Because of the complex and incompletely understood nature of the disease, and because of its heterogeneous and occasionally overlapping presentation, attempts to classify blepharitis have been difficult.¹² In general, blepharitis can be classified etiologically into infectious and noninfectious, or anatomically into anterior and posterior blepharitis,¹,²,³,⁴,⁵,⁶,⁷,⁸,⁹,¹⁰,¹¹,¹² although more elaborate classification schemes that subdivide blepharitis into multiple categories have been proposed.¹,⁴ Numerous subclassification systems were also proposed for meibomian gland dysfunction (MGD), but the most common is to categorize the condition into obstructive, hyposecretory, and hypersecretory forms.⁹,¹³

In an attempt to simplify the diagnostic and therapeutic process of blepharitis, the American Academy of Ophthalmology adopted an anatomical model whereby blepharitis was classified into anterior (seborrheic and staphylococcal) and posterior blepharitis (MGD).⁹ A modified version of this classification scheme is adopted in this chapter, whereby demodicosis is discussed separately in addition to the three main blepharitis subcategories outlined above.¹,⁹,¹⁰

Staphylococcal blepharitis occurs due to bacterial colonization of the anterior lid margin, mostly by Staphylococcus aureus. Other isolates include coagulase-negative staphylococcus (CoNS), Staphylococcus epidermidis, Propionibacterium acnes, and Corynebacterium.¹,⁴ Although S. aureus, and the less virulent commensals CoNS and S. epidermidis, may be isolated from the eyelid margin of normal healthy patients without blepharitis,¹¹,¹⁴ blepharitis patients have a more heavily colonized lid surface than normal controls.¹⁵ Yet despite this heavy load, it is not entirely clear whether the morbidity of staphylococcal blepharitis occurs due to a direct infection by S. aureus, a cell-mediated immunologic allergic response to S. aureus, or indirectly as a reaction to the exotoxin produced by the organism rather than the organism itself.⁴,¹¹

The exact cause of seborrheic blepharitis is also not well understood. The etiology might be inferred indirectly from studying the multifactorial etiology of seborrheic dermatitis, which is a chronic relapsing skin disease affecting the sebaceous gland-rich body areas including the scalp and face.¹⁶ Hormonal influences, a weakened immune system, and lipophilic yeasts of the genus Malassezia (former Pityrosporum) that feed on lipids in the skin may all contribute to seborrheic dermatitis with accompanying blepharitis.¹⁶,¹⁷ Other risk factors for seborrheic dermatitis include HIV/hepatitis C infection, Parkinson disease, Down syndrome, and chronic alcohol pancreatitis.¹⁶,¹⁸ It appears that Malassezia plays a definitive role in the etiology of seborrheic dermatitis/blepharitis, but the exact etiopathogenetic events are not known.¹⁶,¹⁸ The yeast genes are switched on to produce
different irritants or metabolites like malassezin, which may activate an inflammatory pathway eventually leading to the typical clinical signs of the condition.¹⁶,¹⁸ Of all the Malassezia species recognized so far, Malassezia restricta and Malassezia globosa are the most common isolates in seborrheic dermatitis.¹⁶

Although the terms posterior blepharitis and MGD are used synonymously in the literature, they are not unequivocally interchangeable, as other rare causes of posterior blepharitis can occasionally be observed including infectious or allergic conjunctivitis as well as congenital absence of the meibomian glands.⁵,¹² Meibomian gland agenesis is observed in association with the exceedingly rare anhidrotic ectodermal dysplasia.¹² The ectodysplasin A (EDA) gene responsible for the disease controls the development of sebaceous glands throughout the body, including the meibomian glands. The gene expresses the EDA protein, which is detected in tears and helps in maintaining the ocular surface.¹²,¹⁹,²⁰

It is the acquired form of MGD that is far more commonly observed in clinical practice.²¹ The exact cause of acquired MGD is largely unknown. Recent research has provided direct evidence supporting the hypothesis that altered lipid composition of meibomian secretions as well as oxidative stress play a crucial role in the development and/or exacerbation of MGD.²⁰,²²,²³ What exactly changes the lipid composition of meibum is largely unknown, but the biochemical alteration that ensues leads to thickening of the secretions, plugging of the glands, and pouting of the meibomian orifices.¹,²²,²⁴ However, oxidative stress results in a chronic accumulation of reactive oxygen species, which is hypothesized to promote inflammation through the release of proinflammatory cytokines.¹,²²,²³

