Blepharochalasis Syndrome

Etiology

Blepharochalasis syndrome is characterized by recurrent episodes of painless, nonpitting edema in the upper eyelids, leading to gradual atrophy and laxity of the periorbital tissues.[6] Although recognized for over 2 centuries, the precise etiology of this condition remains unclear, with several hypotheses proposed to explain its pathology. While most cases are confined to the eyelids, some reports describe blepharochalasis associated with systemic abnormalities.[7] Consequently, some authors suggest that blepharochalasis may represent part of a broader systemic disorder.[8][9] Proposed etiological theories include hormonal influences, allergies, localized cutis laxa, and idiopathic angioedema. However, recent histopathological studies indicate a potential role for immunoglobulin A (IgA) deposits in the etiopathogenesis of this disease.[10][11]

One theory supports an immunological mechanism underlying blepharochalasis syndrome. Research highlights the involvement of matrix metalloproteinases (MMPs), specifically MMP-3 and MMP-9, in the degradation of elastic fibers within the dermis.[12] Immunohistochemical analyses reveal elevated expression of these enzymes in affected tissues, supporting the hypothesis that postinflammatory MMP release drives elastolytic and collagenolytic activity observed in blepharochalasis patients. Additionally, some studies have identified IgA antibodies directed against elastic fibers, suggesting an autoimmune component in the disease mechanism.

Hormonal factors appear to influence the etiology of blepharochalasis syndrome, as its typical onset occurs during adolescence.[13] The postpubertal emergence of the disorder suggests that hormonal fluctuations may trigger or exacerbate the disease. However, specific hormonal pathways involved remain unidentified, warranting further investigation. Environmental and lifestyle factors have also been proposed as potential triggers for the acute edema episodes characteristic of blepharochalasis syndrome. Various precipitating factors have been reported anecdotally, including menstruation, upper respiratory infections, amyloidosis, bee stings, excessive crying, physical exercise, emotional stress, and minor eyelid trauma.[14][15][16] Despite these associations, definitive causal links remain unproven, and many cases lack identifiable triggers.

A genetic predisposition has been suggested in blepharochalasis syndrome.[17] Although most cases occur sporadically, familial clusters point to a possible hereditary component. Genetic determinants and inheritance patterns remain unclear, necessitating further research into genetics. Isolated cases also document associations between blepharochalasis and systemic abnormalities. In 1920, Ascher described a triad comprising blepharochalasis, cheilitis granulomatosa, and nontoxic thyroid enlargement, now recognized as Ascher syndrome.[18][19]

Epidemiology

Accurate epidemiological data on blepharochalasis syndrome are unavailable due to its rarity. Existing information derives primarily from case reports and small case series. Onset typically occurs in childhood or puberty. Episodes recur every 3 to 4 months over several years, decreasing in frequency with age. Inflammatory attacks eventually cease, and the disease progresses to a quiescent phase.

A retrospective cohort study conducted at Beijing Tongren Eye Center analyzed 93 patients diagnosed with blepharochalasis between January 2009 and December 2019. Results indicated that 72.04% of patients were female, demonstrating a higher incidence in female individuals despite involvement of both sexes. The mean age at onset was 10.09 years, with 83.87% of patients presenting symptoms during puberty, suggesting a predilection for adolescents. The average duration from initial acute attacks to the quiescent stage was approximately 7.33 years, highlighting the chronic course of the disease.

Koursh et al conducted a review summarizing 67 cases of blepharochalasis documented from 1977 to 2006. Among these cases, 45 were female and 22 were male, corroborating the observation of higher prevalence in female patients. However, the limited sample size and potential reporting biases warrant caution when interpreting these results. The average age of onset was 11 years, with a mean follow-up period of 11.4 years. The condition presented unilaterally in 27 cases and bilaterally in 40 cases.

Fuchs’ initial description notably emphasized bilateral involvement. Acute edema attacks typically lasted several hours to a few days, averaging 2 days. In early disease stages, episodes occurred 3 to 4 times a year, though weekly exacerbations have also been reported. The study indicated that episodes of eyelid swelling generally decreased in frequency with age, leading most cases to enter a largely quiescent phase.

