Blepharochalasis Syndrome

Disease Entity

Blepharochalasis is a rare syndrome consisting of recurrent bouts of upper eyelid edema associated with thinning, stretching, and fine wrinkling of the involved skin. The lower eyelids are not commonly involved. These episodes often result in eyelid skin redundancy. This condition was initially described by GJ Beer in 1817, and was named ​blepharochalasis by Ernst Fuchs in 1896.^[1] The term blepharochalasis originates from the Greek words: blepharon (eyelid) and chalasis (a relaxing).^{[2, 3, 4]}

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Bilateral lacrimal gland prolapse in the quiescent stage of blepharochalasis syndrome. Courtesy of Kathleen Duerksen, MD.

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Upper and lower eyelid edema in blepharochalasis syndrome. Notice the left pseudoepicanthal fold. Courtesy of Kathleen Duerksen, MD.

Various disease stages have been observed. In 1926, WL Benedict described a swelling stage and a subsequent stage characterized by thinning skin.^[5] Others have suggested an active, intumescent phase that precedes a quiescent, atrophic phase.^[6]

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Epidemiology

Blepharochalasis is an uncommon disorder with a typical initial presentation in adolescence or young adulthood. A study by Koursh et al that describes 22 male and 45 female cases reports an average age of onset as 11 years.^[2]  Blepharochalasis is a rare disorder and thus has no clear gender predilection; however, many case studies often report more female patients than male patients.^{[2, 7]} The intermittent attacks occur less commonly as the person ages.^[6]

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Etiology

Although the exact cause of this syndrome is unknown, several associations have been noted. A relationship with Ascher syndrome, consisting of upper lip edema and nontoxic thyroid enlargement, has been suggested by multiple cases.^{[8, 9]} One case of blepharochalasis associated with dermatomyositis and lymphocytic leukemia has been reported.^[10] Others have proposed that blepharochalasis is exacerbated by hormonal influences (may explain the common onset with puberty), menstrual cycles, upper respiratory tract infections, and allergies. In several individuals, systemic abnormalities (eg, vertebral anomalies, renal agenesis, congenital heart disease) have been found.^[11]  

Tissue biopsy in an affected patient has revealed the presence of matrix metalloproteinase, indicating a potential immune mechanism.^[12]  

A hereditary form of the disease may exist; Panneton observed varying degrees of the syndrome in many members of a large family.^[13] Autosomal dominance with incomplete penetrance and variable expressivity is possible.^[13]

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Pathophysiology

Blepharochalasis may be a form of chronic angioedema with localized vascular dilation and proteinaceous fluid extravasation. An orbital component has been suggested because, in patients with the syndrome, orbital fat has been noted to contain increased vascularity with dilated capillaries. Multiple triggers have been described, including immune reactions and environmental factors.^[14]

The finding of immunoglobulin A (IgA) deposits in lesional skin has implicated immunopathogenic causes.^[15] Elevated immunoglobulin E (IgE) levels in one case report supports the involvement of atopy in blepharochalasis. Perivascular infiltrates in patients with active disease, along with degradation of both elastin and collagen in the dermis, suggest inflammatory influences. Elastin messenger RNA (mRNA) expression has been shown to be normal compared to controls, indicating an environmental cause of breakdown, such as postinflammatory enzymatic action.^[16]

Matrix metalloproteinase 3 (MMP-3) and MMP-9 may play a role in the development of this disease. One recent study by Browning et al reported a case of blepharochalasis stemming from episodes of nighttime crying, linking the presence of MMP-9 in human tears to the onset of blepharochalasis.^[17]

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Relevant Anatomy

The eyelid skin is extremely thin and distensible, which may promote vulnerability to further thinning and wrinkling after an episode of severe edema. The levator aponeurosis, the tendonous continuation of the levator palpebrae superioris muscle, attaches to the anterior surface of the tarsus in the upper eyelid. This structure may similarly undergo thinning and stretching during edematous attacks, leading to aponeurotic upper blepharoptosis. Likewise, stretching of the orbital septum allows prolapse of the tissues behind (including orbital fat and lacrimal gland).^[18]

