Myasthenia gravis in Iranian children
Subgroup: Volume 10, Issue 1
Date: January 2008
Type: Original Article
Start Page: 22
End Page: 26
- S Inaloo Department of Pediatric Neurology, Shiraz University of Medical Sciences, Nemazee Hospital, Shiraz University of Medical Science, Shiraz, Fars, Iran
- M Ghofrani Department of Pediatric Neurology, Shahid Beheshti University of Medical Sciences, Tehran, Tehran, Iran
- H Eftekharian Department of Anesthesiology, Shiraz University of Medical Sciences, Shiraz, Fars, Iran
City, Province: Shiraz, Fars
Background: Considering the marked difference between the clinical course and management of juvenile myasthenia gravis, congenital/genetic myasthenia gravis and transient neonatal MG, the differential diagnosis is very important. This study was undertaken to evaluate the clinical spectrum of myasthenia gravis in children and determine the factors helping clinicians in their diagnosis and management of the disease.
Methods: In a retrospective study from 1994 to 2002, all pediatric patients with myasthenia gravis (MG) admitted to Department of Pediatric Neurology in Mofid Children Hospital affiliated to Shahid Beheshti University were enrolled.
Results: Of 32 children, 7 and 25 suffered from congenital and juvenile types of MG, respectively. The initial symptoms in congenital MG were ptosis (7/7), limitation of eye movement (2/7) and mild generalized weakness (6/7). Although 85% of cases with congenital MG, tested positive for Tensilon test, no myasthenia crisis or spontaneous remission was observed in any of the patients. The female to male ratio was 1.5/1 which was correlated to adult MG. In children with juvenile MG, the mean age was 5.7±4.2SD years. The most common symptoms were ptosis in 96% and generalized weakness in 76% of the cases. 32% of patients experienced one myasthenia crisis. EMG was diagnosed in 83% and tensilon test was positive in 84% of the cases. One patient had hyperthyroidism and another had hypothyroidism and both were epileptic. Eight patients underwent thymectomy microscopically. Thymic follicular hyperplasia was observed in five cases (62%), and the remaining three cases were normal. 12.5% of patients recovered completely after thymectomy and there was no need for medication during the follow up. 50% of cases showed relative improvement but it was negligible in 37% of patients.
Conclusion: This study revealed that thymectomy lacks remarkable prognostic influence.
Keywords: Myasthenia gravis; Children; Thymectomy; Congenital
Willis first described myasthenia gravis (MG) in 1672,1 the onset of which in childhood was recognized by Erb in 1879.2 Three forms of myasthenia were recognized in autoimmune infants and children juvenile myasthenia gravis (JMG), congenital/genetic myasthenia gravis (CMG), and transient neonatal MG.3,4 Juvenile myasthenia gravis is an autoimmune disease. At least two autoimmune antibody mediated processes underlie autoimmune MG, targeting the acetylcholine receptor (AChR) in the majority and musclespecific kinase (MuSK) in the minority of patients.5 Congenital myasthenia gravis is a multiple inherited disorder of neuromuscular transmission and neonatal MG is a transient disease due to placental transfer of antibodies from a myasthenic mother to her baby during pregnancy.6,7 Three to seven percent of MG cases begin before the age of 10 years and 16-30% before the age of 20 years.8 Considering the marked difference between the clinical course and management of CMG and JMG, the differential diagnosis is very important. The study of the defect causing CMG requires sophisticated techniques which are not available in most centers.6 We studied the series of childhood MG for the clinical features of congenital or juvenile forms which responded to anticholinesterase drugs, steroid and thymectomy.
Materials and Methods
The files of 32 patients with the diagnosis of myasthenia gravis that had referred to our center in Mofid Hospital affiliated to Shahid Beheshti University of Medical Sciences between 1994 and 2002 were reviewed. Data were collected by reviewing the files and making telephone call interview. The diagnosis of MG was based on the association of clinical signs of fluctuating weakness of voluntary muscles with fatigability and at least one of the following criteria including unequivocal improvement after IV edrophonium (positive tensilon test) injection, electrophysiological signs of abnormal neuromuscular transmission such as a decrement more than 10% in compound muscle action potential on a low-rate supramaximal repetitive nerve stimulation, and the ruling out of other causes of muscle weakness. Serum anticholinesterase antibodies were checked only for 5 patients because this test has not been available till recently. The severity of the disease was graded according to Osserman.9 The patients were classified as CMG if they had one of the following criteria: (i) age of onset before 1 year, (ii) age of onset before 5 years and MG history in a sibling or relative and no response to corticosteroid therapy. Other patients were considered as JMG. Parental consanguinity was not included among the criteria since the rate of consanguinity marriage is very common in Iran. Statistical analysis was performed using SPSS software, version 11.
