Ethosuximide Induced Raynaud's Phenomenon in a Child With Childhood Absence Epilepsy

A 6-year-old boy presented to the clinic with his mother with concerns of multiple staring spells associated with upward eye rolling. During these episodes, there were no additional symptoms, such as clonic movements/automatism or urinary incontinence. A 20-minute EEG showed a typical 3-Hz spike-and-slow wave pattern lasting 3-6 seconds, associated with and without clinical symptoms consistent with a diagnosis of childhood absence epilepsy (CAE) (Figure 1). He was started on ethosuximide at a dose of 125 mg twice a day (13.4 mg/kg/d) for 5 days with a plan to increase to 250 mg twice a day (26.7 mg/kg/d). On the third day of ethosuximide treatment, the child complained of swollen and painful legs. Mother noticed his feet were cold and had a frigid sensation in his soles, whereas the legs showed a patchy, white discoloration. She immediately contacted the epilepsy nursing team with pictures of his lower extremities. On closer review, there were well-defined margins on his bilateral toes up to the level of metatarsals, indicative of Raynaud phenomenon (Figure 2A). Ethosuximide was immediately discontinued. The patchy discoloration resolved within 2 days without any intervention, monitored and confirmed with serial home pictures (Figure 2B). Mother denied any instance of stress, trauma, or cold exposure on the previous days. He was exposed to no new medications recently, and ethosuximide was his only medication. There was no familial history of autoimmune conditions.

OPEN IN VIEWER

Figure 1.

Bipolar montage electroencephalography (EEG) with 5 chains, showing a 15-second page during hyperventilation (Sensitivity 30 μv, High Frequency filter(HF) 70 Hz, Time Constant(TC) 0.1 s, Calibration bar 150 μV). The child paused briefly during the first burst of 3-Hz spike-and-wave discharges (blue bracket).

OPEN IN VIEWER

Figure 2.

Mobile phone pictures of feet during ethosuximide (ETX) therapy: (A) Patchy white discoloration (indicated by the blue arrow) on the feet, extending up to the level of the metatarsals. (B) Photograph taken 2 days after cessation of ETX, showing nearly complete resolution of symptom (indicated by the yellow arrow).

Ethosuximide has been widely accepted as a first-line treatment for CAE, with various clinical trials and studies affirming its efficacy. ¹ Ethosuximide had been reported to cause rare idiosyncratic reactions such as lupus like syndrome; however, the most common adverse reactions are nausea/vomiting, asthenia, dizziness, and behavioral changes.^1,2 The pathogenesis of absence epilepsy is hypothesized to be due to tonic and burst firing of synchronized oscillations in thalamo-cortico-thalamic loops. Ethosuximide, a succinimide agent, reduces this threshold by inhibiting T-type calcium channel. ² Ethosuximide, like other antiseizure medications may cause idiosyncratic reactions, by forming reactive metabolite during phase 1 and 2 drug metabolism. These metabolites covalently bind to macromolecules, triggering immune responses. ³ Although antiseizure medications are not inherently immunogenic because of their low molecular weight, binding to a macromolecular carrier can elicit an immune response. ³

Our index case provides confirmation that Raynaud phenomenon can be induced by ethosuximide. The pathophysiology of Raynaud phenomenon is still poorly understood and is often multifactorial with an intermix between vascular, neural, and genetic factors. Drug-induced Raynaud phenomenon depends on the offending medication and is often due to endothelial dysfunction, neurotoxicity, and alteration in monoamine neuro-transmission. ⁴ The primary goal in the treatment of Raynaud phenomenon involves limiting vasoconstriction, augmenting vasodilation and providing supportive measures (such as avoiding cold exposure, smoking cessation, and warm dressing). If Raynaud phenomenon progresses to ischemia or digital ulceration, acute intervention like steroid, prostanoid therapy (iloprost), and immunosuppressants may be required. ⁵ In drug-induced Raynaud phenomenon, the offending medication must be identified and discontinued immediately; treatment should be tailored based on the progression. ⁵ Raynaud phenomenon is a possible side effect of ethosuximide and may present within the first 3 days of initiation. Currently, Raynaud phenomenon is not included in the drug insert of ethosuximide.