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Indications for Surgical Intervention

Surgery is primarily indicated for correction of sequelae in those who have achieved a stable course later in the disease, and usually follows a 6 month to 1 year interval of quiescence to prevent, delay and/or minimize post-operative complications.^[6] Corrective procedures may include levator aponeurosis dehiscence repair, canthal tendon reattachment, eyelid tightening, blepharoplasty, and fat grafting (please see Treatment sectin for additional details).^[19]

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Contraindications to Surgical Intervention

Those experiencing active episodes of edema should not undergo surgery. Surgical candidates should have displayed at least 6 months to 1 year of quiescence.^[6] Systemic steroids, topical steroids, antihistamines, and anti-inflammatory agents have not been shown to alter the course of the disease or to alleviate the symptoms associated with acute episodes.^[2]

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History

Patients report repeated episodes of painless swelling of one or both eyelids with subsequent thinning of eyelid skin, typically starting at approximately age 10–20 years.^[7]  Edema is almost always observed initially in the upper eyelids. Most cases occur bilaterally, but unilateral instances have been reported. The frequency of attacks is widely variable with symptoms lasting anywhere from hours to days, averaging 2 days.^[2]  A preceding period of physical or emotional stress may be reported. A history of allergy is occasionally elicited.^[6]

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Physical Examination

In the early active phase, patients present with nonerythematous edema of one or both upper eyelids. Patients rarely (and only in severe cases) present with nonerythematous edema of the lower eyelids. Thinning of the eyelid skin may be present in the active stage of the disease. Other physical findings include proptosis, blepharoptosis, blepharophimosis, conjunctival injection, and eyelid malposition.

Sequelae of the active phase of the disease characterize the atrophic phase of blepharochalasis. These sequelae include the following:

• Severe thinning of eyelid skin (iris may be visible through the eyelid skin)
• Fine wrinkling of the eyelid skin (cigarette-paper skin)
• Stretched, redundant eyelid skin, occasionally causing visual obstruction
• Subcutaneous telangiectasia
• Pigmentary skin changes (bronze deposits)
• Upper blepharoptosis with levator aponeurosis dehiscence
• Eyelid malposition (ectropion or entropion)
• Acquired blepharophimosis due to canthal tendon dehiscence
• Medial fat pad atrophy with pseudoepicanthal folds
• Orbital fat prolapse
• Lacrimal gland prolapse^{[20, 19]}

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Complications

Complications associated with blepharochalasis include but are not limited to:^[6]  

• Blepharoptosis
• Prominent eyelid vacularity
• Orbital fullness
• Orbital fat pad atrophy

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Approach Considerations

The diagnosis of blepharochalasis syndrome is made through clinical history and physical examination.^[6]

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Laboratory Studies

Laboratory studies do not currently play a role in the diagnosis of blepharochalasis syndrome.^[6]

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Imaging Studies

Ultrasonography, CT scanning, or MRI may be performed to exclude differential diagnoses including dysthyroid orbitopathy, idiopathic orbital inflammation, or other processes that could result in eyelid edema. Imaging may be especially warranted in individuals with atypical clinical presentations.^[2]

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Histologic Findings

Eyelid biopsy of a patient with blepharochalasis may reveal perivascular inflammatory cells, including lymphocytes, plasma cells, mast cells, histiocytes, and eosinophils in the dermis (that stain positive for matrix metalloproteinases 3 and 9), and are associated with a marked decrease in elastic fibers.^[6]  In contrast, eyelid biopsy of affected skin may reveal immunoglobulin A (IgA) deposits in the dermoepidermal junction with loss of collagen elastic fibers in the dermis.^[6]  (Please see the ​Pathophysiology sub-section in the Overview section for additional information).

