作者：彭伟 北京市丰台中西医结合医院

Amyotrophic lateral sclerosis，ALS.“Amyotrophic” refers to the muscle atrophy, weakness, and fasciculation that signify disease of the lower motor neurons.“Lateral sclerosis” refers to the hardness to palpation of the lateral columns of the spinal cord in autopsy specimens, where gliosis follows degeneration of the corticospinal tracts. The clinical results are upper motor neuron signs: overactive tendon reflexes, Hoffmann signs, clonus, and Babinski signs.
ALS has two meanings. In one sense, it refers to several adult-onset conditions characterized by progressive degeneration of motor neurons, In the United Kingdom, the term motor neuron disease is ALS. In the second sense, ALS refers to one specific form of motor neuron disease in which there are both upper and lower motor neuron signs. Motor neuron diseases (MNDs) are a group of diseases which result in progressive destruction of neurons and gradual deterioration of voluntary muscle function, leading to high mortality and morbidity. Degeneration of motor neurons in the motor cortex, brain stem and spinal cord.
UMNs in the primary motor cortex (blue) and bulbospinal LMNs (red) are the preferentially affected sites in ALS. Neurons in the frontotemporal cortex (orange), are frequently involved as well; Ocular (green) and vesicorectal (yellow) motor neuron involvement is rare, and happens mostly in cases of longstanding disease.
A spectrum of extramotor involvement is possible in ALS, ranging from classic ALS with no to mild extramotor involvement to ALS with extrapyramidal, cerebellar, sensory, autonomic, urinary or oculomotor involvement, designated as ‘ALS with multisystem degeneration. In the UMN–LMN spectrum, pure UMN involvement, as in PLS, and pure LMN involvement, as in PMA have a better prognosis than disease with both UMN and LMN involvement. Increasing frontotemporal involvement is associated with shortened survival. Degeneration of all three neuronal systems is associated with the highest disease severity and, hence, the worst prognosis. Patients with age of onset above median had a shorter survival in both countries. Patients with bulbar onset had a shorter survival than patients with spinal onset in both countries. Patients with faster early progression rate (ALS-FRS-R) had a shorter survival in both countries. Patient with BMI above median at the time of their first visit had a longer survival in both countries.Patients with PLS had the longest survival, followed by PMA, FAS/FLS, and classical ALS in both cohorts.
In China, SOD1 mutations constitute the most frequent gene mutations (30%), while C9ORF72 mutations are far less common (2.3%). A younger age of onset and a more benign natural course of disease are the most significant clinical differences in Chinese patients compared to Caucasians. Dysfunction of the astrocytic excitatory amino acid transporter 2 (EAAT2) results in reduced uptake of glutamate from the synaptic cleft and thereby glutamate excitotoxicity. Glutamate-induced excitotoxicity results in increased influx of Na+ and Ca2+ ions and ultimately neurodegeneration through activation of Ca2+-dependent enzymatic pathways. Glutamate excitotoxicity results in the generation of free radicals which in turn contribute to neurodegeneration. Mutations in c9orf72, TDP-43 (TARDBP) and FUS result in dysregulated RNA metabolism that ultimately leads to the formation of intracellular aggregates which are harmful to neurons. Mutant SOD-1 enzymes increase oxidative stress, induce mitochondrial dysfunction, form intracellular aggregates, and adversely affect neurofilament and axonal transport processes. Activation of microglia results in secretion of proinflammatory cytokines, producing further toxicity.
SOD1 mutations were found to cause familial ALS in 1993 , but there was a long hiatus until the discovery of the next ALS gene, TARDBP, in 2008. The genetic architecture of ALS in Asian populations is distinct from that in European populations. There is clear wasting of the first dorsal interosseous (FDI) and thenar complex but sparing of the hypothenar muscle. The neurophysiological definition of lower motor neuron (LMN) dysfunction （rEEC）
(i)presence of fibrillation potentials and positive sharp waves;
(ii)evidence of reinnervation (large amplitude, long duration polyphasic motor unit action potentials);
(iii)reduced interference on full contraction with increased firing rate of motor units on voluntary contraction.
The neurophysiological definition of lower motor neuron (LMN) dysfunction （rEEC） The assessment of upper motor neuron dysfunction remains clinically based. The definition of LMN dysfunction using the Awaji and updated Awaji criteria is as follows:
(i)presence of fibrillation potentials and positive sharp waves or fasciculation potentials;
(ii)evidence of reinnervation (large amplitude, long duration polyphasic motor unit action potentials);
(iii)reduced interference on full contraction with increased firing motor unit rate upon voluntary contraction.
The definition of LMN dysfunction using the Awaji and updated Awaji criteria is as follows: In order for a region to be classified as affected the neurophysiological changes have to be evident in a minimum of 2 muscles innervated by different nerve roots and nerves for spinal and lumbosacral regions; and a minimum of one muscle in the bulbar/thoracic regions. Awaji criteria improves the diagnostic sensitivity in amyotrophic lateral sclerosis. The Awaji criteria increased the sensitivity of diagnosis without affecting the specificity. Competitive endogenous RNA (ceRNA) hypothesis: MicroRNAs (miRNAs) are commonly considered as active negative regulators of gene expression, decreasing the stability of target mRNAs or limiting their translation. miRNAs act through specific complementary binding of its seed region (usually 6–8 nt long) to the 3′ untranslated region (UTR) of target mRNA, called miRNA response elements (MRE).
