On January 18, 2024, in a tearful video, Cai Lei, diagnosed with Amyotrophic Lateral Sclerosis (ALS), expressed that death was looming close. He made a pact with his wife, urging pharmaceutical companies and laboratories to persist in their research efforts. He entrusted his wife and pharmacists to continue developing new drugs to aid in the fight against ALS and to help save fellow sufferers.
Since his diagnosis in 2019, Cai Lei has passionately dedicated himself to battling ALS, a new battlefield in his life. His journey of self-preservation has reignited public interest in ALS, leaving many wondering: How far are we from conquering ALS?
If, a little over a decade ago, Amyotrophic Lateral Sclerosis (ALS) was merely an obscure and bewildering term, it has now entered the public consciousness under the more vivid and descriptive name – ALS, or Lou Gehrig's disease.
From the global phenomenon of the "Ice Bucket Challenge" in 2014, to the legendary struggle of physicist Stephen Hawking against the disease for 55 years, which ended in 2018 garnering significant attention, to the news of ALS-afflicted "anti-epidemic hero" Zhang Dingyu in recent years, this disease is no longer unfamiliar to the public. Cai Lei, the former Vice President of JD.com, has brought attention to this rare disease through his story of confronting ALS, turning it into a hot topic of national concern through the internet.
With extraordinary courage and determination, Cai Lei has devoted all his energy and resources to combat this disease. He established a database platform for ALS patient medical records in China, led and advocated for patients to donate their bodies to the national brain bank for research, and promoted cooperation among doctors, patients, researchers, and pharmaceutical companies to develop new drugs. His spirit and courage are commendable, undoubtedly playing a positive role in advancing ALS research in China.
However, drug development for this poorly understood and fatal disease is challenging. Despite trying various medications, Cai Lei's condition continues to deteriorate gradually. In his own words, "death is very close." So, what exactly is this disease that strikes fear into everyone's hearts?
Most patients are diagnosed in their fifties or sixties, and the disease typically lasts three to five years.
ALS, also known as Motor Neuron Disease (MND), is a neurodegenerative disease that selectively affects upper and lower motor neurons, leading to progressive degeneration of spinal motor neurons, brainstem motor nuclei, and corticospinal tract cells or fibers.
In layman's terms, it's a disease that primarily affects motor function, while perception of cold, heat, pain, and consciousness is usually unaffected. "ALS" is a colloquial term that vividly depicts the clinical characteristics of patients: they are frozen, unable to move, speak, eat, or even breathe.
Most ALS patients develop symptoms in their fifties to sixties (though some may be younger than thirty), showing gradually worsening limb weakness, muscle atrophy, and fasciculations (muscle twitching). Speech difficulties, swallowing problems, and eventually respiratory difficulties may occur, ultimately leading to death from respiratory failure or its complications. The disease typically progresses over three to five years, although some cases can survive for ten years or even thirty years.
The annual incidence rate of ALS is about 1-4 per 100,000, and as of 2021, the estimated prevalence of ALS in China is 2.97 per 100,000, categorizing it as a rare disease. However, due to China's large population, the total number of patients is considerable. About 90% of cases are sporadic, while 10% are familial, with nearly 40 genes associated with the disease. However, only a small percentage of cases are caused by genetic mutations, so for most sporadic cases, there's no need to overly worry about the probability of inheritance.
Excessive focus on fasciculations and fear of ALS lead to many seeking medical consultation.
What symptoms should warrant consideration for this disease, and how is it diagnosed?
From a clinical standpoint, about 70% of patients initially present with weakness or atrophy in a limb, such as difficulty writing or holding a pen, atrophy of the muscles in the hand, or difficulty dorsiflexing the toes. Twenty-five percent of patients present with slurred speech, swallowing difficulties, choking while drinking water, or weak coughing. Five percent of patients develop symptoms due to weakness of the respiratory muscles. All symptoms of the disease begin insidiously and then gradually worsen and spread to other areas.
After a neurological examination, doctors may observe signs such as decreased muscle strength, positive pathological reflexes, and damage to upper and lower motor neurons. Diagnosis of ALS can only be made after extensive acute and chronic nerve damage, as evidenced by electromyography (EMG) testing, ruling out other relevant diseases. EMG can provide evidence of damage to lower motor neurons, making it the primary objective test supporting the diagnosis of this disease. Genetic testing has auxiliary diagnostic value for familial cases.
