Traditional East Asian Herbal Medicine for Amyotrophic Lateral Sclerosis: A Scoping Review

This study aimed to analyze and summarize the existing evidence regarding herbal medicine treatments for amyotrophic lateral sclerosis (ALS). Studies on herbal medicine treatment in patients with ALS were searched within English, Chinese, Japanese, and Korean databases up to July 31, 2021. In the selected studies, we collected the following information: the first author, year of publication, country, language, study methodology, sample size, demographic characteristics of the study participants, disease duration, diagnostic criteria, treatment method, treatment periods, evaluation tools, results, and side effects. The organized data were classified and analyzed narratively. This study included 59 studies. The first clinical study on the effect of herbal medicine was published in 1995; moreover, most studies were conducted in China. Among the 59 selected studies, 47.5% were observational studies, including case reports and case series. Moreover, there was one meta-analysis. The El Escorial criteria were the most commonly used diagnostic criterion for ALS; moreover, the ALS functional rating scale was the most common evaluation tool. Buzhongyiqitang, Sijunzitangjiawei, and Jianpiyifeitang were the most commonly used herbal medicines, with anti-inflammatory, protein aggregation, and anti-oxidant effects. There remain evidence of gaps in the effectiveness of herbal medicine for ALS. To allow effective treatment of patients with ALS using herbal medicine, large-scale and rigorously designed high-quality clinical studies should be performed.


Introduction
Amyotrophic lateral sclerosis (ALS) is a representative motor neuron disease involving invasion of the upper and lower motor neurons. e cerebral cortex, brainstem, and spinal motor nerves are selectively invaded, which results in gradual muscle weakness and death from respiratory muscle paralysis within 2-4 years [1]. e disease was first reported by Charles Bell in 1824 and was termed ALS in 1874 by Jean-Martin Charcot, who linked the symptoms to neurological problems [2]. ALS is also termed Lou Gehrig's disease after a famous baseball player, Lou Gehrig, who suffered from the disease in 1939 [3].
Approximately 90% and 10% of ALS cases are sporadic and familial, respectively. However, the ALS prevalence rate in South Korea remains unclear. A recent study reported an ALS incidence of 0.6 to 3.8/100,000 per year, with men having a slightly higher prevalence rate than women. e age of onset for sporadic and familial ALS is 58-63 years and 47-52 years, respectively; moreover, the incidence rate rapidly decreases after the age of 80 years. Familial ALS is mainly associated with mutations in genes, including superoxide dismutase 1 and transactive response DNAbinding protein.
e cause of sporadic ALS is unknown; however, it involves environmental and genetic risk factors. e underlying pathogenesis of motor neuron degeneration in ALS is protein aggregation and glutamate-induced excitatory toxicity. Neuroinflammation is crucially involved in motor neuron cell death in ALS by accelerating the disease progression; moreover, oxidative stress contributes to motor neuron damage. However, details regarding the underlying mechanism remain to be elucidated [1,[4][5][6].
Currently, the Food and Drug Administration-approved drugs for ALS treatment are riluzole and edaravone. Riluzole is an anti-glutamate drug that can extend the lifespan by 2-3 months, while edaravone is an anti-oxidant drug primarily used for post-stroke recovery. However, these drugs cause side effects, including diarrhea, fever, nausea, vomiting, dizziness, and fatigue; moreover, there is currently no treatment that can fundamentally cure or stop ALS progression [7]. erefore, patients with ALS and their families can consider complementary alternative medicine (CAM) for ALS treatment. A Chinese study [8] reported that 99% of patients with ALS underwent integrative therapy (IT); moreover, a recent South Korean study [9] reported that every patient who participated in the survey received CAM treatment. In a German questionnaire study [10], 54% of patients with ALS reported having received CAM treatment. ese findings suggest that CAM treatment is often used in both Western and Eastern societies.
Herbal medicine is a key CAM therapy; moreover, it may serve as an alternative when no fundamental treatment is available. In particular, in East Asian countries such as China, Korea, and Japan, traditional East Asian herbal medicines, which reflect regional characteristics and share basic concepts, have been applied to the treatment of various diseases. erefore, in these countries, there is a constant demand for treatment using traditional East Asian herbal medicines for intractable neurological diseases, such as ALS, that cannot be significantly effective with conventional therapies alone [8,9]. In response to that demand, research using traditional East Asian herbal medicines continues. As a result, there are currently active studies on whether herbal medicines with anti-glutamate, protein aggregation inhibition, anti-inflammatory, and anti-oxidant properties can be used for ALS treatment. However, there remains a lack of evidence regarding herbal medicine treatment for ALS [4]. erefore, this study aimed to assess and analyze evidence regarding the effects of herbal medicine for ALS treatment and identify future research directions.

