myasthenia gravis in hong kong chinese: 2. paediatric disease

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.

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’

I 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. Un- like 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 Gen- eral 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 MG 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 MG 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,

V. Wong’, B. R. Hawkins’, Y. L . Y u 3 Departments of ’ Paediatrics, Pathology,

Mary Hospital, Hong Kong Medicine, University of Hong Kong, Queen

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 deter- mined.

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. To 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 MG 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 MG 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 MG - which in all other re- spects resembles adult disease but occurs after 2 years and before puberty. All children in this co- hort developed pubertal changes before age 16. The responses to treatment were graded as fol- lows:

68

MG in Chinese children

1) complete remission: no objective weakness and

2) partial remission: no medication needed,

(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 in-

4) deterioration: worse syniptomatology with or crease in drug treatment;

without increase in drug treatment.

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 calcu- lations in this paper. Their diagnostic categories and disease types are shown in Table 1. Twenty patients (20%) had early onset juvenile MG 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 MG were unlikely to be present in our series of patients.

Restricted ocular MG 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 dis- tribution 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 40 32 12 71 Mild generalised 4 13 17 17 Moderate to severe generalised 5 4 9 9 Fulminating 0 3 3 3

F---T All patients IIc----. Males t - + Females

12

1 -

0 I I I I , 2, I I I I I , & , - I I

0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6

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 pa- tient 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, non- toxic 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 MG.

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 13 l 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 MG 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 azathio- prine 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.

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 MG 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 MG who remitted spontane- ously, complete remission occurred in 34% of patients. Our results substantiate predictions that 25 % of patients with childhood MG 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 com- pared 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

70

MG in Chinese children

Table 2. Comparison of major series of childhood myasthenia gravis

Teng & Millichap & Ryniewicz & Osserman Dodge Seybold et al Badurska Snead et al Rodriguez et al Fukuyama et al Wong et al

(31 (4) (9) (11) (181 17) (61 present series

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

New York 21 2 6 13 3.5

1.7:l

0 100

100

-

- -

1 1 84 - -

5

-

-

-

Massachusetts 51 10 6 35 (79% > 101 8.1 6: 1

17 83

40

60 -

85 ” -

- 3

9 3 -

Mayo Clinic 102

0 7 95 10.4 16 2.6: 1

- -

53

47

30 30 18 2 20

4 2

-

thymoma 2 hyperplasia 89 unknown 9

- * Includes good response (14%) and fair response (32%).

Warsaw Alabama 47 32

0 0 32

-

-

- (50% <lo) 7.7 - 6.6

2.4: 1 1:2

- 37 63 -

40 38 34

60 22 -

68 29 - -

MG were on patients with disease onset after 10 years of age. In most cases, thymectomy was performed after 12 years of age (4, 7-11, 18). These studies (Table 2), as ours, are retrospective; but the overall statistics for improvement and remission are similar to those reported in adults with generalised MG (21). All our 12 thymectomized patients showed improvement and in 5 the improvement was marked. However, it is difficult to draw any firm conclusion in view of the small numbers of patients. It is also worth noting that the effect of thymectomy on the immune system of children has not been elucidated, although clinical immunodeficiency has not been reported in thymectomised children.

Despite certain differences in disease profile between Chinese and Caucasoid patients, a major sim- ilarity is the association of M G with autoimmune thyroid disease. Seven percent of our patients also had Graves’ disease, and 7 % had a family history of these conditions. The concurrent existence of systemic lupus erythematosus, epilepsy, nephrotic syndrome, and asthma in patients in this survey is con- sistent with findings in other series (3, 7, 18, 22).

An interesting finding to emerge from our study was that the present classification system for MG

86% of patients remitted after thymectomy and 93% of patients remitted after medication.

