Acta Neurol Scand 2014: 130: 111–117 DOI: 10.1111/ane.12240
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Epidemiological characteristics of motor neuron disease in Chinese patients Cui F, Liu M, Chen Y, Huang X, Cui L, Fan D, Pu C, Lu J, Zhou D, Zhang C, Yan C, Li C, Ding X, Liu Y, Li X, Jiang Y, Zhang J, Shang H, Yao X, Ding Y, Niu Q, Wang L. Epidemiological characteristics of motor neuron disease in Chinese patients. Acta Neurol Scand 2014: 130: 111–117. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background – The epidemiology, diagnosis, and treatment of motor neuron disease (MND) in Chinese patients are ill known. Methods – A registered study of 461 MND patients was conducted across 10 facilities in 7 Chinese cities from February 2009 to March 2010. Results – Patients were classified as amyotrophic lateral sclerosis (ALS) (84.4%), progressive bulbar palsy (PBP) (4.1%), progressive muscular atrophy (PMA) (10.4%), or primary lateral sclerosis (PLS) (0.9%). MND was predominant in men (men/women; 1.6:1.0). Mean onset age was 52.6 years, with the highest incidence being observed between 51 and 60 years. Notably, 26.0% of MND patients were employed in forestry, fishery, or animal husbandry industries. Ten cases (2.7%) reported family history of MND, and 54.2% exhibited cervical onset. MND was also associated with head/neck trauma. Non-invasive positive pressure ventilation was the most common supportive therapy. Conclusion – As a novel comprehensive report of a Chinese population, this study reveals that epidemiological characteristics of MND patients were similar to those observed in international populations. MND is age-related, male gender predominant, and may be associated with both environmental and genetic risk factors.
F. Cui1*, M. Liu2*, Y. Chen3*, X. Huang1, L. Cui2, D. Fan4, C. Pu1, J. Lu3, D. Zhou5, C. Zhang6, C. Yan7, C. Li8, X. Ding9, Y. Liu10, X. Li2, Y. Jiang3, J. Zhang4, H. Shang5, X. Yao6, Y. Ding7, Q. Niu9, L. Wang4 1 Department of Neurology, Chinese PLA General Hospital, Beijing, China; 2Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China; 3 Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China; 4Department of Neurology, Peking University the Third Hospital, Beijing, China; 5 Department of Neurology, West China Hospital, Sichuan University, Chengdu, China; 6Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; 7Department of Neurology, Qilu Hospital, Shandong University, Jinan, China; 8Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China; 9Department of Neurology, Jiangsu Province Hospital, Nanjing, China; 10Department of Neurology, The Second Hospital of Hebei Medical University, Shi jiangzhuang, China
Key words: amyotrophic lateral sclerosis; epidemiology; motor neuron disease; nervous system disease; Riluzole Xusheng Huang, Department of Neurology, PLA General Hospital, 100853 Beijing, China Tel.: +86-10-55499221 Fax: +86-21-64085875 e-mail: [email protected], Liying Cui, Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 100730 Beijing, China Tel.: +86-10-65296371 Fax: +86-21-64085875 e-mail: [email protected] and Dongsheng Fan, Department of Neurology, Peking University Third Hospital, 100191 Beijing, China Tel.: +86-10-82265204 Fax: +86-21-64085875 e-mail: [email protected] *These authors contributed equally to this study. Accepted for publication January 31, 2014
Introduction
Motor neuron disease (MND) is a group of relatively rare conditions affecting the control of
voluntary muscles, generally requiring multidisciplinary treatment (1). The epidemiological characteristics of MND have been well-defined in many populations, but literature is not available 111
Cui et al. for the Chinese Han population. The disease is always progressive with highly variable symptoms, making early and correct diagnosis challenging. MNDs have been reported to progres- sively lead to weakness in the bulbar, limb, thoracic, and abdominal muscles, independently of treatments (1), resulting in respiratory complications leading to death in only 3–5 years. Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, is the most common and severe form of adult-onset MND. In China, ALS onset has been reported to be around 52 years old (2). ALS results in degeneration of LMNs in the anterior horn of the spinal cord or brainstem coupled with degradation of upper motor neurons (UMN) in the brain motor cortex (3). Mortality rates for ALS patients are high, mainly due to ventilation failure (3, 4). Other MNDs involving primarily or isolated lower motor neurons (LMNs) occur less frequently (5). Progressive muscular atrophy (PMA) broadly refers to MNDs affecting only LMNs and producing progressive spinal musculature atrophy (6). Progressive bulbar palsy (PBP) is characterized by LMN dysfunction without overt progression, commonly manifesting as atrophy and weakness in the legs and lower extremities (7). Progressive lateral sclerosis (PLS) is defined as a motor neuron disorder with exclusive UMN involvement (8). Motor neuron disease etiology is ill understood. Both environmental and genetic factors contribute to MND onset in individuals. Familial ALS (fALS) accounts for only 5–10% of all ALS cases; among these, mutations in the Cu/Zn superoxide dismutase gene (SOD1) are responsible for about 20% of familial cases (9, 10). However, some studies have shown that as many as 90–95% of all ALS cases occur without genetic risk factors, underlining the importance of identifying epidemiological risk factors. Roles have been proposed for dysfunctions of glutamate, abnormal autoimmune responses, dietary deficiency, trauma, and toxic/ infectious agents exposure remain controversial, but their epidemiological association with MND is still controversial (10, 11). Because both hereditary and sporadic cases of MNDs may occur, particularly in ALS cases, further study of MND classification and treatment of these diseases is important to enable earlier identification of the disease, to develop better treatment strategies, and to allow for better long-term outcomes. Thus, this study examined the current epidemiological characteristics, treatment outcomes, and classification of MND in a geographically diverse Chinese population to better define the factors influencing the disease in this population. 112
