Skip to main content
  • Systematic review update
  • Open access
  • Published:

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



The aim of this study was to review the scientific evidence and describe the ocular treatment-emergent adverse events (TEAEs) related to pharmacological treatment in patients with multiple sclerosis.


A systematic review of literature was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines in the MEDLINE, LILACS, EMBASE, and COCHRANE databases. Articles were filtered based on title and abstract considering the selection criteria and subsequently filtered by full-text reading. The resulting articles were evaluated using the Joanna Briggs Institute Quality Tools. Study characteristics and results were extracted and presented in structured tables to conduct a narrative synthesis.


A total of 2852 published articles were extracted using our strategy. After removing duplicates, 2841 articles were screened based on title and abstract, 102 articles were evaluated using quality tools, and 69 articles were filtered by full-text reading. Through this search strategy, 60 articles met all the inclusion criteria and seven articles, through a search update conducted in the same manner, were included. This resulted in 67 articles meeting the inclusion criteria, of which 11 were experimental and 56 were observational. The therapies related to ocular TEAEs were alemtuzumab, amantadine, fingolimod, steroids, CTLA-4 Ig, estriol, interferon β, natalizumab, hyperbaric oxygen, rituximab, siponimod, teriflunomide, and tovaxin. Fingolimod and siponimod were commonly associated with macular edema, interferon β was associated with retinopathy, alemtuzumab was associated with thyroid eye disease, amantadine was associated with corneal edema, and steroids were associated with acute retinal necrosis. Opportunistic infections were also found, and there was one life-threatening case.


Our search revealed different methodological assessments of the topic. However, longitudinal studies regarding ocular TEAEs related to multiple sclerosis therapy are necessary to provide evidence-based recommendations, especially in understudied regions such as Latin America and Africa. Physicians should monitor ocular symptoms in patients being treated for multiple sclerosis and consider an interdisciplinary approach.

Systematic review registration

PROSPERO ID CRD42020106886

Peer Review reports

Key points

  • This study was conducted to review the scientific evidence and describe the ocular TEAEs related to pharmacological treatment in patients with multiple sclerosis to provide a theoretical basis and quality literature for ophthalmology specialists, neurologists, and general practitioners, which could help them in making appropriate clinical decisions.

  • Patients under fingolimod and interferon β treatment showed a higher frequency of TEAEs. Alemtuzumab was associated with an autoimmune response that manifested as thyroid eye disease.

  • We recommend physicians to be cautious when treating patients with multiple sclerosis and monitor the ocular symptoms that patients may present. An interdisciplinary approach might be considered to evaluate the patient’s requirements.


Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease with variable clinical, radiological, and pathological characteristics. Since its first description by Charcot, there have been significant efforts to clarify its pathophysiology and progression and determine the best strategies for appropriate management [1]. Currently, the therapy for MS comprises corticosteroids, immunosuppressants, and immunomodulators such as interferon (INF) and monoclonal antibodies. Although several cases of patients with ocular TEAEs have been reported over the years, there is a lack of clear understanding of the TEAEs that are strictly related to the disease and linked only to therapy [2].

Ocular manifestations in patients with MS are not rare and have been described as a major aspect of the disease. Any structure related to visual pathways could be involved in MS, and up to 20% of patients would display optic neuritis as an initial clinical manifestation. Visual field and color vision defects, relative afferent pupillary defect, and other ophthalmological findings could also be present [3].

According to the World Health Organization (WHO), the definition of drug-related adverse events corresponds to an involuntary harmful response to a medication used in a normal dose for a prophylactic, diagnostic, or therapeutic purpose [4, 5]. However, it is necessary to consider that this harmful response, irrespective of how minor it is, must be explained to the patient before initiating any medication to predict, prevent, or treat any possible future event and avoid poor adherence to treatment [5]. Some of the TEAEs that have been described as related to therapy in MS are cataract, glaucoma, chorioretinopathy, visual acuity reduction, macular edema, retinopathy, among others [2].

The aim of this study was to review the scientific evidence and describe the ocular TEAEs related to pharmacological treatment in patients with MS to provide a theoretical basis and quality literature for ophthalmology specialists, neurologists, and general practitioners, which could help them in making appropriate clinical decisions.


This review was written according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) extension statement for reporting systematic reviews. The protocol registration can be found under the PROSPERO ID CRD42020106886.

Study design

A systematic literature review focusing on ocular TEAEs in MS therapy was conducted using the MEDLINE, LILACS, EMBASE, and COCHRANE databases for articles published till November 2018. The search was updated on May 4, 2020. MEDLINE and COCHRANE databases were searched using Medical Subject Headings terms, EMBASE was searched using emtree terms, and LILACS was searched using Descriptores en Ciencias de la Salud terms, using boolean operators, as evidenced in Annex 1. We limited the search only to human studies, although no limits regarding language and period of publication were used.

Study selection

An initial search was conducted by JMO, JRG, LMM, and JARH, based on which a review was prepared to eliminate duplicates. Eligible studies were selected by screening the title and abstract by at least two reviewers independently, and discrepancies were resolved by an expert evaluator (ADLT). A study was included if (a) the abstract was available, (b) it contained original data, (c) the diagnosis of MS was made by a specialist, (d) the individual was being treated for MS, and (e) the ocular manifestations appeared after the initiation of MS treatment. Experimental and observational studies were also included. Articles were excluded from the analysis if they did not provide information regarding ocular TEAEs in individuals undergoing MS therapy.