Pathophysiology

The pathophysiology of blepharochalasis syndrome is controversial, with the precise mechanisms underlying the disease yet to be elucidated. Recent histopathological studies in a limited number of cases offer new insights into the condition's pathogenesis. The defining feature involves recurrent episodic inflammation, which induces tissue edema and subsequent structural damage. Acute episodes produce nonpitting edema caused by increased vascular permeability and localized fluid accumulation within the loose connective tissue of the upper eyelid. Although the edema typically resolves spontaneously and remains asymptomatic, repeated episodes result in permanent changes to eyelid anatomy. These acute inflammatory events resemble localized angioedema, where an unidentified trigger leads to vascular dysfunction, causing fluid extravasation and swelling.

A primary mechanism driving tissue deterioration involves the activity of MMPs, specifically MMP-3 and MMP-9. These enzymes degrade extracellular matrix components, including collagen and elastin, which maintain the structural integrity of the eyelid. Immunohistochemical analyses demonstrate elevated MMP expression during active blepharochalasis stages, implicating increased enzyme activity in ongoing elastolysis and collagen degradation. The loss of elastin and collagen produces clinically apparent atrophic, thin, and redundant skin.

Repeated episodes of skin stretching contribute to fragmentation and eventual loss of elastic fibers, leading to tissue atrophy. The presence of IgA deposits within the dermis and perivascular inflammatory cell infiltrates, reported in multiple studies, suggests a possible immune-mediated process. Kaneoya et al performed reverse transcription-polymerase chain reaction to assess elastin messenger ribonucleic acid expression in cultured fibroblasts from a patient with blepharochalasis. Results showed no difference compared to healthy controls, indicating that environmental factors or other matrix components may contribute to the loss of elastic fibers. Blood tests, including cell counts, circulating immunoglobulins, C-reactive protein, complements C3 and C4, and C1-esterase inhibitor, have been reported as normal in patients.[20]

Histopathology

Histopathological studies of skin biopsies have enhanced understanding of the pathogenesis of blepharochalasis. A consistent finding in these specimens is the loss of dermal elastic fibers, which appear attenuated, fractured, or absent when stained with elastic tissue-specific dyes. This elastic fiber deterioration correlates with the clinical presentation of skin laxity and redundancy in individuals affected by the condition. The initial event likely involves an IgA immune-mediated reaction targeting these fibers, as multiple recent studies have demonstrated IgA antibody deposits via immunofluorescence. Immunohistochemical staining has also revealed positivity for metalloproteinases MMP-3 and MMP-9, which are implicated in other elastolytic disorders, suggesting their involvement in the pathogenesis of this condition. Additional histological features include dermal atrophy affecting various structures, increased number and diameter of skin capillaries, perivascular inflammatory infiltrates, and pigmentation within the papillary and upper reticular dermis.

History and Physical

Blepharochalasis syndrome typically presents with a characteristic clinical history and physical examination findings that reflect its episodic and progressive nature.[21] Understanding these features is essential for prompt diagnosis and differentiation from other eyelid disorders. The average patient experiences recurrent episodes of painless edema primarily affecting the upper eyelids and, less commonly, the lower eyelids (see Image. Blepharochalasis, Acute Eyelid Edema Episode). The edema typically appears nonpitting and is resistant to treatments such as antihistamines and corticosteroids. Conjunctival hyperemia may develop in some cases.

Episodes often last several hours to days and frequently resolve spontaneously without intervention. Edema typically affects both eyelids but can occasionally present unilaterally.[22] Patients commonly report a sensation of weight or fullness during episodes, without accompanying pain or soreness. Potential triggers include minor trauma, illnesses, menstruation, or emotional stress. However, many patients report no identifiable precipitating factors.

Acute episodes of swelling typically persist for several hours to days, with an average duration of 2 days. Initial attacks may occur 3 to 4 times a year, although weekly exacerbations have been documented.[23] The frequency of episodes often declines with advancing age. Painless, nonpitting edema develops during these episodes, frequently accompanied by skin erythema (see Image. Blepharochalasis, Recurrent Unilateral Eyelid Swelling). Patients may also report red eyes and tearing.

Repeated episodes of eyelid swelling produce a characteristic appearance of the eyelids and periocular area, including upper lid ptosis, wrinkled, discolored, and atrophic skin, and dilated visible subcutaneous vessels (see Image. Evolution of Blepharochalasis Syndrome). In advanced disease stages, disinsertion of the ligamentous structures of the lateral canthus causes a rounded lateral angle and shortening of the horizontal palpebral aperture, known as acquired blepharophimosis.[24] Progressive levator aponeurosis dehiscence accentuates upper lid ptosis, particularly medially. Orbital septum weakening facilitates prolapse of orbital fat and lacrimal gland in some patients. Nasal fat pad atrophy in the upper eyelid may create a pronounced nasal hollow and a pseudoepicanthal fold. Unilateral proptosis has also been reported, suggesting possible orbital involvement.