Subjects and methods Patients
A total of 461 MND patients were recruited from 10 MND clinics of the Chinese ALS Association distributed across seven cities (for the north: four clinics in Beijing (n = 248), one in Jinan (n = 42), and one in Shijiazhuang (n = 12); for the west: one in Chengdu (n = 47); for the south: one in Guangzhou (n = 44); and for the east: one in Shanghai (n = 55) and one in Nanjing (n = 13) between February 2009 and March 2010. The study protocol was approved by the ethics committee of the Peking Union Medical College Hospital. All patients provided written informed consent before participation in the study. The inclusion criteria required for registration of ALS in the study were as follows: (i) adult onset with a steady, progressive course; (ii) presence of clinical or electrophysiological evidence of LMN degeneration in at least two topographical anatomical regions (brainstem, cervical, thoracic, or lumbosacral region) together with clinical evidence of UMN degeneration in those regions; and (iii) absence of electrophysiological and pathological evidence of other disease processes that might explain the signs of LMN and/or UMN degeneration and absence of neuroimaging evidence of other diseases that might explain the observed clinical and electrophysiological signs. Therefore, the patients registered in this study satisfied the criteria based on the Awaji diagnostic algorithm for ALS (12). Progressive muscular atrophy (PMA), PBP, and PLS were included and analyzed independently in this study. The diagnosis of PMA was based on the presence of pure LMN findings in two or more regions at the first full evaluation, including evidence of LMN involvement on neurological examination (weakness and atrophy), electrophysiological evidence of LMN involvement on standardized needle electromyography (EMG), and no motor nerve conduction block. The diagnosis of PBP was based on increasing dysarthria and dysphagia with UMN and LMN findings in varying combinations involving the bulbar musculature with no concurrent evidence of other involved regions indicated by neurological examination and EMG studies conducted at the initial visit. The diagnosis of PLS was made based on the pure and progressive UMN disorder, with adult onset (age >20 years) and a disease duration of at least 3 years. Other diseases were excluded by appropriate laboratory investigations (13).
MND in Chinese patients Data collection and storage
Demographic characteristics, personal history, family information, disease classification, and clinical characteristics of all included MND patients were recorded. Patient responses were reported using a standardized questionnaire, including demographic variables (age, gender, nationality, date and place of birth), personal history (cigarette smoking, drinking, substance exposure, occupation, physical trauma, and medication), disease characteristics [symptom onset date, initial diagnosis date, anatomical onset region, classification, neurological findings, and electromyogram (EMG) results], and family medical history. Occupational data were reported by type of industry of (forestry, labor, professional, state, service, financial, business, or other). In cases where the patient did not wish to respond, the occupation was classified as unspecified. Ethnicity was reported as either Chinese Han or other. Age was reported by 10-year groups ranging from 30 to 80 years; all participants outside of these age ranges were reported as either 80 for the purposes of the current study. Family history was defined as an immediate family member with muscular atrophy, tremors, or psychiatric or dementia symptoms usually associated with MND. Statistical analysis
All quantitative data are expressed as means SD. Mean values for different groups were compared using Student’s t-tests. Categorical data are described as absolute frequencies and ratios. A P-value 0.05) (Table 1). Patients reporting occupations in forestry (forestry, fishery, and animal husbandry workers) were much more likely to exhibit MND (n = 120; 26.0%) than other workers, including labor (n = 75;
16.3%), professional (n = 67, 14.5%), state (n = 56, 12.1%), service (n = 20, 4.3%), financial (n = 19, 4.1%), business (n = 26, 5.6%), or other (n = 38, 8.2%) workers. Notably, 40 patients (8.7%) failed to specify an occupation (Table 1). A large proportion of MND patients were current smokers (n = 192; 41.6%) and current drinkers (n = 187; 40.6%) (Table 2). In addition, an important proportion of patients were regularly exposed to toxic substances (n = 71; 15.4%) and had a history of head or neck trauma (n = 30; 6.5%) (Table 2). Very few patients reported a family history of nervous system disease (n = 21; 4.6%) or MND (n = 10; 2.7%) (Table 2). MND classification and onset