The full texts of the selected articles were retrieved and classified according to the type of article/study by at least two reviewers independently, and discrepancies were resolved by an expert evaluator (MGS). They were then evaluated using the Joanna Briggs Institute Quality Tools (JBIQT). If an article was not available, contact with the author was made. The cascade of article selection was managed using the PRISMA flowchart [6]. The following information was extracted from the selected articles: study period, location, number of patients, type of medication, and ocular TEAEs. A dataset was constructed using the information mentioned ahead.

Data synthesis and presentation of results

Microsoft Excel (Microsoft Corp., Redmond, WA, USA) was used as a synthesis tool to organize the results of the search strategy and the information of the articles. The first sheet contained information about the initial search results without duplicates. The next six sheets were asigned to three pairs of authors (LMM vs JARH, WRC vs JRG, and JMO vs LOTG) to filter titles and abstracts in a peered manner. A color code was used to select the articles as follows: green to include, yellow to revise, and red to exclude. The next three sheets were used to evaluate concordance for each pair of authors. The subsequent sheet was used by the expert reviewer (ADLT) to resolve discrepancies from the peered review. An additional sheet was used to classify the methodological design of the studies and record JBIQT grades and the reasons for exclusion. The next sheet was used to record articles included after full-text reading. The final sheet included information regarding ID number, authors, year of application of the study, year of publication, journal, location, title, aim, sample size, population (gender and group characteristics), methodological design, MS type, therapy, time of presentation of TEAEs, symptoms after therapy suspension, statistical analysis, important details from results, important details from discussion, and observations. The same synthesis tool was used for the search strategy update. The extracted data were synthetized in tables and figures to present them in an organized manner throughout the article.

Risk of bias

We retrieved and classified the articles based on study design to evaluate their methodological quality using their respective JBIQT [7]. Each quality tool has a set of questions that are evaluated as yes, no, unclear, or not applicable domains. An expert in epidemiology (MGS) established a minimum cut-off point as the number of items on the tool marked as “Yes,” including the major and minor criteria. Case reports with 5/8 items on the checklist were included; for case series, the minimum cut-off point was 6/10 items; for cross-sectional studies, it was 6/8; for randomized controlled trials (RCTs), it was 10/13; and for nonrandomized experimental studies, it was 6/9 (see Annex 2 for supplementary information).


General description

We extracted 2852 published articles (1756 from MEDLINE, 1093 from EMBASE, three from COCHRANE, and none from LILACS). After removing duplicates, 2841 articles were screened based on title and abstract, and 102 articles were evaluated using JBIQT. After quality evaluation, 33 articles were excluded, and 69 full-text articles were assessed for eligibility. Sixty articles met all the inclusion criteria. Figure 1 shows further detailed information regarding the inclusion of articles.

Fig. 1
figure 1

PRISMA flowchart

The search was updated on May 04, 2020, extracting 202 published articles (117 from MEDLINE, 85 from EMBASE, none from COCHRANE, and none from LILACS). After removing duplicates, 196 articles were screened based on title and abstract. A total of 11 articles were evaluated using JBIQT. After quality evaluation, two articles were discarded, and nine full-text articles were assessed for eligibility. Finally, after discarding two articles, as no ocular TEAEs were reported, seven articles met all the inclusion criteria (Fig. 1).


Our final inclusion strategy yielded 67 published articles, including 20 in the United States of America (USA), 24 in Europe (Germany, Spain, France, Italy, Wales, England, Switzerland, Croatia, and Sweden), three in Canada, three in Australia, nine in Asia (Japan, Israel, Iran, and Turkey), and eight were multicentric across continents.

All studies were published between 1987 and 2020. Most of the studies included only adults, but one retrospective cross-sectional study included adults and children [8]. Of the 67 studies, 38 were case reports, four were case series, 14 were cross-sectional studies, and 11 were experimental studies. Table 1 summarizes the characteristics of the studies included in the present systematic review.

Table 1 Characteristics of studies

Experimental studies

A total of 11 experimental studies were included [9,10,11,12,13,14,15,16,17,18,19], which were published between 2010 and 2019. Six were multicentric across continents, three were conducted in the USA, one was conducted in Japan, and one was conducted in Iran.

After JBIQT qualification, the average number of items marked “Yes” across the studies was 11/13 (range 10–13) for the RCTs, and one study was a nonrandomized controlled trial with 7/9 of the items marked “Yes.” Six studies had a sample size ≤400 patients.

Observational studies

We collected 56 observational studies, of which 38 were case reports [20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58], four were case series [59,60,61], and 14 were cross-sectional studies [8, 62,63,64,65,66,67,68,69,70,71,72,73,74,75]. These studies were published between 1987 and 2020. After JBIQT qualification, the average number of items marked “Yes” across the observational studies was 7/8 (range 6–8) for the cross-sectional studies, 7/8 (range 6-8) for case reports, and 9/10 (range 6-10) for case series.

Adverse events related to each therapy

TEAEs related to alemtuzumab

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].

TEAEs related to amantadine

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].

TEAEs related to fingolimod

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, 20,21,22, 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].

TEAEs related to steroids

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].

TEAEs related to CTLA-4 Ig

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].

TEAEs related to estriol

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].

TEAEs related to interferon β

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].

TEAEs related to natalizumab

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].

TEAEs related to hyperbaric oxygen

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].