Mayo Clinic 157 0 8(<1~1

149 (> 1 y) 13 17

3.4:l

-

-

-

4 57

79 - -

< 10

3 3

normal 16 thymoma 3 hyperplasia 78 unknown 3

Japan 418

0 0

418

-

1.7.1

90 10

-

-

-

55-60

1

Hong Kong 103 2 20 81 5.6 5.7

1 . 1 : l

71 29

100 24 12

34 46* 16 3

- I 3

normal 25 thymoma 8 hyperplasia 50 involution 17

- -

appears unsuitable for describing MG in Chinese children. The original classification proposed by Os- serman and Genkins (1 5 ) was based upon 1200 adult and paediatric patients. Nine percent of patients were classified as having “juvenile onset MG”. This was separated into “congenital MG”, which presented within the first few days of life, and “acquired MG” which presented at any other time before the age of 17 years. Bundey ( 5 ) later reclassified juvenile MG into “early onset”, with onset below 2 years of age, and “late onset” which resembled adult disease, but had onset between the ages of 2 and 20 years. Congenital MG was later shown to consist of distinct types based on biochemical, electrophysiolog- ical and ultrastructural studies on the motor end plate (23-25). Our classification was largely based on that of Bundey (5 ) . However, we found no major differences between early and late onset juvenile MG. There was a similar incidence of remission (complete remission in 25% of early onset and 30‘2, of late onset patients), a predominance of ocular MG, (80% of early onset and 69% of late onset group), a well-balanced sex ratio, and an absence of MG in the siblings. Elsewhere we have shown a high prevalence of HLA-DR9 and, to a lesser extent,

71

Wong et al.

Bw46 in these patients but have not shown any HLA difference between patients with early and late onset juvenile disease (26-28). Also, in our patients, acetylcholine receptor antibody was either absent or of low titre in the majority of patients and showed no relation to early or late onset disease (28). Thus, a cut-off point at 2 years to separate early and late onset juvenile disease appears meaningless when there are no other major differences between the two groups. Indeed, there was a clear peak of onset at 2 to 3 years in our patients and not the bimodal dis- tribution with peaks on either side of 2 years that might be expected if patients with onset before and after 2 years of age were clinically distinct subgroups. There was, in fact, slight evidence for a second peak of onset around 10 years of age but, in view of the relatively small numbers involved, this appears unlikely to be of significance.

Whilst it is not possible to rule out entirely that a few of our patients may have congenital M G ac- cording to the definition which applies in other eth- nic groups (even though none have affected siblings), we would suggest that the majority of our paediatric patients have a variant of MG characterised by absence or low titres of acetylcholine receptor antibody, a predominance of ocular disease, no predi- lection for females and an association with certain haplotype containing HLA-DR9 and Bw46 (28). It is probable that the existence of this variant explains many of the differences in the pattern of MG seen in Chinese and Caucasoid children.

References

I . WILKS S. On cerebritis, hysteria and bulbar paralysis, as il- lustrative of arrest of function of the cerebrospinal centres. Guy's Hosp Reports 1877: 22: 7-55.

2. ERB W. Zur Casuistik der bulbaren Lahmungen. 3 Ueber einen neuen, wahrscheinlich bulbaren Symptomencomple. Archiv fur Psychiatrie und Nervenkrankheiten 1879: 9: 336- 350.

3. TENG P, OSSERMAN KE. Studies in myasthenia gravis: neonatal and juvenile types. J Mt Sinai Hosp 1956: 23: 711-727.

4. MILLICHAP JG. DODGE PR. Diagnosis and treatment of myasthenia gravis in infancy, childhood, and adolescence. A study of 51 patients. Neurology 1960: 10: 1007-1014.

5. BUNDEY S. A genetic study of infantile and juvenile myasthenia gravis. J Neurol Neurosurg Psychiatry 1972: 35: 41- 51.

6. FUKUYAMA Y, HIRAYAMA Y, OSAWA M. Epidemiological and clinical features of childhood myasthenia gravis in Japan. In: SATYOSHI E, ed. Myasthenia gravis - pathogenesis and treatment. Tokyo: Univ Tokyo Press, 1981: 19-27.

7. RODRIGUEZ M, GOMEZ MR, HOWARD FM, TAYLOR WF. Myasthenia gravis in children: long-term follow-up. Ann Neu- rol 1983: 13: 504-510.

8. KEYNES G. Surgery of the thymus gland. Second (and third) thoughts. Lancet 1954: i: 1197-1202.

9. SEYBOLD ME. HOWARD FM, DUANE DD. PAYNE WS, HARRISON EG. Thymectomy in juvenile myasthenia gravis. Arch Neurol 1971: 25: 385-392.

