Cryopyrin-associated Periodic Syndromes and the Eye

Abstract

Aim: To describe the ophthalmologic findings in two patients with Muckle-Wells Syndrome, a phenotype of the Cryopyrin Associated Periodic Syndromes (CAPS) spectrum. There is currently sparse ophthalmic literature regarding the ocular manifestations of CAPS. We hope to increase awareness of this spectrum of diseases and the importance of proper treatment amongst eye care professionals.

Methods: Interventional Case Series.

Results: Patient 1 experienced resolution of aseptic meningitis, papilledema, and anterior uveitis following treatment with anikinra. Patient 2 experienced resolution of panuveitis following treatment with anikinra.

Conclusions: The severe ocular manifestations of the most severe CAPS phenotype, Chronic Infantile Neurological Cutaneous and Articular Syndrome/Neonatal Onset Multisystem Inflammatory Disease Syndrome (CINCA/NOMID) have been previously described. There is increasing evidence that patients may experience similar ocular disease with the milder phenotype of Muckle-Wells Sydnrome. There is also increasing evidence that appropriate therapy can have a profound effect on patient prognosis.

• Apthous ulcers
• conjunctivitis
• Muckle-Wells
• papilledema
• uveitis

The cryopyrin-associated periodic syndromes (CAPS) constitute a systemic autoinflammatory disease spectrum with ophthalmic manifestations. The phenotypic spectrum ranges from the relatively mild familial cold autoinflammatory syndrome (FCAS), to the intermediate Muckle-Wells syndrome (MWS), to the severe chronic infantile neurological cutaneous and articular syndrome/neonatal onset multisystem inflammatory disease syndrome (CINCA/NOMID).

Bilateral conjunctivitis has long been associated with FCAS and MWS,[1],[2] and uveitis, aseptic meningitis, elevated intracranial pressure, and papilledema/optic nerve pallor been associated with CINCA/NOMID.[2–5] There have recently been a handful of reported cases of patients in the MWS spectrum presenting with aseptic meningitis and papilledema.[6],[7] There have also been isolated reports of MWS patients presenting with uveitis (4 cases)[8] and episcleritis (3 cases).[7] To the best of our knowledge, no cases of MWS associated with aseptic meningitis, elevated intracranial pressure, papilledema, anterior uveitis, or panuveitis have been reported in the ophthalmic literature.

The unifying feature of this spectrum of disorders appears to be a genetic defect leading to cryopyrin pathway dysregulation, and subsequent overproduction of interleukin 1β (IL-1β), a proinflammatory cytokine.[2] As this pathway has been elucidated, there has been remarkable success in the treatment of these patients with anti- IL-1β therapies.

The purpose of this small case series is to raise awareness of this disease spectrum among eye care professionals.

Case Reports

Patient 1

This patient has experienced chronic waxing/waning nonpruritic urticarial rashes and conjunctivitis since birth, which worsen in intensity and frequency each winter. At the age of 3, her erythrocyte sedimentation rate (ESR) was found to be elevated at 19 mm/h, prompting genetic testing for CAPS. Both the patient and her mother were found to carry the R260W mutation. At this time she was diagnosed with 2FCAS.

At the age of 8, she developed migraine headaches and progressively worsening joint pain, and was referred for ophthalmic screening. At that time her vision was 20/20 OU, color vision was full OU, motility and alignment were normal, and her pupil exam was normal. Slit-lamp exam revealed a quiet anterior chamber OD and rare cells in the anterior chamber OS. Dilated fundus exam was unremarkable.

She subsequently developed worsening headaches, and lumbar puncture demonstrated an opening pressure of 31 cm H₂O, as well as aseptic meningitis. Repeat eye exam demonstrated persistent anterior uveitis OS and new mild bilateral papilledema. Her diagnosis was then felt to be more consistent with MWS and she was started on anakinra therapy. Repeat exam 1 month later demonstrated persistence of anterior uveitis with resolution of papilledema. Follow-up exam 3 months later demonstrated resolution of anterior uveitis and continued absence of optic nerve edema. At the time of her most recent exam she continues to have 20/20 vision OU, full color vision OU, and a normal pupil exam. Her eyes remain clear of signs of uveitis and optic nerve edema. Humphrey (Carl Zeiss Meditec,INC. Dublin, CA) visual field testing shows full fields bilaterally. Stratus optical coherence tomography (Carl Zeiss, Meditec, INC) demonstrates normal average thicknesses of the nerves bilaterally.

Unfortunately, she has recently been found to have sensorineural hearing loss. As there was no recent audiogram prior to institution of anakinra therapy, we are unable to determine if hearing loss occurred despite appropriate treatment. However, it should be noted that reversal of optic nerve edema and anterior uveitis was demonstrated following treatment with anti-IL1 therapy.

Her family history is significant for her mother having recurrent conjunctivitis, as well as recurrent aphthous mouth and throat ulcers. She had carried the diagnosis of Behçet disease prior to her genetic testing, which demonstrates the CAPS mutation. The patient also has a maternal uncle with presumed serum negative rheumatoid arthritis. He has not undergone genetic testing.

Patient 2

This woman had lifelong episodes of nonpruritic urticaria, conjunctivitis, fevers, and arthropathy. Her son had experienced similar symptoms, which prompted genetic testing at the age of 10. A novel CAPS mutation (T436A) was identified in both mother and son.[9] Both were then diagnosed with Muckle-Wells syndrome.

