Continuing Education Activity

Keratoendotheliitis fugax hereditaria is a rare inflammatory genetic condition characterized by recurrent episodes of debilitating unilateral corneal and conjunctival hyperemia, corneal edema, visual impairment, corneal opacification, and photophobia that last for two to five days. Lacrimation, pain, colored halos, diplopia, a mild anterior chamber reaction, guttata-like changes (pseudoguttata), and a ‘gritty’ feeling may also occur. Its inheritance pattern is autosomal dominant. The pathology generally begins temporally before quickly progressing to surround the entirety of the cornea. In the acute phase, the pain or discomfort is often severe enough to disrupt sleep. This article covers the genetics, pathophysiology, and evaluation of the patient with keratoendotheliitis fugax hereditaria. It also explores what is known about management, potential complications, and prognosis for patients.

Objectives:

• Summarize the most common aspects in the history of a patient with keratoendotheliitis fugax hereditaria.
• Describe the pathophysiology of keratoendotheliitis fugax hereditaria.
• Outline appropriate treatment for keratoendotheliitis fugax hereditaria.
• Summarize the physical exam findings in a patient with keratoendotheliitis fugax hereditaria.

Introduction

Keratoendotheliitis fugax hereditaria is a rare inflammatory genetic condition characterized by recurrent episodes of debilitating unilateral corneal and conjunctival hyperemia, corneal edema, visual impairment, corneal opacification, and photophobia that last for two to five days.[1][2][3] Lacrimation, pain, colored halos, diplopia, a mild anterior chamber reaction, guttata-like changes (pseudoguttata), and a ‘gritty’ feeling may also occur. Its inheritance pattern is autosomal dominant. The pathology generally begins temporally before quickly progressing to surround the entirety of the cornea. In the acute phase, the pain or discomfort is often severe enough to disrupt sleep.

Though both the hyperemia and opacification generally resolve completely within two to four days, localized opacity in the cornea may persist for weeks to months after the acute phase. Initial reports indicated that regardless of the duration of the corneal haze, or the number of episodic incidents a person experiences, the opacification always completely remits and vision returns to normal.[2] However, additional cases have shown individuals with permanent stromal opacification after numerous incidents.[1] These opacities, though evident on examination, may or may not affect visual acuity between episodes. The disease was first described in 1964 and named in a pedigree-based case report of Finnish individuals by Valle.[4] However, later reports hint that small differences in findings may indicate that the patients studied by Valle may have a closely related, but slightly different pathology.

The frequency of these symptomatic inflammatory attacks varies by age demographic. Patients who are 15 to 20 years old experience the most frequent symptoms, occurring one to eight times a year.[2][3] Attacks decrease in frequency and severity as the patient ages, though patients generally still experience moderate to severe events through their forties. However, by their mid-fifties, it appears patients are substantially less affected, with incidents causing comparatively mild symptoms and occurring less frequently.

Etiology

Keratoendotheliitis fugax hereditaria likely results from a missense mutation (c.61G>C) in the first exon of a gene named ‘nucleotide-binding domain, leucine-rich repeat family, pyrin domain-containing 3’ (NLRP3). This gene codes for a protein called NLRP3 or cryopyrin. The mutation results in a partially positively charged histidine, replacing a negatively charged aspartic acid at the genetic locus. As is the case in many mutations, this change likely alters protein folding and function and may cause aberrant activation or dysregulation; this may be problematic as NLRP3 combines with other protein molecules to assemble into inflammasomes, large complex structures that are involved, and upregulated in the process of inflammation.[3]

All thirty cases that have undergone genetically sequencing to assess for the mutation showed to be heterozygotes for the mutant gene. This finding may indicate either that homozygosity may not be compatible with life or is too rare to have been observed and reported. Additionally, the severity and frequency of attacks have varied from generation to generation, indicating a potential for other genetic phenomena such as incomplete penetrance, which has yet to be elucidated in this disease.

