A case report on allopurinol induced crystalline maculopathy

Dear Editor, Allopurinol hypersensitivity among susceptible individuals is widely reported. Nevertheless, ocular manifestations caused by allopurinol are rarely encountered. Here, we describe a case of a young Chinese woman diagnosed with gout and metabolic syndrome, who developed crystalline maculopathy after allopurinol was initiated. A 33-year-old Chinese woman was referred to our center in 2012 at 24 weeks period of gestation. Her presenting complaint was recurrent multiple joint pain for the past 3 years. It was poly-articular, involving both big and small joints. Each episode was associated with swelling and hyperemic skin changes. Attacks were precipitated by intake of high purine diet. The pain resolved gradually without specific treatment. Her attacks became more frequent as her pregnancy progressed. In addition, she had type II diabetes mellitus diagnosed since the age of 30 and had been on treatment since then. There was strong family history of diabetes mellitus. On examination, she was obese with body mass index of 35.2. At presentation, she was normotensive. There were neither skin rashes nor tophi deposits. Joint examinations revealed asymmetry, poly-articular tenderness and swelling involving hands, knees, ankles and feet, with clinical evidence of effusion over both knee joints. There were no joint deformities. Her initial investigations showed elevated C-reactive protein of 11.6 mg/L and erythrocyte sedimentation rate of 86 mm/h. Her fasting blood sugar was 7.6 mmol/L. Fasting lipid profile showed elevated total cholesterol (6.20 mmol/L), elevated triglyceride (4.04 mmol/L), with low high-density lipoprotein-cholesterol (0.90 mmol/L). Otherwise, full blood count, renal profile, liver function test, and thyroid function test showed normal ranges. Rheumatoid factor, anti-cyclic citrullinated peptide antibodies, and anti-nuclear antibodies were all negative. Ultrasound of kidneys showed increased echogenicity in keeping with renal parenchymal disease, with no evidence of renal calculi. Musculoskeletal ultrasound of both knees showed presence of supra-patellar effusion, with power Doppler signals 1+. There was no synovial hypertrophy. Microscopy examinations of the aspirates from the left knee joint showed presence of monosodium urate crystals, thus confirming the diagnosis of gouty arthritis. Serum uric acid (SUA) level was 575 μmol/L. She continued her pregnancy and delivered at term. Post-delivery, she continued to have recurrent arthritis. She was started on allopurinol 150 mg every night with subsequent dose increment to 300 mg every night. Treatment was tolerated well. Follow-up clinics showed decreasing SUA trend. Her other medications included Metformin XR 1500 mg every night, ascorbic acid 500 mg once daily, fenofibrate 145 mg once daily, gliclazide MR 90 mg once daily and URAL™ sachets. Her SUA level reduced to < 360 μmol/L without further gout attack. Six months after initiation of allopurinol, she developed gradual blurring of vision. She was referred for ophthalmological assessment (Figs 1a,b,2a,b). Provisional diagnosis of crystalline maculopathy was made. Crystalline maculopathy refers to the deposition of refractile crystals in the superficial retina around the perifoveal region. It normally involves both eyes, affecting the posterior pole of the fundus. Vision is commonly not affected. However, visual acuity can be reduced due to subfoveal or perifoveal cyst formation. There are numerous causes of crystalline maculopathy: systemic disorders (oxalosis, cystinosis); primary ocular disorders; embolic diseases (calcium emboli, cholesterol emboli); and drug-induced.1 Numerous literatures have reported on ocular and visual side effects of systemic drugs.2 Crystalline maculopathy has been reported among patients on tamoxifen, cisplatin, canthaxanthine, clofazamin, aminoglycosides, nitrofurantoin, and talc.3-5 Dr. Gerald Pinnas had reported a case of possible association between macular lesions and allopurinol.6 It was further concurred by Dr. Joseph Laval.7 In both cases, patients developed sudden decrease in vision after initiation of allopurinol. Eye lesions involved include macular hemorrhage, exudates and drusen. Marked recovery of vision observed after allopurinol was withheld. There were also several reports on allopurinol-induced cataract.8 To our knowledge, this is the first reported case of crystalline maculopathy possibly related to allopurinol. We used Heidelberg Spectralis optical coherence tomography (OCT) on our patient. OCT showed hyper-reflective intraretinal crystals at the macula area, which was in keeping with crystalline maculopathy. Other possible diagnoses that may give rise to similar OCT findings include: hard exudates; intraretinal infiltrates; rare genetic mutations such as fleckled retinal syndromes; as well as crystalline maculopathy caused by other drugs. Hard exudates secondary to diabetes mellitus may show similar OCT findings. However, the lesions caused by hard exudates are larger in size and irregular in shape. Our patient's fundus did not show other features of diabetic retinopathy, making such diagnosis unlikely. In the case of intraretinal infiltrates, the hyper-reflective lesion is usually ill-defined and fuzzy. Apart from allopurinol that showed temporal relationship with the visual symptom and OCT findings, she was never exposed to other drugs that were associated with crystalline maculopathy. Allopurinol was not discontinued in this patient but dosage was reduced. This decision was made due to clear benefits of optimal SUA control that out-weighed the possible visual risks. In fact, to date patient's vision remained stable without worsening of macular crystal deposits. This case illustrates crystalline maculopathy as an adverse effect of allopurinol. The rarity of this condition poses challenges in making a diagnosis. Physicians treating gout patients need to be aware of such possible complication. Early referral to an ophthalmologist is warranted for early detection. Timely intervention may halt the progression of this problem, hence preventing troubling visual disturbances. All three authors mentioned above have contributed to the conception of producing this manuscript. Dr Chee Ken, Cheah and Dr Suk Chyn, Gun were involved in initial case identification, with further ophthalmology assessment done by Dr Nandini Vijaya Singham. All three authors have discussed and analyzed the findings, were involved in literature search and writing of the manuscript. All three authors have agreed on the final version of manuscript to be published, and will be accountable to the content (integrity and accuracy) of the manuscript.

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