Figure 1 shows the patients that were initially misdiagnosed with diseases other than MND. Of the 461 MND cases examined, 389 (84.4%) were determined to be ALS, 19 (4.1%) were determined to be PBP, 49 (10.4%) were determined to be PMA, and 4 (0.9%) were determined to be PLS. The most common age of onset for MND was between 51 and 60 (n = 139; 30.2%), followed, in decreasing order, by age groups 41–50 (n = 121; 26.2%), 61–70 (n = 89; 19.3%), 30–40 (n = 49; 10.6%), 71–80 (n = 39; 8.5%), 80 (n = 6; 1.3%). MND was found to start significantly more commonly in the cervical region (n = 250; 54.2%; P < 0.05) than in other common locations, such as the lumbosacral (n = 96; 20.8%), bulbar (n = 94; 20.3%), or thoracic (n = 3; 0.7%) regions. Treatment for MND
Treatment through combined therapy using medication, alternative therapy, and supportive management was provided to each patient. Patients were treated with medications such as riluzole (n = 133, 28.9%); creatine (n = 13, 2.8%); CoQ10 (n = 117, 25.4%); vitamin B1 (n = 229, 49.7%); vitamin B12 (n = 225, 48.8%); vitamin E (n = 161, 34.9%); and antidepressant and/or antianxiety medications (n = 13, 2.8%) (Fig. 2). Notably, 25 patients (5.4%) indicated discontinuation of riluzole treatment due to either cost or excessive gastrointestinal discomfort. In combination with prescribed medications, 48 patients (10.4%) participated in physical therapy, 49 patients (10.6%) underwent psychotherapy, seven patients (1.5%) were treated with stem cells, and 201 patients (43.6%) agreed to undergo life health education instruction by their physician in combination with other therapies. Life 113
Cui et al. Table 1 Demographic characteristics for motor neuron disease (MND) (N = 461) patients
Characteristic Gender Male Female Age (years) Male 80 Female 80 Nationality Chinese Han Other Occupation (industry)* Forestry Labor Professional State Service Financial Business Other Unspecified
No. cases (n) (Total N = 461)
Constituent ratio (%)
286 175
62.0 38.0
6
1.3
30 66 91 63 27 3
6.5 14.3 19.7 13.7 5.9 0.7
8
1.7
19 57 50 26 12 3
4.1 12.4 10.8 5.6 2.6 0.7
451 10
97.8 2.2
120 75 67 56 20 19 26 38 40
26.0 16.3 14.5 12.1 4.3 4.1 5.6 8.2 8.7
*Occupation descriptions: Forestry workers (forestry, fishery, and animal husbandry workers); labor (production, transportation, and factory floor workers); professional (professionally certified workers, including medical, teaching, paraprofessionals and technology workers); state (state organization and enterprise principal workers); service (various service-based workers, such as painting, construction, and building workers); clerk (clerical, banking, and accounting workers); business (business organizational leaders, such as facility managers, operations managers, and business owners); other professions (any professional not listed in the previous categories); unspecified (no response or refusal of response from patient).
health education, including information on healthy lifestyle choices and managed care, was deemed acceptable by many patients. This suggests that earlier health education interventions may be able to help improving patient outcomes with minimal discomfort. Additional supportive management in some MND patients
Over the course of the disease, a notably large group of MND patients required additional supportive management: percutaneous endoscopic gastrostomy (PEG) (n = 125, 27.1%); nasal feed 114
Table 2 Medical and family history of 461 motor neuron disease (MND) patients
Characteristics* Current lifestyle Smoking Drinking Substance exposure Total Pesticide(s) Organic solvents Benzene Industrial chemicals Trauma Head/neck Family history Nervous system disease MND
No. cases (n) (Total N = 461)
Constituent ratio (%)
192 187
41.6 40.6
71 23 9 9 30
15.4 5.0 1.9 1.9 6.5
48
10.6
21 10
4.6 2.7
*Current lifestyle (current smoking/drinking was measured) without lifestyle historical data; substance exposure (defined as regular occupational exposure to toxic substances. Organic solvents included a variety of commercial solvents and gasoline. Industrial chemicals are considered to be formaldehyde, heavy metal(s), inorganic acids, and other common chemicals); trauma history was self-reported; and family history was self-reported.
Figure 1. Number and type of motor neuron disease (MND) cases misdiagnosed at initial assessment. Secondary diagnoses revealed initial misdiagnosis of MND in 9 (2.0%) misdiagnosed cervical spondylosis, 42 (9.1%) misdiagnosed cerebral infarction, 19 (4.1%) misdiagnosed lumbar spondylosis, and 12 (2.6%) misdiagnosed peripheral neuropathy patients.
(n = 134, 29.1%); non-invasive positive pressure ventilation (NIPPV) (n = 159, 34.5%); and mechanical ventilation (n = 83, 18.0%) (Fig. 3). The prevalence of these interventions suggests that better understanding of the cause and prevention of these diseases is necessary. Notably, additional supportive management is likely to be required to reduce the occurrence and progression of MND. Discussion
In a primarily Chinese Han population, ALS was the most commonly diagnosed MND, with a
MND in Chinese patients
Figure 2. Medication treatment regimens prescribed in motor neuron disease (MND) patients. MND patients (n = 461) were prescribed with riluzole (n = 133, 28.9%); creatine (n = 13, 2.8%); CoQ10 (n = 117, 25.4%); vitamin B1 (n = 229, 49.7%); vitamin B12 (n = 225, 48.8%), vitamin E (n = 161, 34.9%); and antidepressant and/or antianxiety medications (n = 13, 2.8%) Notably, patients treated with riluzole indicated that 25 (5.4%) discontinued their treatment due to cost or excessive gastrointestinal discomfort.