TEAEs related to rituximab

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].

TEAEs related to siponimod

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].

TEAEs related to teriflunomide

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].

TEAEs related to tovaxin

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].


Methodological assessment of TEAEs

In 2016, PRISMA published an article about harm-reporting in systematic reviews, where terms such as adverse drug reaction, adverse effect, adverse event, complication, harm, side effect, and toxicity were discussed [80]. However, there exists a large heterogeneity when using these terms and reporting TEAEs. This represents a difficulty at the time of reading and interpreting articles about drug safety. Moreover, the diversity between the different analytic and data collection strategies, the different forms of presentation of TEAEs, and the variety among the study designs represented additional challenges in this systematic review.

Two available strategies should be used to record information about TEAEs, i.e., active monitoring, when an event is known or suspected to be associated with an intervention, and spontaneous monitoring for new or unexpected events [81]. Different methodological designs were included in this systematic review because active monitoring generally evaluates long-term TEAEs in RCTs and short-term TEAEs in large cohort studies or case-control studies [81], whereas spontaneous monitoring commonly describes TEAEs in case series and case reports. Each study included in this systematic review had to be carefully evaluated, because spontaneous reports may lead to underreporting and false positives, RCTs may not identify new events, observational studies may require a large sample size, and case reports may not be well documented and have a long-time elapse until publication [82].

Geographical distribution

Developed countries have a higher incidence of MS. As the populations in these countries have better access to healthcare and early treatment strategies, it is expected that most of the studies that evaluated adverse ophthalmological events - and adverse events in general - had been conducted in these countries. This is consistent with our results, which indicated that studies were largely conducted in Europe, North America, and Japan. A few case reports were described in Australia and Israel. Some multicentric studies included a couple of Asian countries apart from Japan as well. There were no reports of adverse events from other countries or regions, which may result in a poor understanding of the entire picture worldwide.

Pregnancy and hormones in MS

MS relapses are decreased during pregnancy (primarily during the third trimester) and influenced by sex hormones such as estriol [16]. One RCT demonstrated that estriol was related to visual defects (blurred or double vision); nonetheless, the same visual defects were reported in the placebo group. In clinically isolated syndromes, the incidence of some of the typical features such as visual acuity and color vision was reduced [83]; therefore, the findings might not be directly related to estriol-associated TEAEs. These manifestations have also been described in acute optic neuritis, in which patients described blurred vision [84]. Furthermore, optic neuritis was related to different MS treatments such as INFβ-1b, siponimod, and teriflunomide [14, 15, 85]. However, the resolution of TEAEs after medication withdrawal was not described.

Follow-up recommendations

Optic neuritis is one of the primary manifestations of MS; therefore, ophthalmological follow-up is mandatory in these patients. Complete ophthalmological examination with attention to the efferent visual system and ancillary studies such as VEP and optic nerve optical coherence tomography (OCT) should be available for these patients [86].

Based on the present study, fingolimod-related TEAEs were highly common. We suggest the following American Academy of Ophthalmology recommendations for patients with MS being treated with fingolimod published in October 2011: 1) A screening evaluation for pre-existing uveitis or macular or retinal vascular disease before starting, or within the first few weeks of starting fingolimod. 2) A single re-evaluation at 3–4 months of therapy. 3) Patients should be advised that the incidence of macular edema is low (~2/1000), but if there is a history of uveitis, the incidence may be as high as 20%. 4) Visual acuity check and a complete eye exam, including a dilated fundus exam, is a proper ophthalmic screening protocol. 5) Patients with abnormalities on the exam or unexplained decreased visual acuity might benefit from diagnostic imaging with macular OCT [87]. These recommendations are supported by the methodology used in the study conducted by Zarbin et al. in 2013, who reported differences in different times of evaluation of these patients [73].

Regarding the use of alemtuzumab in patients with MS and thyroid disease, it was reported that up to 22% of patients treated with alemtuzumab would develop GD [53]. In almost 90% of the cases, GD and Graves ophthalmopathy (GO) co-occur; nevertheless, GO can develop after up to 1 year from being diagnosed with GD [88]. Therefore, we suggest an annual check-up by ophthalmologists, neurologists, and endocrinologists. This follow-up is important to ensure that patients undergo timely ophthalmological treatment while simultaneously ensuring the continued success of alemtuzumab treatment in the management of MS [53, 59, 70].

In contrast, one of the studies on patients treated with alemtuzumab reported Herpes zoster ophthalmicus infection [70]. Previous trials have identified Herpes simplex virus and Varicella-zoster virus systemic opportunistic infections are among the most common infections in patients treated with alemtuzumab and recommended preventive measures, including antiherpetic prophylaxis [89].

Studies evaluating the presence of corneal edema secondary to the use of amantadine in patients with MS corresponded to case reports. Considering that corneal findings can occur from two months to six years after medication initiation, we recommend that the neurologist treating the patient be aware of the warning signs to immediately consult the ophthalmology specialist and prevent irreversible endothelial failure [30, 35].

Another study evaluated the presence of dry eye after the use of anticholinergics, based on which we recommend that the neurologist treating patients with MS must be aware of this TEAE. Although the symptoms should not be the reason to stop an efficient treatment, it is recommended to conduct an ophthalmological evaluation to treat dry eye [71].

