Myasthenia gravis in Hong Kong Chinese 2. Paediatric disease Wong V, Hawkins BR, Yu YL. Myasthenia gravis in Hong Kong Chinese, 2. Paediatric disease. Acta Neurol Scand 1992: 86: 68-72.
I
In a study covering 850, of the population of Hong Kong, 39% of all myasthenia gravis (MG) patients, i.e. 103 individuals (54 girls and 49 boys) were found to have had MG with onset before puberty. Two patients had transient neonatal MG, 20 had early onset juvenile MG and 81 had late onset juvenile MG. Restricted ocular M G occurred in 71 of patients and the remainder had generalised MG. The median age at onset was 4 years. Complete remission occurred in 34 patients (34%), a good response in 14 (14%), and fair response in 32 (32%). The clinical course remained static in 16 patients (16%) and 3 patients deteriorated. Two patients died, 1 with myasthenic crisis and the other with cholinergic crisis. All patients, except 2 with neonatal MG, were initially treated with anticholinesterase, but 24‘2 also required steroid therapy. Thymectomy was performed for 12 patients, of whom 5 (42%) showed marked improvement. Thymic histology was normal in 3, showed hyperplasia in 6, non-invasive thymoma in 1 and involution in 2. The most commonly associated disease was Graves’ disease which occurred in 7 patients (7%)
Myasthenia gravis (MG) was first described in children by Wilks (1) in 1877 and Erb (2) in 1879. Unlike in adult patients, large studies of M G in children are relatively few. In 1956 Teng & Osserman (3) described 2 1 childhood patients attending Mount Sinai Hospital over a 4-year period and reviewed a further 196 cases reported in literature; 8% of the total had transient neonatal M G and the remainder had juvenile MG. Millichap & Dodge (4) reported 51 patients with childhood M G among a total of 447 myasthenic patients attending Massachusetts General Hospital between 1935 and 1959. Of the paediatric patients, 10 (20%) had transient neonatal MG, 6 (12%) had persistent neonatal (congenital) MG, and 35 (68%) had juvenile MG. Bundey ( 5 ) summarised the data in 4 series from Great Britain, United States of America and the Netherlands which collectively showed that 4.3 % of all M G occurred before the age of 10 years and 24% before 20 years. Fukuyania et al. (6) reported an extensive epidemiological study of 1430 patients with MG distributed throughout 800 major hospitals in Japan; 418 patients (29.2%) were aged below 15 years. Rodriguez et al. (7) documented the clinical findings in 149 patients with onset of M G between 1 and 17 years of age. These and other studies (8-1 1) have considered the role of thymectomy in childhood MG; but in view of the relatively small number of cases, 68
V. Wong’, B. R. Hawkins’, Y. L . Y u 3
’
Departments of Paediatrics, Pathology, Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong
Key words: myasthenia gravis; Chinese; juvenile-onset Dr. V. Wong. Department of Paediatrics, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Accepted for publication November 29, 199 1
its value in pediatric therapy remains to be determined. A previous study of Chinese children with MG in Hong Kong (12, 13) noted that the clinical manifestations were different from those typically seen in Caucasoids. T o further delineate these differences and to evaluate management strategy in Chinese children we have conducted a wider survey amongst Chinese in Hong Kong.
Patients and methods
Full details of the study population and selection criteria are given elsewhere (14). This paper reports on 103 patients with M G in childhood. The patients were classified by age at onset ( 5 , 15), as: 1) transient neonatal M G - babies born to mothers with MG, and with onset of M G within the first few days of life; 2) early onset juvenile MG - presenting at any time from birth to two years of age and born to mothers who are not myasthenic; 3) late onset juvenile M G - which in all other respects resembles adult disease but occurs after 2 years and before puberty. All children in this cohort developed pubertal changes before age 16. The responses to treatment were graded as follows:
MG in Chinese children 1) complete remission: no objective weakness and no medication needed, 2) partial remission: (a) good response: markedly improved symptomatology while on the same or reduced dosage of drugs; (b) fair response: slightly improved symptomatology ; 3) static; same symptomatology with or without increase in drug treatment; 4) deterioration: worse syniptomatology with or without increase in drug treatment.
