The disease is a neurodegenerative disease of unknown etiology that mainly involves motor neurons in the cerebral cortex, brainstem, and spinal cord, and includes four clinical types: amyotrophic lateral sclerosis (ALS), progressive amyotrophy, progressive medullary paralysis, and primary lateral sclerosis. ALS is the most common type of motor neuron disease and is usually seen in middle-aged and elderly people, with progressive skeletal muscle weakness, atrophy, myotonic fibrillation, medullary palsy and pyramidal fasciculus as the main clinical manifestations, and survival is usually 3-5 years.
The early clinical manifestations of ALS are diverse and lack specific biological confirmatory indicators. A detailed history, meticulous physical examination and standardized neurophysiological examination are crucial for early diagnosis, and other ancillary examinations such as imaging have some value in differential diagnosis. During the clinical diagnosis, determining the extent of upper and lower motor neuron involvement is a key step in the diagnosis. According to the anatomical site where the patient presents symptoms and signs, the extent of involvement is usually divided into four regions: brainstem, cervical segment, thoracic segment and lumbosacral segment.
I. Clinical examination
Through detailed history taking and physical examination, evidence of common involvement of upper and lower motor neurons in the four regions of brainstem, cervical segment, thoracic segment and lumbosacral segment is the basis for the diagnosis of ALS. Depending on the situation, appropriate ancillary tests can be selected to exclude other diseases, such as neurophysiology, imaging, and laboratory tests. For ALS diagnosed at early onset, especially when the clinical manifestations are atypical or the course of progression is unclear, regular (3-month) follow-up should be performed to re-evaluate the diagnosis.
1. Medical history: It is the main basis for confirming the progressive development of the disease, and should start from the site of the first weakness and follow up the time course of the development and exacerbation of the symptoms and their expansion from one area to another. Pay attention to the swallowing condition, respiratory function and the presence of sensory disorders, urinary and stool disorders, etc.
2. Physical examination: The presence of signs of both upper and lower motor neuron involvement in the same region is the key point for the diagnosis of ALS
(1) Signs of lower motor neuron involvement mainly include muscle weakness, atrophy and tremor of muscle bundles. Usually, the tongue, face, throat, neck, different muscle groups of the limbs, back, and thoracic and abdominal muscles are examined.
(2) Signs of upper motor neuron involvement mainly include increased muscle tone, tendon reflex hyperactivity, clonus, and positive pathological signs. The sucking reflex, gag reflex, chin reflex, palmar chin reflex, tendon reflexes of the limbs, muscle tone, Hoffmann’s sign, pathological signs of the lower limbs, abdominal wall reflexes, and the presence of pseudomyelination such as strong crying and laughing are usually examined.
(3) Clinical physical examination is the main method to detect upper motor neuron involvement. In areas presenting with significant muscle atrophy and weakness, if the tendon reflexes are not low or active, it may suggest damage to the pyramidal fasciculus, even in the absence of pathological signs.
(4) Follow-up of the patient and dynamic observation of changes in signs can also reflect the progressive course of the disease.
(3) When certain manifestations that cannot be explained by ALS are found in the medical history and physical examination, such as stable or improving disease course, numbness and pain in the limbs, etc., the diagnosis of ALS needs to be cautious and attention should be paid to whether there are other diseases in combination.
II. Neurophysiological examination
When ALS is clinically considered, neurophysiological examination is required to confirm the clinical involvement of the area with lower motor neuron lesions and to detect the presence of lower motor neuron lesions in the clinically uninvolved area, as well as to exclude other diseases. Neuroelectrophysiological examination can be considered as an extension of the clinical physical examination and should be done by professional electromyographers and technologists and judged according to clear criteria.
1. Nerve conduction measurement: Nerve conduction measurement is mainly used to diagnose or exclude peripheral nerve diseases. Motor and sensory nerve conduction measurements should include at least two nerves in each of the upper and lower extremities.
(1) Motor nerve conduction measurement: distal motor latency and nerve conduction velocity are usually normal, and there is no partial motor nerve conduction block or abnormal waveform dispersion. As the disease progresses, the amplitude of compound muscle action potentials may decrease significantly, and the conduction velocity may also be mildly slowed.