There are no risk factors proven to evoke episodes of this sporadic disease, and seasonal changes have reportedly had no inciting effect on incident frequency. However, patients have anecdotally linked mild viral illnesses, cooler temperatures (i.e., “sitting in the draught”), and the relief of physical or mental stress to the recurrence of symptomatic attacks.[1][2]

Additionally, several individuals in one pedigree were also affected by various collagen-based diseases. Since collagen and the neural crest cells from which the cornea derives are both mesodermal in origin, there may be an underlying association.

Epidemiology

To our knowledge, no epidemiologic study has taken place to assess for cases of keratoendotheliitis fugax hereditaria. However, reportedly the associated NLRP3 gene mutation appears in about 0.02% of Finnish people and 0.01% of non-Finnish European individuals, indicating that although all published case reports currently discuss families of Finnish ancestry, individuals of other hereditary lineages may carry the mutation.[3]

Pathophysiology

Several NLRP3 mutations have been grouped into a category of autosomal dominantly inherited autoinflammatory diseases termed cryopyrin-associated periodic syndrome (CAPS). This group of autoimmune inflammatory conditions also includes familial cold autoinflammatory syndrome (FCAS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). However, these mutations are at different genetic loci.[3][5] These syndromes have ocular symptoms that overlap with keratoendotheliitis fugax hereditaria, including keratitis, conjunctivitis, episcleritis, and clouding of corneal stroma; corneal involvement appears in 40% of patients with CAPS syndromes. However, unique characteristics of these diseases separate them from keratoendotheliitis fugax hereditaria, including papilledema, uveitis, and corneal neovascularization, in addition to their systemic symptoms such as fever.[5][6][7][8]

The NLR family of proteins encodes for inflammatory-based molecules in numerous cell lines. NLRP3 is expressed specifically in peripheral leukocytes as well as ocular structures such as lens epithelium and corneal endothelium and plays a central role in the activation of the NLRP3 inflammasome.[3][9][10][11] The inflammasome is a proinflammatory complex of proteins assembled, that regulates proinflammatory processes and caspase (pro-apoptotic) activity. Understandably, such processes are under tight regulation on a cellular level. Activation of this inflammasome is associated with several autoimmune conditions, including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and irritable bowel disease.[11][12]

It has been shown that activation of the NLRP3 inflammasome is associated with corneal inflammation, and inhibition of NLRP3 has been shown to improve corneal wound healing.[13][14][9] Additionally, mice with inactivated NLRP3 genes were shown to have decreased corneal scarring and significantly decreased opacity grade after sterile burn injury compared to mice with functional NLRP3 genes.[15] Taken together, we can surmise that aberrant activation of the NLRP3 inflammasome due to a mutation may cause inflammatory signs and symptoms with resultant corneal opacification or scarring. The c.61G>C NLRP3 mutation that causes keratoendotheliitis fugax hereditaria may lead to defects in the structure of the protein; the poorly functioning protein may allow for premature or easy activation of the inflammasome, and thus, may be responsible for the sporadic inflammatory response that typifies the disease.

As a result of the inflammatory effects, swelling and edema may develop in the corneal stroma. Proposals exist, suggesting that this occurs secondarily to a vasogenic process, thus resulting in visual impairment and symptomatic halos and diplopia.[2] This intracellular and intercellular edema and subsequent ‘looseness’ have also been proposed to cause the pseudoguttata observed in imaging, and are less prominent outside of acute episodes.[1][16][17][18] Pseudoguttata appear similar to guttata but have distinct histopathological differences and resolve, unlike the permanent Descemet membrane effects seen in true guttata. In addition to pseudoguttata, there is also a proposal that a decreased number of endothelial cells, seen in some individuals, is the result of cell death secondary to the observed inflammation.[1] However, not all reports have shown this observed decrease in cell count.[3]

History and Physical

The presentation of endotheliitis fugax hereditaria can vary, though characteristically, patients will complain of an incapacitating painful red eye with decreased visual acuity, which may begin with a foreign body sensation or stiff neck before quickly progressing. There may be associated lacrimation and congestion of the ipsilateral nostril with a watery discharge that occurs in about 50% of patients. The symptoms are typically unilateral, but bilateral or sequentially unilateral (i.e., one eye develops symptoms immediately after the initial flare resolves in the opposing eye) cases are not uncommon.[2] As the initial pain and hyperemia resolve, the patient’s remaining complaint will be a decreased visual acuity from resultant corneal edema and haze.[1]

