Cryopyrin-Associated Periodic Syndrome in Neuro-Ophthalmology

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Gour Wang, MD Cryopyrin-Associated Periodic Syndrome in NeuroOphthalmology Shruthi Harish Bindiganavile, MD, Shannon Beres, MD, Nita Bhat, MD, Andrew G. Lee, MD C ryopyrin-associated periodic syndromes (CAPS) are a set of rare inflammatory conditions related to disorders of the protein, cryopyrin. CAPS manifests as recurrent coldinduced urticaria, fever, hearing loss, and meningitis which vary by severity: a milder form (familial cold autoinflammatory syndrome [FCAS]); an intermediate form (Muckle–Wells syndrome [MWS]); and a more severe form (chronic infantile neurological cutaneous and articular syndrome [CINCA]), previously called neonatal-onset multisystem inflammatory disease (1,2). We describe 2 cases of CAPS presenting with neuro-ophthalmic findings including optic neuropathy. To the best of our knowledge, these are the first such cases in the English language neuro-ophthalmic literature. CASE 1 A 70-year-old woman had multiple recurrent episodes of unexplained fever and cold-induced urticaria since childhood and an unexplained hearing loss at age 30. Her ocular history included steroid-induced cataracts and bilateral corneal stromal opacities for which she underwent penetrating keratoplasty of both eyes. At age 70, she presented with bilateral sequential acute on chronic vision loss in the left eye (left eye) followed by the right eye (right eye) over a period of 4 years associated with headache and jaw pain. The serum erythrocyte sedimentation rate (ESR) was elevated at 68 mm/hour, and C-reactive protein (CRP) was increased at 6.1 mg/dL. A temporal artery biopsy showed transmural lymphocytic and histiocytic infiltrate Department of Ophthalmology (SHB, NB, AGL), Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas; Departments of Neurology and Ophthalmology (SB), Stanford University, Palo Alto, California; The Houston Methodist Research Institute (AGL), Houston Methodist Hospital, Houston, Texas; Departments of Ophthalmology, Neurology, and Neurosurgery (AGL), Weill Cornell Medicine, New York, New York; Department of Ophthalmology (AGL), University of Texas Medical Branch, Galveston, Texas; University of Texas MD Anderson Cancer Center (AGL), Houston, Texas; Texas A and M College of Medicine (AGL), Bryan, Texas; and Department of Ophthalmology (AGL), The University of Iowa Hospitals and Clinics, Iowa City, Iowa. This work was presented in part at the 2018 Frank B. Walsh Society Meeting, March 3, 2018, Waikoloa, Hawaii. The authors report no conflicts of interest. Address correspondence to Andrew G. Lee Blanton Eye Institute, Houston, Methodist Hospital, 6560 Fannin Street, Suite 450, Houston, TX 77030; E-mail: [e-mail] Harish Bindiganavile et al: J Neuro-Ophthalmol 2021; 41: e297-e299 involving the intima, media, and adventitia with segmental loss and giant cell infiltration of the internal elastic lamina. On examination, her vision was 20 of 70 in the right eye and count fingers at 5 feet in the left eye, with sluggish pupil responses. The anterior segment examination showed previous bilateral clear corneal grafts and posterior chamber intraocular lenses. Her fundus examination showed optic disc edema both eyes followed by bilateral optic atrophy (Fig. 1). She was treated with oral steroids and was tapered after a course of tocilizumab. As part of her work-up for chronic recurrent cold-induced urticaria, the patient underwent genetic testing for CAPS, and she was found to have the pathogenic mutation for NRLP3 c.1061C . T (p.Ala354Val) which codes for cryopyrin, confirming the diagnosis of MWS. The patient was started on canakinumab injections after which her urticaria improved. Her vision has remained stable at Count fingers at 5 feet in both eyes. CASE 2 A 35-year-old man with no ocular history presented with slowly progressive bilateral blurred vision and headache over 2 months. He had unexplained bilateral sensorineural hearing