Figure 3. Supportive management care provided to motor neuron disease (MND) patients. Additional supportive management was necessary, using percutaneous endoscopic gastrostomy (PEG) (n = 125, 27.1%), nasal feed (n = 134, 29.1%), non-invasive positive pressure ventilation (NIPPV) (n = 159, 24.5%), and mechanical ventilation (MV) (n = 83, 18.0%).
greater occurrence in men than in women. Additionally, individuals 51–60 years old were the most commonly affected, followed by individuals 41–50 and 61–70 years old. Notably, individuals working in forestry, fishery, and animal husbandry professions were much more likely to develop MNDs, potentially due to increased exposure to toxic substances. An association between alcohol consumption and smoking and increased MND occurrence was also observed. For MND patients, NIPPV was the most common supportive therapy required by MND patients. Riluzole and vitamin B1, B12, and E treatments were the most commonly prescribed treatments.
Motor neuron diseases, particularly ALS, represent a significant portion of all neuromuscular diseases, with nearly 120,000 cases diagnosed in diverse populations each year (11, 14). In the US population, over 5000 new diagnoses are made annually: Men are affected more frequently than women, and the most common age at onset is between 40 and 60 years (11). Furthermore, onset in the bulbar region is generally associated with shorter survival in US patients (15). In Guam, men were shown to be affected in greater numbers than women. In addition, metal intoxication with iron, silicon, cobalt, or nickel found in the soil or in water supplies was associated with increased MND occurrence (16). Similarly, a Scottish study indicated higher MND prevalence in men, and further described the dangers of misdiagnosis due to symptom mimicry (17). In Iran (18), Italy (19), and Buenos Aires (20), similar trends revealed higher occurrence rates in men than in women, and a most common age of occurrence between 70– 74 years. Notably, in the Chinese Han population, the most common age of occurrence, 51–60 years, was relatively lower than that observed in most global populations. The onset age of ALS in China has been reported to be 52.4 12.1 years (2). The pathogenesis of sporadic and genetic MNDs remains largely unknown. In response, a spectrum approach has been adopted, involving the classification of cases using electrophysiological analyses and clinical presentations (21). An update of an evidence-based review allowed the identification of exogenous risk factors, such as smoking (22), physical activity (23), toxic substance exposure (17), trauma (24), residence in rural areas (24), and alcohol consumption (24). The present study suggests that tobacco use, alcohol consumption, and rural employment may be associated with MND. In addition, low correlations were observed between MND and trauma, as suggested by previous studies (25, 26). Indeed, the study by Pupillo et al. (26) suggested that a history of trauma, repeated trauma, and a severe trauma were all potential risk factors for ALS. Controversy still surrounds the role of toxic substance exposure in MND onset. However, if true, this correlation may provide justification for the observed risks observed in rural workers exposed to potentially toxic gasoline, fertilizers, and pesticides. A recent review indicated that early studies consistently reported no significant variations between diverse populations, with an increased incidence in men, and maximum occurrence around age 70. This is one of the few reports including prevalence data for South-East Asian countries, indicating a MND prevalence of 115
Cui et al. approximately 1–7 per 100,000 individuals and an ALS prevalence of approximately 2–7 per 100,000 individuals, with only isolated Japanese regions showing higher prevalence (27). The benefits of riluzole are generally modest because it is often discontinued due to excessive cost, gastrointestinal discomfort, and modest efficacy (2- to 3-month improved survival) (28), as suggested in the present study. Our rate of mechanical ventilation was within the range reported in a recent review (29). The present study examined a limited population comprised of primarily Chinese Han individuals from similar facilities. Thus, further studies will be required to assess whether this sampling is representative of the general Chinese population and whether variations exist between different facilities. Because no long-term follow-up data were included, further exploration of long-term MND treatment strategies is required. Furthermore, as a very large proportion of the Chinese population is smoking or has been exposed to tobacco smoke (30), we could not assess any cause–effect relationship between this factor and MND in our study, despite the fact that it has been pointed out in previous studies (22). More effective classification and treatment for MND patients, particularly ALS patients, can be achieved through epidemiological studies of different populations. These studies identified exogenous risk factors and confirmed previously identified genetic risk factors. This information may also help clinicians to avoid misdiagnoses delaying MND treatment. In a Chinese Han population, the condition was shown to be more common in males and in patients 51–60 years old, occurring in relatively younger ranges in Chinese Han than in most international populations, with the notable exception of US populations. Predominantly, epidemiological factors associated with MND in the Chinese Han population closely reflect those previously reported in diverse international populations. Acknowledgement The work was supported by the fund from PLA General Hospital (2012FC-TSYS-4012).
