Neuropediatrics 2003; 34(5): 276-277
DOI: 10.1055/s-2003-43257
Letter to the Editor

Georg Thieme Verlag Stuttgart · New York

Antibody Positive Myasthenia Gravis Following Treatment with Carbamazepine

A Chance Association?M. A. Kurian 1 , M. D. King 1
  • 1Department of Paediatric Neurology, The Children's University Hospital, Dublin, Ireland
Further Information

Publication History

Received: July 23, 2002

Accepted after Revision: May 27, 2003

Publication Date:
04 November 2003 (online)

Sir,

Three girls who developed myasthenia gravis either during, or following treatment with carbamazepine for partial epilepsy are described. The association of epilepsy, carbamazepine therapy and subsequent development of myasthenia gravis may be a chance association. However, from the following results, one could also postulate that such a phenomenon could occur in individuals with a susceptible haplotype.

All three cases are currently eighteen years old (Table [1]). They all presented between the ages of six and eleven with recurrent partial (non-rolandic) seizures, associated with focal electroencephalogram spike discharges in either temporal region. Magnetic resonance imaging of the brain was normal in all patients. Carbamazepine was introduced and was continued for between five and six years in all three patients. All three girls had a two year seizure-free period prior to stopping drug therapy.

Table 1 Patient characteristics Patient 1 2 3 Patient current age (years) 18 18 18 Age at first seizure (years) 7 11 6 Family history of autoimmune disease Nil Nil Thyrotoxicosis, rheumatoid arthritis Interictal electroencephalogram findings Right centrotemporal spike discharges Right frontotemporal spike discharges Left temporal spike discharges Magnetic resonance imaging Normal Normal Normal Duration of carbamazepine therapy (years) 6 6 5 Age at stopping therapy (years) 14 Ongoing 10 Age of presentation of myasthenia gravis (years) 14 17 10 Time of onset after stopping therapy 3 months During treatment 13 months Clinical findings Clumsiness, bilateral ptosis Proximal weakness, bilateral ptosis Fatigue on exercise, ptosis Edrophonium testing Marked improvement Improved eye opening Dramatic response Acetylcholine receptor antibody titre (Mol × 10 -9) 165 476 420 Thymic involvement Enlarged on CT Normal Thymectomy for enlarged thymus (B cell follicular hyperplasia) HLA haplotype B8 B8 B8

Symptoms of classical myasthenia (proximal girdle weakness, bilateral ptosis and fatigability) developed while on carbamazepine therapy in one case and between three and thirteen months after stopping the drug in the other two cases. The response to the edrophonium test was dramatic in all cases. Acetylcholine receptor autoantibodies were strongly positive in all three patients, and titres ranged from 165 - 476 mol × 10 -9. There was no other clinical evidence of autoimmune disease in the three patients, who were all negative for other autoantibodies. One child showed a strong family history of autoimmune diseases with thyrotoxicosis and rheumatoid arthritis affecting three other female family members. All three girls had a positive HLA B8 haplotype. Thymic involvement was also evident in two cases: one child had enlargement of the thymus on computerised tomography (CT); another showed evidence of thymic involvement on histology.

Following diagnosis all three girls were started on pyridostigmine. Two out of three girls were successfully treated with medical therapy. However, one patient continued to have intractable symptoms of fatigability despite incremental doses of pyridostigmine and proceeded to have a thymectomy. Marked B cell follicular hyperplasia was evident on histology. Post-operatively there was a marked improvement in symptoms.

Associations between myasthenia gravis and central nervous system functions have been made for over 80 years. An increased incidence of psychiatric disorders, multiple sclerosis, abnormal evoked responses, electroencephalographic changes and epilepsy [[6]] have all been noted in patients with myasthenia gravis. However, a review by Keesey et al [[5]] argues that the association of myasthenia gravis with epilepsy is either coincidental or the result of uncontrolled disease, where hypoxia during myasthenic crises may affect the brain.

The association of partial epilepsy, carbamazepine and the subsequent onset of myasthenia gravis may be coincidental, especially as both gender and HLA B8 association are typical for onset of myasthenia at this age. Over this time period in our tertiary referral centre, only 2 other children have been diagnosed with myasthenia gravis, both antibody negative. It is not possible to exactly quantify the total number of patients attending this centre and taking carbamazepine over the same period of time, but it is estimated to be greater than 600.

It is possible that carbamazepine used in the therapy of partial onset non-rolandic epilepsy may trigger an autoimmune response in an HLA B8 susceptible individual. Carbamazepine is already linked with drug-induced systemic lupus erythematosus-like syndromes (associated with positive anti-nuclear antibodies and anti-double-stranded DNA antibodies) [[2], [3], [4]]. It may be postulated that carbamazepine may similarly induce acetylcholine receptor antibodies and induce myasthenic symptoms.

Drug-induced neuromuscular blockade causing myasthenia gravis is well described [[1], [7]]. Carbamazepine may unravel symptoms of underlying myasthenia much faster, similar to phenytoin and in analogy to lithium salts. Ronziere et al [[8]] reports 3 such cases of lithium-induced myasthenia (secondary to a dysfunction of the neuromuscular junction) and one case where underlying antibody positive myasthenia was disclosed only after treatment with lithium.

In conclusion, we present an unusual association between partial epilepsy, carbamazepine therapy and the subsequent onset of myasthenia gravis. This has not been previously reported in children. It is possible that our findings are a chance association. However, it may be considered necessary to include clinical myasthenic syndrome as a possible complication and part of the side effect profile of carbamazepine therapy.

References

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  • 5 Keesey J C. Does myasthenia gravis affect the brain?.  J Neurol Sci. 1999;  170 77-89
  • 6 Kwan S Y, Lin J H, Su M S. Co-existence of epilepsy, myasthenia gravis and psoriasis vulgaris.  Chin Med J. 2000;  63 153-157
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  • 8 Ronziere T, Auzou P, Ozsancak C, Magnier P, Senant J, Hannequin D. Myasthenic syndrome induced by lithium.  Presse Med. 2000;  29 1043-1044

Dr. Mary D. King

Department of Paediatric Neurology, The Children's University Hospital

Temple Street

Dublin

Ireland

Email: mary.king@tsch.ie