Sino-US expert summit dialogue, focusing on the latest progress in the diagnosis and treatment of Huntington's disease

*For medical professionals to read and reference to do a good job in the diagnosis and treatment of Huntington's disease, you must watch this wonderful academic feast! Huntington's disease (hereinafter referred to as "HD"), also known as Huntington's chorea, is an autosomal dominant neurodegenerative disease with the main clinical manifestations of chronic progressive chorea involuntary movements, mental disorders and cognitive impairment.
People may not be familiar enough with this rare disease to mistake symptoms in patients for other diseases
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 However, HD patients will not only significantly affect the quality of life due to the core clinical manifestations of chorea symptoms, but also directly threaten their lives by the disease.
Studies have shown that adult HD patients generally die within 15 to 20 years after the onset [1]
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Today, there is still a lack of effective interventions for HD, and the treatment needs of patients need to be met urgently
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On December 20, 2021, the "Concentration - Sino-US Expert Summit Dialogue" co-organized by the "Medical Community" and Teva Pharmaceuticals ushered in a special session on Huntington's disease.
Professor Wu Zhiying from the Second Affiliated Hospital of Zhejiang University School of Medicine was invited to serve as the meeting.
Chairman, Professor Pei Zhong of the First Affiliated Hospital of Sun Yat-sen University, Professor Cao Li of the Sixth People's Hospital Affiliated to Shanghai Jiaotong University, and Professor Ma Jinghong of Xuanwu Hospital of Capital Medical University were invited to attend the meeting, and invited the University of Alabama through online connection.
Professor Victor Wai-Da Sung from the University of Birmingham attended the meeting as an overseas expert and brought wonderful academic sharing on related topics
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 Part 1 Research progress of Huntington's disease.
Prof.
Zhong Pei from the First Affiliated Hospital of Sun Yat-sen University firstly focused on the latest research progress of HD, from three aspects: staging and classification of HD motor symptoms, preliminary experience of HD cloud platform and network evaluation, and HD gene therapy.
Excellent report
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 The traditional clinical staging of HD is generally divided into early, middle and late stages according to the length of the disease course.
In recent years, the disease course is often combined with the comprehensive ability assessment (TFC) score of HD patients (see Table 1) to judge the motor symptoms and treatment opportunities of patients.

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 Table 1.
Clinical staging of HD patients When classifying HD patients, it is necessary to score according to symptom scales such as chorea, rigidity and dystonia.
However, HD patients in clinical treatment often have different types of motor symptoms at the same time.
ENROLL- HD research shows that "mixed" patients account for about 80% [2], so classification is also a common clinical difficulty
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Accurate motor classification can help to assess the disease progression and prognosis of HD patients, and can also be used as a reference for accurate patient grouping in clinical studies related to disease-modifying therapy
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 The cloud platform and network evaluation for HD diagnosis and treatment are aimed at the current situation of rare HD patients and a small number of professional doctors in China, and carry out comprehensive disease management with patients as the center, so as to improve the service quality of patients and promote relevant clinical research.
The current work is mainly based on WeChat public accounts and patient groups, which can benefit more patients in the middle and late stages, and patients in rural and remote areas, and reduce the burden of patients on medical treatment
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 The method of uploading videos by patients and doctors evaluating motor symptoms according to the videos has shown good consistency with the assessment in the clinic (see Figure 1).
Online scales are also being used to assess cognitive and mental aspects.
In the future, cloud platform video recording and online evaluation are expected to become a good alternative for evaluating the efficacy of clinical research drugs
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 Figure 1.
The cloud platform video to evaluate the patient's motor symptoms, which has good consistency with the clinic evaluation.
Gene therapy based on pathophysiological basis, removing toxic proteins or correcting mutant genes is one of the most anticipated directions for HD treatment.
Currently, related explorations It is still in the preclinical or clinical research stage, and problems such as off-target effects (correction of mutated genes) need to be solved.
Professor Pei Zhong and his team have participated in the exploration of gene editing therapy, exosomal RNA interference and other therapeutic methods
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 Part 2 Drug selection for Huntington's disease Prof.
