2.1. Literature Search Strategy

The study was designed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

The MEDLINE/PubMed and Embase databases were comprehensively searched without time limitations up to May 2022 to identify eligible articles. No specialized software was used in this process. To identify all relevant publications, the search terms included “periorbital,” “palpebral,” “eyelid,” “edema,” “swelling,” “drug-induced,” and “drug-related,” which were searched across all fields.

We also manually searched the references of included articles for any additional studies meeting the predefined inclusion criteria not identified in the initial searches.

2.2. Eligibility Criteria

All eligible case reports and case series worldwide were included. For this systematic review, inclusion criteria were patients with isolated eyelid or periorbital edema as an adverse drug effect (administered systemically or injected in the head and neck area).

After duplicate removal, articles were excluded based on titles and abstracts with the following criteria: (1) articles not focused on human patients, (2) articles not focused on eyelid edema, (3) articles not in English, and (4) abstracts or articles not available.

Articles remaining after the initial screening underwent a full-text review for inclusion. Subsequently, articles were excluded if they did not (1) focus on eyelid edema, (2) clearly state whether it was isolated, and (3) describe a clear etiological role of a specific drug in the onset of edema. Figure 1 shows the detailed search strategy.

2.3. Data Extraction

Four authors (I.T., J.T., L.G., and F.C.) independently evaluated the titles and abstracts from the aforementioned databases. For each selected study, we collected data on the first author, publication year, number of patients, patient’s age and sex, indication for treatment, drug causing eyelid edema, route of drug administration, time of onset of periorbital edema, clinical management, and outcomes.

3.1. Bias and Quality Assessment

It is important to acknowledge that even if the level of certainty of evidence derived from case series or case reports is typically considered low, the inferences drawn from such reports can still offer valuable contributions to the decision-making process.

4.1. Sirolimus and Everolimus

In our systematic literature review, nine cases of isolated palpebral edema were associated with sirolimus and everolimus. Sirolimus, also known as rapamycin, belongs to a class of drugs that inhibit mTOR. Moreover, everolimus is a chemically modified form of sirolimus with improved bioavailability and reduced half-life. Initially approved for preventing acute rejection episodes in kidney transplantation, it has also gained approval for treating postmenopausal breast cancer, well-differentiated gastrointestinal or lung neuroendocrine tumors, giant cell subependymal astrocytoma associated with tuberous sclerosis, and metastatic pancreatic neuroendocrine tumors [51, 52]. The most commonly reported adverse events of everolimus include anemia, nephrotoxicity, hypertension, gastrointestinal disorders, and increased susceptibility to infections [53, 54], which are similar to those reported for other immunosuppressive drugs.

Nonetheless, some patients may have atypical manifestations. These include arthralgia, hyperlipemia, lymphocele, and edema. Edema induced by mTOR inhibitors can take different clinical forms, such as lymphocele, angioedema, pleural and pericardial effusions, edema of the extremities and lymphedema, and finally, eyelid edema [55].

Although eyelid edema is among the possible adverse effects, only a few cases are reported. Mohaupt et al. published a case series of five patients experiencing significant eyelid edema caused by sirolimus [11].

Edema can be mono- or bilateral and is typically painless and nonpruritic. The development of noninflammatory eyelid edema tends to be gradual, progressing over several months [55].

The molecular mechanism underlying this manifestation is unknown. However, several hypotheses have been proposed. Sirolimus has been shown to increase prostacyclin production in rabbit endothelial cells [56]. Increased prostacyclin levels lead to vasodilation, resulting in fluid accumulation in the interstitial space. The alteration of lymphatic drainage is another pathophysiological mechanism [57]. Moreover, important effectors involved in lymphangiogenesis are regulated by the mTOR complex. Inhibition of mTOR leads to the reduced proliferation and migration of lymphatic endothelial cells driven by vascular endothelial growth factor-C [58]. Interestingly, although sirolimus and everolimus are hydrophobic macrocyclic lactones, similar to macrolides, eyelid edema is not frequently reported as an adverse effect in the latter drug group. This could potentially be related to the short course of antibiotic therapy compared with long-lasting immunosuppressive therapy or a specific molecular consequence of mTOR inhibition.