F---T
12
IIc----.
t-
+
All patients Males Females
Results
Of 262 patients included in the overall study of adults and children, 103 were classified as paediatric cases. Two children, both female, had transient neonatal MG and are not considered further in this paper. The remaining 101 patients form the basis of calculations in this paper. Their diagnostic categories and disease types are shown in Table 1. Twenty patients (20%) had early onset juvenile M G and 81 patients (800/,) had late onset juvenile MG. None of the patients with early onset juvenile M G had siblings with MG; thus, congenital M G and familial infantile M G were unlikely to be present in our series of patients. Restricted ocular M G occurred in 72 patients (7 1%) and generalised M G occurred in the remainder. The overall female to male ratio was 52:49, or 1.1 :1. The ratios were 0.8: 1 and 1.1: 1 in the early and late onset juvenile groups respectively. When the patients were separated into ocular and generalised MG, the female to male ratios were 0.8: 1 and 2.2: I respectively. Age at onset
The age at onset of disease ranged from 1 month to 15 years (mean 5.6 years, median 4.0 years). The age of presentation ranged from 0.17 to 16 years (mean = 6.5 years, median = 5 years). The sex distribution by age at onset is shown in Fig. 1. There is a clear peak of onset centred around 2 to 3 years of age, with evidenced for a second peak around 10
Table 1. Disease type in 101 patients with childhood myasthenia gravis Total Disease type
M
F
Total
%
Ocular Mild generalised Moderate to severe generalised Fulminating
40 4 5 0
32 13 4 3
12 17 9 3
71 17
9 3
1-
0
I
I
I
I
,
0 1 2 3 4 5
2,
I
I
I
I
I
, & , - I
I
6 7 8 910111213141516
Age at Onset (Years)
Fig. I . Age- and sex-specific incidencc of myasthenia gravis by onset of the disease.
years. However, in view of the relatively small numbers, the latter peak is not considered to be of significance. Associated diseases
The most commonly associated disease was Graves’ disease which occurred in 7 patients (72,). One patient had Graves’ disease and concomitant myasthenic symptoms at presentation. Three patients had epilepsy and 2 had asthma. Systemic lupus erythematosus, nephrotic syndrome and dystonia each occurred in 1 patients. Four patients had close relatives with Graves’ disease and 4 had relatives with autoimmune thyroiditis. Rheumatoid arthritis, nontoxic goitre, and insulin dependent diabetes mellitus occurred occasionally in close relatives. No patients had siblings with M G although 1 had a maternal uncle with MG. Presenting features, clinical features and course
Patients with restricted ocular involvement presented with unilateral or bilateral ptosis. Both ptosis and ophthalmoplegia occurred in 3 1 patients, and were the initial presenting features in 8 patients with early onset juvenile M G (i.e. 40%) and 23 (i.e. 28%) with late onset juvenile M G . Patients were followed-up for periods ranging from 26-468 months (mean=95 months, median = 69 months). Five children with initial ocular manifestations subsequently developed generalised MG, which was mild in 1 and moderate to severe in 4. All these children had late onset juvenile MG. The
69
Wong et al. median interval from initial ocular to final generalised involvement was 13l months (range = 25-468 months). Five patients had 8 crises, of which 6 were myasthenic and 2 cholinergic. A 9-year-old girl died of myasthenic crisis and a 3-month-old boy died of cholinergic crisis. Three of the 6 myasthenic crises were precipitated by upper respiratory tract infection and one was precipitated by bronchopneumonia. Medical treatment
All patients were given anticholinesterase. Thirteen of 20 patients ( 6 5 % ) with early onset juvenile M G were given anticholinesterase alone; 5 achieved complete remission, 2 a good response, 1 a fair response, 4 remained static and 1 died. Five patients (25%) with early onset juvenile disease were also treated with steroids; 1 showed a good response, 2 a fair response, 1 remained static and 1 deteriorated. Two patients who did not respond to anticholinesterase and steroids underwent thymectomy and achieved a fair response. Fifty-six of 81 patients (70%) with late onset juvenile ocular/generalised M G were treated with anticholinesterase alone; 24 achieved complete remission, 7 a good response, 13 a fair response, 9 remained static, 2 deteriorated and 1 died. Fifteen patients (18 ”/,) were given both anticholinesterase and steroids; 3 achieved complete remission, 2 a good response, 8 a fair response and 2 remained static. Two were subsequently treated with azathioprine and thymectomy, and the clinical course remained static. Overall, amongst 89 cases given medical treatment alone, 32 (36%) achieved complete remission, 12 (1 3 %) a good response, 24 (27 %) a fair response and 16 (18%) a static course. Three patients (3%) deteriorated and 2 (2%) died. Thyrnectorny
Thymectomy was performed in 12 patients (8 girls and 4 boys) with a median age at onset of 9.0 years (range 1.5 to 13.75 years). All had moderately severe generalised MG which failed to respond to medical treatment. The thymectomised patients were followed up for 13-176 months (mean 104 months, median 102 months). Thymic histology was normal in 3 patients, showed hyperplasia in 6, non-invasive thymoma in 1, and involution in 2. In the 6 patients with thymic hyperplasia, 2 had complete remission, 1 good response and 3 fair response. The child with thymoma had a fair response 4 months after thymectomy. Both patients with thymic involution had a fair response. Of the 3 patients with a normal thymus, 1 achieved a good response and 2 a fair response.