(2) Sensory nerve conduction measurements: generally normal. When there is a combination of entrapment peripheral neuropathy or other peripheral neuropathies, sensory nerve conduction may be abnormal.
(3) F wave measurement: usually normal. When muscle atrophy is apparent, the F wave rate of the corresponding nerve decreases, while the conduction velocity is relatively normal.
2. Electromyography with core needle: The determination of lower motor neuron lesions is mainly made by electromyography with core needle, which can confirm the manifestation of progressive and chronic denervation. When EMG shows the presence of lower motor neuron involvement in a certain area, its diagnostic value is the same as that of clinical findings of muscle weakness and atrophy.
(1) Progressive denervation manifestations: mainly include fibrillation potentials and positive sharp waves. When chronic denervation is also present in the measured muscle, the fasciculation potential has the same clinical significance as the fibrillation potential and the positive sharp wave.
(2) The manifestations of chronic denervation.
(1) Widening of the time frame and increasing amplitude of motor unit potentials, usually accompanied by an increase in polyphasic waves.
(ii) Reduced motor unit recruitment and increased wave amplitude during vigorous contractions, and in severe cases, simple phase.
(3) Most ALSs are seen to issue unstable motor unit potentials with complex waveforms.
(3) When the same muscle EMG shows a coexistence of progressive denervation and chronic denervation, it has a stronger supporting value for the diagnosis of ALS. In some muscles, only chronic denervation may be present without fibrillatory potentials or positive sharp waves. If there is no progressive denervation in all measured muscles, the diagnosis of ALS needs to be made with caution.
(4) Scope of electromyography in diagnosing ALS: Electromyography should be performed in all four regions. The brainstem region can be selected to measure one muscle, such as the sternocleidomastoid, lingual, facial or biting muscles. In the thoracic segment, the paraspinal muscle or the rectus abdominis muscle below the level of thorax 6 can be selected for determination. In the cervical and lumbosacral segments, at least 2 muscles innervated by different nerve roots and different peripheral nerves should be measured.
(5) Early in the course of ALS, the EMG may show damage in only one or two regions of the lower motor neurons, and patients with clinically suspected ALS should be followed up at 3-month intervals.
（The electrophysiological findings should be analyzed in close clinical context to avoid isolated interpretation of EMG findings.
3. motor evoked potentials: help to detect upper motor neuron lesions under the clinical of ALS, but the sensitivity is not high.
III. Neuroimaging
1. Imaging examinations do not provide a definitive diagnosis of ALS, but help to differentiate ALS from other diseases and exclude structural damage. For example, when structural lesions of the skull base, brainstem, spinal cord, or spinal canal lead to upper and/or lower motor neuron involvement, MRI of the corresponding area can be performed to help in the differential diagnosis.
2. In ALS, MRI can detect abnormal signals in the cone bundle travel areas.
3. Some common diseases, such as cervical spondylosis and lumbar spondylosis, may coexist with ALS and need to be differentiated.
IV. Diagnostic criteria of ALS
1.The basic conditions for the diagnosis of ALS are
(1) Progressive progression of the disease: Progressive development of clinical symptoms or signs in one region or from one region to other regions is confirmed by medical history, physical examination or electrophysiological examination.
(2) Clinical, neurophysiological or pathological examination confirms evidence of lower motor neuron involvement.
(3) Evidence of upper motor neuron involvement confirmed by clinical physical examination.
(4) Exclude other diseases.
2.Diagnostic classification of ALS.
(1) Clinical diagnosis of ALS: Evidence of simultaneous involvement of upper and lower motor neurons in at least three of the four regions is confirmed by clinical or neurophysiological examination.
(2) Clinically probable ALS: Evidence of simultaneous involvement of upper and lower motor neurons in at least 2 of the 4 regions confirmed by clinical or neurophysiological examination.
(3) Clinically probable ALS: Evidence of simultaneous involvement of upper and lower motor neurons in only 1 region, or evidence of upper motor neuron involvement in 2 or more regions, confirmed by clinical or neurophysiological examination. Imaging and laboratory tests have been performed to exclude other diseases.
