Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease, the most common type of Motor Neuron Disease (MND). The pathogenesis of the disease is not fully understood, but the lesions involve both upper and lower motor neurons. The most common cause of death in ALS is respiratory failure and some patients die from malnutrition or aspiration pneumonia.
The incidence of ALS is low, varying from 0.40 to 2.96 per 100,000 person-years, and the etiology of ALS is still unclear, with significant heterogeneity in clinical manifestations and different diagnostic criteria used around the world, making clinical data collection and statistics difficult. Therefore, epidemiological and etiological studies on ALS may be biased. The establishment of population-based registries and the use of new research methods have improved the data to a certain extent and reduced the bias in the studies. The clinical manifestations, staging, diagnostic criteria, and treatment of ALS are reviewed, and the relationship between various aspects of ALS characteristics and disease prognosis and current research progress are discussed.
I. Clinical manifestations
The characteristic clinical manifestation of ALS is the simultaneous involvement of upper and lower motor neurons in multiple segments of the medulla oblongata and spinal cord. Upper motor neuron involvement includes hyperreflexia, increased muscle tone, muscle spasm, etc.; lower motor neuron involvement includes limb weakness, muscle atrophy, muscle fiber tremor (fibrillation), decreased or absent tendon reflexes, etc.; medulla oblongata involvement includes dysphagia, slurred speech, tongue muscle atrophy and fibrillation, etc. A few patients may show respiratory muscle weakness such as breath-holding and shortness of breath after activity in the early stage of the disease. The first symptom is even respiratory muscle involvement. The most common complaint and first symptom is usually progressive weakness. Some patients may have complaints of sensory abnormalities, but there are usually no signs of sensory abnormalities or evidence of ancillary tests, and bladder and rectal sphincter function is well preserved. Weakness usually begins unilaterally in a single spinal cord segment, with other segments becoming involved as the disease progresses. Other atypical first symptoms may manifest as weight loss, muscle spasm and fibrillation without significant weakness, personality changes, and frontotemporal lobe cognitive dysfunction.
Clinical typing
There are various ways to classify ALS, the most common one is to classify ALS according to the different sites of onset and clinical manifestations.
(1) Limb-initiated ALS (limb-onset ALS), in which upper and lower motor neuron involvement is first seen in the upper or lower extremities, accounting for 70% of the total number of patients.
(2) bulbar-onset ALS, in which slurred speech and dysphagia are the first manifestations, followed by symptoms of limb involvement; this type accounts for 25% of patients.
(3) primary lateral sclerosis (PLS), which is a rare type of ALS that starts after the age of 40 and has only upper motor neuron involvement without lower motor neuron involvement within 4 years, and is diagnosed as upper motor neuron involvement as the main manifestation of ALS (upper motor neurondominant ALS, UMN-D-) if lower motor neuron involvement is present within 4 years. ALS).
(4) Progressive muscular atrophy (PMA), which has only signs of lower motor neuron involvement and has significant clinical heterogeneity.
(5) Other rare types, such as flail-arm syndrome (FAS) and flail-leg syndrome (FLS), both FAS and FLS present with symptoms and signs confined to one region of the limb for more than 12 months without signs of involvement of other regions.
It is still controversial whether PLS and PMA are special phenotypes of ALS, but clinical studies have found that most patients with PLS and PMA will eventually show both upper and lower motor neuron involvement as their disease progresses, and their clinical manifestations will be the same as those of classic ALS, so some scholars believe that PLS and PMA are special types of ALS.
Studies have confirmed that there are differences in survival between the subtypes, with the exception of PLS, which has the longest survival, and ALS with a shorter survival in the medullary onset and longer survival in the limb onset. In some studies, the survival of specific subtypes of ALS such as FAS, FLS or PMA is significantly longer than that of classic ALS, and it has been reported in the literature that respiratory muscle weakness is an important factor contributing to poor prognosis. In a study of 1188 British ALs and 432 Australian patients followed for 14 and 12 years, respectively, FAS and FLS had a longer survival time and a higher 5-year survival rate than limb-initiated ALS, and Kaplan-Meier survival analysis confirmed that FAS, FLS, and PMA all had significantly longer survival than limb-initiated ALS. Forbes et al. also showed that the survival time was shorter for those with medullary onset than for those with limb onset, and that those with both upper and lower motor neuron involvement had a shorter survival time than those with lower motor neuron involvement only, as shown in Kihira et al.’s study of the Japanese population.
III. Diagnostic criteria
The World Federation of Neurology (WFN) first proposed the El Escorial diagnostic criteria for ALS in 1990, which classified ALS into four levels: confirmed ALS, proposed ALS, probable ALS, and suspected ALS, based on the presence or absence of upper and lower motor neuron involvement in the medulla oblongata, cervical segment, thoracic segment, and lumbosacral segment. In order to improve the sensitivity and accuracy of diagnosis, WFN revised the diagnostic criteria of El Escorial in 1998 and named it Airlie House diagnostic criteria, in which the concept of laboratory support for proposed ALS was introduced, and electromyography was used as an important tool to detect lower motor neuron damage. With the further understanding of ALS and the widespread use of neurophysiological examination, the Awaji-shima diagnostic criteria were proposed in 2006 based on the E1 Escorial diagnostic criteria and Airlie House diagnostic criteria, which pointed out that clinical manifestations and EMG manifestations are equally important in the diagnosis of lower motor neuron damage. Therefore, it was not necessary to distinguish laboratory support for proposed ALS, so the diagnostic levels of ALS were reclassified as confirmed ALS, proposed ALS and probable ALS, and it was considered that bundle fibrillation potentials are as much a sign of muscle denervation changes as fibrillation potentials and positive sharp waves on the premise of chronic neurogenic damage on needle electrode EMG.