Of the thirty-two patients suffering from myasthenia weakness, seven (two girls and five boys) were affected by CMG. The onset of disease was at birth in 3 patients and in the remaining 4, within the first year. Family history was positive in 3 patients (42.8%). Tensilon test was positive in 6 patients (85.7%) and EMG with repetitive stimulation was positive in 4 patients (57%). Three patients had only ophthalmic involvement and 3 of them had ptosis associated with mild generalized weakness and one patient had generalized weakness, ptosis and bulbar involvement. None of the patients with CMG developed any acute crisis. One patient was not followed and the others were followed from 3 months to 9 years with a mean of 3.017±3.26 years. Out of 6 patients followed, 5 subjects had relatively good response to mestinone and one patient with ophthalmic myasthenia had no response to mestinone, while for this patient, steroid and IVIG were tried but no response was observed.
In 25 patients with JMG including 15 girls and 10 boys (F/M=1.5/1), the onset age was 1.2- 12.5 years. No patient had a family history of muscle weakness. Six patients (24%) complained of ocular myasthenia (Osserman’s grade I) and the other 19 cases had generalized MG: mild disease (grade 2A) in 7 cases (28%), moderately severe (grade 2B) in 4 (16%) and very severe with respiratory crises (grade 3 and 4) in eight patients (32%). Three patients had 4 crises and one patient experienced two. One patient (4%) had hyperthyroidism, one patient (4%) hypothyroidism and two patients (8%) epilepsy. Two patients had a positive family history of hypothyroidism in the first degree relatives. Anticholinesterase antibodies were checked in 5 patients, being positive in 3 patients (60%). Tensilon test was positive in 21 out of 25 patients (84%). Electromyogram with repetitive stimulation test was done in 18 patients, being positive in 15 (83%). In nineteen patients, chest X-ray or CT scan was done, showing increased thymus shadow in four cases (21%).
Anticholinesterase was administered to all patients and for ten patients steroid therapy was also added. For seven patients with myasthenic crisis, IVIG was administered; plasma exchange was also used for one patient with crisis. Follow-up ranged from 0.2 to 7 years (mean 3.03±3.2 years). Thymectomy was performed in seven patients who did not have a good response to anticholinesterase and steroids. None of them underwent early thymectomy. Histological examination showed that 57% of them had hyperplastic thymuses and three didn’t. One patient (14%) had complete recovery after thymectomy, requiring no medication. Two patients (28%) showed a relative improvement and four patients (57%) had no improvement following thymectomy. Five patients (20%) had remission lasting for several months, 4 with genenralized MG and one with ocular myasthenia. Three patients were treated only with anticholinesterase. One patient received steroid and anticholinesterase while one patient had remission several months after thymectomy. Moderate improvement was observed in fifteen patients (60%), whereas five (20%) had no good response, and three improved after thymectomy (Tables 1, 2).