The study that evaluated CTLA-4 Ig treatment in patients with MS demonstrated  blurred vision in 10% of the patients. However, the cause of blurred vision was not clear, and the spectrum of MS manifestations included blurred vision secondary to optic neuritis and uveitis. This is why further studies are required to evaluate the safety of this drug in patients with MS, assess whether the ocular compromise corresponds to a TEAE, and generate recommendations on this issue [17].

The clinical trial comparing estriol combined with glatiramer acetate and placebo for women with RRMS reported six blurry and double vision events after six months of follow-up. However, the study did not report the etiology of the visual problems, and hence it is not possible to know whether it corresponds to the natural course of the disease. Further studies are necessary to evaluate the safety of this medication [16].

Two case reports described acute retinal necrosis caused by HSV-2 and Varicella-zoster virus in patients undergoing high-dose steroid therapy [45, 49]. Therefore, we recommend a retina specialist evaluation for patients showing ocular symptoms such as floaters, blurred vision, and sudden vision loss after treatment with steroid pulses.

Patients undergoing INFβ-1a therapy showed multiple ocular TEAEs in a duration range of three months to 10 years (Table 1). Given the wide timeframe for the establishment of TEAEs, and that some of the pathologies may correspond to manifestations or associations of MS, we consider that the most appropriate recommendation for these patients is the evaluation by an ophthalmologist before starting treatment and at least once a year after the start of treatment.

We consider that there is insufficient information to provide screening recommendations regarding natalizumab, hyperbaric oxygen, rituximab, siponimod, teriflunomide, and tovaxin. Nevertheless, in the presence of any ocular symptoms, we strongly recommend an immediate evaluation by an ophthalmology specialist.

Table 2 shows the referral recommendations for each TEAE reported in this systematic review, based on our clinical experience. However, it is important to consider that each patient's case should be individualized, and disease guidelines should be followed.

Table 2 Referral recommendations for each TEAE


Considering that ophthalmological TEAEs are generally undermined in clinical trials, different methodological designs were included in this systematic review. In light of this, it is necessary to conduct longitudinal studies to provide evidence-based recommendations.

Despite the diverse geographical distribution of the studies, there were scarce data from Latin America and African countries. Therefore, we strongly encourage healthcare providers to conduct pilot studies in these regions.

We suggest that physicians perform a comprehensive interrogatory and evaluation for ocular signs and symptoms during the follow-up of patients receiving treatment for MS and refer when necessary. An interdisciplinary approach might be considered to evaluate the patient’s requirements.

Availability of data and materials

The datasets used and/or analyzed during the current study are available by the corresponding author on reasonable request.



Alejandra de-la-Torre


Descriptores en Ciencias de la Salud


Estefanía Zapata-Bravo


EMBASE subject headings


German Registry of Autoimmune Diseases


Graves’ disease


Graves ophthalmopathy


Herpes simplex virus




Juliana Muñoz-Ortiz


Juliana Reyes-Guanes


Juan Antonio Reyes-Hurtado


Joanna Briggs Institute Quality Tool


John Cunningham virus


Laura Mora-Muñoz


Luis Octavio Tierradentro-García


Literatura latinoamericana y del Caribe en Ciencias de la Salud


Multiple sclerosis


Medical Subject Headings


Marcela Gómez-Suarez


Magnetic Resonance Imaging


Preferred Reporting Items for Systematic Reviews and Meta-Analysis


Progressive multifocal leukoencephalopathy


Relapsing-remitting multiple sclerosis


Randomized controlled trials




Treatment-emergent adverse events


United States of America


United Kingdom


Visual evoked potentials


Varicella-zoster virus


William Rojas-Carabali


  1. Kantarci OH. Phases and phenotypes of multiple sclerosis. Continuum (Minneap Minn). 2019;25(3):636–54.

    Article  PubMed  Google Scholar 

  2. Heath G, Airody A, Gale RP. The ocular manifestations of drugs used to treat multiple sclerosis. Drugs. 2017;77(3):303–11.

    Article  PubMed  Google Scholar 

  3. Chen L, Gordon LK. Ocular manifestations of multiple sclerosis. Curr Opin Ophthalmol. 2005;16(5):315–20.

    Article  PubMed  Google Scholar 

  4. Safety Monitoring of Medicinal Products. Guidelines for setting up and running a Pharmacovigilance Centre. Uppsala Monitoring Centre - WHO Collaborating Centre for International Drug Monitoring, EQUUS, London, 2000. [Internet]. Accessed4 May 2020.

  5. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. 2000;356(9237):1255–9.

    Article  CAS  PubMed  Google Scholar 

  6. Moher D. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264–9, W64.

    Article  PubMed  Google Scholar 

  7. Joanna Briggs Institute Global. EPB Resources & Publications | Joanna Briggs Institute. 2021. [online] Available at:  Accessed 20 May 2021.

  8. Tremlett HL, Oger J. Ten years of adverse drug reaction reports for the multiple sclerosis immunomodulatory therapies: a Canadian perspective. Mult Scler. 2008;14(1):94–105.

    Article  CAS  PubMed  Google Scholar 

  9. Calabresi PA, Radue EW, Goodin D, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(6):545–56. Erratum in: Lancet Neurol. 2013 Jun;13(6):536.

  10. Cohen J, Barkhof F, Comi G, Hartung H, Khatri B, Montalban X et al. Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis. New England Journal of Medicine. 2010;362(5):402-415. [Internet].  Accessed 5 May 2020.