Materials and Methods
is was a scoping review of clinical studies on herbal medicine for ALS treatment. A scoping review is a research method that rapidly maps key concepts, sources, and evidence types supporting the research area. is helps identify gaps in evidence by determining areas with insufficient research areas based on conclusions from the literature regarding the status of overall research activity. is study was conducted in sequence following the scoping review guidelines suggested by the Joanna Briggs Institute and based on the checklists of Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping review (PRISMA-ScR) [11,12].

Research Questions.
is study aimed to analyze studies on herbal medicine treatment for ALS to assess the treatment effects, evidence regarding the effects, and the type of future studies required for further evidence.

Research Design Type.
is study aimed to examine and connect the contents regarding the research questions. erefore, we included various types of clinical studies, including case reports, retrospective and prospective observational studies, clinical trials, narrative reviews, systematic reviews, and meta-analyses.

Research Subject Type.
is study included patients with confirmed ALS. We included studies that reported ALS diagnosis without specifying the diagnostic criteria. However, studies that presumed an ALS diagnosis were excluded. Moreover, we excluded studies on ALS comorbid with other diseases, including myasthenia gravis and progressive muscular atrophy. Additionally, we excluded studies on cell and animal models that were not conducted on humans.

Intervention Type.
We included studies that provided oral herbal medicine treatment as an intervention, regardless of the dosage form. We included typical types of herbal prescriptions, including traditional Chinese medicine (TCM), traditional Korean medicine (TKM), and Japanese Kampo medicine, which have been mainly used as traditional medicine in Northeast Asian countries. Moreover, we included studies that used herbal medicine in combination with other treatment methods or that compared the effects of herbal medicine with those of other treatments. We excluded studies that assessed vitamins and other food supplements, as well as herbal products and extracts that are not commonly used in traditional medicine in Northeast Asian countries, including South Korea, China, Japan, and Taiwan. Moreover, medicinal herbs that are currently not being used, including bear gall bladders, were excluded.

Research Measurement Type.
All study results, including changes in clinical symptoms, measurement of various evaluation tools, total effective rate (TER), and the average symptom score after herbal treatment, were assessed. We excluded studies that did not state the effects of herbal medicine treatments.

