Keratoendotheliitis Fugax Hereditaria

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Article initiated by:

Jordan Hastings, Majid Moshirfar, M.D., Yasmyne C. Ronquillo

All contributors:

Vatinee Y. Bunya, MD, MSCE, Sezen Karakus, MD, Majid Moshirfar, M.D.

Assigned editor:

Sezen Karakus, MD

Review:

Assigned status Up to Date

 by Sezen Karakus, MD on September 2, 2024.

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Contributing Editors:	add

Disease Entity

Keratoendotheliitis fugax hereditaria is an autosomal dominant condition that results in episodic debilitating inflammatory attacks that result in unilateral pain, corneal edema and opacification, conjunctival injection, and a decrease in visual acuity; these episodes last 2-5 days. Episodes occur 1-8 times a year, and an increased number of total attacks may contribute to corneal scarring. It is classically associated with individuals of Finnish descent. A recent report showed that this disease can also be seen in non-Finish European populations. The associated gene mutation has been reported in about 0.02% of Finnish people and 0.01% of non-Finnish European individuals.

Etiology

The disease has been linked to a guanine-to-cytosine missense mutation (c.61G>C) in the "nucleotide-binding domain, leucine-rich repeat family, pyrin domain-containing 3" (NLRP3) gene and resultant NLRP3 protein (also called cryopyrin). The resultant amino acid change causes a difference in protein charge and may result in protein misfolding. The NLRP3 protein is a major contributor to the NLRP3 inflammasome. An inflammasome is a multi-protein complex that induces inflammatory changes when assembled and activated. Poor protein folding mechanics may inadvertently cause this process to become dysregulated or prematurely activated.

Risk Factors

Risk factors for the onset of inflammatory episodes are unestablished. However, patients have anecdotally reported that mild viral illnesses, exposure to cooler temperatures, and the relief of mental or physical stress may be associated. In one affected lineage, patients were also reported to have collagen-based pathologies, and an association may exist.

Pathophysiology

NLRP3 mutations can give rise to a group of inheritable autoinflammatory processes that fall under the umbrella of cryopyrin-associated periodic syndromes (CAPS),, and some of these syndromes have overlapping ocular manifestations with keratoendotheliitis fugax hereditaria. Mutations in this gene affect the NLRP3 inflammasome whose activation is associated with various autoimmune conditions. The specific mutation in keratoendotheliitis fugax hereditaria likely causes unnecessary activation of the inflammasome, resulting in a clinically significant inflammatory attack. Several autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, as well as irritable bowel disease, have been associated with activated inflammasome. A review is a review of

Inflammatory responses are often associated with edema. In the case of keratoendotheliitis fugax hereditaria, edema is present in the corneal stroma, and pseudoguttata (edematous endothelial cells) have been noted on imaging, perhaps secondary to a vasogenic process. Unlike true guttata, pseudoguttata resolve after the episode.

History

Patients typically experience their first episodes at age 10-11 years (range, 3-28 years),, and tend to be of Finnish ancestry. The patient may initially report a stiff neck or foreign body sensation that quickly develops into an incapacitating painful red eye with blurry vision. Lacrimation and ipsilateral nasal congestion are also commonly observed. Following the resolution of the pain, the corneal edema and resultant corneal haze with decreased visual acuity slowly resolves. Typically, episodes are observed in one eye; however, cases have been reported simultaneously in both eyes, or initially in one eye, and after its resolution, in the other eye.

Physical examination

If the patient is examined during an acute attack, conjunctival injection, and corneal edema, in addition to an increase in corneal thickness and pseudoguttata, may be observed. A central stromal corneal opacity is likely to be present, and keratic precipitates may be seen. Outside of an acute inflammatory event, the eye will generally appear quiet, though residual corneal scarring from multiple attacks may be present in adults.

Diagnosis

Genetic testing is available, though likely unnecessary, in patients with classic symptoms and positive family history. However, cases attributed to spontaneous mutations, or cases that may be more ambiguous may benefit from genetic testing. Specular or confocal microscopy may be helpful to image pseudoguttata as black, non-reflecting areas between normal hexagonal cells during an episode. Corneal thickness may be measured as increased by 5% to 14% during an episode. Additionally, specular microscopic changes, including pleomorphism and dark spots within cells, may be present outside of an episode and can help with diagnosis.

Differential diagnosis

If patients are seen as the acute episode resolves, a diagnosis of anterior uveitis may be mistakenly made. Other inflammatory conditions, such as infectious, autoimmune, or drug-induced endotheliitis, should be considered. Other rare genetic diseases may be considered, such as iridocorneal endothelial syndrome, Chandler syndrome, Brown-McLean syndrome, and posterior polymorphous corneal dystrophy.

Management

Treatment modality recommendations are based on case reports. Supportive therapy with topical steroids is the most effective option, though not all patients respond. The frequency and dose of topical steroids have not been established. Oral antihistamines have also been reported to have a beneficial effect on symptoms due to their sedative effects. Topical or oral NSAIDs may be used to target the associated pain.

Attempts to use agents that target the NLRP3 inflammasome pathway have not been reported. As many of these are newly elucidated and studied, no published cases exist. However, many of these agents have been shown to limit inflammation in ocular cell lines. and their use may help prevent the frequency or severity of attacks and limit corneal scarring.

Initiation of treatment should begin as soon as the patient perceives symptoms, as rapid treatment may abate the attack or result in quicker resolution.

Complications

Although initial episodes are self-resolving, recurrent attacks may result in permanent corneal opacification and decreased visual acuity.