Collin proposed a classification scheme based on a series of 30 patients. The system distinguished between an active or early phase, characterized by swelling episodes, and a quiescent or late stage, defined by at least 2 years without attacks.[25] Blepharochalasis may also present as part of a systemic disease. In such cases, examination of additional anatomical regions is necessary. The most frequent associations include Ascher syndrome, characterized by blepharochalasis, double lip, and nontoxic thyroid enlargement, as well as acquired cutis laxa, which features redundant skin, skeletal anomalies, and multiple organ impairments.[26]

Evaluation

The diagnosis of blepharochalasis syndrome is based on its characteristic natural history and clinical findings during both acute and quiescent stages. A thorough differential diagnosis must be established to exclude other conditions. Although blood tests and imaging may be performed in some cases, their primary role is to rule out alternative diagnoses, as complementary test results in blepharochalasis syndrome are typically normal. Thyroid function panels, complete blood count, erythrocyte sedimentation rate, C-reactive protein, and autoimmune markers may help exclude disorders such as thyroid eye disease or systemic lupus erythematosus.

Imaging investigations are seldom required but may be beneficial in atypical cases or when ocular fat prolapse or orbital masses are suspected. High-resolution magnetic resonance imaging or computed tomography scans can delineate soft tissue involvement and help exclude neoplastic or inflammatory diseases.[27][28] Ultrasound biomicroscopy may also aid in identifying changes within the eyelid soft tissues.

Histopathologic assessment through biopsy is rarely performed but can offer diagnostic insight in uncertain cases. The presence of elastin degradation, vascular changes, IgA deposits, and dermal atrophy can help differentiate blepharochalasis syndrome from other eyelid disorders.[29][30] Visual field testing, particularly automated perimetry, is important for evaluating functional visual impairment in patients with significant eyelid laxity or ptosis, informing management decisions, especially regarding surgical intervention.[31]

Treatment / Management

Managing blepharochalasis syndrome is complicated by its chronic and recurrent nature and the lack of standardized treatment guidelines. The primary objectives are to manage acute edema episodes, prevent long-term tissue damage, and address both functional and aesthetic eyelid deformities. Treatment should focus on reducing swelling during the acute phase and correcting structural changes during the quiescent stage.

Protocols have not been established for treating the inflammatory attacks. During acute episodes of swelling, conservative approaches, such as cold compresses, may be used to minimize inflammation and edema. Nonsteroidal anti-inflammatory drugs may provide symptomatic relief. However, evidence supporting medical treatment is limited. Several authors have reported favorable outcomes with systemic or topical corticosteroids, although these findings are based on small case series and indicate only partial improvement.[32] Given the risk of adverse effects, particularly with systemic steroid use, corticosteroids are not widely accepted as standard therapy for blepharochalasis syndrome, though they may be considered selectively.[33] Other immunosuppressive agents, including topical tacrolimus, have also been explored as therapeutic options.[34](B2)

Karakonji et al reported improvement in 2 patients with blepharochalasis syndrome during the acute stage using oral doxycycline, based on its properties as an MMP inhibitor.[35] Oral acetazolamide has been reported in 2 case series with good outcomes. The rationale for using this diuretic is based upon the suggestion that blepharochalasis syndrome represents a localized eyelid form of angioedema.[36](B3)

Apart from these varied attempts with limited success in managing the acute inflammatory attacks, the treatment of blepharochalasis syndrome is primarily surgical and aims to correct the resulting complications. Surgery is indicated for patients in the quiescent phase, provided the disease has remained inactive for 6 to 12 months. Performing surgery during active disease significantly increases the likelihood of treatment failure. The most frequent sequelae include dermatochalasis with either fat prolapse or fat atrophy, upper lid ptosis, lacrimal gland prolapse, and malposition of the lateral canthus or lower eyelid.