Conflict of interests The authors declare that they have no conflict of interest.
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© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Epidemiological characteristics of motor neuron disease in Chinese patients Cui F, Liu M, Chen Y, Huang X, Cui L, Fan D, Pu C, Lu J, Zhou D, Zhang C, Yan C, Li C, Ding X, Liu Y, Li X, Jiang Y, Zhang J, Shang H, Yao X, Ding Y, Niu Q, Wang L. Epidemiological characteristics of motor neuron disease in Chinese patients. Acta Neurol Scand 2014: 130: 111–117. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Background – The epidemiology, diagnosis, and treatment of motor neuron disease (MND) in Chinese patients are ill known. Methods – A registered study of 461 MND patients was conducted across 10 facilities in 7 Chinese cities from February 2009 to March 2010. Results – Patients were classified as amyotrophic lateral sclerosis (ALS) (84.4%), progressive bulbar palsy (PBP) (4.1%), progressive muscular atrophy (PMA) (10.4%), or primary lateral sclerosis (PLS) (0.9%). MND was predominant in men (men/women; 1.6:1.0). Mean onset age was 52.6 years, with the highest incidence being observed between 51 and 60 years. Notably, 26.0% of MND patients were employed in forestry, fishery, or animal husbandry industries. Ten cases (2.7%) reported family history of MND, and 54.2% exhibited cervical onset. MND was also associated with head/neck trauma. Non-invasive positive pressure ventilation was the most common supportive therapy. Conclusion – As a novel comprehensive report of a Chinese population, this study reveals that epidemiological characteristics of MND patients were similar to those observed in international populations. MND is age-related, male gender predominant, and may be associated with both environmental and genetic risk factors.
F. Cui1*, M. Liu2*, Y. Chen3*, X. Huang1, L. Cui2, D. Fan4, C. Pu1, J. Lu3, D. Zhou5, C. Zhang6, C. Yan7, C. Li8, X. Ding9, Y. Liu10, X. Li2, Y. Jiang3, J. Zhang4, H. Shang5, X. Yao6, Y. Ding7, Q. Niu9, L. Wang4 1 Department of Neurology, Chinese PLA General Hospital, Beijing, China; 2Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China; 3 Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China; 4Department of Neurology, Peking University the Third Hospital, Beijing, China; 5 Department of Neurology, West China Hospital, Sichuan University, Chengdu, China; 6Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; 7Department of Neurology, Qilu Hospital, Shandong University, Jinan, China; 8Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China; 9Department of Neurology, Jiangsu Province Hospital, Nanjing, China; 10Department of Neurology, The Second Hospital of Hebei Medical University, Shi jiangzhuang, China
Key words: amyotrophic lateral sclerosis; epidemiology; motor neuron disease; nervous system disease; Riluzole Xusheng Huang, Department of Neurology, PLA General Hospital, 100853 Beijing, China Tel.: +86-10-55499221 Fax: +86-21-64085875 e-mail: [email protected], Liying Cui, Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 100730 Beijing, China Tel.: +86-10-65296371 Fax: +86-21-64085875 e-mail: [email protected] and Dongsheng Fan, Department of Neurology, Peking University Third Hospital, 100191 Beijing, China Tel.: +86-10-82265204 Fax: +86-21-64085875 e-mail: [email protected] *These authors contributed equally to this study. Accepted for publication January 31, 2014
Introduction
Motor neuron disease (MND) is a group of relatively rare conditions affecting the control of
voluntary muscles, generally requiring multidisciplinary treatment (1). The epidemiological characteristics of MND have been well-defined in many populations, but literature is not available 111
Cui et al. for the Chinese Han population. The disease is always progressive with highly variable symptoms, making early and correct diagnosis challenging. MNDs have been reported to progres- sively lead to weakness in the bulbar, limb, thoracic, and abdominal muscles, independently of treatments (1), resulting in respiratory complications leading to death in only 3–5 years. Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, is the most common and severe form of adult-onset MND. In China, ALS onset has been reported to be around 52 years old (2). ALS results in degeneration of LMNs in the anterior horn of the spinal cord or brainstem coupled with degradation of upper motor neurons (UMN) in the brain motor cortex (3). Mortality rates for ALS patients are high, mainly due to ventilation failure (3, 4). Other MNDs involving primarily or isolated lower motor neurons (LMNs) occur less frequently (5). Progressive muscular atrophy (PMA) broadly refers to MNDs affecting only LMNs and producing progressive spinal musculature atrophy (6). Progressive bulbar palsy (PBP) is characterized by LMN dysfunction without overt progression, commonly manifesting as atrophy and weakness in the legs and lower extremities (7). Progressive lateral sclerosis (PLS) is defined as a motor neuron disorder with exclusive UMN involvement (8). Motor neuron disease etiology is ill understood. Both environmental and genetic factors contribute to MND onset in individuals. Familial ALS (fALS) accounts for only 5–10% of all ALS cases; among these, mutations in the Cu/Zn superoxide dismutase gene (SOD1) are responsible for about 20% of familial cases (9, 10). However, some studies have shown that as many as 90–95% of all ALS cases occur without genetic risk factors, underlining the importance of identifying epidemiological risk factors. Roles have been proposed for dysfunctions of glutamate, abnormal autoimmune responses, dietary deficiency, trauma, and toxic/ infectious agents exposure remain controversial, but their epidemiological association with MND is still controversial (10, 11). Because both hereditary and sporadic cases of MNDs may occur, particularly in ALS cases, further study of MND classification and treatment of these diseases is important to enable earlier identification of the disease, to develop better treatment strategies, and to allow for better long-term outcomes. Thus, this study examined the current epidemiological characteristics, treatment outcomes, and classification of MND in a geographically diverse Chinese population to better define the factors influencing the disease in this population. 112