Most studies have shown that the different diagnostic levels are one of the important factors affecting the prognosis of ALS, with patients having shorter survival at the confirmatory level of ALS compared to other diagnostic levels. However, some studies suggest that the diagnostic level derived from the E1 Escorial and Airlie House diagnostic criteria is not predictive of ALS prognosis. Regarding the reason for the correlation between the diagnostic level and the prognosis of ALS patients, some scholars believe that, regardless of the diagnostic level, the presence of upper and lower motor neuron involvement in three segments is required to reach the diagnostic level, suggesting that the prognosis is poor because of the extensive involvement of the disease at the time of consultation.
Clinical characteristics
1. Age of onset.
It is generally accepted that the peak age of onset of ALS is 50-75 years old, but the median age of onset reported in different studies is inconsistent, with a few studies reporting a mean age of onset below 50 years. Some studies have shown that the median age of onset varies among different subtypes of ALS, with a later age of onset in those with medullary onset. Most studies have shown that the later the age of onset, the worse the prognosis of patients, i.e., age of onset is an important predictor of prognosis in ALS patients. However, an analysis of 121 patients in Italy by Bettoni et al. showed no significant correlation between age and prognosis. There is still no consistent explanation for the correlation between age and prognosis of ALS patients, as older patients have more comorbid diseases, later presentation, higher rate of misdiagnosis, and a smaller proportion of medication users, all of which may have an impact on survival, so further studies are needed to distinguish whether age itself or other age-related factors influence the prognosis of ALS patients.
2. Gender.
The incidence of ALS varies between genders, with a higher incidence in males than in females, ranging from 1.1:1 to 3:1, while in the specific subtype of ALS, FAS, there are significantly more males than females. Wijesekera et al. reported that females predominate in the medullary onset type of ALS (male:female = 0.9:1). The incidence of ALS in women has been on the rise in recent years, which may be due to.
(1) the progressive similarity of women’s lifestyles and work environments to those of men
(2) an increase in the number of women smoking
(3) differences in experimental design methods and geographical characteristics among studies.
The relationship between gender and the prognosis of ALS is controversial among different studies. Some studies have shown no significant correlation between gender and survival in ALS patients, but others have shown a poorer prognosis for women than for men, while a few studies have found a better prognosis for women. This difference between studies is related to factors such as study design, geographical distribution and differences in living environment and habits in different places, so the association between gender and ALS prognosis needs to be further confirmed in larger studies.
3. Time to diagnosis delay.
Because of the large differences in economic development and medical care between countries and regions, the delay in diagnosis between the onset and diagnosis of ALS patients reported in different studies varies greatly. Studies have shown that the delay in diagnosis ranges from 240 to 389 d in different regions of Europe, and the difference in the delay in diagnosis between medullary onset and limb onset ALS is not statistically significant. Another study showed that the UK population had the longest delay in diagnosis for FAS and FLS (median 24.8 and 27.4 months, respectively), the shortest delay for medullary onset (median 11.2 months), and intermediate delay for limb onset ALS (median 14.7 months). There is no consensus on the relationship between delay in diagnosis and survival in ALS. Most studies show that a shorter delay in diagnosis suggests a poor prognosis for ALS patients, but some studies show no significant correlation. The better prognosis of those with a longer delay in diagnosis can be explained by the longer time between the onset of symptoms and the visit to the clinic suggesting a slower progression of the disease and therefore a relatively late visit to the clinic, but it is important to exclude.
(1) differences in medical conditions.
(2) objective factors such as limited mobility and underdeveloped transportation that make it difficult for patients to seek medical care.
(3) misdiagnosis and other reasons.
4. Survival.
Most studies show that the median survival time of ALS patients from onset to death is 3–5 years, but ALS has significant clinical heterogeneity, with some patients progressing very rapidly, with a disease duration of <12 months, and some patients progressing extremely slowly, with a disease duration of >120 months or even >240 months. The median survival time of ALS patients in the Chinese and Taiwanese populations is 66.6 months, Nalini et al. reported a median survival time of 114.8 months in Indian ALS patients, Martinez et al. reported a mean survival time of 68.6 months in the Caucasian population, while Zoccolella et al. reported a survival time of only 28 months for ALS patients in the Italian population, and O’Toole et al. reported a median survival time from diagnosis to death of 16.4 months for ALS patients in Ireland. The wide variation in survival times reported in various studies should take into account the effects of differences in ethnicity and lifestyle, in addition to differences in study methodology, data processing and analysis methods. Survival time is influenced by a variety of factors, the most significant ones being age at onset, delay in diagnosis, site of onset, gender, level of diagnosis, and treatment measures, etc. Forbes et al. concluded that the survival time of elderly patients was significantly shorter than that of other patients, and the reasons for this may be related to the lower proportion of elderly patients using medications, more difficult access to medical care, and more comorbid diseases.
V. Treatment
Riluzole is a neuroprotective agent that blocks glutamatergic neural pathways within the CNS, which in turn blocks voltage-dependent Na+ channels on glutamatergic nerve endings and activates G protein-dependent signal transduction pathways. Currently, riluzole is the only drug proven by evidence-based medical evidence to treat ALS, and its long-term application can significantly prolong the survival of ALS patients. To date, there is controversy about whether mechanical ventilation and gastrostomy can improve the prognosis of ALS patients. As the understanding of the causative genes, pathogenesis and clinical characteristics of ALS progresses, it is believed that more effective treatments will be discovered to prolong survival, improve the prognosis and enhance the quality of life of patients.