The prevalence of autoimmune MG in patients with the onset in the first decade is lower than that in the general population, with the exception of Chinese and Japanese patients in whom a high incidence of ocular MG is reported.7 In our center, there are no data available on the prevalence of myasthenia gravis in children and adults. During a 10-year period, only 25 patients with juvenile myasthenia and 7 patients with congenital myasthenia were recorded. Although sometimes difficult, it is important to distinguish the congenital and juvenile from childhood myasthenia due to differences in their treatment measures. Symptoms starting in infancy indicate CMG,6 but the reported ages of the onset of CMG and JMG overlap. MG in first-degree relatives, if present, strongly suggests hereditary MG syndromes, but the incidence of autoimmune MG in relatives of JMG patients is also higher than that in the normal population (4%).8 Acetylcholin receptor antibody may be absent in up to 44% of JMG cases, limiting the value of this test in the diagnosis of JMG.1 Detailed electrophysiological and morphological studies of the muscle indicate various defects causing CMG, but few centers can perform such evaluations. In our center, diagnosis of congenital cases is based on the onset of the disease and a positive family history. We studied our series of childhood MG for the clinical features of family history associated autoimmune disease and response to congenital MG was significantly more common in males (5/2=M/F), being different from Anlar et al.’s findings (2000).9 Nevertheless, the proportion of JMG cases was similar to that of this study, i.e. slightly more common in females.9,10 These results are in contrast with the strong female prevalence in late-onset patients (4.2/1) and can confirm the influence of sex hormones on the disease pathogenesis at this age.11 In our study, 28% of JMG patients had only ocular myasthenia, 32% had severe disease with respiratory involvement, showing that JMG is more benign than late-onset MG, in the same line with the study of Andews, and different from the study of Evoli and Anlar that showed 42.1% respiratory involvement.9,11,2 Positive family history of myasthenia was 42.8% in our study as compared with 70% in Evoli et al’s study.11
Tensilon test and electrodiagnostic study are also beneficial in the diagnosis of prepubertal JMG. In our study, 84% of JMG and 59% of CMG had positive tensilon test, 83% of JMG and 85.7% of CMG had positive EMG that were compatible with the findings of another study.12 Although the seropositive rate varies in the literature on JMG,1,13 acetylcholin receptor antibodies were checked only in five patients being positive in 3 of them, as other studies have demonstrated and less than that reported by the adult onset MG.1,2,9 Various diseases of autoimmune and nonautoimmune origin have been described in association with JMG in childhood.1,14,15 Most autoimmune diseases associated with JMG in our study were thyroid diseases. Also epilepsy was more common in JMG cases in comparison with general population, but none of CMG patients had any other associated diseases. In our study, like other studies thymoma was not visible in patients’ pathology.9,10,11 Some authors reported good results after surgery in prepubertal children.16-20 Rodriguez showed that early surgery, presence of bulbar symptoms, absence of ocular sign or generalized symptoms, onset of symptoms between age 12 and 16 and presence of other autoimmune diseases were associated with increased post-operative remission rates.21 Others described a lower remission rate in younger ages than in older ones.2,22 In our study, also no beneficial results were noted after thymectomy; in 57% no response to thymectomy might be the reason for the delayed onset of thymectomy. The best result was observed, if thymectomy was performed within 2 years of the disease onset.
We showed that Myasthenia gravis was a relatively rare disease in our center. Clinical presentation, response to treatment and prognosis are similar to those described elsewhere, and the reason for the poor response to thymectomy in our patients was delay in operation. Hence, early thymectomy for myasthenic patients with no response to steroid and anticholin esterase drugs is recommended.
The authors would like to thank the Office of Vice Chancellor for Research of Shiraz University of Medical Sciences for financial support of this study and Dr. D. Mehrabani, Miss Gholami and Mrs. Ghorbani at Center for Development of Clinical Research of Nemazee Hospital for editorial and typing assistance.
- Willis T, Brutorum DA. In: portage S. ed. Two discuses concerning the Soul of Brutes. Translated by Pordage S. London, 1683 Oxford: Theatrosheldoniano; 1672.
- Erb W. Zur Casuistik der bulbaren lahmungen. (3) Uebereinen neuen, wahrscheinlich bulbaren symptomencomplex. Arch Psychiatr Nervenkr 1879;9:336-50.
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- Anlar B, Ozdirim E, Renda Y, Yalaz K, Aysun S, Topçu M, Topaloğlu H. Myasthenia gravis in childhood. Acta Pediatr 1996;85:838-842.
- Batocchi AP, Evali A, Palmisani MT, Lo Monaco M, Bartocccioni M, Tonali P. Early onset myasthenia gravis: clinical characteristics and response to therapy. Eur J Pediatr 1990;150 (1):66-68.
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- Essa M, Medany YE, Hajjer W, Hariri Z, Al-Mulhim F. Maximal thymectomy in children with myasthenia gravis. Eur J Cardio Thorasic Surg 2003;24(2):187-91.
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