, complicate palliative care planning, and
exacerbate psychological distress for patients and caregivers . The 2015 revisions to the El
Escorial criteria acknowledge that ALS can be diagnosed even without clinical UMN signs,
provided there is documented disease progression involving new levels of the cerebrospinal axis
during follow-up . However, this requirement itself delays diagnosis, particularly in patients with
localized forms (FAS, FLS), where pathology remains confined to one cerebrospinal level for
years after onset. Additionally, the high frequency of diagnostic errors in ALS cases lacking
UMN involvement complicates the practical application of these guidelines.
The integration of instrumental methods for detecting upper motor neuron (UMN) lesions into
clinical practice holds significant potential for improving early diagnosis of ALS. This has
driven considerable interest in exploring the utility of transcranial magnetic stimulation (TMS)—
the only currently available neurophysiological method for assessing the functional integrity of
upper motor neurons and advanced neuroimaging techniques in ALS diagnostics.
References
1. Ammar Al-Chalabi , Orla Hardiman. The epidemiology of ALS: a conspiracy of genes,
environment and time/ //BMJ.-2023 march.
2. Hristelina Ilieva, Mithila Vullaganti, Justin Kwan. Advances in molecular pathology,
diagnosis, and treatment of amyotrophic lateral sclerosis //BMJ.-2023 July
3. Justin Kwan , Mithila Vullaganti. Amyotrophic lateral sclerosis mimics/ //Willey 2022 y 24
May
https://doi.org/10.1002/mus.27567
4. Nikol Jankovska , Radoslav Matej. // Molecular Pathology of ALS: What We Currently Know
and What Important Information Is Still Missing/
MDPI journal 2021y 29 July PMID: 34441299 PMCID: PMC8391180 DOI:
10.3390/diagnostics11081365
5. Ryan G. Brotman , Maria C. Moreno-Escobar , Joe Joseph , Sunil Munakomi , Gauri Pawar.
Amyotrophic Lateral Sclerosis/ //StatPearls [Internet]. Treasure Island (FL): StatPearls
Publishing; 2025 Jan.
6. Stephen A Goutman , Orla Hardiman , Ammar Al-Chalabi , Adriano Chió , Masha G
Savelieff , Matthew C Kiernan , Eva L Feldman. Recent advances in the diagnosis and prognosis
of amyotrophic lateral sclerosis. PMID: 35334233 PMCID: PMC9513753 DOI: 10.1016/S1474-
4422(21)00465-8
7. Акбарова С. Ш., Абдукадирова Д.Т.,Рахимбаева Г. С. Atypical forms of ALS: review and
observation from practice. British Medical Journal. voleum 2. No 1.1, 11-15. January 2022
https://ejournals.id/index.php/bmj/article/view/387/364
8. Бакулин, И.С. Боковой амиотрофический склероз: клиническая гетерогенность и
подходы к классификации / И.С. Бакулин, И.В. Закройщикова, Н.А. Супонева, М.Н.
Захарова // Нервно- мышечные болезни. - 2017. - Т. 7, № 3. - С. 10-20.
https://ijmri.de/index.php/jmsi
volume 4, issue 2, 2025
513
9. Бакулин, И.С. Структурная и функциональная нейровизуализация при боковом
амиотрофическом склерозе / И.С. Бакулин, А.В. Червяков, Е.И. Кремнева, Р.Н. Коновалов,
М.Н. Захарова // Анналы клинической и экспериментальной неврологии. - 2017. - Т. 11, №
2. -
10. Бакулин, И.С. Воксель-ориентироанная морфометрия при боковом амиотрофическом
склерозе / И.С. Бакулин, Р.Н. Коновалов,
М.В. Кротенкова, Н.А. Супонева, М.Н. Захарова // Вестник рентгенологии и радиологии. -
2018.
11. Бакулин, И.С. Методика выявления поражения верхнего мотонейрона при боковом
амиотрофическом склерозе с помощью транскраниальной магнитной стимуляции / И.С.
Бакулин, А.Г. Пойдашева, А.Ю. Чернявский, Н.А. Супонева, М.Н. Захарова, М.А.
Пирадов // Анналы клинической и экспериментальной неврологии. - 2018. - Т. 12, № 2.