All these complications require tailored surgical correction using a broad range of techniques that must be combined based on individual presentation. Blepharoplasty, ptosis repair, and canthal procedures are technically more challenging in these patients due to the unique alterations affecting periocular tissues. Reconstructive efforts often involve tissue repositioning, fat grafting, and surgical modification of tendons, the levator aponeurosis, and the lacrimal gland.[37](B3)

Differential Diagnosis

Blepharochalasis syndrome presents significant diagnostic challenges due to its rarity and the clinical overlap it shares with other eyelid disorders characterized by edema, laxity, or structural skin changes. Precise differentiation is essential to avoid inappropriate treatment and guide appropriate management. Diagnostic confusion is most likely during the acute phase, particularly at the onset of inflammatory episodes. A thorough differential diagnosis must be considered, encompassing all possible causes of acute or acute-on-chronic eyelid swelling, including the following:

• Allergic reactions [38]
• Local eyelid infection or inflammation (eg, stye, chalazion) [39]
• Orbital inflammation
• Ocular cellulitis [40]
• Contact dermatitis [41]
• Angioedema [42]
• Melkersson–Rosenthal syndrome [43]
• Rosacea [44] 

During the quiescent phase, the following entities may mimic blepharochalasis:

• Dermatochalasis [45]
• Floppy eyelid syndrome [46]
• Lax eyelid syndrome [47]
• Upper lid ptosis [48]
• Acquired cutis laxa [49]
• Prolapsed orbital adipose tissue [50]
• Eyelid or orbital masses and tumors [51]
• Lymphoma [52]

The differential diagnosis varies significantly between the acute and quiescent phases. Clinicians must tailor their assessment to the disease stage to avoid misdiagnosis.

Staging

Currently, a globally recognized staging system for blepharochalasis syndrome does not exist, primarily due to the rarity of the condition and its heterogeneity in clinical presentation. Nonetheless, proposed classifications aim to describe the severity of the disease based on clinical features and functional impairment, providing a framework to inform therapeutic strategies. Blepharochalasis syndrome may progress through distinct clinical phases. Recognizing the phase of progression is critical for appropriate diagnosis and intervention. In the active phase, patients experience recurrent episodes of painless, nonpitting edema affecting the upper eyelids. These episodes occur without lasting skin changes, and visual function typically remains intact. Ptosis is generally absent or only mildly present.

During the transitional phase, repeated episodes of edema result in intermittent eyelid laxity and moderate ptosis. Early signs of skin atrophy, wrinkling, and minor orbital fat protrusion may become apparent. The frequency of edema episodes often declines as structural tissue changes become more pronounced. The quiescent phase represents the chronic stage of the disease. At this point, persistent eyelid skin laxity, thinning, and redundancy are observed. Mechanical ptosis may develop, sometimes resulting in visual field restriction due to excessive skin. Orbital fat herniation is often present, and episodes of edema are infrequent or absent. This phase-based framework helps determine the appropriate timing for surgical intervention. Surgery is typically reserved for the quiescent phase, when the disease has stabilized, and functional or cosmetic concerns warrant correction.

Prognosis

The natural course of blepharochalasis syndrome typically involves a gradual reduction in the frequency of eyelid edema episodes with advancing age. Most cases eventually enter a predominantly dormant phase. The episodic swelling often resolves spontaneously over several years, frequently after puberty or in early adulthood, leading to a quiescent stage marked by infrequent episodes. The damage to the eyelid skin caused by repeated inflammatory events is generally irreversible, resulting in cosmetic deformity and functional impairment, particularly ptosis that affects the superior visual field. Early diagnosis and appropriate monitoring can help prevent unnecessary interventions during the active stage. The extent and severity of complications vary among patients.

Surgical correction performed during the quiescent phase generally yields favorable outcomes in restoring eyelid function and appearance. Multiple procedures may be required due to progressive tissue laxity. Recurrence of edema following surgery is uncommon when the operation is appropriately timed during disease inactivity. Long-term follow-up is advised to identify potential complications such as eyelid malposition or scarring. The influence of surgical intervention on future recurrence remains uncertain.

Complications

Blepharochalasis syndrome is a non-sight-threatening disease. Complications are rare and primarily affect periocular anatomy. However, recurrent episodes of eyelid swelling can lead to the following:

• Dermatochalasis, with periocular fat atrophy in some cases and fat prolapse in others
• Thin, wrinkled, atrophic, and discolored skin
• Upper eyelid ptosis with preserved levator function, suggesting aponeurotic dehiscence
• Lateral, and occasionally medial, canthal disinsertion, causing a rounded canthal angle and shortening of the horizontal palpebral fissure (acquired blepharophimosis)
• Pseudoepicanthal fold formation
• Lacrimal gland prolapse
• Lower eyelid laxity and malposition
• Secondary ocular surface irritation

Although complications are uncommon, their potential to cause functional and cosmetic impairment should be recognized. Early detection and intervention can help mitigate these effects and preserve eyelid function.