Subjects and methods Patients
A total of 461 MND patients were recruited from 10 MND clinics of the Chinese ALS Association distributed across seven cities (for the north: four clinics in Beijing (n = 248), one in Jinan (n = 42), and one in Shijiazhuang (n = 12); for the west: one in Chengdu (n = 47); for the south: one in Guangzhou (n = 44); and for the east: one in Shanghai (n = 55) and one in Nanjing (n = 13) between February 2009 and March 2010. The study protocol was approved by the ethics committee of the Peking Union Medical College Hospital. All patients provided written informed consent before participation in the study. The inclusion criteria required for registration of ALS in the study were as follows: (i) adult onset with a steady, progressive course; (ii) presence of clinical or electrophysiological evidence of LMN degeneration in at least two topographical anatomical regions (brainstem, cervical, thoracic, or lumbosacral region) together with clinical evidence of UMN degeneration in those regions; and (iii) absence of electrophysiological and pathological evidence of other disease processes that might explain the signs of LMN and/or UMN degeneration and absence of neuroimaging evidence of other diseases that might explain the observed clinical and electrophysiological signs. Therefore, the patients registered in this study satisfied the criteria based on the Awaji diagnostic algorithm for ALS (12). Progressive muscular atrophy (PMA), PBP, and PLS were included and analyzed independently in this study. The diagnosis of PMA was based on the presence of pure LMN findings in two or more regions at the first full evaluation, including evidence of LMN involvement on neurological examination (weakness and atrophy), electrophysiological evidence of LMN involvement on standardized needle electromyography (EMG), and no motor nerve conduction block. The diagnosis of PBP was based on increasing dysarthria and dysphagia with UMN and LMN findings in varying combinations involving the bulbar musculature with no concurrent evidence of other involved regions indicated by neurological examination and EMG studies conducted at the initial visit. The diagnosis of PLS was made based on the pure and progressive UMN disorder, with adult onset (age >20 years) and a disease duration of at least 3 years. Other diseases were excluded by appropriate laboratory investigations (13).
MND in Chinese patients Data collection and storage
Demographic characteristics, personal history, family information, disease classification, and clinical characteristics of all included MND patients were recorded. Patient responses were reported using a standardized questionnaire, including demographic variables (age, gender, nationality, date and place of birth), personal history (cigarette smoking, drinking, substance exposure, occupation, physical trauma, and medication), disease characteristics [symptom onset date, initial diagnosis date, anatomical onset region, classification, neurological findings, and electromyogram (EMG) results], and family medical history. Occupational data were reported by type of industry of (forestry, labor, professional, state, service, financial, business, or other). In cases where the patient did not wish to respond, the occupation was classified as unspecified. Ethnicity was reported as either Chinese Han or other. Age was reported by 10-year groups ranging from 30 to 80 years; all participants outside of these age ranges were reported as either 80 for the purposes of the current study. Family history was defined as an immediate family member with muscular atrophy, tremors, or psychiatric or dementia symptoms usually associated with MND. Statistical analysis
All quantitative data are expressed as means SD. Mean values for different groups were compared using Student’s t-tests. Categorical data are described as absolute frequencies and ratios. A P-value 0.05) (Table 1). Patients reporting occupations in forestry (forestry, fishery, and animal husbandry workers) were much more likely to exhibit MND (n = 120; 26.0%) than other workers, including labor (n = 75;
16.3%), professional (n = 67, 14.5%), state (n = 56, 12.1%), service (n = 20, 4.3%), financial (n = 19, 4.1%), business (n = 26, 5.6%), or other (n = 38, 8.2%) workers. Notably, 40 patients (8.7%) failed to specify an occupation (Table 1). A large proportion of MND patients were current smokers (n = 192; 41.6%) and current drinkers (n = 187; 40.6%) (Table 2). In addition, an important proportion of patients were regularly exposed to toxic substances (n = 71; 15.4%) and had a history of head or neck trauma (n = 30; 6.5%) (Table 2). Very few patients reported a family history of nervous system disease (n = 21; 4.6%) or MND (n = 10; 2.7%) (Table 2). MND classification and onset