There are several possible management options for sirolimus- and everolimus-induced eyelid edema, including drug discontinuation, clinical observation, and surgical therapy. In most cases, the edema is mild and can be effectively managed with furosemide. In this case, drug discontinuation or dose reduction is not necessary. However, in severe cases where the edema is causing compromised visual function, discontinuing the drug and administering diuretics may not lead to improvement [10]. In such instances, surgical removal of the edematous eyelid has shown positive outcomes with stable results over time and without recurrence of edema even after drug readministration. Furthermore, drug discontinuation may not be a feasible option in some patients. Overall, the surgical approach is recommended for severe and persistent cases with visual field defects and significant skin redundancy, as it is associated with the most favorable risk-to-benefit ratio.

4.2. Imatinib

Imatinib is an oral signal transduction inhibitor that specifically targets protein tyrosine kinases, such as ABL, Arg (ABL-related gene), stem cell factor receptor (c-KIT), platelet-derived growth factor receptor (PDGF-R), and their oncogenic forms, most notably BCR-ABL [59]. It was the first protein kinase inhibitor to be clinically used in 2001 and is currently approved for treating CML and malignant gastrointestinal stromal tumors (GIST) [59, 60].

During imatinib therapy, adverse events may occur, including hematological side effects mostly consisting of cytopenia (anemia, neutropenia, and thrombocytopenia) as well as nonhematologic events such as fluid retention, biochemical abnormalities, and gastrointestinal and musculoskeletal disorders [61].

In our review, we identified five patients receiving imatinib therapy who developed eyelid edema as a side effect. Four patients had CML, and one had metastatic GIST. All patients developed bilateral eyelid edema within 1 month of starting therapy, suggesting that imatinib-induced eyelid edema seems to be an early adverse reaction.

The precise mechanism for imatinib-induced periorbital edema is not yet fully understood, but several hypotheses have been proposed. The most widely accepted theory involves the inhibition of PDGF-R signaling [25]. Histopathological findings have revealed that dermal dendrocytes, which are abundant in periocular skin, express PDGF-R [6]. Furthermore, PDGF-R signaling cascade inhibition by imatinib may result in increased capillary permeability and fluid extravasation, leading to localized edema. Another hypothesis suggests that the unique anatomical characteristics of the orbit, characterized by a dense collagenous orbital septum and poorly developed lymphatic system, predispose this region to edema [6].

Among the available treatment options, surgery has proven to be the most effective in resolving the edema in all reported cases, while conservative management only achieved a partial response.

4.3. Pemetrexed

Pemetrexed is a multitargeted antifolate drug that inhibits enzymes involved in folate metabolism and DNA synthesis. It is commonly used in the treatment of non–small-cell lung carcinoma and mesothelioma [62]. Although generally well tolerated, pemetrexed has a broad spectrum of adverse reactions, ranging from mild to moderate adverse reactions, such as fatigue, mucositis, and skin rashes, to severe adverse reactions, such as renal failure, neutropenia, anaphylactic shock, and toxic epidermal necrolysis [63].

Although rare, isolated periorbital edema has been described among the adverse reactions related to pemetrexed [30]. A study conducted by Eguia et al. in 2011, involving 107 patients treated with pemetrexed, reported periorbital edema in 15% (16/107) [64]. So far, eight cases of pemetrexed-induced isolated eyelid edema have been documented. Most patients experienced bilateral periorbital edema, but unilateral edema was also reported. The time elapsed between the first drug administration and the onset of edema varied widely, ranging from the first to the fifth cycles of chemotherapy.

The exact mechanisms underlying pemetrexed-induced eyelid edema remain unclear. One theory suggests that soft tissue swelling and the accumulation of noncancerous fluid in the eyelids, similar to the effects observed with agents such as tyrosine kinase inhibitors (such as imatinib and nilotinib) and mTOR inhibitors (such as sirolimus), may be attributed to the leakage of proteins from capillaries [30].

Treatment options include conservative measures such as systemic corticosteroids and diuretics, which can lead to partial improvement of the edema. However, it has been observed that the edema tends to recur upon readministration of pemetrexed. In most cases, antineoplastic therapy discontinuation was not a feasible option [65], but in some rare cases, when the benefit-risk balance allows for it, discontinuation of pemetrexed therapy has been attempted, leading to a partial improvement of the eyelid edema.

In some cases, surgical intervention such as blepharoplasty has shown to be effective in achieving complete and lasting resolution of the edema [10]. However, it should be noted that the long-term efficacy of these treatments for eyelid edema in the context of advanced non–small-cell lung carcinoma is not well documented, given the poor prognosis associated with the disease. Nevertheless, considering the benefit-risk ratio, blepharoplasty may be a reasonable choice for managing pemetrexed-induced eyelid edema.