V. Differential diagnosis
In the diagnosis of ALS, depending on the symptoms and signs, it is necessary to differentiate from a variety of diseases, such as cervical spondylosis, lumbar spondylosis, multifocal motor neuropathy, Hirayama disease, spinal muscular atrophy, Kennedy’s disease, hereditary spastic paraplegia, and paraneoplastic syndrome.
VI. Treatment of ALS
Although ALS is still an incurable disease, there are many ways to improve the quality of life of patients, and early diagnosis and early treatment should be used to prolong survival as much as possible. In addition to the use of drugs to slow down the progression of the disease, the treatment also includes nutritional management, respiratory support and psychotherapy.
1. Drugs to delay the progression of the disease.
(1) riluzole: chemically known as 2-amino-6(trifluoromethoxy)-benzothiazole, its mechanism of action includes stabilizing the inactivation of voltage-gated sodium channels, inhibiting presynaptic glutamate release, and activating postsynaptic glutamate receptors to promote glutamate uptake, etc. A clinical study conducted in France in 1994 reported for the first time that this drug could slow down the progression of ALS disease. rilutek was approved by the U.S. Food and Drug Administration for the treatment of ALS and is the only drug that has been shown in several clinical studies to slow the progression of the disease to some extent. Common adverse effects include fatigue and nausea, and elevated alanine aminotransferase in some patients, requiring monitoring of liver function. It is not recommended to continue when patients with advanced disease are already on invasive ventilator-assisted ventilation.
(2) Other drugs: In animal experiments, although several drugs have shown some efficacy in the treatment of animal models of ALS, such as creatine, high-dose vitamin E, coenzyme Q10, lithium carbonate, ciliary neurotrophic factor, insulin-like growth flash, and lamotrigine, they have not been proven effective in clinical studies of patients with ALS.
2. Nutritional management.
(1) A balanced diet should be used when normal feeding is possible, and a high-protein, high-calorie diet is appropriate to ensure nutritional intake when swallowing is difficult.
(2) Patients with chewing and swallowing difficulties should change their recipes and eat soft, semi-liquid foods and small, frequent meals. For those with limb or neck weakness, adjust the eating posture and utensils.
(3) Percutaneous endoscopic gastrostomy (PEG) should be performed as soon as possible to ensure nutritional intake, stabilize body weight, and prolong survival when the patient has significant swallowing difficulties, weight loss, dehydration, or risk of choking and aspiration. It is recommended that PEG be performed as early as possible before the forced vital capacity (FVC) drops to 50% of the expected value, otherwise it needs to be performed with assessment of anesthetic risk and ventilatory support. For those who refuse or are unable to perform PEG, a nasogastric tube may be used for feeding.
3. Respiratory support.
(1) Regular pulmonary function checks are recommended.
(2) Pay attention to early manifestations of respiratory muscle weakness in patients and use Bi-level positive airway pressure (BiPAP) as early as possible. Indications for starting noninvasive ventilation include: seated breathing, or forceful inspiratory nasal pressure (SNP) <1000pxH2O (25pxH2O=0.098kPa), or maximal inspiratory pressure (MIP) <1500pxH2O, or reduced nocturnal oxygen saturation, or FVC <70 percent.
(3) When the patient has a weak cough (peak cough expiratory airflow below 270 L/min), use an aspirator or manually assisted cough to remove airway secretions.
(4) When ALS disease progresses, non-invasive ventilation cannot maintain oxygen saturation > 90%, partial pressure of carbon dioxide < 50 mmHg (1 mmHg = 0,133 kPa), or too much secretion cannot be expelled, invasive ventilator-assisted breathing can be chosen. After using invasive ventilator-assisted breathing, it is usually difficult to get off the machine.
4. Comprehensive treatment: At different stages of the course of ALS, patients face different problems, such as depression and anxiety, insomnia, salivation, dysarthria, communication difficulties, limb spasms, pain, etc. Targeted guidance and treatment, selection of appropriate drugs and auxiliary facilities, improvement of quality of life, strengthening of nursing care and prevention of various complications should be given according to patients’ specific conditions.