It is worth noting that ALS is a rare disease characterized by a combination of specific symptoms and signs, and self-diagnosis should be avoided. In outpatient clinics, many young and middle-aged individuals seek medical attention due to fear of ALS. After learning about Cai Lei's story, these individuals become overly focused on fasciculations and muscle atrophy, fearing that they have ALS, leading to intense anxiety. Some patients continue seeking medical attention even after receiving multiple normal EMG reports, always worrying that they have "developed the disease too early" and that the EMG "cannot detect it."
In reality, fasciculations can occur when peripheral nerves and anterior horn cells are stimulated. Additionally, benign fasciculations refer to physiological muscle twitching. They can occur during periods of stress, anxiety, excitement, intense exercise, or prolonged muscle fatigue, or after consuming large amounts of stimulating substances like strong tea or coffee. Rest or improvement in mood can alleviate symptoms. Moreover, EMG testing can often detect damage to lower motor neurons that have not yet manifested clinically, so there's no need to repeatedly undergo testing due to doubts about its accuracy.
The same applies to muscle atrophy, which can occur due to damage to muscles, peripheral nerves, motor neurons, and even disuse (such as after immobilization due to fracture). It should not be equated simply with ALS and should be judged by specialists. Clinicians should both avoid misdiagnosing ALS as cervical spondylosis, lumbar spondylosis, peripheral nerve entrapment, or stroke, and prevent overdiagnosis.
The development of new drugs continues, with cutting-edge technologies like brain-computer interfaces "hitting the shelves."
As of now, there is still a lack of effective cure for amyotrophic lateral sclerosis (ALS), but the exploration for breakthrough treatments never ceases.
Currently, the approved drugs for slowing disease progression and extending survival mainly include riluzole and edaravone. In 2023, a combination of sodium benzoate and tauroursodeoxycholic acid was conditionally approved for sale in the United States and Canada.
Since its introduction to the market in 1996, riluzole has been available not only in tablet form but also in an oral suspension formulation for patients having difficulty swallowing, which is now supplied domestically and covered by medical insurance. Edaravone, administered through intermittent intravenous infusion over six months, was approved by the U.S. Food and Drug Administration (FDA) for ALS treatment in 2017. Its indication for ALS treatment has also been approved domestically and covered by medical insurance. In 2023, oral formulations of edaravone, such as oral suspension and sublingual tablets, were also launched domestically and internationally, providing convenience for administration and the possibility of long-term drug use. For patients with SOD1 mutations, in 2023, the U.S. FDA accelerated the approval of Tofersen for intrathecal injection, a gene therapy.
It can be said that in recent years, global drug development has significantly accelerated, and the support from the Chinese government for the research and marketing of orphan drugs has also led to the implementation of many favorable policies.
In addition, symptomatic supportive treatment for ALS patients is also crucial. When patients experience severe swallowing difficulties, percutaneous endoscopic gastrostomy (PEG) should be performed early to ensure adequate nutrition. Compared to nasogastric tube feeding in earlier years, PEG surgery now involves making a "small hole" in the abdominal wall to insert the gastrostomy tube into the stomach, reducing the risk of lung infections caused by inserting a gastric tube and providing a better experience for patients. When respiratory function declines, early use of non-invasive bilevel positive airway pressure ventilation should be initiated. Some patients are reluctant to use it early for fear of dependence. However, clinical studies have shown that starting intermittent ventilation when respiratory function declines can slow the rate of decline in lung function. Non-invasive ventilators are compact and convenient, similar to machines used for treating sleep apnea, with different models having varying functionalities, which can be very beneficial for extending survival and improving quality of life.
Currently, simultaneous progress is also being made in rehabilitation exercises and psychological therapy. In addition, high-end scientific and technological aids such as wearing cervical collars, electric wheelchairs, eye trackers, and even electronic larynxes (based on research results from Tsinghua University to improve pronunciation, as tested by Cai Lei) and brain-computer interfaces are all being explored to better improve the quality of life of patients.
ALS is a serious neurological disease. We need to have a correct understanding and scientific discrimination to avoid detours and blind fear. We should also believe that with the development of technology and the efforts of the whole society, we will one day overcome this stubborn disease. (Writer is an Associate Chief Physician of Neurology Department, Huashan Hospital Affiliated to Fudan University)
