Severe Raynaud’s phenomenon from ethosuximide raised concern over possible onset of systemic vasculitis: a case report

Raynaud’s phenomenon is a multifactorial vasospastic disorder characterized by a transient, recurrent, and reversible constriction of peripheral blood vessels. Different forms of Raynaud’s phenomenon (RP) may sometimes be hard to differentiate. Primary RP (i.e., Raynaud’s disease) should be distinguished from secondary Raynaud’s phenomenon (i.e., Raynaud’s syndrome), as long-term morbidity differs greatly between the two conditions [1]. Secondary RP is associated with an underlying disease.

In pediatric rheumatology, RP may occur in various inflammatory systemic diseases, but a more severe presentation is most commonly part of a mixed connective tissue disease or juvenile systemic scleroderma.

One of the drugs occasionally suspected of causing adverse events mimicking a vasculitis-like disease is ethosuximide. Ethosuximide is still the first-line treatment for absence epilepsy that develops during childhood [2]. Together with carbamazepine, phenytoin, primidone, and phenobarbital, it is one of the older anti-epileptic drugs still in use.

Adverse events in ethosuximide treatment have mostly been associated with nausea, vomiting, and behavioral/psychiatric changes [2], but idiosyncratic side effects, such as lupus-like reactions and vasculitis, have also been reported [3‐6], although a severe Raynaud’s phenomenon leading to a series of iloprost infusions and concomitant occurrence of anti-Scl-70 antibodies has not been described previously.

We present the case of a girl born to unrelated parents. The father suffered from febrile seizures during childhood and the mother had migraines and tension headaches. Beyond that, there was no medical history of any illness. The girl had a previous medical history of infectious asthma, viral croup, and treatment with tympanostomy tubes because of recurrent otitis media infections. She had no previous history of reactive circulation in fingers or toes. At the age of four years, she had been observed over night because of a suspect vasovagal reaction. At the age of twelve years, friends noticed that she had short periods of absence and she was referred for an electroencephalography (EEG). The EEG showed typical 3 Hz spike-slow wave configurations during photo stimulation and sleep and she was diagnosed with juvenile absence epilepsy (JAE) by a consultant at the pediatric neurology clinic. Treatment with ethosuximide, oral solution 50 mg/ml, was initiated. The starting dose was 7.5 mg/kg/day and the dose increase was halted at 15 mg/kg/day due to nausea, heartburn, and fatigue. Serum concentration was 378 µM (280–700 µM) and the patient was then seizure-free, attending school, and playing soccer. Three months after ethosuximide treatment was initiated and two months after the last dose adjustment, her fingers began to ache (primarily her middle fingers, digit III, bilaterally) and color changes were noticed in her fingers, which alternated between being white, blue, and normal-colored. Two weeks later, her fingertips were cold and had changed in color, her left digits II and III and right digits II–IV were blueish-black distal to the distal interphalangeal joints, Fig. 1. There was no extreme cold exposure or stressful episode prior to those symptoms and no symptoms of any infection. Her mother contacted the epilepsy nurse and the girl was admitted to hospital. Peripheral circulation was affected also in her toes, but to a much lesser extent and nailfold qualitative capillary microscopy was normal. There were no signs of edematous swelling of fingers or presence of inelastic skin, hyper- or hypopigmentation of the skin, joint contractures, or synovitis and no complaints of decreased esophageal motility or breathing problems. At admission, ANA was strongly positive with a pattern specific for anti-Scl-70 (AC-29; see www.​anapatterns.​org). Occurrence of specific anti-Scl-70/topoisomerase 1 antibodies was independently confirmed with three techniques: double immune diffusion, enzyme-linked immunosorbent assay, and line immunoassay. Anti-Scl-70 and the corresponding ANA pattern were still detected after almost four months. IgG -antibodies against nDNA, Sm, RNP, SSA/Ro52, SSA/Ro60, SSB, and Jo-1 were negative. Rheumatoid factor (IgM), proteinase 3 antineutrophil cytoplasmic antibodies, and myeloperoxidase antibodies were negative as were the antiphospholipid antibodies lupus anticoagulant, anti-cardiolipin and anti-beta-2 glycoprotein-1. The peripheral blood count was normal, but activated partial tromboplastine time (APTT) was increased to 50 s (ref 20–42 s) and increases in complement C3d and the C3d/C3 ratio were found, indicating possible complement activation. See Table 1 for detailed laboratory test results. There was suspicion of an unusual onset of juvenile systemic scleroderma, but also that the symptoms could be caused by ethosuximide. Treatment was stopped and changed to lamotrigine. Due to the severity of the symptoms, the girl received 1 mg/kg of prednisolone for seven days with tapering over four weeks.

Seven days after prednisolone treatment was initiated, the pain had started to decrease, but the fingers were still severely discolored. Doppler evaluation of the arterial blood flow in the fingers indicated reduced arterial blood flow in the distal phalanxes of the affected fingers. After discussion with an adult rheumatologist, a vascular surgeon, and a pediatric cardiologist, echocardiography of the heart was performed and found to be normal. Treatment with daily infusions with iloprost for five days was then initiated: 0.9 µg/kg for six hours. The discoloring and symptoms started to disappear, but infusions with iloprost were continued for another five days. Nifedipine 10 mg daily and acetylsalicylic acid 75 mg daily were added after the iloprost infusions. At this point, the severe effect on the digital circulation was considered to be a non-vasculitic vasculopathy, for which reason no more prednisolone was given after the first four weeks.

Approximately 3 weeks after admission, the discoloring and discomfort was very much improved, but the girl developed small ulcers on some of the affected fingertips. Those healed without complication within approximately 2.5 months. Upon evaluation 5 months after the start of treatment, the girl was free of symptoms and sensory function in the hands was normal.

Acetylsalicylic acid was stopped after 4 months and nifedipine was stopped after approximately 6 months. After normalization of ANA, levels remained normal 2.5 years after onset of symptoms, with negative immunofluorescence and anti-Scl-70 undetectable using line immunoassay and addressable laser bead immunoassay on three different occasions. The girl did not have any other signs of systemic sclerosis or systemic lupus erythematosus (SLE).

Today, more than seven years after onset of symptoms, the girl has no signs or symptoms of any rheumatic disease. Her laboratory work-up were normal for another three years and no more blood analyses were performed after that.

Ethosuximide may cause severe Raynaud’s phenomenon with a transient increase in anti-Scl-70 antibodies.