This patient presented for ophthalmologic care at the age of 28 with abrupt onset of redness, decreased vision, pain, and pruritus in the right eye. Vision was hand motions OD and 20/15 OS, intraocular pressures were 19 mmHg OD and 19 mmHg OS, and motilities were normal. Slit-lamp exam of the right eye demonstrated diffuse conjunctival injection, a healthy cornea, inferior peripheral anterior synechiae, and a 1.15-mm hypopyon. There was no view possible to the posterior segment. The left eye was normal. She was treated with an aggressive topical and oral steroid regimen, as well as topical mydriatics. Testing consisted of complete blood count, ESR, HLA-B27, rapid plasma reagin, anti-nuclear antigen, purified protein derivative, and chest radiograph, all of which returned with normal or negative results.

One week later she received follow-up care with a uveitis specialist. Her vision had improved to 20/30 OD and remained 20/15 OS, intraocular pressures were 20 mmHg OD and 21 mmHg OS, and motility was full OU. Slit-lamp exam of the right eye revealed continued mild diffuse conjunctival injection, a healthy cornea, resolution of the hypopyon, and 1+ cell and flare. Dilated fundus exam of the right eye revealed a healthy appearing optic nerve, an epiretinal membrane with no macular edema, and moderate to severe cell and haze in the posterior segment. Peripheral exam revealed a focus of inflammatory debris associated with an elevated, white lesion inferiorly. Her left eye remained unaffected. Anakinra therapy was then introduced and the steroid treatments were gradually tapered.

At 4-month follow-up, her vision had improved to 20/15 OD and remained 20/15 OS, intraocular pressures remained normal, motility was full OU, and the right iris was round and reactive. Slit-lamp exam of the right eye demonstrated continued normal appearance of the cornea and resolution of the conjunctival injection and peripheral synechiae, and the anterior chamber was deep and quiet. Dilated fundus exam revealed resolution of the cell and haze as well as resolution of the peripheral elevated lesion, thus demonstrating reversal of panuveitis with appropriate therapy. The nerve remained healthy and the epiretinal membrane was unchanged.

Discussion

While some clinically diagnosed cases have no identifiable gene mutation, the overwhelming majority of CAPS disorders can be traced to missense mutations on chromosome 1q44. These mutations lead to gain-of-function of the NLRP3 gene (formerly known as CIAS1) that encodes cryopyrin. As previously mentioned, a unifying feature of the subsequent cryopyrin pathway dysregulation is overproduction of interleukin 1β (IL-1β), a proinflammatory cytokine.[2]

Since first identifying the causative gene in 2000, 118 sequence variants have been identified.[10] Most mutations are inherited in an autosomal dominant fashion, but sporadic occurrences are also seen.[8] The same mutation may cause a different phenotype, as evidenced by patient 1 and her mother, and as previously described.[7],[8],[11] This variable expressivity is not well understood but likely involves mutations with reduced penetrance and contributions from other genetic factors producing varied phenotypes.[8]

Prior to gene identification, the three disorders were thought to be distinct entities. It has become more evident that CAPS actually represents a diverse spectrum, with the three classic phenotypes serving as anchor points for classification based on the severity of disease involvement.

FCAS represents the mild end of the spectrum, characterized by recurrent nonpruritic urticaria, arthralgia, and fever, often triggered by exposure to cold. Conjunctivitis may be present during flares. MWS is characterized by the addition of amyloidosis, with more than 25% of patients demonstrating autoimmune amyloidosis (AA).[11] Sensorineural hearing loss and conjunctivitis are also seen.[2],[11] CINCA/NOMID is the most severe form and manifests in the neonatal period. It comprises the triad of arthropathy, urticaria, and central nervous system (CNS) involvement. The CNS involvement commonly encountered by ophthalmologists includes aseptic meningitis with associated papilledema, optic nerve pallor from previous episodes of papilledema, and uveitis.[2–5],[11],[12] CINCA/NOMID may also present with dry eye, conjunctivitis, band keratopathy, and corneal neovascularization.[3]

In addition to our 2 cases, only a handful of patients have been reported in recent literature to have the MWS spectrum of disease and papilledema, uveitis, or episcleritis.[6–8],[11] As the pathophysiology of CAPS has become better understood, therapies targeting IL-1β, such as anakinra, rilonacept, and canakinumab, have demonstrated great success.[2] There have now been reported cases of reversal of papilledema, nephrotic syndrome, and hearing loss, as well as relief of presumed elevated intracranial pressure headaches following treatment.[6],[7],[11] Of note, patient 1 demonstrated reversal of optic nerve edema and anterior uveitis following treatment, and patient 2 demonstrated reversal of panuveitis following treatment.

Summary

CAPS is a disease with myriad manifestations. Due to its variable expressivity, it is often difficult to predict which symptoms will occur even in family members with identical mutations. With the recent introduction of such powerful medical therapies, it is imperative that these patients be diagnosed and treated as expeditiously as possible.

It is becoming evident that CAPS patients may have ocular manifestations of greater consequence than recurrent conjunctivitis in phenotypes outside the classic CINCA/NOMID. As such, ophthalmologists will likely be called upon to perform a greater number of screening exams in patients with known CAPS. In addition, a more detailed/thorough review of systems and family history may help point the ophthalmologist toward a diagnosis in an otherwise baffling case, should a patient present with findings such as those described above and no other clear explanation.

There is information in the ophthalmic literature regarding the ocular manifestations of CINCA/NOMID.[3],[5],[12] As far as we are aware, this represents the first cases of MWS associated with anterior uveitis, aseptic meningitis and papilledema, and panuveitis reported in the ophthalmic literature. We hope these cases help raise awareness among eye care professionals of this rare, potentially devastating, but treatable disease. We have included Table 1 as a brief diagnostic reference guide.

Table 1. Diagnostic clues relating to a possible CAPS spectrum disorder.

Panuveitis

Episodic urticaria, cold related or not

Absence of periodic fever

Aseptic meningitis

Sensorineural hearing loss

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

This project was supported in part by the Research to Prevent Blindness foundation, New York, NY.