  11. Fox E, Wynn D, Cohan S, Rill D, McGuire D, Markowitz C. A randomized clinical trial of autologous T-cell therapy in multiple sclerosis: subset analysis and implications for trial design. Mult Scler. 2012;18:843–52.

    Article  CAS  Google Scholar 

  12. Kappos L, Bar-Or A, Cree BAC, Fox RJ, Giovannoni G, Gold R, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391(10127):1263–73.

    Article  CAS  PubMed  Google Scholar 

  13. Saida T, Kira JI, Kishida S, Yamamura T, Sudo Y, Ogiwara K, et al. Efficacy, safety, and pharmacokinetics of natalizumab in Japanese multiple sclerosis patients: A double-blind, randomized controlled trial and open-label pharmacokinetic study. Mult Scler Relat Disord. 2017;11:25–31.

    Article  PubMed  Google Scholar 

  14. Selmaj K, Li DKB, Hartung HP, Hemmer B, Kappos L, Freedman MS, et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol. 2013;12(8):756–67.

    Article  CAS  PubMed  Google Scholar 

  15. Vermersch P, Czlonkowska A, Grimaldi LME, Confavreux C, Comi G, Kappos L, et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler. 2014;20(6):705–16.

    Article  CAS  PubMed  Google Scholar 

  16. Voskuhl RR, Wang H, Wu TCJ, Sicotte NL, Nakamura K, Kurth F, et al. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(1):35–46.

    Article  CAS  PubMed  Google Scholar 

  17. Viglietta V, Bourcier K, Buckle GJ, Healy B, Weiner HL, Hafler DA, et al. CTLA4Ig treatment in patients with multiple sclerosis: an open-label, phase 1 clinical trial. Neurology. 2008;71(12):917–24.

    Article  CAS  PubMed  Google Scholar 

  18. Pakdaman H, Abbasi M, Gharagozli K, Ashrafi F, Delavar Kasmaei H, Amini HA. A randomized double-blind trial of comparative efficacy and safety of Avonex and CinnoVex for treatment of relapsing-remitting multiple sclerosis. Neurol Sci. 2018;39(12):2107–13.

    Article  PubMed  Google Scholar 

  19. Cohen JA, Comi G, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, et al. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 2019;18(11):1021–33.

    Article  CAS  PubMed  Google Scholar 

  20. Afshar AR, Fernandes JK, Patel RD, Ksiazek SM, Sheth VS, Reder AT, et al. Cystoid macular edema associated with fingolimod use for multiple sclerosis. JAMA Ophthalmol. 2013;131(1):103–7.

    Article  PubMed  Google Scholar 

  21. Akiyama H, Suzuki Y, Hara D, Shinohara K, Ogura H, Akamatsu M, Hasegawa Y. Improvement of macular edema without discontinuation of fingolimod in a patient with multiple sclerosis: A case report. Med (Baltim). 2016;95(29):e4180.

  22. Asensio-Sánchez VM, Trujillo-Guzmán L, Ramoa-Osorio R. Cystoid macular oedema after fingolimod treatment in multiple sclerosis. Arch Soc Esp Oftalmol. 2014;89(3):104–6.

    Article  PubMed  Google Scholar 

  23. Bakri SJ, Swanson JW. Asymptomatic peripheral retinal hemorrhages as a manifestation of interferon beta 1a retinopathy. Semin Ophthalmol. 2015;30(1):56–7.

    Article  PubMed  Google Scholar 

  24. Bhatti MT, Freedman SM, Mahmoud TH. Fingolimod therapy and macular hemorrhage. J Neuroophthalmol. 2013;33(4):370–2.

    Article  PubMed  Google Scholar 

  25. Boster AL, Nicholas JA, Topalli I, Kisanuki YY, Pei W, Morgan-Followell B, et al. Lessons learned from fatal progressive multifocal leukoencephalopathy in a patient with multiple sclerosis treated with natalizumab. JAMA Neurol. 2013;70(3):398–402.

    Article  PubMed  Google Scholar 

  26. Christopher KL, Elner VM, Demirci H. Conjunctival lymphoma in a patient on fingolimod for relapsing-remitting multiple sclerosis. Ophthal Plast Reconstr Surg. 2017;33(3):e73–5.

    Article  PubMed  Google Scholar 

  27. Chui J, Herkes GK, Chang A. Management of fingolimod-associated macular edema. JAMA Ophthalmol. 2013;131(5):694–6.

    Article  PubMed  Google Scholar 

  28. de Massougnes S, Borruat FX, Ambresin A. Peripheral bilateral telangiectasiae in multiple sclerosis patients treated with interferon b1a. Klin Monbl Augenheilkd. 2016;233(4):438–40.

    Article  PubMed  Google Scholar 

  29. De Santi L, Costantini MC, Annunziata P. Long time interval between multiple sclerosis onset and occurrence of primary Sjögren’s syndrome in a woman treated with interferon-beta. Acta Neurol Scand. 2005;112(3):194–6.

    Article  PubMed  Google Scholar 

  30. Esquenazi S. Bilateral reversible corneal edema associated with amantadine use. J Ocul Pharmacol Ther. 2009;25(6):567–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gaetani L, Menduno PS, Cometa F, Di Gregorio M, Sarchielli P, Cagini C, et al. Retinopathy during interferon-β treatment for multiple sclerosis: case report and review of the literature. J Neurol. 2016;263(3):422–7.

