First-Ever Case Report Highlights Potential for Acute Retinal Necrosis While on Dimethyl Fumarate

Claire M. Rice, PhD, FRCP

A recently published case study described the story of a 44-year-old man on dimethyl fumarate (DMF; Tecfidera; Biogen) with relapsing-remitting multiple sclerosis who developed acute retinal necrosis (ARN) due to varicella zoster virus (VZV) infection while on treatment. Investigators concluded that this specific instance highlights the importance of considering causes other than optic neuritis (ON) for reduced visual acuity in patients with MS.¹

The 44-year-old man, a non-smoker with a history of cluster headache, presented to the emergency ophthalmology service with left conjunctival injection, mild eye pain, and impaired vision. At the time, the patient’s Expanded Disability Status Scale (EDSS) score was 4.5, with no new inflammatory changes on MR head scan despite being on DMF for the preceding 6 years.

At initial ophthalmaologic assessment, sub-retinal fluid of uncertain cause was observed at the left macula. One week later, he re-presented with worsening photophobia, ocular discomfort, and declining vision. Visual acuity measured 47 letters (ETDRS; 0.76 LogMAR; ~6/36 Snellen) in the left eye and 85 letters (0 LogMAR; 6/6 Snellen) in the right. Examination revealed left-sided panuveitis with retinal arteritis, venulitis, and multifocal retinitis consistent with ARN.

Study authors, including senior investigator Claire M. Rice, PhD, FRCP, an associate professor in neuroinflammation at the University of Bristol, noted that this was the first reported case of ARN in a young person on DMF. Prior to this case study, it was known that DMF can deplete T-cells, particularly CD8+ cells, with 4 previously documented cases of severe herpes zoster while on the drug.

"The absence of a relative afferent pupillary defect or color vision deficit should prompt careful ophthalmological assessment, and the features of retinal vasculitis, retinitis and vitritis should lead to consideration of an infective etiology,” Rice et al wrote.¹ "While an episode of ON typically features pain on eye movement, ocular pain associated with anterior uveitis is usually accompanied by conjunctival injection and photophobia, and these features should highlight the likelihood of an alternative diagnosis."

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The patient’s lymphocyte count, which had occasionally been low during DMF therapy (nadir 0.7 x 109/L) was within normal limits at presentation. Screening for HIV, syphilis, and tuberculosis was negative, while vitreous PCR confirmed VZV. Management for the condition included cyclopentolate and prednisolone acetate eye drops, initiation of oral valaciclovir with intravitreal foscarnet, and oral prednisolone 60 mg added 48 hours after starting antiviral therapy.

Ultimately, DMF was discontinued, and by 6 weeks, left-side visual acuity had improved to 77 letters (0.16 LogMAR; ~6/9 Snellen). In addition, investigators observed complete resolution of sub-retinal fluid and intraocular inflammation, and near resolution of an inferonasal retinal hemorrhage.

Prior to this case study, a 2023 study published in the Multiple Sclerosis Journal showed that increased CD4+:CD8+ ratios were associated with herpes zoster in patients treated with DMF. Overall, 18 patients developed herpes zoster while on DMF, with linear mixed-effects models demonstrating a significant difference in CD4+:CD8+ ratio between the herpes zoster and non-herpes zoster groups (P = .033). Notably, the study found that this ratio decreased over time in the herpes zoster group and increased over time in the non-herpes zoster group.²

REFERENCES
1. Paisey C, Curtin K, Epps SJ, Rice CM. Acute retinal necrosis associated with dimethyl fumarate. Published online May 4, 2025. doi:10.1177/13524585251326475
2. Balshi A, Saart E, Pandeya S, Dempsey J, Baber U, Sloane JA. High CD4+:CD8+ ratios with herpes zoster infections in patients with multiple sclerosis on dimethyl fumarate. Mult Scler. 2023;29(11-12):1465-1470. doi:10.1177/13524585231189641.