The disease typically presents around age ten to eleven (although there are reports that it develops as early as three years of age and as late as twenty-eight), and the possibility of an initial attack merits strong consideration in younger children with a positive family history. In older individuals, a history of similar events that occur between one and six times a year may be present, though reports exist of spontaneous mutations. As the disease is genetically linked, family history is an essential aspect of making a correct diagnosis. Complete hereditary history will likely show the disease inherited in an autosomal dominant fashion, although spontaneous mutations apparently can occur.[2][3]

On slit-lamp examination in the acute phase, conjunctival injection and corneal edema will likely be present. An opacity in the central stroma, with or without keratic precipitates on the posterior surface of the cornea, is a common aspect of the disease and may be seen.[1][2] Furthermore, a ‘beaten silver’ appearance of the endothelium may be present, and central pseudoguttata (edematous endothelial cells) have been described. Corneal thickness may increase by 5% to 14% during an acute attack, though one patient presented with thinner than normal areas in the center.

However, If the patient presents following the initial acute phase (i.e., two to four days following the onset of symptoms), the only visible sequela of the disease still likely to be present is the stromal opacification or posterior precipitates.[1][2] This opacity may be a permanent aspect of the disease and can be vision-effecting outside of acute incidents. Other findings include occasional corneal erosions, and one patient had prominent iris atrophy.[3] Tomography, ocular coherence tomography (OCT), and corneal thickness are typically unremarkable between attacks, except for patients with stromal scarring and opacification.

Endothelial specular photography may reveal a decreased number of endothelial cells.[1][3] During an attack, specular imaging may show normal hexagonal cells with adjacent large, black, non-reflecting areas between them (pseudoguttata), and the changes may be apparent. Between incidents, marked pleomorphism, and black spots in the center of cells may be visible in an otherwise normal-appearing endothelial mosaic.

Evaluation

Although genetic testing is confirmatory, such methods may not be practical or necessary for all patients, especially those with known family history and characteristic symptoms. Proposed spontaneous cases in which the diagnosis is more ambiguous may, however, benefit from genetic confirmation.

Evaluation of the eye differs on whether the patient is experiencing an acute attack, a phenomenon that may be difficult to assess in the clinic due to the short duration of symptoms. In an acute attack, there may be an increase in the corneal thickness (which may be associated with pseudoguttata formation).[2][19] Pseudoguttata may present using confocal, specular, or light microscopy.[17]

Outside of an attack, imaging and testing can rule out other potential causes. Intraocular pressure is expected to be stable, even in acute disease. Since the pathology is primarily in the cornea, aqueous humor will be clear. Additionally, synechiae do not appear to develop.[2] As noted earlier in the text, OCT is not particularly helpful, and tomography and topography are typically normal outside of an acute episode.

Since specular photographic changes are evident even in between attacks, this imaging modality may be the most useful in determining patients who may have the disease when it is not an acute episode.[1]

Treatment / Management

As the underlying etiology of keratoendotheliitis fugax hereditaria is genetic, and the pathophysiology is incompletely understood, treatment is mainly supportive based on published case reports. As reported, the best treatment is topical corticosteroids, though the frequency and dose have not been published. However, not all patients respond to topical steroid treatment. Also, reports exist that oral antihistamines have been of symptomatic benefit to patients, and drowsiness typically associated with some drugs in this class may help patients who struggle to sleep through their symptoms.[2] Topical or oral NSAIDs are additional modalities that can relieve the pain associated with attacks.[1][3]

Regardless of the treatment choice selected, therapy should begin immediately as early intervention reportedly limits symptoms. Delaying treatment until corneal inflammation is apparent seems not to affect recovery. Many patients have reported that early treatment with topical steroid drops or ointments may stop symptoms from progressing or alleviate symptoms more rapidly.[1][2][3] No invasive or surgical management has been reported.