Data Analysis.
First, the title and abstract of each study were reviewed; subsequently, the full texts of studies that met the selection criteria were reviewed. Each paper was reviewed regardless of the original language, and when the professional translation was required, a translation expert in the relevant language was consulted. Two researchers (Suh WJ and Seo YN) independently reviewed the literature. In cases of disagreement, the studies were reviewed together to reach a consensus. When a consensus could not be reached, a third researcher (Kwon S) was consulted. e selected studies were reviewed; moreover, the contents of each study were organized based on the data collection form. e form included the first author, year of publication, country, language, research methods, number of study participants, demographic characteristics of the participants, study duration, diagnostic criteria, treatment method, treatment duration, evaluation tools, outcomes, and side effects. e country was based on the location of the author's organization/institute; moreover, the language referred to the language used to write the manuscript. e research methodology was largely divided into observational studies, intervention studies, and literature studies based on the classification of research methods used by the National Institute for Health and Care Excellence, which were further divided into case reports, case series, prospective and retrospective observational studies, randomized control studies, narrative reviews, systematic reviews, and meta-analyses. Case reports describe the intervention and results of the patient cases. A single case was referred to as a single case report, while two or more cases were classified as a case series. Observational studies on natural interventions were divided into prospective and retrospective observational studies. Before-and-after studies compared the results before and after the interventions. Randomized control studies included clinical trial studies where participants were randomly assigned to an experimental or control group with a certain follow period for assessing specific outcomes. Systematic review studies referred to studies that used explicit and systematic methods to identify, evaluate, and summarize the literature using predefined criteria. If there was no explanation regarding the criteria, those studies were considered narrative review studies. Meta-analyses statistically combine and analyze the findings from at least two studies. Studies that performed meta-analysis after a systematic review of the literature were considered meta-analyses. Studies without a clearly specified methodology were assigned to the most appropriate group based on the study contents. Demographic characteristics of the study participants included sex and age. e diagnostic criteria used to confirm ALS are summarized. In case no diagnostic criteria were mentioned, we assessed the tests performed for diagnosis, excluding clinical symptoms. All evaluation tools used in the studies were reviewed; moreover, those that yielded meaningful results were separately summarized. Subsequently, the organized data were classified and analyzed based on the research methods.

Results
3.1. Literature Selection. We searched 746 studies; among them, we reviewed the titles and abstracts of 472 studies after excluding 274 duplicates. In case the abstract was unavailable, the full text was reviewed. We excluded 3 studies without abstract and full text, as well as 366 articles that did not meet the selection criteria. e full text of the remaining 103 studies was reviewed; among them, 44 studies were excluded based on the selection criteria as follows: 8, 25, 6, 3, and 2 studies that did not have the full text, did not satisfy the type of study participants, did not use herbal medicine treatment, did not mention the effects after herbal medicine treatment, and were duplicates, respectively. Finally, 59 articles were included in the analysis (Figures 1 and 2).

