Text/ Xin Ying
Editor / Wang Xiao
Photo/pixabay
On the morning of January 1, 2022, the day of the implementation of the new medical insurance catalogue, two children with spinal muscular atrophy (SMA) completed drug injections at Peking University First Hospital (hereinafter referred to as "Peking University Hospital").
The six-year-old GuoGuo lay on his side on the hospital bed, the needle was slowly pierced into about 4 cm to 5 cm perpendicular to the spine, successfully entered the intervertebral space, first introduced 5 ml of cerebrospinal fluid, and then a little bit of bolus injected 5 ml of medicinal liquid into the body of Guo Guo, through the cerebrospinal fluid circulation, acting on the central nervous system, exerting a therapeutic effect.
Guo Guo was diagnosed with spinal muscular atrophy ten months after birth and was unable to stand and walk alone. The rare disease he suffered from was a recessive genetic disease caused by a loss of genes or pathogenic variants.
The treatment of the drug is called Northinal sodium injection, which used to be 700,000 yuan a shot, because the family can not afford the sky-high drug cost, guoguo has not been systematically treated.
Since January 1, the drug has dropped to more than 30,000 yuan, and the price reduction was promoted by the national medical insurance negotiations. "After medical insurance reimbursement, the patient's self-payment for a needle is about 10,000 yuan." Yu Nan, deputy director of the medical department of Peking University Hospital, introduced it to "Finance and Economics Great Health".
Guo Guo and his patients are fortunate that more rare disease patients are still plagued by the disease.
Of the more than 7,000 rare diseases known worldwide, only 5% are treated with drugs. Up to now, more than 60 kinds of rare disease drugs in China have been approved for marketing, and more than 40 kinds have been included in the national medical insurance drug list, involving 25 diseases.
Not only are rare disease patients "lonely", but medical workers working on rare diseases are also "lonely".
Li Linkang, executive director of the China Rare Disease Alliance, and the team once did a survey, among more than 40,000 medical staff, 65% of medical workers do not know much about rare diseases, nearly 40% of medical workers have never been exposed to rare diseases, and 40% of doctors have difficulty obtaining rare disease diagnosis and treatment information.
As a result, the rate of delayed diagnosis of rare diseases is high, with 60% of patients experiencing misdiagnosis and an average diagnosis time of nearly four years.
Professor Xiong Hui, deputy director of the Department of Pediatrics of Peking University Hospital, lamented as early as five years ago that some diseases were encountered for the first time and the diagnosis was not clear; some diseases, although the diagnosis was clear, did not have effective treatment drugs; some diseases had therapeutic drugs that were not listed in China; a small number of diseases, although treatment drugs could be bought in China, were expensive, and many families were ruined.
Although, in recent years, it has gradually improved. However, "due to the large economic burden and uneven development of medical resources, there are still many patients in counties and rural areas, and they do not even have the opportunity to diagnose and understand the treatment plan, and this series of problems needs to be solved by more social forces." Li Chunde, director of the Department of Orthopedics of Peking University Hospital, pointed out.
Wait ten years for diagnosis
Fan Fan, 18, is a freshman. Because of congenital muscular dystrophy, Fan Fan weighs only 18 kilograms, his muscles are unable to support the uprightness of his head, and the largest range of motion of his elbows is to pan tens of centimeters on the table and slide to complete the book and write. These small movements are also accompanied by discomfort, and every time you insist on sitting and listening to the lecture for half an hour, you must lie down and rest.
Paying beyond the efforts of ordinary people, Fan Fan stepped into the university campus life, and the Beijing University of Aeronautics and Astronautics where he studied also arranged special channels for him in terms of eating, living and traveling, and accompanied by his mother, Fan Fan could study and live smoothly on campus.
Fan Fan is still waiting for a drug that can treat himself, and the doctor told him and his family that the drugs that can treat this disease are still in the experimental stage of laboratory mice, and it will take at least ten years to succeed.