In regards to visual acuity, some patients have found more satisfactory results with rigid contact lenses than with glasses.[3]

As NLRP3 activation plays a central role in inflammation, the mutation that causes keratoendotheliitis fugax hereditaria may cause dysregulation of the protein and resultant inflammation, modulators that inhibit activating upstream effects or subsequent proinflammatory downstream effects may be of benefit in the treatment of this disease. Inhibitors of NLRP3 effects including MCC950, beta-hydroxybutyrate, type 1 interferon, and interferon beta, resveratrol, arglabin, CB2R agonists, and MicroRNA-223 may, therefore, prove beneficial in the treatment or prevention of acute attacks and prevent corneal scarring.[11][12][9] Many of these agents have already demonstrated a capacity to limit the inflammatory response in various inflammatory ocular pathologies and cell lines with varying effects.[20][21][22][23] More research is needed to further understand the effect of these inhibitors on corneal cells and keratoendotheliitis specifically.

Differential Diagnosis

Cases with an established genetic lineage and typical symptoms may be diagnosed clinically, but sporadic cases are especially challenging to diagnose. As keratoendotheliitis fugax hereditaria in the acute phase dies down, clinicians may incorrectly diagnose the residual inflammation as acute anterior uveitis.[3] Differential diagnoses, therefore, generally revolve around other inflammatory eye diseases, including uveitis or endotheliitis, with or without pseudoguttata. The etiologies may include infectious (e.g., bacterial, viral, fungal, etc.), autoimmune, drug-induced, or other rare genetic causes.[17][24]

• Iridocorneal endothelial syndrome
• Anterior uveitis
• Chandler syndrome
• Angle-closure glaucoma
• Relative anterior microphthalmos
• Brown-McLean syndrome,
• Posterior polymorphous corneal dystrophy

Prognosis

The prognosis for patients with keratoendotheliitis fugax hereditaria is fair. While the frequency and severity of the condition lessen with time, stromal scarring, seen in 50% of patients, may permanently affect vision. These permanent opacifications seem to increase with repeated attacks as they are denser and more debilitating in older patients.[3]

It is possible that other individuals with less severe forms of the mutation exist, or that less severe expressivity in an individual may result in mild or subclinical symptoms. If these cases do exist, the prognosis is likely good to excellent, and may not need treatment.

Complications

Aside from the pain and discomfort that may be associated with acute episodes, the primary long-term complication is a decline in visual acuity. An increased number of attacks may contribute to permanent corneal scarring and a decrease in the quality of life.[3]

Deterrence and Patient Education

As the disease is genetic, and without an identified trigger for incidental episodes, there are no known preventative or prophylactic steps that patients can take to limit or decrease the frequency, duration, or severity of attacks. Patients should be educated that any episodes of decreased vision should warrant an ophthalmologic examination.

Pearls and Other Issues

• Keratoendotheliitis fugax hereditaria is an autosomal dominantly inherited condition that presents with sporadic episodes of pain, conjunctival hyperemia and corneal edema, which can lead to decreased visual acuity. These incidents last two to five days.
• A corneal opacity, keratic precipitates, pseudoguttata, and a ‘beaten silver’ appearance of the endothelium are common findings
• Patients are generally children to teenagers of Finnish descent with a strong family history, though sporadic cases exist.
• Episodes are self-resolving, with minimal acute complications; however, permanent corneal scarring and decreased visual acuity may develop after recurrences.
• The condition is usually unilateral, though there have also been bilateral episodes reported.
• The condition is likely the result of an NLRP3 gene mutation that causes easily activated inflammatory responses.
• Treatment is aimed at symptomatic relief using a topical steroid, topical NSAIDs, and/or oral antihistamine medications.
• Molecules that inhibit the effects of NLRP3 may help to treat this disease, though more research is necessary to understand the effect of these drugs on corneal cells.

Enhancing Healthcare Team Outcomes

Patients with suspected keratoendotheliitis fugax hereditaria require a referral to an ophthalmologist familiar with the disease. Genetic counselors or geneticists should also be included as part of the healthcare team for these patients to provide information and resources to patients. Prescriptions of topical or oral medications may be of some benefit to these individuals. As newer immunologic inflammatory inhibitors become available as pharmaceutical options, the healthcare team should also include a pharmacist familiar with the pharmacokinetics of these drugs to help optimize outcomes. [Level 5]