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Staging

1) Earlier active phase: non-pitting edema of the eyelid is most prominent

• Hypertrophic variant: fuller appearance of the orbit secondary to orbital fat prolapse as a result of orbital septum weakness
• Atrophic variant: hollow appearing globes secondary to fat atrophy

2) Late phase: eyelids are characterized by increased laxity and thinning

3) Quiescent disease: no acute flare-ups for 2 or more years ^[21]

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Medical Therapy

No pharmacologic agents have proven to be beneficial in the treatment of blepharochalasis. The ability of antihistamines, steroids, sympathomimetics, mast-cell stabilizers, and cool compresses to modify the symptoms of acute attacks has not been determined.^[6]

Angioedema relief has been reported in a small case series using oral acetazolamide in conjunction with topical hydrocortisone.^{[22, 6]}

Oral doxycycline has also been suggested as an inhibitor of matrix metalloproteinase activity, which may be increased in those affected by blepharochalasis.^{[12, 6]}

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Surgical Therapy

Surgery is performed in patients after at least 6 months of disease inactivity to correct anatomical defects resulting from previous bouts of swelling.^[19]

Redundant upper eyelid skin is corrected with the usual blepharoplasty techniques, which may include reforming the eyelid crease with sutures. Excision or sculpting of prolapsed orbital fat may be considered but often in a conservative fashion. A prolapsed lacrimal gland, when present, may also be resuspended.^[21]

Upper blepharoptosis is preferably corrected through repair of levator dehiscence or levator advancement. A Fasanella-Servat procedure has been described to repair blepharoptosis associated with this syndrome, but the technique does not precisely address the anatomical defect in question.^[23]

Lateral canthoplasty is often effective in repairing blepharophimosis because of attenuation of the lateral canthal support structures. Repair may be accomplished with the attachment of a lateral tarsal tongue to the periosteum on the internal aspect of the lateral orbital rim with nonabsorbable sutures. A periosteal flap or lateral orbital rim drill holes may also be used.^[21]

Fat atrophy and a significant superior sulcus defect may be addressed with autologous grafting techniques, including orbital fat repositioning, dermis fat grafting, fat pearl grafts, and aspirated fat transfer. Consider injectable synthetic fillers, such as hyaluronic acid or calcium hydroxylapatite.^[24]

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Complications

After correction of the abnormalities present in blepharochalasis, pronounced or prolonged edema may complicate the postsurgical course. The edema may be a manifestation of the underlying disease process responsible for blepharochalasis syndrome. Surgical interventions may be of limited benefit in treating recurrent postsurgical episodes of disease, and this may make postsurgical expectations less predictable.^[2]

Overcorrection with levator resection surgeries has been reported to be associated with complications and so intentional undercorrection have been advocated.^{[19, 25]}

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Outcome and Prognosis

As individuals age, the frequency of attacks typically decrease; however, there is insufficient data regarding changes to the frequency of attacks following surgical correction.^[6] Because surgical correction does not treat the underlying pathophysiology of the disease, post-surgical complications may recur and include blepharoptosis and fat prolapse. Reports of post-surgical attacks range from as early as a month to 6 years after surgery.^[19] In order to minimize and/or delay these post-surgical recurrences, it is recommended that surgeons defer surgical correction until remission has been maintained for at least 6 months to 1 year.^[6]

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Future and Controversies

Blepharochalasis may have an orbital component. This has been implied in patients who exhibit proptosis with the disease, and histologic findings in orbital fat biopsies further suggest orbital involvement. Future studies may elucidate this point.

As immunologic and genetic methodologies continue to improve, the etiology of blepharochalasis syndrome will likely be further elucidated. Effective treatments of this potentially disfiguring syndrome will hopefully follow.^[16]

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Prevention

Future interventions will likely be towards prevention of blepharochalasis in order to avoid the need for surgical correction and therefore avoid post-surgical complications.^[21]

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