Thiamazole-Associated Neuropathy

Dear Editor:

Thiamazole is the antithyroid drug of choice in the treatment of Graves' disease. Thiamazole is associated with major side effects such as agranulocytosis, Stevens–Johnson syndrome, and vasculitis, occurring in 1% of children. Minor side effects, reported in up to 30% of children, include skin rashes and arthralgia, which are often self-limiting. The thiamazole drug label also lists peripheral neuropathy as a minor side effect. However, in large patient series, neuropathy is not reported, suggesting that it may be a very rare side effect. At the Department of Pediatric Endocrinology in Amsterdam, we see 5–10 newly diagnosed children with Graves' disease each year. In the last two years, we encountered three cases of neuropathy during thiamazole treatment.

Case 1: A 13-year-old girl presented with classic symptoms of hyperthyroidism and initial blood results consistent with Graves' disease (thyrotropin [TSH] 0.02 mIU/L, reference interval [RI] 0.4–4.0 mIU/L; free thyroxine (fT4) 75 pmol/L, RI 10–22 pmol/L; anti-TSH-receptor antibodies >20 IU/L, RI <1 IU/L). Treatment was started with thiamazole 0.5 mg/kg/day. Because of continuing complaints of hyperthyroidism and persisting high triiodothyronine (T3) levels (4.1 nmol/L, RI 1.3–2.7 nmol/L), thiamazole was gradually increased, and six months after initial presentation, she was using thiamazole 1 mg/kg/day and levothyroxine 137.5 μg/day. Ten months after diagnosis, while euthyroidism was achieved, she complained of a burning sensation in her hand palms and foot soles. Neurologic examination was normal. Nerve conduction studies were normal, but temperature threshold testing indicated small-fiber neuropathy. Blood analysis was negative for Lyme disease, celiac disease, diabetes mellitus, and autoimmune disease (anti-nuclear antibodies). Since neuropathy is a possible side effect of thiamazole and since the probability of long-term remission at this young age is low, the patient was counseled on other treatment options and underwent thyroidectomy. The burning suggestions disappeared within three weeks after surgery and discontinuation of thiamazole.

Case 2: A seven-year-old girl with Graves' disease (initial blood results TSH <0.06 mIU/L, fT4 100 pmol/L, anti-TSH-receptor antibodies 15 IU/L) was treated with thiamazole (0.4 mg/kg/day). Within a few weeks, she developed a tingling sensation in the palms of her hands and in her fingers. The symptoms persisted after euthyroidism had been achieved. The neurologist suspected paresthesia due to peripheral neuropathy, probably associated with thiamazole use. Thyroidectomy was performed (six months after initial Graves' diagnosis), and the complaints resolved within three weeks after surgery.

Case 3: A boy with Down syndrome developed Graves' disease at the age of 14 years (TSH 0.005 mIU/L, fT4 25 pmol/l, anti-TSH-receptor antibodies 27.7 IU/L). He was treated with thiamazole 0.4 mg/kg + levothyroxine 137 μg. After three years on treatment, and during persisting euthyroidism, he complained of a painful sensation in palms of his hands and the soles of his feet. Thiamazole-associated small-fiber neuropathy was suspected, and alternative treatment options were discussed. Thyroidectomy was performed, and within three weeks after surgery, the neuropathy complaints disappeared.

Very few cases of thiamazole-associated neuropathy have been reported, dating back to the 1950s to the 1980s (1 –4). Although in our cases a causal relationship between the complaints suggestive of neuropathy and thiamazole is not definitely demonstrated, the association seems very plausible because (i) the patients were not using any other drugs, (ii) neuropathy developed after starting thiamazole therapy, (iii) neuropathy persisted after euthyroidism was achieved, and (iv) neuropathy resolved soon after surgery and discontinuation of thiamazole therapy. Drug-induced neuropathy usually improves after cessation of treatment, but residual deficits can remain. Here, we describe three children with Graves' disease with complaints suggestive of small-fiber peripheral neuropathy associated with thiamazole treatment, suggesting that this side effect may be more common than previously reported.