loss, fevers, pruritic maculopapular rash on the chest and abdomen (Fig. 2), lymphadenopathy, and an unintentional weight loss of .35 lb over the past 6 months. The medical history was significant for a positive Purified Protein Derivative test during his childhood. On examination, the visual acuity was 20 of 70 in the right eye and 20 of 50 in the left eye. Color vision was 4 of 8 and 6 of 8 with Ishihara color plates. The fundus examination showed bilateral optic disc edema (Fig. 3). Visual field testing showed enlargement of the blind spots with some central defects. Complete blood count showed a neutrophilic leukocytosis with elevated serum white blood cell count of 26.4 cells/mL (normal less than 11 cells/mL). The differential showed 87% neutrophils. The patient had thrombocytosis with a platelet count of 596 per microliter (normal values 150–400) and an elevated ESR of 74 mm/hour. The computed tomography scan of the chest abdomen and pelvis showed bilateral axillary and inguinal lymphadenopathy with mild hepatosplenomegaly. A lymph node biopsy revealed reactive hyperplasia. The brain MRI with contrast showed enhancement in the left Meckel’s cave and left lacrimal gland enlargement, with no e297 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Fundus examination showing bilateral optic atrophy in Case 1. optic nerve enhancement. A lumbar puncture showed an elevated opening pressure of 27 cm of water. Cerebrospinal fluid (CSF) white cell count was elevated at 456 cells per mm3 with 73% neutrophils, protein elevated at 229 mg/dL (normal less than 60 mg/dL), and normal glucose. CSF cytopathology showed acute inflammatory cells, and cytology was negative for leukemia and lymphoma. He was prescribed empiric fluconazole 200 mg QID for possible fungal infection. Serologic testing for HIV, syphilis, tuberculosis, Cryptococcus, Histoplasma, Brucella, and Bartonella were negative. Skin biopsy was consistent with urticaria. A bone marrow biopsy and a lacrimal gland biopsy were unrevealing. Genetic testing for CAPS was performed and returned negative. However, given the constellation of clinical FIG. 2. Multiple erythematous maculopapular rashes on the chest and abdomen. e298 findings, the patient was diagnosed clinically with CAPS and was started on oral steroids as a bridge to start IL-1 inhibitor, anakinra. After starting anakinra, the optic disc edema resolved with remaining gliosis over a few months to a final visual acuity of 20 of 70 both eyes, with a resolution of his rash and headache. DISCUSSION Cryopyrinopathies include a recently identified group of hereditary diseases characterized by recurrent febrile episodes associated with multisystem inflammatory symptoms. The inheritance pattern is autosomal dominant, or a de novo mutation traced to a missense mutation on chromosome 1q44 (3). The protein isolated from the genetic mutations is called cryopyrin, which regulates of inflammation and apoptosis (4) mediating its effects by forming an inflammasome which causes caspase-1 mediated activation of IL-1 (2). IL-1 is the primary mediator of downstream inflammatory processes and hence is a primary target for treatment. A second inflammatory agent implicated is IL-6 (2) and an increase in serum levels of IL- 6 have been noted in patients with CAPS (5). Three IL-1 inhibitors are currently available—anakinra, canakinumab, and rilonacept. Resolution of ocular findings has been reported with use of anakinra. Tocilizumab, a humanized monoclonal antibody against Il-6 has been tried (2); however, mixed results have been reported with its use (3). The ultimate goal of these therapeutic interventions is to avoid chronic inflammation and end organ damage by amyloidosis. An international consensus panel of experts defined clinical and laboratory criteria for CAPS with a sensitivity of 81% and a specificity of 94%. The criteria include raised serum inflammatory markers (e.g., CRP, serum amyloid A); plus $2 of 6 CAPS-typical clinical findings: urticaria-like