In 2004, some abnormalities shown when Fan Fan took commemorative photos on the 100th day of his birth attracted the attention of photographers, "he can't sit up straight and grasp things like other children", Fan Fan's father only then linked the details of the child's inactivity and little movement on weekdays and went to the hospital for consultation.
In less than two months, I ran through the major tertiary hospitals in Jilin City, but I was unable to confirm the diagnosis. "Every hospital suspected cerebral palsy, and they had taken some drugs to treat cerebral palsy, but they had no effect." His father said.
Subsequently, transferred to the top three hospitals in Changchun, from pediatrics to specialists, after a series of examinations, the doctors "ruled out" all the diseases they could think of, but the doctors still could not diagnose the diagnosis.
"It happened that a doctor from Peking University Hospital returned to Jilin City to visit relatives, and asked a friend to introduce him to see, although he was not a pediatric doctor, but he had seen such cases before, suspecting that it was a neuromuscular-related disease", suggesting that Fan Fan go to Beijing to see a doctor.
With the mentality of trying it out, Fan Fan's parents bought the "Scalper" and brought their six-month-old child to the Pediatric Neurology Department of Peking University Hospital. He became one of the first patients with congenital muscular dystrophy (CMD) to be treated by the neuromuscular disease team at Peking University Hospital.
About 7 to 12 CMD patients per 100,000 babies occur at birth or within the first half of life. Children with maximum motor ability can only sit, and rarely can stand or walk.
Doctors at Peking University Hospital have preliminarily diagnosed LAMA2-related congenital muscular dystrophy (LAMA2-CMD) from both clinical symptoms and pathological examination, which is caused by mutations in the LAMA2 gene. But it took nearly 10 years to confirm this diagnosis genetically.
18 years ago, the level of domestic genetic diagnosis was limited, coupled with the huge LAMA2 gene, "to test it, you have to send a sample to Japan", so there has been no real diagnosis. Moreover, because doctors still know very little about the disease, there are no symptomatic drugs and treatment methods, and even targeted rehabilitation training programs cannot be given.
After returning to his hometown, Fan Fan's mobility is regressing with age, and he can sit from one year old, but he has not been able to stand and walk, and his erect head is weak. Polyarticular contractures develop at the age of six, and scoliosis is evident at the age of nine, with impaired respiratory function.
During this period, doctors constantly sought cutting-edge technology to try to help Fan Fan diagnose the diagnosis. For example, several remote delivery of Fanfan's blood samples, in 2005, was also confirmed to be LAMA2-CMD from the molecular pathological level by the detection method of biosynthetic staining of slices.
Until 2013, second-generation gene sequencing technology began to be applied in China, achieving a larger amount of genetic testing in a shorter period of time, and the cost of detection also decreased.
Fan Fan was invited to Peking University Hospital again to participate in the Congenital Muscular Dystrophy Translational Medicine Seminar. At that time, he had developed severe respiratory insufficiency and could not adapt to a noninvasive ventilator to assist in breathing.
Experts from the United States conducted a detailed assessment and comprehensive guidance of Fan Fan's condition. Subsequently, Dr. Xiong Hui and Dr. Song Shujuan, Department of Medical Genetics, Peking University Medical College, finally found that there was a compound heterozygous pathogenic variant in the LAMA2 gene of Fanfan, combined with immunohistochemical staining of muscle biopsy tissues to indicate merison protein deficiency, and the diagnosis was lama2-CMD. And this is the most important basis for finding a "future" treatment plan.
To get a clear diagnosis, van has been considered lucky. It is not uncommon for patients with rare diseases who have been misdiagnosed for a long time.
The diagnosis and treatment of rare diseases is a worldwide problem. According to a UK survey, 20% of patients need five years to wait for the final diagnosis; 12% wait for the final diagnosis for more than ten years; 25% have been to three to four different hospitals for the disease; 22% have consulted six or more doctors before the final diagnosis; and 52% of patients believe that the patient mutual aid organization is their main source of information.
