Extensive bilateral lower extremity deep venous thrombosis in a patient on dimethyl fumarate
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- Ratchford, E.V., Baldanza, J.T. & Pardo, C.A. J Neurol (2014) 261: 831. doi:10.1007/s00415-014-7288-9
Dimethyl fumarate (Tecfidera; BG-12) is the third oral disease-modifying therapy for multiple sclerosis (MS) approved in the U.S. After only a month on the market, 53 % of surveyed U.S. neurologists reported prescribing dimethyl fumarate to at least one of their MS patients . We report a case of extensive bilateral lower extremity deep vein thrombosis (DVTs) in a patient recently started on dimethyl fumarate.
An active 45-year-old man was diagnosed with MS in April of 2013. His initial symptom was numbness in the right foot which began during a ski trip in February. Over 2 months, the symptoms progressed to include weakness and tingling in the affected foot, gait impairment, and severe fatigue. His neurological work-up demonstrated demyelination in the spinal cord and centrum semiovale. Cerebrospinal fluid analysis showed a pattern 2 of oligoclonal bands and increased IgG index. He was initially treated with intravenous methylprednisolone followed by a prednisone taper, along with physical therapy. His symptoms improved. Skin exam revealed melanoma in situ which was successfully excised. He received a second course of intravenous methylprednisolone for left arm paresthesias. His gait completely normalized; he was able to bike 12 miles, and he exercised 5 days per week. Given the aggressive nature of his presentation (both clinically and by neuroimaging), the initial plan was to treat him with natalizumab, but he tested positive for anti-JCV antibodies. Thus, he was started on dimethyl fumarate. On Day 1, he had some flushing and arm itching; otherwise, the first week of treatment at 120 mg twice daily was unremarkable. He continued to exercise regularly. On Day 8, the dose was increased to 240 mg twice daily. On Day 12, he developed progressive nausea, vomiting, diarrhea, and fever. By his report, he lost 15 pounds over 3 weeks. The dose was decreased as the fever was thought to be a drug reaction; aspirin and antacids were prescribed, but the fever persisted. He developed bilateral discomfort in the medial thighs on Day 19. He had worsening leg pains, difficulty walking, and fever up to 102.8 F. White blood cell count was 17.09 K/cu mm with 7.6 % eosinophils (normal range 1–4 %); his metabolic panel was normal. He discontinued dimethyl fumarate on Day 22. His right ankle became slightly swollen, prompting a lower extremity venous ultrasound on Day 24 which revealed extensive bilateral DVTs extending from the calf veins to the origin of the deep femoral veins. His symptoms gradually abated after anticoagulation. His only risk factor for deep venous thrombosis (DVT) was a body mass index of 30.6. He was physically active, did not smoke, and had no recent surgeries, hormone exposure, plane travel, or family history of thrombosis.
Two large phase III trials involving a total of >2,400 patients showed dimethyl fumarate significantly reduces relapses and development of new MRI lesions in patients with relapsing forms of MS. The CONFIRM trial was a randomized, multicenter, double-blind, 2-year study evaluating the efficacy and safety of BG-12 versus placebo. Adverse events reported more frequently with BG-12 than with placebo included flushing, gastrointestinal side effects, upper respiratory tract infections, and erythema . In the DEFINE study published simultaneously, adverse events seen more frequently with BG-12 included flushing, gastrointestinal events, proteinuria, and pruritus . In an earlier phase IIb trial, patients were randomly assigned to BG-12 either 120 mg once daily (n = 64), 120 mg three times daily (n = 64), 240 mg three times daily (n = 64), or placebo (n = 65) . Adverse events more common in patients receiving BG-12 240 mg three times daily compared to placebo included abdominal pain and flushing. One phlebitis event was reported in the 120 mg three times daily group. Otherwise, to our knowledge no other thrombotic events have been reported. A transient eosinophilia during the first 2 months of therapy is common according to the Tecfidera prescribing information .
This newly approved medication for MS holds significant promise as a safe and effective oral MS treatment option. The main side effects are gastrointestinal symptoms, and it has not been linked to thrombosis. Since its approval, one death has been reported, in a 59-year-old woman 2 weeks after she stopped dimethyl fumarate due to gastrointestinal side effects. In the present case, several factors may have predisposed the patient to DVT including dehydration, fever, and systemic inflammation. In conclusion, clinicians should be aware of the possible (but not yet proven) association between dimethyl fumarate and venous thrombosis, particularly among patients who experience severe gastrointestinal side effects, dehydration, or fever.
Conflicts of interest
Dr. Ratchford’s spouse has consulted for Biogen-Idec, CDMI, Diogenix, and Genzyme, and receives research funding for clinical trials from Biogen-Idec, Novartis, and Sun Pharmaceuticals. J. Todd Baldanza: none. Dr. Pardo receives research funding from Project Restore and The Bart McLean Fund for Neuroimmunology Research.