Riluzole typically extends survival by 2–3 months and increases the chance of an additional year of survival by ~9%. The improvement in survival was greater in patients with bulbar-onset disease than in those with limb onset. Efficacy and safety results suggest that the 100 mg dose of riluzole has the best benefit-to-risk ratio. This study confirms that riluzole is well tolerated and lengthens survival of patients with ALS. Adverse reactions: asthenia, dizziness, gastrointestinal disorders, and rises in liver enzyme activities.
Riluzole therapy improves ALS survival. The efficacy of the drug was present amongst bulbar-onset ALS and older patients, but not in subjects with limb-onset. The favourable effect of the drug was transient, as it was lost in prolonged follow-up. Our observations support the use of riluzole at an early stage of ALS in bulbar and elderly patients. The Kaplan–Meier analysis did not reveal any significant differences in the median survival time of the riluzole group and the control group. The survival of the beyond quartile 3 subgroup was significantly better than that of the other groups (quartile 1:2800mg, quartile 3:16,800 mg )
The survival times of the riluzole group and the control group did not significantly differ in any of the phenotypes. In the age between 42.0 and 58.0 years old group, median survival was prolonged by 24.0 months (the riluzole group, 83.0 months; the control group, 59.0 months) . The subgroup analysis showed that the prognosis of the beyond quartile 3 subgroup was significantly better than that of the control group.
Riluzole could only slow down the progression of the disease rather than reverse it. The faster the disease progressed or the more severe the disease, the more willing the patients were to use riluzole. The prognosis of the riluzole users seemed to be better only in the limb-onset patients. The long-term use of riluzole could improve ALS patient survival. It appears that the use of riluzole over approximately 6 months may improve ALS patient survival. Older age at onset, male gender, lower BMI, shorter diagnostic delay from symptom onset, residence in a rural area, and lower FRS score at presentation were also related to poorer ALS patient prognosis.
The reduction of ALSFRS-R was smaller in the edaravone group than in the placebo group, but efficacy of edaravone for treatment of ALS was not demonstrated. Levels and frequencies of reported adverse events were similar in the two groups. Edaravone 60mg/d i.v. infusion over 60 min for the first 14 days in cycle 1, and for 10 of the first 14 days during cycles 2 to 6. Edaravone inhibited the progression of functional disorder in patients with ALS in the EESP and dpEESP2y subpopulations, especially in the latter. FAS=full analysis set.（grade 1: able to work or perform housework; grade 2: independent living but unable to work; grade 3: requiring assistance for eating …) EESP=efficacy-expected subpopulation of ALS patients (% forced vital capacity of ≥ 80% before treatment and ≥ 2 points for all item scores in ALSFRS-R before treatment). dpEESP2y-subgroup of the EESP, containing patients with a diagnosis of ‘definite’ or ‘probable’ ALS according to the El Escorial revised Airlie House diagnostic criteria and with disease duration of ≤ 2 years.
Edaravone exhibited efficacy in the dpEESP2y subgroup (those with preserved vital capacity and shorter disease duration). Now the FDA-approved Riluzole and Edaravone are only limited to short-term prolonged patients’ survival, without fundamentally relieving the symptoms of ALS. High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study.
Neither the primary nor the secondary outcome measures could determine whether a megadose of vitamin E is efficacious in slowing disease progression in ALS as an add-on therapy to riluzol（but the functional assessments showed a marginal trend in favour of vitamin E, without reaching significance.）Although it was not statistically significant, the efficacy data in the other outcomes also showed a trend favoring oral solubilized UDCA. Gastrointestinal adverse events developed more frequently in patients treated with oral solubilized UDCA. This pilot study provides preliminary clinical data indicating that TUDCA is safe and may be effective in ALS. There was no difference between groups in the primary outcome of survival, although post-hoc analysis suggested that rasagiline might modify disease progression in patients with an initial slope of ALSFRS-R greater than 0.5 points per month at baseline.
Repeated intrathecal injections of BM-MSCs demonstrated a possible clinical benefit lasting at least 6 months, with safety. BM-MSCs mediate switching from pro to anti-inflammatory conditions. There was no significant difference in long-term survival between groups. Nanocurcumin（ 80 mg/d）is safe and might improve the probability of survival as an add-on treatment in patients with ALS, especially in those with existing bulbar symptoms. Curcumin,might have a beneficial effect on neurodegenerative diseases, such as AD, PD, and ALS, through its antiinflammatory and antioxidant properties.
High-frequency physical exercise was not superior to UER on ALSFRS-R scores, motor and respiratory functions, survival, fatigue, and quality of life of ALS patients. The toxicity of SOD1 is the result of a gain of toxic function rather than a loss of enzymatic function; Reducing concentrations of the mutant protein is predicted to slow progression of SOD1-linked ALS. Antisense oligonucleotides function is by binding to a specific target mRNA and causing degradation of the mRNA by activation of the nuclear enzyme RNase H. Antisense oligonucleotides do not cross the blood–brain barrier-- intrathecally into the CSF.
Conclusions: in adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture–related adverse events were observed in most participants.
Above all, ALS is a treatable disease even though it is not curable.

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