70
Discussion
The present series, the largest of childhood MG in the Chinese so far reported, illustrates some important difference from the findings in other racial groups (Table 2). The overall female to male ratio in this study was l . l : l , which contrasts sharply with figures as high as 6: 1 in North American children (4). The well balanced sex ratio did not remain when our patients were separated on the basis of disease type: there was a slight excess of males among patients with ocular disease, while females predominated in the generalised M G group. The finding that 7 1 ‘%, of our patients had ocular M G contrasts with figures typically less than 20% in Caucasoids (4) but is similar to the Japanese (6, 16). Also similar to the Japanese is the finding of a peak onset at around 2 to 3 years of age (6). Progression from ocular to generalised MG is common in Caucasoids and occurs in up to 35‘2 of patients (17, 18). The duration of ocular disease plays an important part in assessing the likely progression to generalised MG in Caucasoids. In a retrospective study of 108 patients, Bever et al. (9) showed a decreased risk of progression to generalised MG as the duration of restricted ocular disease increased. Roach et al. (20) reported that progression from ocular to generalised M G rarely occurs more than 2 years after disease onset and showed that ocular M G has a higher rate of spontaneous recovery and a more favorable prognosis. In our study, with follow-up periods ranging from 26 to 468 months, only 5 patients ( 5 % ) progressed from ocular to generalised disease. Prognosis in our patients was good. Excluding the patients with neonatal M G who remitted spontaneously, complete remission occurred in 34% of patients. Our results substantiate predictions that 25 % of patients with childhood M G will achieve complete remission ( 3 , 9). Our findings are also similar to those of Fukuyama et al. (6) who showed that 55-60% of Japanese patients with onset before 15 years of age were either cured or improved while less than 10% worsened or died. Steroid therapy was used more often in our patients than has been reported elsewhere: 24% were treated with steroids and anticholinesterase as compared with a few as 4% reported by Rodriguez et al. (7). whether this reflects a poorer response to anticholinesterase in Chinese than in Caucasoids is not clear. However, of 24 patients treated with steroids when anticholinesterase failed to improve symptomatology, 16 (80%) showed improvement. Thus, it is clearly worthwhile attempting steroid therapy in paediatric patients when anticholinesterase has proved unsuccessful. The majority of reports on thymectomy in juvenile
MG in Chinese children Table 2.Comparison of major series of childhood myasthenia gravis Teng & Osserman
Location No. of patients Transient Neonatal Early Onset Juvenile Late Onset Juvenile Mean age of onset (y) Mean follow up (y) Sex ratio F:M Disease type at presentation ocular (%) generalised 1%) Treatment (%I Anticholinesterase Steroid Thymectomy Treatment Response (%I Complete Remission Partial Remission Static Relapse/aggravation Death Associated Disease (%) Thyroid Epilepsy Thymic Histology (%I
(31
(4)
New York
Massachusetts
21 2 6 13 3.5
Seybold et al
(9) Mayo Clinic 102
Ryniewicz & Badurska
Snead et al
Rodriguez et al
Fukuyama et al
(11)
(181
17)
(61
Wong et al present series
Warsaw
Alabama
Mayo Clinic
Japan
Hong Kong
47
32 0 0 32 7.7 6.6 1:2
1.7:l
51 10 6 35 (79% > 101 8.1 6:1
0 100
17 83
-
-
-
-
100
40
53
40
-
-
-
-
60
47
11 84
85
-
-
2.4:1
-
5
3
-
9 3
4 2
-
-
-
-
7 95 10.4 16 2.6:1
-
-
”
-
0
30 30 18 2 20
-
(50%
I