    Article  PubMed  Google Scholar 

  32. Gallego-Pinazo R, España-Gregori E, Casanova B, Pardo-López D, Díaz-Llopis M. Branch retinal vein occlusion during fingolimod treatment in a patient with multiple sclerosis. J Neuroophthalmol. 2011;31(3):292–3.

    Article  PubMed  Google Scholar 

  33. Fan Gaskin JC-C, Coote M. Postoperative cystoid macular oedema in a patient on fingolimod. BMJ Case Rep. 2015;2015(may12 1):bcr2015210415.

    Article  PubMed Central  Google Scholar 

  34. Jasani KM, Sharaf N, Rog D, Aslam T. Fingolimod-associated macular oedema. BMJ Case Rep. 2017;2017:bcr-2016.

    Article  Google Scholar 

  35. Jeng BH, Galor A, Lee MS, Meisler DM, Hollyfield JG, Schoenfield L, et al. Amantadine-associated corneal edema potentially irreversible even after cessation of the medication. Ophthalmology. 2008;115(9):1540–4.

    Article  PubMed  Google Scholar 

  36. Jenisch T, Dietrich-Ntoukas T, Renner AB, Helbig H, Gamulescu MA. Combined retinal artery and vein occlusions associated with interferon beta therapy. Ophthalmologe. 2012;109(1):71–5.

    Article  CAS  PubMed  Google Scholar 

  37. Kim MJ, Bhatti MT, Costello F. Famous. Surv Ophthalmol. 2016;61(4):512–9.

    Article  PubMed  Google Scholar 

  38. Lambrou GN, Kopferschmitt J, Jaeger A, Brini A. Slowly reversible central scotoma: iatrogenic effect of hyperbaric oxygenation in the treatment of multiple sclerosis. J Fr Ophtalmol. 1987;10(1):51–9.

    CAS  PubMed  Google Scholar 

  39. Longmuir R, Lee AG, Rouleau J. Cotton wool spots associated with interferon beta-1 alpha therapy. Semin Ophthalmol. 2007;22(1):49–53.

    Article  PubMed  Google Scholar 

  40. Mallada-Frechín J, Abellán-Miralles I, Alfaro-Beltra ML, Medrano V, Muñoz-Gil MB, Fernández-Izquierdo S, et al. Retinopathy secondary to treatment with interferon beta-1a in a patient with multiple sclerosis. Rev Neurol. 2005;40(8):482–4.

    Article  PubMed  Google Scholar 

  41. Minuk A, Belliveau MJ, Almeida DRP, Dorrepaal SJ, Gale JS. Fingolimod-associated macular edema: resolution by sub-tenon injection of triamcinolone with continued fingolimod use. JAMA Ophthalmol. 2013;131(6):802–4.

    Article  PubMed  Google Scholar 

  42. Ohira M, Ito D, Shimizu T, Shibata M, Ohde H, Suzuki N. Retinopathy: an overlooked adverse effect of interferon-beta treatment of multiple sclerosis. Keio J Med. 2009;58(1):54–6.

    Article  CAS  PubMed  Google Scholar 

  43. Post JW, Colleaux K. Interferon beta retinopathy in a patient with multiple sclerosis. Can J Ophthalmol. 2009;44(5):e37.

    Article  PubMed  Google Scholar 

  44. Pul R, Osmanovic A, Schmalstieg H, Pielen A, Pars K, Schwenkenbecher P et al. Fingolimod associated bilateral cystoid macular edema—wait and see? [Internet]. Int J Mol Sci. 2016;17(12)

  45. Saatci AO, Ayhan Z, Arikan G, Sayiner A, Ada E. Unilateral acute retinal necrosis in a multiple sclerosis patient treated with high-dose systemic steroids. Int Ophthalmol. 2010;30(5):629–32.

    Article  PubMed  Google Scholar 

  46. Saito H, Suzuki M, Asakawa T, Kato S. Retinopathy in a multiple sclerosis patient undergoing interferon-therapy. Mult Scler. 2007;13(7):939–40.

    Article  PubMed  Google Scholar 

  47. Sallansonnet-Froment M, Roux X, de Greslan T, Bounolleau P, Taillia H, Ricard D, et al. Interferon-beta retinopathy. Rev Neurol (Paris). 2009;165(11):971–4.

    Article  CAS  Google Scholar 

  48. Schröder K, Finis D, Harmel J, Ringelstein M, Hartung HP, Geerling G, et al. Acetazolamide therapy in a case of fingolimod-associated macular edema: early benefits and long-term limitations. Mult Scler Relat Disord. 2015;4(5):406–8.

    Article  PubMed  Google Scholar 

  49. Sheikh Z, Jain S, Hillen M. Acute retinal necrosis in multiple sclerosis: A neuroimmunologic challenge! Neurology. 2016;86(10):972–3.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Sommer S, Sablon JC, Zaoui M, Rozot P, Hosni A. Interferon beta-1b retinopathy during a treatment for multiple sclerosis. J Fr Ophtalmol. 2001;24(5):509–12.

    CAS  PubMed  Google Scholar 

  51. Spierer O, Leibovitch I. Recurrent orbital inflammation in a patient with multiple sclerosis treated with interferon-beta. Clin Exp Ophthalmol. 2011;39(8):835–7.

    Article  PubMed  Google Scholar 

  52. Thoo S, Cugati S, Lee A, Chen C. Successful treatment of fingolimod-associated macular edema with intravitreal triamcinolone with continued fingolimod use. Mult Scler. 2015;21(2):249–51.