Although the underlying pathogenetic events are hypothetical, there are several established local and systemic risk factors that may influence the structure and function of the meibomian glands.¹²,²⁵,²⁶ Aging is a major factor influencing the dynamics of meibomian function. The critical etiologic role of aging is probably related either to the buildup of reactive oxygen species or due to an age-related decline in androgen level because androgen is a potent regulator of sebaceous gland function.²⁶,²⁷,²⁸,²⁹,³⁰ Likewise, androgen deficiency is also implicated in MGD associated with conditions like menopause, antiandrogen treatment, complete androgen insensitivity syndrome, and Sjögren syndrome (SS).²⁶,²⁷,²⁸,²⁹,³⁰ Of note is that patients with SS do not only suffer from evaporative tear deficiency, but they suffer from MGD as well. Rosacea is also an important risk factor in posterior (90% of rosacea patients) as well as in anterior blepharitis (50%).¹² Demodicosis is also a suspected but unconfirmed risk factor for MGD.¹² Medications including 13-cis retinoic acid, postmenopausal hormone therapy, antihistamines, and antidepressants may all be associated with MGD.¹²

An often overlooked cause of MGD is facial nerve palsy.³¹ The muscle of Riolan plays a direct role in the expression of meibomian gland secretions, and its paralysis is implicated as the cause of this entity.³¹,³² Environmental factors (geographic location, temperature, and humidity), as well as contact lens wear, may also play a role in MGD pathogenesis.¹² Other possible associations include chronic graft-versus-host disease after hematopoietic stem cell transplantation and the S-1 combination chemotherapy regimen, which causes irreversible destruction of the meibomian glands.²⁰,³³

The role of Demodex mites is well established as a separate entity causing either anterior blepharitis (Demodex folliculorum) or posterior blepharitis (Demodex brevis). As its name implies, D. folliculorum is a microscopic obligate hair follicle mite that together with D. brevis favorably inhabits the eyelids.³⁴,³⁵ Demodex spp. are generally considered nonpathogenic parasites that can normally exist in asymptomatic individuals and can only induce signs and symptoms in immune-deprived patients.³⁴,³⁵ The exact etiopathogenic events underlying Demodex blepharitis are not exactly known, but there are theories. The most plausible theory is a direct infestation by the Demodex mite, which lives on the skin of the eyelid causing direct damage by consuming epithelial cells and inducing microabrasions that result in epithelial hyperplasia and reactive hyperkeratinization around the base of the lashes.³⁵,³⁶ Also, their debris and excretory waste may elicit a host inflammatory response via a delayed hypersensitivity reaction. Both mechanisms ultimately cause chronic blepharitis, conjunctival inflammation, and MGD.³⁵,³⁶ An alternative theory is that the parasite simply acts as a carrier host for the symbiotic gram-negative bacterium Bacillus oleronius, which grows in the Demodex intestine. It is excreted by the parasite releasing several proteins, which in turn stimulate an inflammatory response in infected patients.³⁵,³⁶ It is not entirely implausible that both the Demodex spp. and B. oleronius function as copathogens in the development or exacerbation of blepharitis.³⁵,³⁶ Of note is that some authors deny the pathogenic role of Demodex mites in blepharitis considering the mites to be innocuous saprophytes of the skin.³⁴

Because of its definitional uncertainty and the ubiquity of the condition, accurate data about the prevalence of blepharitis are largely lacking or inconsistent.³,⁹,²⁰ The condition is very common, as blepharitis is frequently observed by optometrists and ophthalmologists alike (47% and 37% of their practice, respectively).³ Posterior blepharitis may be twice as common as anterior blepharitis (12% vs 24%),³,³⁷ and asymptomatic MGD may be far more common than symptomatic MGD (18% vs 29.5%).³⁸ The prevalence data available for MGD are also inconsistent and vary between 3.5% and 70%, again because of the lack of standardization between clinical trials,³,¹²,²⁰ but the striking trend is that MGD is generally more common in Asians than in Caucasians.¹²,²⁰ The prevalence increases markedly with age, rising from 0% for subjects younger than 10 years to 67.2% for those older than 60 years.²²

Blepharitis patients complain of a burning, itching, gritty or foreign body sensation, crusting and redness or irritation of the lid margins, and occasionally gluing of the lashes upon waking.¹,³ Because these symptoms are shared by both types of blepharitis as well as patients with dry eye disease, it is difficult to establish a diagnosis based on symptomatology alone.¹,¹² Patient history may still help if there is an underlying skin condition.¹⁵,³⁹ A history of seborrheic dermatitis, atopic eczema, or rosacea may suggest the coexistence of seborrheic blepharitis, staphylococcal blepharitis, or MGD, respectively.¹,¹⁵,³⁹ Blepharitis may also amplify the symptoms of coexisting ocular surface disease, including dry eye disease or allergy.⁹ Although patients with posterior blepharitis may be more symptomatic than anterior blepharitis, some patients with overt clinical signs of MGD may be entirely asymptomatic.¹,⁵