In a study covering 850, of the population of Hong Kong, 39% of all myasthenia gravis (MG) patients, i.e. 103 individuals (54 girls and 49 boys) were found to have had MG with onset before puberty. Two patients had transient neonatal MG, 20 had early onset juvenile MG and 81 had late onset juvenile MG. Restricted ocular M G occurred in 71 of patients and the remainder had generalised MG. The median age at onset was 4 years. Complete remission occurred in 34 patients (34%), a good response in 14 (14%), and fair response in 32 (32%). The clinical course remained static in 16 patients (16%) and 3 patients deteriorated. Two patients died, 1 with myasthenic crisis and the other with cholinergic crisis. All patients, except 2 with neonatal MG, were initially treated with anticholinesterase, but 24‘2 also required steroid therapy. Thymectomy was performed for 12 patients, of whom 5 (42%) showed marked improvement. Thymic histology was normal in 3, showed hyperplasia in 6, non-invasive thymoma in 1 and involution in 2. The most commonly associated disease was Graves’ disease which occurred in 7 patients (7%)
Myasthenia gravis (MG) was first described in children by Wilks (1) in 1877 and Erb (2) in 1879. Unlike in adult patients, large studies of M G in children are relatively few. In 1956 Teng & Osserman (3) described 2 1 childhood patients attending Mount Sinai Hospital over a 4-year period and reviewed a further 196 cases reported in literature; 8% of the total had transient neonatal M G and the remainder had juvenile MG. Millichap & Dodge (4) reported 51 patients with childhood M G among a total of 447 myasthenic patients attending Massachusetts General Hospital between 1935 and 1959. Of the paediatric patients, 10 (20%) had transient neonatal MG, 6 (12%) had persistent neonatal (congenital) MG, and 35 (68%) had juvenile MG. Bundey ( 5 ) summarised the data in 4 series from Great Britain, United States of America and the Netherlands which collectively showed that 4.3 % of all M G occurred before the age of 10 years and 24% before 20 years. Fukuyania et al. (6) reported an extensive epidemiological study of 1430 patients with MG distributed throughout 800 major hospitals in Japan; 418 patients (29.2%) were aged below 15 years. Rodriguez et al. (7) documented the clinical findings in 149 patients with onset of M G between 1 and 17 years of age. These and other studies (8-1 1) have considered the role of thymectomy in childhood MG; but in view of the relatively small number of cases, 68
V. Wong’, B. R. Hawkins’, Y. L . Y u 3
’
Departments of Paediatrics, Pathology, Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong
Key words: myasthenia gravis; Chinese; juvenile-onset Dr. V. Wong. Department of Paediatrics, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Accepted for publication November 29, 199 1
its value in pediatric therapy remains to be determined. A previous study of Chinese children with MG in Hong Kong (12, 13) noted that the clinical manifestations were different from those typically seen in Caucasoids. T o further delineate these differences and to evaluate management strategy in Chinese children we have conducted a wider survey amongst Chinese in Hong Kong.
Patients and methods
Full details of the study population and selection criteria are given elsewhere (14). This paper reports on 103 patients with M G in childhood. The patients were classified by age at onset ( 5 , 15), as: 1) transient neonatal M G - babies born to mothers with MG, and with onset of M G within the first few days of life; 2) early onset juvenile MG - presenting at any time from birth to two years of age and born to mothers who are not myasthenic; 3) late onset juvenile M G - which in all other respects resembles adult disease but occurs after 2 years and before puberty. All children in this cohort developed pubertal changes before age 16. The responses to treatment were graded as follows:
MG in Chinese children 1) complete remission: no objective weakness and no medication needed, 2) partial remission: (a) good response: markedly improved symptomatology while on the same or reduced dosage of drugs; (b) fair response: slightly improved symptomatology ; 3) static; same symptomatology with or without increase in drug treatment; 4) deterioration: worse syniptomatology with or without increase in drug treatment.