rash, cold-triggered episodes, sensorineural hearing loss, musculoskeletal symptoms, chronic aseptic meningitis, and skeletal abnormalities (4). Both of our patients met the clinical criteria for CAPS. Harish Bindiganavile et al: J Neuro-Ophthalmol 2021; 41: e297-e299 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 3. Bilateral optic disc edema seen in Case 2. Ophthalmic manifestations in CAPS are rare, but optic neuropathies have been sparsely reported (1,5). Ocular affections include corneal topographic abnormalities, posterior stromal opacities, corneal leukomas, band shaped keratopathy, recurrent conjunctivitis, anterior and panuveitis, iris synechiae, cataracts, optic nerve pallor, and epiretinal membrane (1,3). Although the most severe manifestations are reported in CINCA (5), milder phenotypes occur in MWS and FCAS (3). It is important to know the ocular involvement in these conditions to avoid sight threatening complications and systemic implications, which can be prevented by the timely use of IL-1 inhibitors. Both cases had typical CAPS findings over years including cold-induced urticaria, hearing loss, and elevated acute phase reactants. Case one also had temporal artery biopsy findings consistent with giant cell arteritis, the pathophysiology of which also has elevated serum levels of IL-6, as seen in CAPS. Although there is a possibility that the patient had both CAPS and GCA, the possibility that autoimmune disease and autoinflammatory disorders might occur in the same patient is intriguing. The “immunological continuum model” proposed by McGonagle in 2006 suggests that all immunemediated diseases can be classified as “autoinflammatory,” “autoimmune,” or “mixed” based on the relative contributions of innate and adaptive immune responses (6). Autoinflammatory diseases (AIDs) such as CAPS are usually characterized by tissue inflammation and aberrant activation of the innate immune system and autoreactive T-lymphocyte activation but without autoantibodies (6). Autoimmune diseases (ADs) such as GCA however are typically associated with an abnormal activation of the adaptive rather than innate immune system (6). Some authors believe that AIDs and ADs are 2 opposite ends of a continuum of immunemediated disorders and the possibility that our patient one had both CAPS and GCA cannot be excluded. Case 2 had bilateral disc edema with mildly elevated intracranial pressure with skin, lymphoreticular, and neurologic involvement. The Harish Bindiganavile et al: J Neuro-Ophthalmol 2021; 41: e297-e299 visual acuity loss was likely from optic nerve inflammation with possibly some contribution from increased intracranial pressure. There was no uveitis or macular pathology to explain the visual acuity loss. Clinicians should consider CAPS in patients with multiple recurrent bouts of cold-induced urticaria with or without fever (i.e., CAPS), hearing loss, or visual loss (anterior or posterior segment related). STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: S. Harish Bindiganavile, S. Beres, A. G. Lee, and N. Bhat; b. Acquisition of data: S. Harish Bindiganavile and S. Beres; c. Analysis and interpretation of data: A. G. Lee, S. Harish Bindiganavile, and S. Beres. Category 2: a. Drafting the manuscript: S. Harish Bindiganavile, S. Beres, and A. G. Lee; b. Revising it for intellectual content: A. G. Lee and S. Beres. Category 3: a. Final approval of the completed manuscript: A. G. Lee and S. Beres. REFERENCES 1. Cekic S, Yalcinbayir O, Kilic SS. Ocular involvement in Muckle-Wells syndrome. Ocul Immunol Inflamm. 2020;28:70–78. 2. Han JH, Je YJ, Yoon HJ, Ahn JG, Lee JS, Park JW, Park HJ. The first case series of cryopyrin-associated periodic syndrome in Korea. Allergy Asthma Immunol Res. 2019;11:583–588. 3. Snegireva LS, Kostik MM, Caroli F, Ceccherini I, Gattorno M, Chasnyk VG. Failure of tocilizumab treatment in a CINCA patient: clinical and pathogenic implications. Rheumatology. 2013;52:1731–1732. 4. 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