Ding Jie, chairman of the Rare Disease Branch of the Beijing Medical Association, introduced that there are more than 30 patients who have encountered the longest misdiagnosis period, during which patients have constantly traveled to multiple hospitals, spending energy and financial resources, and some diseases that should have been cured by taking medicines have been operated on; some misdiagnosed with the wrong drugs, and some drugs have strong toxic side effects.
"Minor diseases" are also a problem
In the process of growing up, the family is worried not only that there is no medicine to treat ordinary diseases, but also the dilemma of no hospital to go to after the occurrence of common diseases.
Fan Fan in the careful care of his parents under the body immunity has been good, during the primary school period rarely cold, the number of fevers is not much, occasionally need to see a doctor, because the local hospital does not have a doctor to understand Fan Fan's condition, looking at Fan Fan's skin and bone body and too light weight, they all say that it can not be treated, it is recommended to transfer.
"After being rejected by the hospital several times, the infusion treatment after several fevers was completed in some private small clinics, and no large hospital dared to accept it." Fan Fan's father said.
After 18 years, daily medical treatment is still a problem for fanfan. In September 2020, Fan Fan, who was in his third year of high school at the time, studied until more than 1 a.m., when his father was ready to carry him back to bed to rest, he accidentally pinned his arm and fractured. Rushed to the hospital urgently, the doctor saw Fan Fan's situation or recommended transfer.
Fan Fan's father can also understand the doctor's difficulties, "If it is an ordinary patient, it is necessary to punch steel nails to help the bones heal." But Fan Fan's bones are too thin to withstand steel nails. Now the doctor-patient relationship is so tense, and the situation is so special, treatment is risky. ”
In the end, Fan Fan's father found a doctor friend who knew him well, and he reluctantly accepted him in the hospital. After several consultations, I chose conservative treatment and bought some special fixtures online to fix the bones for recovery. Because of this accident, the range of motion of the arm was reduced by nearly 30 degrees.
The more pressing problem is that due to the inability of muscles to support, Fanfan's spine has become C-shaped scoliosis, which leads to multisystem dysfunction, including respiratory insufficiency and lung infections.
Photo/ Dr. Li Chunde consulting a child with spinal deformities in neuromuscular disease Photo / Xin Ying
Fan Fan was first transferred to the Department of Orthopedics at Peking University Hospital in 2018, two years after the establishment of the Multidisciplinary Diagnosis and Treatment (MDT) team of Peking University Hospital. At this time, Fan Fan's spine had been obviously scoliosis for six years, and he had run all over the orthopedic clinics of major hospitals in Beijing.
As a result of the consultation, it is necessary to first perform spinal orthopedic surgery to reduce the pressure on other organs. But Fan Fan's weight is too low and he is severely malnourished. Not only can it not withstand anesthesia, but it is also difficult to suture the wound after surgery, and surgery is difficult to achieve.
Li Chunde, director of the Department of Orthopedics of Peking University Hospital, the first contact with children with scoliosis similar to Fan Fan, was in 1995 when he studied at the Spine Center of the Hebrew University of Israel, he had to follow his mentor to a church hospital every Tuesday, and as soon as he entered the hall, sometimes there were several electric wheelchairs shuttling and playing, and the operators were "thin bodies with big heads, just like Hawking." At that time, one or two orthopedic surgeries were performed every month for children with such rare diseases. Li Chunde said.
At that time, hospitals in China had not seen such cases, on the one hand, doctors did not pay much attention to this disease, on the other hand, parents did not know which hospital could see the disease, and children often died before they could be treated.
A few years after returning to China, there began to be scattered neuromuscular disease patients found Peking University Hospital, and nearly 75% of the more than 1,000 SMA patients registered in the rare disease joint outpatient clinic were accompanied by spinal deformities. Li Chunde began to systematically study the spinal correction treatment of patients with neuromuscular disease, but there are too few patients who can really do surgery, and Li Chunde has slowly accumulated more than 100 such surgeries for more than 20 years.
In recent years, Li Chunde has received more SMA children, the main reason is that since 2019, two drugs for the treatment of SMA have been approved in China, which has given patients hope.