F---T
12
IIc----.
t-
+
All patients Males Females
Results
Of 262 patients included in the overall study of adults and children, 103 were classified as paediatric cases. Two children, both female, had transient neonatal MG and are not considered further in this paper. The remaining 101 patients form the basis of calculations in this paper. Their diagnostic categories and disease types are shown in Table 1. Twenty patients (20%) had early onset juvenile M G and 81 patients (800/,) had late onset juvenile MG. None of the patients with early onset juvenile M G had siblings with MG; thus, congenital M G and familial infantile M G were unlikely to be present in our series of patients. Restricted ocular M G occurred in 72 patients (7 1%) and generalised M G occurred in the remainder. The overall female to male ratio was 52:49, or 1.1 :1. The ratios were 0.8: 1 and 1.1: 1 in the early and late onset juvenile groups respectively. When the patients were separated into ocular and generalised MG, the female to male ratios were 0.8: 1 and 2.2: I respectively. Age at onset
The age at onset of disease ranged from 1 month to 15 years (mean 5.6 years, median 4.0 years). The age of presentation ranged from 0.17 to 16 years (mean = 6.5 years, median = 5 years). The sex distribution by age at onset is shown in Fig. 1. There is a clear peak of onset centred around 2 to 3 years of age, with evidenced for a second peak around 10
Table 1. Disease type in 101 patients with childhood myasthenia gravis Total Disease type
M
F
Total
%
Ocular Mild generalised Moderate to severe generalised Fulminating
40 4 5 0
32 13 4 3
12 17 9 3
71 17
9 3
1-
0
I
I
I
I
,
0 1 2 3 4 5
2,
I
I
I
I
I
, & , - I
I
6 7 8 910111213141516
Age at Onset (Years)
Fig. I . Age- and sex-specific incidencc of myasthenia gravis by onset of the disease.
years. However, in view of the relatively small numbers, the latter peak is not considered to be of significance. Associated diseases
The most commonly associated disease was Graves’ disease which occurred in 7 patients (72,). One patient had Graves’ disease and concomitant myasthenic symptoms at presentation. Three patients had epilepsy and 2 had asthma. Systemic lupus erythematosus, nephrotic syndrome and dystonia each occurred in 1 patients. Four patients had close relatives with Graves’ disease and 4 had relatives with autoimmune thyroiditis. Rheumatoid arthritis, nontoxic goitre, and insulin dependent diabetes mellitus occurred occasionally in close relatives. No patients had siblings with M G although 1 had a maternal uncle with MG. Presenting features, clinical features and course
Patients with restricted ocular involvement presented with unilateral or bilateral ptosis. Both ptosis and ophthalmoplegia occurred in 3 1 patients, and were the initial presenting features in 8 patients with early onset juvenile M G (i.e. 40%) and 23 (i.e. 28%) with late onset juvenile M G . Patients were followed-up for periods ranging from 26-468 months (mean=95 months, median = 69 months). Five children with initial ocular manifestations subsequently developed generalised MG, which was mild in 1 and moderate to severe in 4. All these children had late onset juvenile MG. The
69
Wong et al. median interval from initial ocular to final generalised involvement was 13l months (range = 25-468 months). Five patients had 8 crises, of which 6 were myasthenic and 2 cholinergic. A 9-year-old girl died of myasthenic crisis and a 3-month-old boy died of cholinergic crisis. Three of the 6 myasthenic crises were precipitated by upper respiratory tract infection and one was precipitated by bronchopneumonia. Medical treatment
All patients were given anticholinesterase. Thirteen of 20 patients ( 6 5 % ) with early onset juvenile M G were given anticholinesterase alone; 5 achieved complete remission, 2 a good response, 1 a fair response, 4 remained static and 1 died. Five patients (25%) with early onset juvenile disease were also treated with steroids; 1 showed a good response, 2 a fair response, 1 remained static and 1 deteriorated. Two patients who did not respond to anticholinesterase and steroids underwent thymectomy and achieved a fair response. Fifty-six of 81 patients (70%) with late onset juvenile ocular/generalised M G were treated with anticholinesterase alone; 24 achieved complete remission, 7 a good response, 13 a fair response, 9 remained static, 2 deteriorated and 1 died. Fifteen patients (18 ”/,) were given both anticholinesterase and steroids; 3 achieved complete remission, 2 a good response, 8 a fair response and 2 remained static. Two were subsequently treated with azathioprine and thymectomy, and the clinical course remained static. Overall, amongst 89 cases given medical treatment alone, 32 (36%) achieved complete remission, 12 (1 3 %) a good response, 24 (27 %) a fair response and 16 (18%) a static course. Three patients (3%) deteriorated and 2 (2%) died. Thyrnectorny
Thymectomy was performed in 12 patients (8 girls and 4 boys) with a median age at onset of 9.0 years (range 1.5 to 13.75 years). All had moderately severe generalised MG which failed to respond to medical treatment. The thymectomised patients were followed up for 13-176 months (mean 104 months, median 102 months). Thymic histology was normal in 3 patients, showed hyperplasia in 6, non-invasive thymoma in 1, and involution in 2. In the 6 patients with thymic hyperplasia, 2 had complete remission, 1 good response and 3 fair response. The child with thymoma had a fair response 4 months after thymectomy. Both patients with thymic involution had a fair response. Of the 3 patients with a normal thymus, 1 achieved a good response and 2 a fair response.