Cao Li from the Sixth People's Hospital Affiliated to Shanghai Jiaotong University discussed the current status of drug treatment and drug selection for HD.
The proportion of drugs to relieve motor symptoms was about 35%, and the two most commonly used drugs were tiapride hydrochloride and haloperidol, but only 12.
3% of patients believed that the drugs were effective
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A cross-sectional study conducted by Prof.
Cao Li's team showed that HD patients' low recognition of drug efficacy will affect their compliance with follow-up.
Patients who do not recognize the efficacy are more pessimistic about curing the disease and are reluctant to comply with long-term management [3]
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 The pathophysiological basis of abnormal movements in HD patients is mainly the absence of spiny neurons (MSNs) and dysregulation of regulatory pathways in the indirect or direct pathway (advanced dyskinesia).
Excess dopamine plays an important role in hyperkinesia leading to chorea.
It is also the main target for the intervention of new drugs for HD treatment such as vesicular monoamine transporter-2 (VMAT2) inhibitors (see Figure 2).
Effective treatment should aim to inhibit the release of presynaptic dopamine and antagonize postsynaptic dopamine receptors.
However, traditional antipsychotic drugs have many problems in the treatment of HD, such as unclear efficacy and mechanism of action, possible accelerated functional decline, and significant side effects
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 Figure 2.
Regulatory pathways related to HD chorea Data, the number of included patients is often not more than 30 cases, and the evidence level of evidence-based medicine is low
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The pivotal clinical study First-HD of the VMAT2 inhibitor deuterotetrabenazine is a standard randomized, double-blind, placebo-controlled, parallel group study with a more rigorous and scientific design (see Figure 3), and the number of patients included is also large 90 cases [4]
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 Figure 3.
First-HD study design The results of the study showed that deuterotetrabenazine treatment significantly improved the patients' highest total score of chorea symptoms (TMC score) compared with baseline, and the improvement was significantly better than that of the placebo group (4.
4 points vs.
1.
9 points).
The safety of deuterotetrabenazine treatment was good, and the common adverse events (AEs) were diarrhea, drowsiness, dizziness, etc.
, which were generally similar to those in the placebo group, and no drug-related cognition was found.
Significant changes in functions such as behavior, language,
etc.

 Figure 4.
The efficacy data of the First-HD study In addition, in clinical practice, in order to control the mental/emotional symptoms of patients, doctors often prescribe multiple antipsychotic drugs at the same time, but the combination of drugs may increase adverse reactions.
Monotherapy is recommended as the first choice [1,5]
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In an open-label clinical study of the VMAT2 inhibitor tetrabenazine, concomitant antidepressant and antipsychotic medication did not significantly affect the duration of tetrabenazine treatment, nor was it the main reason for discontinuation, nor did the patient benefit from treatment.
significantly affected [6]
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 In the era of evidence-based medicine, the 2019 edition of the International Guidelines for the Treatment of HD has been recommended as Class A, and the first-line treatment is the preferred VMAT2 inhibitor tetrabenazine/deuterotetrabenazine monotherapy (patients with uncontrollable Depression or suicidal tendencies are excluded), and antipsychotics such as tiapride are used in patients with psychiatric/affective symptoms (see Figure 5)
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Because the actual situation of HD clinical diagnosis and treatment is complex, doctors can also make personalized medication adjustments based on guidelines and experience
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 Figure 5.
The 2019 International Guidelines for HD Chorea Treatment Recommendations Part 3 Management of Huntington's Disease Patients As a world-renowned expert in the field, Professor Sun Huida from the University of Alabama at Birmingham, USA, mainly focused on the management of HD patients.
The typical triad of HD patients , that is, movement disorders (mainly chorea), cognitive function (such as attention), and neuropsychiatric symptoms (such as depression), all significantly affect the quality of daily life, function and mood, so targeted interventions are required
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 For example, the VMAT2 inhibitor tetrabenazine/deuterotetrabenazine can significantly improve the chorea symptoms of patients, antipsychotic drugs can be used for the management of neuropsychiatric symptoms, and cognitive impairment is mainly intervened by non-drug means.
It is necessary to pay attention to the side effects during the treatment, and to dispel the relevant concerns of patients and their families through doctor-patient communication
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 In addition, a successful experience of HD management in the United States is that 60 "Excellence Programs" all over the country provide multidisciplinary management, in addition to neurologists, psychiatrists, social workers, rehabilitation specialists, nutritionists, genetic counseling It allows patients to meet various needs in one visit and reduce the burden of patients’ visits and treatment
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Professor Sun Huida combined two typical cases to demonstrate the necessity of multidisciplinary diagnosis and treatment of HD and the actual benefits it brings to patients
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 Part 4 Discussion and Exchange In the final discussion session of the meeting, Professor Ma Jinghong from Xuanwu Hospital of Capital Medical University presided over the meeting.
The experts at the meeting had a wonderful exchange on the following issues: Q1 For HD patients with different motor symptoms, the treatment strategy What are the differences? What precautions? Professor Ma Jinghong: For patients with chorea-like symptoms that significantly affect the quality of life, we may give priority to VMAT2 inhibitors, but for patients with cognitive impairment or neuropsychiatric symptoms, we should give priority to their Symptoms are treated symptomatically, but extrapyramidal reactions to some drugs need to be considered
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 Q2How to follow up HD patients? What are some good recommendations for long-term management of HD patients? Professor Ma Jinghong: New technologies and new concepts such as the Internet + medical model and artificial intelligence are important directions for improving the long-term management effect of HD patients.
China has also accumulated rich experience in the management of neurological diseases such as Parkinson's disease.
Similar management models Helps in the management of patients after discharge
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 Professor Sun Huida: HD patients, their families and related staff in the United States can log in to a special consultation platform through their mobile phones to conduct free consultations throughout the whole process, which significantly lowers the threshold for consultation for HD patients.
In the center model, medical staff from various disciplines take turns to diagnose patients, and pay attention to psychological support for patients
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Q3HD is a progressive disease, and there is still no cure.
How to establish an effective doctor-patient "alliance" to improve patient compliance? Professor Ma Jinghong: HD patients' access to medical treatment is still not smooth, and the effect of previous drug treatment is poor.
These two factors affect the patient's compliance with treatment.
We should focus on improving related aspects.
Pay attention to adequate support for patients and their families in psychological and other aspects
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 Q4 What are the differences between Chinese HD patients and Western populations in terms of clinical phenotypes, treatment patterns and responses to drugs? Professor Ma Jinghong: Due to the lack of relevant research, the clinical phenotypic characteristics and drug response of HD patients in China are still unclear, but the availability of drugs is obviously limited.
Conditions also limit the long-term medication of some patients
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 References: [1] Parkinson's Disease and Movement Disorders Group of Neurology Branch of Chinese Medical Association.
Guidelines for the diagnosis and treatment of Huntington's disease [J].
Chinese Journal of Neurology, 2011, 44(9): 638-641.
[2 ]Achenbach J, von Hein SM, Saft C.
Functional and cognitive capacity differ in dystonic motor subtypes when compared to choreatic and hypokinetic‐rigid motor subtypes in Huntington's disease[J].
Brain and Behavior, 2020, 10(8): e01704.
[3]Ke H, Cao X, Song Y, et al.
Health services utilization of Chinese patients with Huntington's disease: a cross-sectional study [J].
BMC Health Services Research, 2021, 21(1): 806.
[4 ]Frank S, Testa CM, Stamler D, et al.
Effect of deutetrabenazine on chorea among patients with Huntington disease: a randomized clinical trial[J].
JAMA, 2016, 316(1): 40-50.
[5]Bachoud- Lévi AC, Ferreira J, Massart R, et al.
International guidelines for the treatment of Huntington's disease[J].
Frontiers in Neurology, 2019, 10: 710.
[6]Shen V,Clarence-Smith K, Hunter C, et al.
Safety and efficacy of tetrabenazine and use of concomitant medications during long-term, open-label treatment of chorea associated with Huntington's and other diseases[J].
Tremor and Other Hyperkinetic Movements, 2013, 3.
*This article is only used to provide scientific information to medical and health professionals and does not represent the platform's views