    Article  PubMed  Google Scholar 

  53. Trinh T, Haridas AS, Sullivan TJ. Ocular findings in alemtuzumab (Campath-1H)-induced thyroid eye disease. Ophthal Plast Reconstr Surg. 2016;32(6):e128–9.

    Article  PubMed  Google Scholar 

  54. Turaka K, Bryan JS. Does fingolimod in multiple sclerosis patients cause macular edema? J Neurol. 2012;259(2):386–8.

    Article  PubMed  Google Scholar 

  55. Ueda N, Saida K. Retinal hemorrhages following fingolimod treatment for multiple sclerosis; a case report. BMC Ophthalmol. 2015;15(1):135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zecca C, Nessi F, Bernasconi E, Gobbi C. Ocular toxoplasmosis during natalizumab treatment. Neurology. 2009;73(17):1418–9.

    Article  PubMed  Google Scholar 

  57. Cifuentes-Canorea P, Nieves-Moreno M, Sáenz-Francés F, Santos-Bueso E. Edema macular precoz y recurrente en paciente en tratamiento con fingolimod. Neurología. 2019;34(3):206–7.

    Article  CAS  PubMed  Google Scholar 

  58. Husmann R, Davies JB, Ghannam M, Berry B, Kelkar P. Fingolimod-associated macular edema controlled with nepafenac non-steroidal anti-inflammatory opthalmologic applications. Clin Mol Allergy. 2020;18(1):3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Tsourdi E, Gruber M, Rauner M, Blankenburg J, Ziemssen T, Hofbauer LC. Graves’ disease after treatment with alemtuzumab for multiple sclerosis. Hormones (Athens). 2015;14(1):148–53.

    Article  Google Scholar 

  60. Williams KE, Johnson LN. Neuroretinitis in patients with multiple sclerosis. Ophthalmology. 2004;111(2):335–40; discussion 340-1.

    Article  PubMed  Google Scholar 

  61. Roos JCP, Moran C, Chatterjee VK, Jones J, Coles A, Murthy R. Immune reconstitution after alemtuzumab therapy for multiple sclerosis triggering Graves’ orbitopathy: a case series. Eye (Lond). 2019;33(2):223–9.

    Article  PubMed  Google Scholar 

  62. Holmén C, Piehl F, Hillert J, Fogdell-Hahn A, Lundkvist M, Karlberg E, et al. A Swedish national post-marketing surveillance study of natalizumab treatment in multiple sclerosis. Mult Scler. 2011;17(6):708–19.

    Article  PubMed  Google Scholar 

  63. Lapierre Y, O’Connor P, Devonshire V, Freedman MS, Kremenchutzky M, Yeung M, et al. Canadian experience with fingolimod: adherence to treatment and monitoring. Can J Neurol Sci. 2016;43(2):278–83.

    Article  PubMed  Google Scholar 

  64. Laroni A, Brogi D, Brescia Morra V, Guidi L, Pozzilli C, Comi G, et al. Safety and tolerability of fingolimod in patients with relapsing-remitting multiple sclerosis: results of an open-label clinical trial in Italy. Neurol Sci. 2017;38(1):53–9.

    Article  PubMed  Google Scholar 

  65. Liscić RM, Brecelj J. Visual evoked potentials in multiple sclerosis patients treated with interferon beta-1a. Croat Med J. 2004;45(3):323–7.

    PubMed  Google Scholar 

  66. Makioka H, Nakaya F, Ling Y, Torii S, Saida T, Kira JI. Safety and effectiveness of interferon β-1a intramuscular therapy: results of the postmarketing drug surveillance in Japan. Rinsho Shinkeigaku. 2017;57(10):553–61.

    Article  PubMed  Google Scholar 

  67. Ontaneda D, Hara-Cleaver C, Rudick RA, Cohen JA, Bermel RA. Early tolerability and safety of fingolimod in clinical practice. J Neurol Sci. 2012;323(1–2):167–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Rommer PS, Dörner T, Freivogel K, Haas J, Kieseier BC, Kümpfel T, et al. Safety and clinical outcomes of rituximab treatment in patients with multiple sclerosis and neuromyelitis optica: experience from a national online registry (GRAID). J Neuroimmune Pharmacol. 2016;11(1):1–8, 1.

  69. Smith MY, Sabidó-Espin M, Trochanov A, Samuelson M, Guedes S, Corvino FA, et al. Postmarketing safety profile of subcutaneous interferon beta-1a given 3 times weekly: A retrospective administrative claims analysis. J Manag Care Spec Pharm. 2015;21(8):650–60.

    Article  PubMed  Google Scholar 

  70. Tuohy O, Costelloe L, Hill-Cawthorne G, Bjornson I, Harding K, Robertson N, et al. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J Neurol Neurosurg Psychiatry. 2015;86(2):208–15.

    Article  PubMed  Google Scholar 

  71. Weglinski L, Manceau P, Thomas-Pohl M, Le Breton F, Amarenco G. Prospective evaluation of mouth and eye dryness induced by antimuscarinic drugs used for neurogenic overactive bladder in 35 patients with multiple sclerosis. Prog Urol. 2017;27(4):253–60.