70
Discussion
The present series, the largest of childhood MG in the Chinese so far reported, illustrates some important difference from the findings in other racial groups (Table 2). The overall female to male ratio in this study was l . l : l , which contrasts sharply with figures as high as 6: 1 in North American children (4). The well balanced sex ratio did not remain when our patients were separated on the basis of disease type: there was a slight excess of males among patients with ocular disease, while females predominated in the generalised M G group. The finding that 7 1 ‘%, of our patients had ocular M G contrasts with figures typically less than 20% in Caucasoids (4) but is similar to the Japanese (6, 16). Also similar to the Japanese is the finding of a peak onset at around 2 to 3 years of age (6). Progression from ocular to generalised MG is common in Caucasoids and occurs in up to 35‘2 of patients (17, 18). The duration of ocular disease plays an important part in assessing the likely progression to generalised MG in Caucasoids. In a retrospective study of 108 patients, Bever et al. (9) showed a decreased risk of progression to generalised MG as the duration of restricted ocular disease increased. Roach et al. (20) reported that progression from ocular to generalised M G rarely occurs more than 2 years after disease onset and showed that ocular M G has a higher rate of spontaneous recovery and a more favorable prognosis. In our study, with follow-up periods ranging from 26 to 468 months, only 5 patients ( 5 % ) progressed from ocular to generalised disease. Prognosis in our patients was good. Excluding the patients with neonatal M G who remitted spontaneously, complete remission occurred in 34% of patients. Our results substantiate predictions that 25 % of patients with childhood M G will achieve complete remission ( 3 , 9). Our findings are also similar to those of Fukuyama et al. (6) who showed that 55-60% of Japanese patients with onset before 15 years of age were either cured or improved while less than 10% worsened or died. Steroid therapy was used more often in our patients than has been reported elsewhere: 24% were treated with steroids and anticholinesterase as compared with a few as 4% reported by Rodriguez et al. (7). whether this reflects a poorer response to anticholinesterase in Chinese than in Caucasoids is not clear. However, of 24 patients treated with steroids when anticholinesterase failed to improve symptomatology, 16 (80%) showed improvement. Thus, it is clearly worthwhile attempting steroid therapy in paediatric patients when anticholinesterase has proved unsuccessful. The majority of reports on thymectomy in juvenile
MG in Chinese children Table 2.Comparison of major series of childhood myasthenia gravis Teng & Osserman
Location No. of patients Transient Neonatal Early Onset Juvenile Late Onset Juvenile Mean age of onset (y) Mean follow up (y) Sex ratio F:M Disease type at presentation ocular (%) generalised 1%) Treatment (%I Anticholinesterase Steroid Thymectomy Treatment Response (%I Complete Remission Partial Remission Static Relapse/aggravation Death Associated Disease (%) Thyroid Epilepsy Thymic Histology (%I
(31
(4)
New York
Massachusetts
21 2 6 13 3.5
Seybold et al
(9) Mayo Clinic 102
Ryniewicz & Badurska
Snead et al
Rodriguez et al
Fukuyama et al
(11)
(181
17)
(61
Wong et al present series
Warsaw
Alabama
Mayo Clinic
Japan
Hong Kong
47
32 0 0 32 7.7 6.6 1:2
1.7:l
51 10 6 35 (79% > 101 8.1 6:1
0 100
17 83
-
-
-
-
100
40
53
40
-
-
-
-
60
47
11 84
85
-
-
2.4:1
-
5
3
-
9 3
4 2
-
-
-
-
7 95 10.4 16 2.6:1
-
-
”
-
0
30 30 18 2 20
-
(50%