10. FONKALSRUD EW, HERRMANN C, MULDER DG. Thyniec- tomy for myasthenia gravis in children. J Paed Surg 1970: 5: 157-165.

11. RYNIEWICZ B, BADURSKA B. Follow-up study of myasthenic children after thymectomy. J Neurol 1977: 217: 133- 138.

12. CHAN-LUI WY, LEUNG NK, LAU TTY. Myasthenia gravis in Chinese children. Dev Med Child Neurol 1984: 25: 717- 724.

13. CHAN-LUI WY, HAWKINS BR. Infantile myasthenia. Neu- ropediatrics 1985: 16: 24-28.

14. Y u YL, HAWKINS BR, IP MSM, WONG V. W o o E. My- asthenia gravis in Hong Kong Chinese, 1. Epidemiology and adult disease. Acta Neurologica Scandinavia 1992: (in press).

15. OSSERMAN KE, GENKINS G. Studies in myasthenia gravis: review of a twenty-year experience in over 1200 patients. J Mt Sinai Hosp 1971: 38: 497-537.

16. FUKUYAMA Y, SUGIURA S, HIRAYAMA Y, SEGAWA M . The prognosis of myasthenia gravis in infancy and childhood. In: KAKULAS B, ed. Clinical studies in myology. Amsterdam: Excerpta Medica, 1973: 552-559.

17. FENICHEL GM. C!inical syndromes of myasthenia in infancy and childhood. A review. Arch Neurol 1978: 35: 97-103.

18. SNEAD OC, BENTON JW, DWYER D el al. Juvenile myasthenia gravis. Neurology 1980: 30: 732-739.

19. BEVER CT, AQUINO AV, PENN AS, LOVELACE RE, Row- LAND LP. Prognosis ofocular myasthenia. Ann Ncurol 1983: 14: 516-519.

20. ROACH ES, BUONO G , MCLEAN WT, WEAVER RG. Early- onset myasthenia gravis. J Paed 1986: 108: 193-197.

21. OOSTERHUIS HJGH. Myasthenia gravis. Edinburgh: Churchill Livingstone, 1984: 5 1-76.

22. KIESSLING WR, PFLUCHAUPT KW, RICKER K, HAUBITZ I, MERTENS HG. Thyroid function and circulating antithy- roid antibodies in myasthenia gravis. Neurology 198 I : 3 1:

23. ENGEL A. Morphologic and immunopathologic findings in myasthenia gravis and in congenital myasthenic syndromes. J Neurol Neurosurg Psychiatry 1980: 43: 577-589.

24. ENGEL AG, LAMBERT EH, MULDER D M et al. Recently recognised congenital myasthenic syndromes: (a) end-plate acetylcholine (ACh) esterase deficiency (b) putative abnor- mality of the ACh induced ion channel (c) putative defect or ACh resynthesis or mobilization - clinical features, ultra- structure and cytochemistry. Ann NY Acad Sci 1981: 377: 614-639.

25. ENGEL AG, LAMBERT EH, MULDER D M et al. A newly recognised congenital myasthenic syndrome attributed to a prolonged open time of the acetylcholine-induced ion channel. Ann Neurol 1982: 11: 553-569.

26. HAWKINS BR, CHAN-LUI WY. CHOI EKK, HO AY. Strong association of HLA Bw46 with juvenile onset myasthenia gravis in Hong Kong Chinese. J Neurol Neurosurg Psychiatry

27. HAWKINS BR, IP MSM, LAM KSL et al. HLA antigens and acetylcholine receptor antibody in the subclassification of myasthenia gravis in Hong Kong Chinese. J Neurol Neurosurg Psychiatry 1986: 49: 3 16-3 19.

28. HAWKINS BR, Y u YL, WONG V, Woo E, IP MSM, DAWK- INS RL. Possible evidence for a variant of myasthenia gravis based on HLA and acetylcholine receptor antibody in Chi- nese patients. Q J Med 1989: 70: 235-241.

771-774.

1984: 47: 555-557.

12

myasthenia gravis in hong kong chinese: 2. paediatric disease

Documents