    Article  CAS  PubMed  Google Scholar 

  72. Willis MD, Harding KE, Pickersgill TP, Wardle M, Pearson OR, Scolding NJ, et al. Alemtuzumab for multiple sclerosis: long term follow-up in a multi-centre cohort. Mult Scler. 2016;22(9):1215–23.

    Article  CAS  PubMed  Google Scholar 

  73. Zarbin MA, Jampol LM, Jager RD, Reder AT, Francis G, Collins W, et al. Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis. Ophthalmology. 2013;120(7):1432–9.

    Article  PubMed  Google Scholar 

  74. Gugliandolo A, Longo F, Marrosu MG, Mancardi GL, Gandoglia I, Melis M, et al. A multicentric pharmacovigilance study: collection and analysis of adverse drug reactions in relapsing-remitting multiple sclerosis patients [Internet]. Ther Clin Risk Manag. 2018;14:1765–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Fruschelli M, Capozzoli M, Gelmi MC, Masi G, Annunziata P. Longitudinal quantitative assessment of macula during therapy with fingolimod in relapsing–remitting multiple sclerosis. Int Ophthalmol. 2019;39(4):777–81.

    Article  PubMed  Google Scholar 

  76. Lim LL, Silva DG, Lo TC, Pimentel RS, Butzkueven H, Hall AJ. Uveitis in patients with multiple sclerosis in clinical trials of fingolimod: incidence, prevalence, and impact on disease course. Ophthalmology. 2019;126(3):438–44.

    Article  PubMed  Google Scholar 

  77. Comi G, Kappos L, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, et al. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (sunbeam): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 2019;18(11):1009–20.

    Article  CAS  PubMed  Google Scholar 

  78. Brown BA. Natalizumab in the treatment of multiple sclerosis. Ther Clin Risk Manag. 2009;5(3):585–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899–910.

    Article  CAS  PubMed  Google Scholar 

  80. Zorzela L, Loke YK, Ioannidis JP, Golder S, Santaguida P, Altman DG, et al. PRISMA harms checklist: improving harms reporting in systematic reviews. BMJ. 2016;352:i157.

    Article  PubMed  Google Scholar 

  81. Peryer G, Golder S, Junqueira D, Vohra S, Loke YK. Chapter 19: Adverse effects. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021.  Available from

  82. Management Sciences for Health and World Health Organization. Drug and Therapeutics Committee Training Course. Submitted to the U.S. Agency for International Development by the Rational Pharmaceutical Management Plus Program. Arlington: Management Sciences for Health; 2007.

  83. Miller DH, Chard DT, Ciccarelli O. Clinically isolated syndromes. Lancet Neurol. 2012;11(2):157–69.

    Article  PubMed  Google Scholar 

  84. Frohman TC, Graves J, Balcer LJ, Galetta SL, Frohman EM. The neuro-ophthalmology of multiple sclerosis. Continuum (Minneap Minn). 2010;16(5 Multiple Sclerosis):122–46

  85. Bomprezzi R, Powers JM. IFN-β1b may severely exacerbate Japanese optic-spinal MS in neuromyelitis optica spectrum. 2020. Accessed 5 May 2020.

  86. Pula JH, Reder AT. Multiple sclerosis. Part I: Neuro-ophthalmic manifestations. Curr Opin Ophthalmol. 2009;20(6):467–75.

    Article  PubMed  Google Scholar 

  87. Andrew L. Ophthalmic screening recommendation for new MS drug. [online] The Ophthalmic News and Education Network. 2018. Available at: Accessed 20 May 2021.

  88. Wiersinga WM, Smit T, van der Gaag R, Koornneef L. Temporal relationship between onset of Graves’ ophthalmopathy and onset of thyroidal Graves’ disease. J Endocrinol Invest. 1988;11(8):615–9.

    Article  CAS  PubMed  Google Scholar 

  89. Buonomo AR, Zappulo E, Viceconte G, Scotto R, Borgia G, Gentile I. Risk of opportunistic infections in patients treated with alemtuzumab for multiple sclerosis. Expert Opin Drug Saf. 2018;17(7):709–17.[Editor1].

    Article  CAS  PubMed  Google Scholar 

Download references


We thank Universidad del Rosario for financing the proofreading of this manuscript and Enago ( for the English language review.


No funding was required to conduct this study.

Author information

Authors and Affiliations



JMO, JRG, JARH, LMM: Management, research idea, protocol registration, protocol writing, title and abstract reading, manuscript writing and discussion, and manuscript final approval. EZB: Protocol registration, protocol writing, title and abstract reading, quality evaluation, data extraction, manuscript writing and discussion, and manuscript final approval. LOTG, WRC: Title and abstract reading, quality evaluation, data extraction, manuscript writing and discussion, and manuscript final approval. MGS: Methodology adviser. Protocol reviewing, results interpretation, and manuscript final approval. ADLT: Management, research idea, protocol writing, manuscript final approval, and thematic authority.

Corresponding author

Correspondence to Alejandra de-la-Torre.

Ethics declarations

Ethics approval

The present study was performed according to the ethical principles for research involving human beings established by the Declaration of Helsinki, the Belmont Report, and Colombian Resolution 008430 of 1993. As it is a systematic review of the literature, it does not require approval by the ethics committee.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Muñoz-Ortiz, J., Reyes-Guanes, J., Zapata-Bravo, E. et al. Ocular adverse events from pharmacological treatment in patients with multiple sclerosis—A systematic review of the literature. Syst Rev 10, 280 (2021).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: