Ocular adverse events from pharmacological treatment in patients with multiple sclerosis—A systematic review of the literature

Five studies from Germany, USA, and the United Kingdom (UK) referred to TEAEs when using alemtuzumab, of which three reported the development of thyroid eye disease (TED) [53, 59, 61].

One of the studies was a case series extracted from two clinical trials (CARE-MS1 and CARE-MS2) where five patients developed Graves’ disease (GD), but only two patients had TED [59]. According to Trinh et al [53], there was a female patient who developed bilateral ocular hyperemia, photophobia, proptosis, and upper eyelid retraction, consistent with TED, after three years of treatment [53]. A similar study from the UK reported 10 patients of 162 with GD, but only six patients presented TED, with a period of 26 months, 20 months, four years, 10 months, four years, and 48 months after the last infusion of alemtuzumab, respectively [61].

In a cross-sectional study conducted by Tuohy et al, thyroid autoimmunity developed in 35/87 patients (40.2%) of whom 22/35 (63%) had hyperthyroidism. Although the study reported GD, it was not clear whether the patients had any ophthalmological manifestation. Two patients in that study developed Herpes zoster ophthalmicus [70]. In another study, the use of alemtuzumab was related to thyroid gland autoimmunity (35%), but no TED was reported, and 1% of the patients presented conjunctivitis; however, the study did not specify the etiology of conjunctival inflammation [72].

We found two case reports from the USA that described four cases of bilateral corneal edema as a TEAE related to amantadine used for managing tremor and fatigue in patients with MS [30, 35]. The duration of amantadine treatment before the onset of symptoms in all cases ranged from two months to six years, and the range of corneal thickening was 677 μm to >1000 μm [30, 35]. In two cases, the corneal edema resolved approximately one month after amantadine was suspended [30, 35]; in one case, the corneal edema resolved two months after amantadine suspension [35]; and in one case, the corneal edema required management with bilateral penetrating keratoplasty [35].

A total of 25 studies reported ocular TEAEs in patients treated with fingolimod. Of these studies, 18 were case reports, mostly from the USA, Australia, Spain, and Germany; two were experimental studies, both multicentric; and five were cross-sectional studies, one from Canada, one from Italy, one from the USA, and two were multicentric.

Macular edema was reported in 21 studies [9, 10, 20‐22, 27, 33, 34, 37, 41, 44, 48, 52, 54, 55, 57, 58, 63, 64, 67, 73]; five were classified as cystoid macular edema [20, 22, 33, 44], and one study reported associated retinal hemorrhages [55]. One study described that the symptoms entirely resolved after the discontinuation of medication; when the medication was restarted after two months, the symptomatology reappeared [57]. One patient had macular edema and retinal branch vein occlusion [73], and one patient had macular hemorrhage [24]. In one case report, fingolimod was not withdrawn, and topical nepafenac was used, which improved the macular edema [58]. Of the remaining three studies, one [26] reported conjunctival lymphoma, one reported retinal branch vein occlusion [32], and one described uveitis complicated with macular edema. In the last study, the authors inferred that the TEAE could not be exclusively attributed to fingolimod because uveitis can by itself cause macular edema [76].

We found two case reports that described acute retinal necrosis as a TEAE after high-dose steroid treatment for relapsing-remitting multiple sclerosis (RRMS), one from Turkey and the other from the USA [45, 49]. In the first report, the patient received an IV steroid pulse of 1000 mg/day for three days and was continued with 10 mg of daily prednisolone. After two months, the visual symptoms started and the diagnosis of acute retinal necrosis caused by the Varicella-zoster virus was made [45]. In the other case report, the patient received three courses of high-dose methylprednisolone (1000 mg/day for three days) for recurrent relapses five months before the presentation of visual symptoms. The diagnosis of Herpes simplex virus type 2 infection was made [49].

This immunoglobulin was used in a Phase 1 clinical trial conducted on 20 patients with RRMS from the USA, which evaluated its safety and tolerability in different doses. This study reported, a visual field defect in one patient receiving a 2 mg/kg dose of the drug within the first 24 h of infusion. During the long-term follow-up, 10% of the enrolled patients had blurred vision [17].

A Phase 2 clinical trial conducted on patients with RRMS from 16 academic neurology clinics in the USA, evaluating the effect of estriol treatment in the reduction of MS relapses in women, reported TEAEs within 24 months of treatment. There were six events of visual defects (blurred vision or diplopia) reported in four patients receiving estriol compared to seven of the same visual defects reported in seven placebo patients [16].

Our review included 21 studies that involved TEAEs after INF therapy, mostly in patients with RRMS.

There were 13 case reports, mostly from Europe (n = 7), USA (n = 2), Japan (n = 2), Canada (n = 1), and Israel (n = 1). Most of the patients were women (n = 8). Patients’ age ranged from 30 to 58 years. The majority of them complained about symptoms after 11 months since the initiation of the treatment. The TEAEs reported in these patients included unilateral/bilateral asymptomatic retinopathy (peripheral intraretinal hemorrhages and cotton wool spots), unilateral/bilateral symptomatic retinopathy (blurred vision, progressive visual field loss, and peripheral telangiectasia), central vein and arterial branch occlusions, Sicca syndrome, and recurrent idiopathic orbital inflammation [23, 28, 29, 31, 36, 39, 40, 42, 43, 46, 47, 50, 51].

One study was a case series that reported three patients with neuroretinitis after INF β therapy, of whom two had been undergoing INF therapy for around a year before the symptoms appeared, the other patient presented with a macular star exudate on funduscopic examination concurrently with the initiation of treatment [60].

There were five cross-sectional studies (one each from Japan, the USA, Canada, Croatia, and Italy). Makioka et al. reported only one case of retinopathy in a postmarketing drug surveillance study for INFβ-1a intramuscular injection in Japan, among a sample of 1441 patients [66]. Smith et al. conducted a postmarketing safety profile study in adult patients with MS with a prescription of INFβ-1a SC three times a week between 2006 and 2012. Some of the patients complained about abnormal vision and xerophthalmia. There were reports of retinal artery or vein obstructions and retinopathy [69]. Tremlett et al. summarized the reported TEAEs for 10 years in Canada in the adult and children population. A 43-year-old female patient presented with papilledema and visual disturbance related to malignant neoplasm aggravation and resulted in death [8]. Liscić et al. evaluated pattern-reversal visual evoked potentials (VEP) in patients with RRMS on INFβ-1a treatment (n = 9 patients, 18 eyes). Those with previous optic neuritis (n = 3 patients, 3 eyes) exhibited visual evoked potential impairment with a delay in P100 latency before treatment. Moreover, some patients (n = 2 patients, 3 eyes) without previous impairment exhibited increased P100 latency after INF therapy. It is not clear whether this impairment is due to INF therapy or MS itself [65]. A multicentric pharmacovigilance study conducted to analyze 10 drugs used for MS treatment over a period of 24 months recorded 411 adverse reactions. Approximately 42% of the TEAEs were due to INF, from which approximately 9% were unexpected, and 5.8% were severe events. Two patients presented ophthalmological manifestations. The first patient, associated with peginterferon-β-1a, with  previous use of dimethyl fumarate, presented mild-moderate eyelid edema. The second patient, associated with glatiramer acetate, with  previous use of INFβ-1a, presented moderate-severe visual field defect, which resolved within a day [74].

Finally, we included two experimental studies. The first one was a double-blind RCT evaluating the comparative efficacy and safety of two different trademarks of INFβ-1a in patients with RRMS conducted by Pakdaman et al. It included 182 participants, of whom 89 received trademark A and 93 trademark B. Regarding TEAEs, 3.4% of participants receiving trademark A and 1.1% receiving trademark B reported visual disturbances [18]. The second study was a multicentric, randomized Phase 3 clinical trial conducted by Comi et al. The aim was to evaluate the safety and efficacy of ozanimod compared with INFβ-1a in patients with RRMS. It enrolled 1346 participants, of whom 447 received 1 mg of ozanimod, 451 received 0.5 mg of ozanimod, and 448 received INFβ-1a. One participant in each treatment group reported a TEAE. The patient in the INFβ-1a group presented macular edema [77].

We found four articles regarding natalizumab [13, 25, 56, 62], including two case reports (one from the USA and the other from Switzerland), one cross-sectional study (from Sweden), and one RCT (from Japan).

Of the two case reports, one [25] reported a case of progressive multifocal leukoencephalopathy (PML) associated with John Cunningham virus (JVC) that started with a subacute onset of bilateral blindness after the 44th dose of natalizumab. The second study reported the first published case of ocular toxoplasmosis reactivation during natalizumab treatment [56].

A web-based MS registry cross-sectional Swedish national postmarketing surveillance study reported 19 patients with TEAEs related to ocular inflammation, herpes simplex, herpes zoster, urinary tract infection, enterovirus meningitis, increased infection susceptibility, and hepatitis C infection. However, the study did not clarify how many of the 19 patients presented the eye compromise. Furthermore, the study reported three cases of PML that occurred during these trial periods, including two cases in the open-label extension phase of the SENTINEL trial and one case in a clinical trial for Crohn’s disease [78, 79]. There was no information regarding the visual compromise in the follow-up of patients who developed PML [62].

The RCT reported a patient with retinal detachment 75 d after the first dose of natalizumab [13].

Of the 62 included articles, only one case report published in 1986 described TEAE due to hyperbaric oxygen in a patient with MS who presented slow-recovering central bilateral scotoma [63].

One case of ocular inflammation as a TEAE was found after the initiation of treatment, which was reported at the German Registry of autoimmune diseases (GRAID) in a multicentric retrospective study. The time between treatment onset and the TEAE was not determined [68].

We found two studies regarding siponimod. One was a multicentric Phase 2 clinical trial conducted on patients with RRMS from 73 specialized MS centers in Canada, the USA, Russia, and nine European countries, wherein the patients were divided into cohort 1 (n = 188) and cohort 2 (n = 109). It reported that one patient with a history of uveitis presented macular edema with the highest dose of the drug (10 mg), and one patient presented optic neuritis with 0.5-mg dose of the drug [14]. The second study was a Phase 3 clinical trial conducted on patients with secondary progressive multiple sclerosis (SPMS) from 292 hospitals, clinics, and specialized MS centers in 31 countries. It reported that 2% (n = 18) of patients receiving siponimod presented macular edema compared to <1% (n = 1) of those receiving placebo [12].

In an experimental study conducted on patients with RRMS from different countries of America, Europe, and Africa, 324 patients were divided into the following three treatment groups: INFβ-1a (n = 104), teriflunomide 7 mg (n = 109), and teriflunomide 14 mg (n = 111). The second group was treated for 66.6 weeks, and the third group was treated for 64.2 weeks. The ocular TEAEs reported were optic neuritis, macular edema, and ischemic optic neuropathy in the second group of patients who received 7 mg of teriflunomide. No ocular TEAEs were observed in groups 1 and 3 [15].

We found an experimental study that evaluated the safety of tovaxin for 24 weeks in patients with RRMS from 30 to 40 different sites in the USA. Neither deaths nor discontinuations due to safety reasons were reported in that study. Diplopia was the only reported ocular event, and it was considered as a major reaction because of the necessity of in-hospital attention of the patient, but not because of the event itself. The authors did not consider this reaction as secondary to the drug and evaluated tovaxin as a safe treatment for the course of 24 weeks [11].