4.4. Olanzapine, Clozapine, and Risperidone

Atypical antipsychotics may be a cause of isolated eyelid edema and must be included in the differential diagnosis. Twelve cases of isolated eyelid edema associated with olanzapine, clozapine, and risperidone have been reported in the literature.

Olanzapine is commonly used for the management of both negative and positive symptoms of schizophrenia [66]. Several adverse effects are described, including numerous cases of peripheral edema [67]. In our systematic review of the literature, five cases of isolated eyelid edema related to olanzapine were reported. The period between the start of therapy and the onset of edema varied widely, ranging from 1 day to 7 months. Interestingly, all reported patients responded to drug discontinuation. Similarly, three casesof isolated eyelid edema were associated with clozapine, which is used as a second-line drug in treatment-resistant schizophrenia. The time interval between the first drug administration and the onset of edema was longer than olanzapine (between 19 days and 6 years). All patients responded to drug discontinuation, but systemic steroids, antibiotics, and antihistamines were ineffective. In one case, the edema recurred after drug readministration, postoperatively. Risperidone is a benzisoxazole antipsychotic drug, and its activity is mediated through a combination of D2 and 5-HT2 receptor antagonism. Four cases of risperidone-induced periorbital edema have been reported. The time interval between the start of risperidone use and the onset of edema was shorter than olanzapine and clozapine, ranging from 2 to 19 days. Similar to other atypical antipsychotics, eyelid edema completely resolved after the drug discontinuation.

The exact mechanism underlying eyelid edema induced by atypical antipsychotics is unknown, but renal D4 receptor inhibition may lead to reduced natriuresis and, therefore, eyelid edema. Other hypotheses include vasodilation induced by blockade of the alpha-1 adrenergic receptors and stimulation of muscarinic, serotonergic, and adrenergic receptors [16].

4.5. HA Filler

In our review, we identified several cases of isolated eyelid edema following soft tissue filler injections, mostly HA, but also including nonresorbable agents such as polyalkylimide. The majority of affected patients were middle-aged women, who underwent the procedure for esthetic reasons. HA fillers are among the most commonly used materials for periorbital rejuvenation, offering temporary and reversible esthetic enhancement with an acceptable safety profile. Nevertheless, periorbital edema is a recognized adverse effect, which may appear acutely or manifest with a significant delay [37]. Delayed periorbital edema typically occurs months to years after the procedure—on average 27.1 months in reported cases—and is often associated with persistent filler material within the eyelid tissues [38]. In the case of HA, its cross-linked structure contributes to prolonged tissue retention and fluid attraction, while in the case of polyalkylimide, the material may migrate from distant facial regions and provoke a granulomatous reaction or space-occupying effect. Both mechanisms can ultimately result in lower eyelid swelling, even in the absence of recent injections or inflammatory signs.

The pathophysiology of this phenomenon remains incompletely understood. Hypersensitivity to filler components has been proposed but is considered unlikely in the absence of overt inflammation. Several authors have suggested that fillers may exacerbate pre-existing anatomical predispositions to fluid retention by impairing lymphatic or venous drainage in the periorbital region [36, 68]. Moreover, delayed edema may be due to reactions to cross-linkage breakdown products [69], or by chronic low-grade inflammation and tissue remodeling around the filler [70].

A recent review by Eshraghi et al. highlighted key diagnostic and therapeutic strategies in patients presenting with late-onset periorbital edema after HA injection, emphasizing the value of ultrasound and the efficacy of hyaluronidase in cases of suspected retained filler [70].

When isolated eyelid edema is observed in patients with a history of facial filler injection, clinicians should maintain a high index of suspicion, even if the procedure was performed years earlier. In cases related to HA, intralesional hyaluronidase represents the treatment of choice and may require repeated sessions to achieve complete resolution [36]. In contrast, excision may be necessary for persistent or granulomatous lesions, particularly those related to permanent fillers such as polyalkylimide. Blepharoplasty can be considered in refractory cases.

4.6. Other Drugs

Isolated eyelid edema has been sporadically associated with other drugs, including apixaban [47], sorafenib [48], emactuzumab [49], and nifedipine [50]. However, limited data are available regarding the specific relationship between these drugs and eyelid edema.