General Characteristics of the Literature.
To assess the general characteristics of the literature, the studies were cataloged and analyzed according to the year of publication, research method, country, and language. Tables 1 and 2 summarize the results.
Luo et al. [34] used 3,200 diagnostic criteria for medical diseases to diagnose ALS. ree studies reported conducting EMG without mentioning the diagnostic criteria [32,33,35]; moreover, one study performed a biopsy examination to confirm ALS [35]. Byun et al. [36] and Ryu et al. [37] did not mention a diagnostic method.
(3) Retrospective Observational Study. We included two retrospective observational studies [38,39]; among them, one was published in 1997 [38] in Korea, while the other was published in 2017 in China [39]. e two studies included 305 participants (181 males and 124 females). In the study by Jeon et al. [38], the mean age of the participants was 52.4 years. Li et al. [39] did not report the mean age of the participants. None of the studies reported the mean disease duration. Li et al. used the El Escorial criteria for ALS diagnosis, while Jeon et al. [38] used the diagnostic criteria of Jokelainen et al. Table 4 summarizes the details.
Li et al. [39] assessed the medical records of 288 hospitalized patients with ALS and analyzed the treatment methods, survival rate, and pattern identification types. In total, 152 (52.8%), 23 (8%), and 113 (39.2%) patients underwent herbal medicine treatment only, riluzole treatment only, and combination treatment with herbal medicine and riluzole, respectively.
ere was no significant among treatment difference in the survival period, as well as the 3and 5-year survival rates. Analysis of the pattern identification types revealed 112 (39%) cases of spleen-stomach weakness pattern, 97 (34%) cases of spleen-kidney weakness pattern, 42 (15%) cases of liver-kidney yin deficiency pattern, 27 (9%) cases of phlegm-dampness pattern, 7 (2%) cases of static blood pattern, and 3 (1%) cases of dual deficiency of qi and yin pattern.
(4) Prospective Observational Study. We included one prospective observational study conducted by Pan et al. [8] in China that was published in 2013. Specifically, Pan et al. conducted a questionnaire on 231 patients with ALS (148 men and 83 women) who were treated at 12 hospitals in Shanghai to analyze the basic characteristics, current status, and reason for undergoing IT, use of herbal medicine, and integrated treatment efficacy and cost. e mean age of the participants and disease duration was 62.3 years and 2.1 years, respectively. e El Escorial criteria were used to diagnose ALS. Table 5 summarizes the details.
El Escorial criteria were used for ALS diagnosis in eight studies [42][43][44][45][46][47][48][49]. e remaining studies used the latest domestic and foreign disease diagnosis guidelines [40], the Chinese Medical Association Neurology Branch [41], and the Chinese guidelines for the diagnosis and treatment of ALS [50,51]. ese criteria were almost similar to the El Escorial criteria and had been translated into Chinese.
No side effects were reported in three studies [53,57,58]; moreover, two studies did not mention the side effects [55,56]. Chin et al. [52] reported two cases of diarrhea in the experimental group, while Pan et al. [54] reported two cases of constipation and two cases of nausea in the experimental group. Yang [59] reported two cases of anxiety, two cases of cough, two cases of sputum, one case of insomnia, one case of hyperlipidemia, one case of shoulder pain, one case of low back pain, one case of tingling sense, one case of arm pain, one case of frequent voiding, and one case of upper respiratory infection in experimental group. e details are summarized in Table 7.
Qiu [60] classified ALS into the liver-kidney yin deficiency pattern, spleen-stomach weakness pattern, and invading lung pattern. Huqianwanjiajian, Buzhongyiqitang + Shiquandabutang, and Baoyuanjian + Qingzaotangjiajian were mainly used for liver-kidney yin deficiency patterns, spleen-stomach weakness patterns, and invading lung patterns, respectively. Moreover, TCM has been reported as effective for improving symptoms such as shortness of breath, fatigue, sweating, heart burning, and lumbar pain in patients with ALS, as well as for extending the survival period and improving the quality of life of patients, which suggests the need for a well-designed study.
Zhao [61] classified ALS into the lung heat damaging fluid pattern, spleen-stomach weakness pattern, liver-kidney yin deficiency pattern, yin deficiency moving wind pattern, and spleen-kidney yang deficiency pattern. e most common treatments were Huqianwan, Dihuangyinzi, Bazhentang, Liuweidehuangwan, Zuoguiwan, Youguiwan, Dabuyinwan, and Tongqiaohuoxuetang. e authors classified and analyzed clinical studies on herbal medicine treatment for ALS based on the treatment method.
Xu et al. suggested that [62] Yiqiqiangjitang, Jianpibushenxifeng decoction, Zhiweitang, Qiangjinwan, Fuyuanshengji granule, Jiweiling extraction, and Shengjiqiangjinzhichantang can be used as herbal medicines for improving clinical symptoms, improving the quality of life, and reducing the financial burden on patients.
Mao [64] described findings regarding the effects of Sijunzitang, Yisuitang, Fuyuanshengji granule, Huqianwan, Jiweiling capsule, and Jiweiling injection on ALS. ey suggested that compared with riluzole treatment, herbal medicine treatment had better outcomes in terms of cost and patients' quality of life.
Li and Zhan [65] described ALS as belonging to "wilting disease" and "impediment disease." ey classified ALS as dual deficiency of the lung-spleen pattern, dual deficiency of the spleen-kidney pattern, liver-kidney yin deficiency pattern, kidney yin, and yang deficiency pattern, and liver wind pattern based on scleral pattern identification. Furthermore, ALS can be classified into deficiency of original qi pattern, dual deficiency of qi and blood pattern, static blood pattern, and dampness obstruction pattern using qi-blood-phlegm-stasis pattern identification, as well as into disease of collateral vessels, governor vessels, and extra meridians using meridian pattern identification. e treatment used in the related studies included Qingjijianliyin; Qiangjijianli capsule; Qiangjijianli oral liquid; Shengyangyiweitang, Buzhongyiqitang, and Fujining capsule types 1 and 2; Buzhongyiqitang + Chaihushugansan; Mahuangfuzixixintang; Yiqijianpibuyuantang; Wenshenjianpishuangbu decoction; Zibuganshenyiqitang; Rencanhajietang; and Maqianzi powder.
Cai and Yang [7] analyzed studies on the CAM effects on ALS and reported that herbal medicine treatment improved disease symptoms. However, they indicated the need for large-scale clinical trials to allow the development of effective herbal medicine treatments. Related studies in this review used Buzhongyiqitang, Jiaweixiaoyaosan, Ziyinjianghuotang, Huolingshengji decoction, Dihuangyinzi, and Jiaweisijunzitang for prescription.
(2) Systematic Reviews. We included three systematic reviews [4,66,67]; among them, two studies were published in 2015 in Korea [66,67] and one study was published in 2017 in China [4]. Kim et al. [66] reviewed 21 related studies to summarize the therapeutic effects of oriental medicine and TKM in patients with ALS. ey observed that patients often underwent combined oriental treatment with herbal medicine as the main treatment; moreover, it was difficult to identify commonalities in selecting herbal medicine prescriptions. None of the studies reported the cure for ALS. However, combined oriental treatment was found to improve the main ALS symptoms, including muscle weakness, dysphagia, dysarthria, and respiratory muscle weakness, which leads to long-term management.
Lee et al. [67] reviewed 18 studies, including retrospective observational studies, prospective clinical studies, and case reports, on oriental medicine treatment for ALS in South Korea. It was found that IT using herbal medicine, acupuncture, and herbal acupuncture was the most commonly used; moreover, there were cases with short-term positive improvements in the main ALS symptoms.
Zhu et al. [4] analyzed the literature to summarize the characteristics of TCM and other drugs used for ALS prevention and treatment. However, they did not mention the number of studies reviewed. ey found that tonifying kidney, tonifying lung, tonifying qi, and modulating meridian can be performed for treatment; moreover, TCM has several benefits, including low treatment cost, minor side effects, longevity, and improved quality of life.
(3) Meta-Analysis. Only Li et al. conducted a meta-analysis after a systematic review of the literature [68]. is study was conducted in China and published in 2016. ey assessed the efficacy and safety of tonifying and replenishing medicinal prescriptions for ALS. Seven randomized controlled trials were selected that analyzed 411 cases (257 and 154 cases in the treatment and control groups, respectively).
e El Escorial criteria were used as the diagnostic criteria. e treatment group received tonifying and replenishing medicinal prescriptions, including Buyitangjiajian, Fuyuanshengji granule, Shengjiqiangjinzhichantang, Jiaweisijunzitang, and Yiqiqiangjitang. On the other hand, the control group received riluzole except in one study. TER was significantly higher in the treatment group than in the control group; furthermore, the decrease in the Norris score was significantly lower in the treatment group than in the control group. Additionally, the decrease in the average TCM syndrome score was significantly higher in the treatment group than in the control group. erefore, compared with riluzole, TCM was more effective in delaying disease progression without significantly improving or treating the symptoms. However, TCM is cheaper than riluzole and can be conveniently stored, which reduces the economic burden on patients.
ere were no reports of serious safety-related adverse events.

Discussion
We conducted a scoping review on Korean and other international studies to understand the research trends in ALS herbal medicine treatment. Regarding the year and format of the published studies, studies on herbal medicine treatment for ALS have been published since 1995. Moreover, approximately 70% of the studies were published from 2010 to 2019, which indicates that studies have been more actively conducted in recent years. e included studies were conducted in China and South Korea, with over 70% of the studies being conducted in China. Accordingly, most of the studies were published in Chinese (over 60%). Among the 59 selected studies, a majority were observational studies (47.5%), followed by intervention studies (33.9%) and literature studies (18.6%). Further classification revealed that case reports (single case reports and case series) and beforeand-after studies accounted for 42.4% and 20.3% of all the studies, respectively. Randomized controlled studies and narrative review studies accounted for 13.6% and 11.9% of the included studies. Among the included studies, randomized controlled trials, systematic reviews, and metaanalyses have been published since 2012; moreover, only one meta-analysis, which presented the highest level of evidence, was published in China by Li et al. in 2016 [68]. To select relevant studies, we searched for herbal medicines used in South Korea, China, and Japan; accordingly, studies on other herbal products and single extracts from other countries were excluded. Consequently, the selected studies were limited to East Asia. e ALS prevalence in South Korea is low; therefore, it is difficult to recruit participants in South Korea, which led to the inclusion of a significantly smaller number of clinical studies conducted in South Korea compared with those conducted in China. ere is a need for a review that includes a greater scope of interventions to assess global research trends.
ALS is mostly diagnosed based on symptoms of progression of the upper and lower motor nerves, which are mainly assessed through medical history and neurological examinations. Furthermore, it is important to conduct EMG, nerve conduction velocity tests, laboratory tests, and imaging tests to exclude other possible nervous system disorders with similar symptoms, including peripheral neuropathy, muscle disease, neuromuscular junction disease, and central nervous system disease [1]. e most commonly used diagnostic criteria are the El Escorial criteria revised in 2000 (Table 8). ese diagnostic criteria are based on identifying lower motor neuron abnormalities through Evidence-Based Complementary and Alternative Medicine clinical symptoms and EMG, assessing upper motor neurons through clinical manifestations [69], and evaluating the invasion level in the soft, cervical, thoracic, and lumbar plexus [69]. Among the 59 selected studies, only 19 studies (approximately 32%) mentioned the El Escorial criteria [8, 29, 39, 42-49, 52, 54, 56-59, 66, 68]. In China, there are diagnostic criteria similar to the El Escorial criteria, including the Chinese Medical Association Neurology Branch [41], Guidelines for the diagnosis and treatment of ALS in China [50,51,55], and the latest domestic and foreign disease diagnosis guidelines [40]. Most of the included case reports mentioned that EMG, nerve conduction velocity tests, and magnetic resonance imaging tests were performed without using the diagnostic criteria. ALS is often misdiagnosed due to the low ALS incidence rate, atypical clinical symptoms in the early stage of onset, and low awareness among doctors of specialties other than neurologists [39]. erefore, there is a need to explain the diagnosis process of the disease based on the diagnostic criteria in case reports to provide clear evidence regarding the diagnosis.
In the selected studies, ALS was diagnosed as a "wilting disease." Additionally, prescriptions with anti-inflammatory, protein aggregation inhibition, and anti-oxidant properties, including Buzhongyiqitang, Jiaweisijunzitang, Qiangjijianli decoction, Jianpiyifei decoction, Dihuangyinzi, Bawutang, Huqianwan, Fuyuanshengji granule, and Mecasin were mostly used [4,59]. In China, ALS is thought to involve the liver, spleen, lungs, and kidneys; moreover, different treatments are provided based on the ALS type. Contrastingly, in South Korea, treatment was selected on an individual basis to treat the main and secondary clinical symptoms. erefore, it was difficult to determine common points in the herbal medicine prescription between South Korean and Chinese studies; moreover, we could not determine the association between specific prescriptions and outcome improvement. erefore, future studies should investigate the prescription types based on comparisons between the characteristics of TCM and TKM.
e selected studies used various evaluation tools to assess ALS progression. e most representative tool was ALSFRS, which is a motor ability evaluation index for patients with ALS that was developed by Brooks. It comprises 10 items evaluated on a total of 40 points with a maximum of four points for each item. is tool assesses the physical functions required for daily life. Moreover, it has been supplemented with detailed items regarding respiratory function in the ALSFRS-Revised (ALSFRS-R) [70]; furthermore, the K-ALSFRS-R was developed for use in South Korea with translation and modification of the tool to suit the characteristics of South Korean patients [71]. e ALSFRS-R is relatively easy to use since it allows assessment of the patient via a phone call through a guardian [72]. Among the selected studies, 28 (47.5%) studies used the ALSFRS [14-17, 23, 27, 28, 35-37, 42-51, 53-55, 57-59, 66, 67]; furthermore, the ALSFRS score was significantly increased in three studies [17,27,50]. Yeon et al. [17] reported that acupuncture; burning acupuncture; electroacupuncture; cupping therapy; and physical therapy involving herbal medicine with dispelling wind-dampness, relieving meridian, and sinew-and bone-strengthening properties improved lumbar pain, K-ODI scores, and K-ALSFRS-R scores. Kim et al. [27] reported an improvement in the GAS scores, K-ALSFRS-R scores, and gait distance after administration of Jianghuodihuangtang and Wujiapizhuangjitang, followed by acupuncture and Saam acupuncture for 11 days, in a 52-year-old female patient. Moreover, Meng [50] reported an improvement in the scores of the ALSFRS-R and ADL-Barthel index after the prescription of Cervi parvum cornu extraction and acupuncture in 29 patients with ALS. Sixteen studies [15, 16, 28, 35, 36, 42-44, 46-49, 51, 55, 58, 59] reported no or nonsignificant changes in the ALSFRS scores. Jin [53], Pan et al. [54], Zhu et al. [57], and Yang [59] reported a decrease in the ALSFRS score; however, the decrease was significantly less than that in the control group. is suggests that compared with the control group, the treatment group showed slower disease progression. However, this study did not consider the disease duration, which decreased the objectivity of the findings. e progression rate of ALS (ΔFS) is a quantitative index used for assessing disease progression in patients.
is was calculated by determining the difference between the ALSFRS-R scores at the evaluation time and symptom onset, followed by dividing it by the number of months from the time of symptom onset to the evaluation time.
is yields the progression speed and prognosis of a disease, which allows objective assessment of the treatment effects [72,73]. No study on herbal medicine has used ΔFS, which may be useful for future studies.
Among the selected studies, only two reported cases of ALS being cured [13,25]. Other studies reported delayed disease progression after herbal medicine treatment or combined herbal treatment, as well as improvements in appetite loss, drooling, muscle spasms, fatigue, shortness of breath, constipation, gait, and sweating. However, there remains no objective evaluation tool for assessing clinical symptoms. erefore, patient symptoms were subjectively evaluated. Future studies should employ objective tools for assessing the clinical symptoms of patients.
Adverse events were reported in three randomized controlled studies. Chin et al. [52] reported two cases of diarrhea in the experimental group, while Pan et al. [54] reported two cases of diarrhea and nausea in the experimental group. Yang et al. [59] reported two cases of anxiety, two cases of cough, two cases of sputum, one case of insomnia, one case of hyperlipidemia, one case of shoulder pain, one case of low back pain, one case of tingling sense, one case of arm pain, one case of frequent voiding, and one case of upper respiratory infection in the experimental group. Although most studies reported no side effects, some studies did not mention side effects at all. erefore, future studies should further assess the side effects of herbal medicine treatment.
A study conducted by the German Association for Neuromuscular Diseases [10] reported that 54% of patients with ALS had received CAM; among them, 60% had experienced positive effects. e reasons for using CAM included improving general health, delaying disease progression, improving muscle strength, and treating the disease [10]. A Chinese study reported that 99% of patients with ALS had received IT, while 94.8% and 90.6% had used herbal extraction and decoction, respectively. e reasons for using IT included weakness, fatigue, muscle atrophy improvement, and delayed disease progression. However, only 9.37% of the participants answered that the treatment was effective with most of them considering IT as ineffective [8]. In a study conducted in South Korea, all patients used CAM with the expectation of improvement in symptoms. However, 70.6% of the patients were not satisfied with the outcome and discontinued CAM; furthermore, only 14.5% reported intending to recommend CAM to others [9]. ALS progression is rapid and fatal. However, there remains no fundamental cure for ALS; moreover, treatment is difficult in many cases. Consequently, there is increased interest in CAM and integrative medicine among patients with ALS. However, no studies have investigated patients' perceptions of and demand for CAM [74]. erefore, there is a need for future studies on CAM and IT to provide better herbal medicine treatment to patients.
is current systematic scoping review analyzed studies in electronic academic databases to understand the research trend of herbal medicine treatment for ALS. ALS shows rapid progression with a high mortality rate, which makes it difficult to conduct randomized controlled studies. Specifically, there are few randomized controlled studies and meta-analysis studies on ALS in East Asia. In the selected case report studies, a detailed assessment of the effects of herbal medicine treatment alone could not be achieved since they administered herbal medicine together with acupuncture, pharmacopuncture, cupping therapy, or physical therapy. e present scoping review has the strength of being the first study to systematically search the electronic database and synthesize the results of the latest studies related to East Asian herbal medicine published up to 2021. In this review, not only representative domestic databases of China, Korea, and Japan but also international databases such as PubMed, Embase, Scopus, and Cochrane have been used to collect published studies. e previously published narrative reviews did not use a systematic search method [7,[60][61][62][63][64][65], and systematic reviews also had limitations in that they contained content limited to one of the East Asian countries such as China [4] or Korea [66,67]. Furthermore, the metaanalysis published in 2016 [68] did not include relatively high-quality randomized controlled trials published after 2017 [57][58][59].
Among the selected 59 studies, we focused on two recent randomized controlled studies published by Zhu et al. [57] and Yang [59]. According to our search results, randomized controlled trials evaluating the clinical effects of traditional East Asian herbal medicine on ALS have been published since 2012 [52]. In both studies, higher-level research methodologies were used compared to the existing randomized controlled trials [52][53][54][55][56]. Both studies used placebo as a control treatment, and ALSFRS-R scores, one of the most standard evaluation tools, were used to evaluate the effects of interventions on the progression of ALS. In each study, Jiaweisijunzitang and Mecasin were used, respectively. As a result, it was confirmed that the progression of ALS was slowed after 9 months and 12 weeks, respectively, compared to the control group. Although the level of evidence is not yet high, as mentioned above, Jiaweisijunzitang and Mecasin are also noteworthy as future therapeutic agents for ALS, as they also have mechanisms of pharmacological effects such as antiinflammatory, protein aggregation inhibition, and antioxidant effect [4,59]. Given that there remains no fundamental cure for ALS, CAM is commonly used for ALS treatment. Among CAM, herbal medicine treatment can improve the immune response, slow disease progression, and improve symptoms through anti-inflammatory, antioxidant, and protein-aggregation inhibition effects. is study is significant since it highlights the shortcomings of existing studies to suggest possible directions and aims for future studies. Future studies with detailed designs could yield evidence regarding the effects of herbal medicine treatment for ALS and develop better treatments for patients with ALS.

Conclusion
is scoping review revealed that there remained insufficient data on the effects of herbal medicine treatment for ALS even though there has been active research in recent years. To provide effective herbal medicine treatment to patients with ALS, systematic and elaborately designed high-quality clinical studies are required to demonstrate the benefits of herbal medicine treatment.

Evidence-Based Complementary and Alternative Medicine
Data Availability e data used to support the findings of this study are included within the article.

Conflicts of Interest
e authors declare that there are no conflicts of interest regarding the publication of this paper.