Figure 1 shows the patients that were initially misdiagnosed with diseases other than MND. Of the 461 MND cases examined, 389 (84.4%) were determined to be ALS, 19 (4.1%) were determined to be PBP, 49 (10.4%) were determined to be PMA, and 4 (0.9%) were determined to be PLS. The most common age of onset for MND was between 51 and 60 (n = 139; 30.2%), followed, in decreasing order, by age groups 41–50 (n = 121; 26.2%), 61–70 (n = 89; 19.3%), 30–40 (n = 49; 10.6%), 71–80 (n = 39; 8.5%), 80 (n = 6; 1.3%). MND was found to start significantly more commonly in the cervical region (n = 250; 54.2%; P < 0.05) than in other common locations, such as the lumbosacral (n = 96; 20.8%), bulbar (n = 94; 20.3%), or thoracic (n = 3; 0.7%) regions. Treatment for MND
Treatment through combined therapy using medication, alternative therapy, and supportive management was provided to each patient. Patients were treated with medications such as riluzole (n = 133, 28.9%); creatine (n = 13, 2.8%); CoQ10 (n = 117, 25.4%); vitamin B1 (n = 229, 49.7%); vitamin B12 (n = 225, 48.8%); vitamin E (n = 161, 34.9%); and antidepressant and/or antianxiety medications (n = 13, 2.8%) (Fig. 2). Notably, 25 patients (5.4%) indicated discontinuation of riluzole treatment due to either cost or excessive gastrointestinal discomfort. In combination with prescribed medications, 48 patients (10.4%) participated in physical therapy, 49 patients (10.6%) underwent psychotherapy, seven patients (1.5%) were treated with stem cells, and 201 patients (43.6%) agreed to undergo life health education instruction by their physician in combination with other therapies. Life 113
Cui et al. Table 1 Demographic characteristics for motor neuron disease (MND) (N = 461) patients
Characteristic Gender Male Female Age (years) Male 80 Female 80 Nationality Chinese Han Other Occupation (industry)* Forestry Labor Professional State Service Financial Business Other Unspecified
No. cases (n) (Total N = 461)
Constituent ratio (%)
286 175
62.0 38.0
6
1.3
30 66 91 63 27 3
6.5 14.3 19.7 13.7 5.9 0.7
8
1.7
19 57 50 26 12 3
4.1 12.4 10.8 5.6 2.6 0.7
451 10
97.8 2.2
120 75 67 56 20 19 26 38 40
26.0 16.3 14.5 12.1 4.3 4.1 5.6 8.2 8.7
*Occupation descriptions: Forestry workers (forestry, fishery, and animal husbandry workers); labor (production, transportation, and factory floor workers); professional (professionally certified workers, including medical, teaching, paraprofessionals and technology workers); state (state organization and enterprise principal workers); service (various service-based workers, such as painting, construction, and building workers); clerk (clerical, banking, and accounting workers); business (business organizational leaders, such as facility managers, operations managers, and business owners); other professions (any professional not listed in the previous categories); unspecified (no response or refusal of response from patient).
health education, including information on healthy lifestyle choices and managed care, was deemed acceptable by many patients. This suggests that earlier health education interventions may be able to help improving patient outcomes with minimal discomfort. Additional supportive management in some MND patients
Over the course of the disease, a notably large group of MND patients required additional supportive management: percutaneous endoscopic gastrostomy (PEG) (n = 125, 27.1%); nasal feed 114
Table 2 Medical and family history of 461 motor neuron disease (MND) patients
Characteristics* Current lifestyle Smoking Drinking Substance exposure Total Pesticide(s) Organic solvents Benzene Industrial chemicals Trauma Head/neck Family history Nervous system disease MND
No. cases (n) (Total N = 461)
Constituent ratio (%)
192 187
41.6 40.6
71 23 9 9 30
15.4 5.0 1.9 1.9 6.5
48
10.6
21 10
4.6 2.7
*Current lifestyle (current smoking/drinking was measured) without lifestyle historical data; substance exposure (defined as regular occupational exposure to toxic substances. Organic solvents included a variety of commercial solvents and gasoline. Industrial chemicals are considered to be formaldehyde, heavy metal(s), inorganic acids, and other common chemicals); trauma history was self-reported; and family history was self-reported.
Figure 1. Number and type of motor neuron disease (MND) cases misdiagnosed at initial assessment. Secondary diagnoses revealed initial misdiagnosis of MND in 9 (2.0%) misdiagnosed cervical spondylosis, 42 (9.1%) misdiagnosed cerebral infarction, 19 (4.1%) misdiagnosed lumbar spondylosis, and 12 (2.6%) misdiagnosed peripheral neuropathy patients.
(n = 134, 29.1%); non-invasive positive pressure ventilation (NIPPV) (n = 159, 34.5%); and mechanical ventilation (n = 83, 18.0%) (Fig. 3). The prevalence of these interventions suggests that better understanding of the cause and prevention of these diseases is necessary. Notably, additional supportive management is likely to be required to reduce the occurrence and progression of MND. Discussion
In a primarily Chinese Han population, ALS was the most commonly diagnosed MND, with a
MND in Chinese patients
Figure 2. Medication treatment regimens prescribed in motor neuron disease (MND) patients. MND patients (n = 461) were prescribed with riluzole (n = 133, 28.9%); creatine (n = 13, 2.8%); CoQ10 (n = 117, 25.4%); vitamin B1 (n = 229, 49.7%); vitamin B12 (n = 225, 48.8%), vitamin E (n = 161, 34.9%); and antidepressant and/or antianxiety medications (n = 13, 2.8%) Notably, patients treated with riluzole indicated that 25 (5.4%) discontinued their treatment due to cost or excessive gastrointestinal discomfort.
Figure 3. Supportive management care provided to motor neuron disease (MND) patients. Additional supportive management was necessary, using percutaneous endoscopic gastrostomy (PEG) (n = 125, 27.1%), nasal feed (n = 134, 29.1%), non-invasive positive pressure ventilation (NIPPV) (n = 159, 24.5%), and mechanical ventilation (MV) (n = 83, 18.0%).
greater occurrence in men than in women. Additionally, individuals 51–60 years old were the most commonly affected, followed by individuals 41–50 and 61–70 years old. Notably, individuals working in forestry, fishery, and animal husbandry professions were much more likely to develop MNDs, potentially due to increased exposure to toxic substances. An association between alcohol consumption and smoking and increased MND occurrence was also observed. For MND patients, NIPPV was the most common supportive therapy required by MND patients. Riluzole and vitamin B1, B12, and E treatments were the most commonly prescribed treatments.
Motor neuron diseases, particularly ALS, represent a significant portion of all neuromuscular diseases, with nearly 120,000 cases diagnosed in diverse populations each year (11, 14). In the US population, over 5000 new diagnoses are made annually: Men are affected more frequently than women, and the most common age at onset is between 40 and 60 years (11). Furthermore, onset in the bulbar region is generally associated with shorter survival in US patients (15). In Guam, men were shown to be affected in greater numbers than women. In addition, metal intoxication with iron, silicon, cobalt, or nickel found in the soil or in water supplies was associated with increased MND occurrence (16). Similarly, a Scottish study indicated higher MND prevalence in men, and further described the dangers of misdiagnosis due to symptom mimicry (17). In Iran (18), Italy (19), and Buenos Aires (20), similar trends revealed higher occurrence rates in men than in women, and a most common age of occurrence between 70– 74 years. Notably, in the Chinese Han population, the most common age of occurrence, 51–60 years, was relatively lower than that observed in most global populations. The onset age of ALS in China has been reported to be 52.4 12.1 years (2). The pathogenesis of sporadic and genetic MNDs remains largely unknown. In response, a spectrum approach has been adopted, involving the classification of cases using electrophysiological analyses and clinical presentations (21). An update of an evidence-based review allowed the identification of exogenous risk factors, such as smoking (22), physical activity (23), toxic substance exposure (17), trauma (24), residence in rural areas (24), and alcohol consumption (24). The present study suggests that tobacco use, alcohol consumption, and rural employment may be associated with MND. In addition, low correlations were observed between MND and trauma, as suggested by previous studies (25, 26). Indeed, the study by Pupillo et al. (26) suggested that a history of trauma, repeated trauma, and a severe trauma were all potential risk factors for ALS. Controversy still surrounds the role of toxic substance exposure in MND onset. However, if true, this correlation may provide justification for the observed risks observed in rural workers exposed to potentially toxic gasoline, fertilizers, and pesticides. A recent review indicated that early studies consistently reported no significant variations between diverse populations, with an increased incidence in men, and maximum occurrence around age 70. This is one of the few reports including prevalence data for South-East Asian countries, indicating a MND prevalence of 115
Cui et al. approximately 1–7 per 100,000 individuals and an ALS prevalence of approximately 2–7 per 100,000 individuals, with only isolated Japanese regions showing higher prevalence (27). The benefits of riluzole are generally modest because it is often discontinued due to excessive cost, gastrointestinal discomfort, and modest efficacy (2- to 3-month improved survival) (28), as suggested in the present study. Our rate of mechanical ventilation was within the range reported in a recent review (29). The present study examined a limited population comprised of primarily Chinese Han individuals from similar facilities. Thus, further studies will be required to assess whether this sampling is representative of the general Chinese population and whether variations exist between different facilities. Because no long-term follow-up data were included, further exploration of long-term MND treatment strategies is required. Furthermore, as a very large proportion of the Chinese population is smoking or has been exposed to tobacco smoke (30), we could not assess any cause–effect relationship between this factor and MND in our study, despite the fact that it has been pointed out in previous studies (22). More effective classification and treatment for MND patients, particularly ALS patients, can be achieved through epidemiological studies of different populations. These studies identified exogenous risk factors and confirmed previously identified genetic risk factors. This information may also help clinicians to avoid misdiagnoses delaying MND treatment. In a Chinese Han population, the condition was shown to be more common in males and in patients 51–60 years old, occurring in relatively younger ranges in Chinese Han than in most international populations, with the notable exception of US populations. Predominantly, epidemiological factors associated with MND in the Chinese Han population closely reflect those previously reported in diverse international populations. Acknowledgement The work was supported by the fund from PLA General Hospital (2012FC-TSYS-4012).
Conflict of interests The authors declare that they have no conflict of interest.
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