Every first Thursday afternoon of each month, it is the consultation time of the MDT team of Peking University Hospital. In 2021, 16-year-old Xiaole, who had been completely incapacitated for three years, was diagnosed with SMAIII. type 3, accompanied by severe spinal deformities, resulting in severe physical pain and further deterioration of lung function.
Figure/Pre- and post-operative comparison Figure Source/Courtesy of interviewee
The twisting of the spine increases the difficulty of finding the intrathecal injection point of the drug, allowing the drug to pass smoothly in the spinal canal. After the pediatric department received the treatment, it was repeatedly communicated with various departments, and finally decided to let Xiaole undergo spinal deformity orthopedic surgery first.
In September 2021, Li Chunde completed the operation of correcting spinal deformities, and at the same time, he also removed part of the lumbar lamina and reserved a bone channel for the back injection of drugs. Although the operation was smooth, Xiao Le's waist could not be bent after the operation, there were no anatomical signs like normal people, and the reserved channel was difficult to find. Hu Xiao, deputy director of the Department of Anesthesiology, repeatedly explored through ultrasound guidance, found the reserved bony channel, and finally successfully punctured, and completed the first SMA spinal deformity orthopedic surgery combined with Northinason intrathecal injection.
Since 2022, after The Sodium Northinal is included in the medical insurance reimbursement, Li Chunde has seen some old patients in the hospital, who have previously undergone spinal correction surgery, and at that time, there was no injection drug at the sky-high cost of 700,000 yuan a needle, but Li Chunde has helped the patients leave the injection channel.
At the beginning of the year, they came from all over the world to inject drugs.
Let the knowledge of rare diseases first spread to the grassroots level
Li Chunde received patients, and there were not many patients who were really referred through the hospital, and most of them were the parents of the patients who felt the stones and crossed the river to find a doctor. This means that in the county, there are more patients who have been misdiagnosed or have not had the opportunity to receive treatment.
"The number of doctors in China who can comprehensively provide internal medicine treatment and surgical orthopedics for patients with neuromuscular diseases is concentrated in university-type hospitals in a few large cities." Li Chunde said.
The United Kingdom launched a response strategy from 2010, in addition to improving the financial security and information assistance for patients with rare diseases, but also strengthening the training of doctors, including high-quality training for medical undergraduates, postgraduates and others on the awareness of rare diseases, and clarifying the identified medical pathways, some of which also include primary care, local hospitals, community centers and clinical expert centers. There is also a need to work together to identify the risk of rare diseases so that patients can get a quick diagnosis without having to restart an indeterminate test result each time.
Photo / Dr. Li Chunde analyzes the condition of children with spinal deformities with neuromuscular disease during the rounds / Xin Ying
Li Chunde pointed out that the more rare the disease, the more it tests the overall level of a hospital, rather than the high level of a certain expert. At this stage in China, hierarchical diagnosis and referral, so that patients can find a capable hospital, is very critical for the diagnosis and treatment of rare diseases.
Although it started relatively late, China's emphasis on rare diseases is also increasing. In 2019, the National Health Commission organized the establishment of a national rare disease diagnosis and treatment cooperation network, and Peking Union Medical College Hospital, Peking University Hospital and other hospitals took the lead to form a collaborative network of 291 hospitals.
"Now The weekly MDT online and offline synchronous consultation of Concord Hospital solves the problems of many patients through telemedicine, and there are hundreds of hospitals learning synchronously, and when there are fewer, there are more than a dozen hospitals online." Li Linkong introduced.
However, the alliance is still at the provincial level, ensuring that doctors in the province have seen rare diseases and know which hospital to refer to when they meet patients. Li Linkang said that in the future, the number of hospitals accessing the collaboration network will be gradually expanded.
This is only the first step.
"For areas that the collaboration network cannot cover for the time being, more social forces are needed to support and organize qualified and experienced doctors to diagnose and screen at the county level to provide more patients with the opportunity to seek medical treatment." Li Chunde said.
(Guo Guo, Fan Fan and Xiao Le are pseudonyms)