Idiopathic Polypoidal Choroidal Vasculopathy in a Patient With

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general deterioration and evidence of liver dis- retinal detachment and a tumoral image Br J Ophthalmol: first published as 10.1136/bjo.85.8.1007d on 1 August 2001. Downloaded from function, the previous treatment could not be resembling a choroidal metastasis. The ocular LETTERS TO given and a palliative symptomatic treatment computed tomography scan showed no other was undertaken. alterations than the apparently ocular meta- THE EDITOR static tumour. Liver function and enzymes Case 2 were normal. A 39 years old healthy female patient suVered Because of the family history of ocular a sudden loss of vision in November 1994 and melanoma, enucleation of the right eye was a left eye retinal detachment was found at the performed in June 2000 (despite the ocular Familial uveal melanoma: report on ocular examination. The orbital ultrasound ultrasound and the CT scan oriented to a three sibling cases suggested a typical choroidal melanoma on metastatic breast tumour). the left eye. The orbital CT scan showed an The histopathology showed a mixed cell EDITOR,—Uveal melanoma is the most com- intraocular tumour on the nasal side of the malignant uveal melanoma with predomi- mon primary malignant intraocular tumour in posterior pole of the left eye, in contact with nance of epithelioid variant. adults, representing 70% of all malignant ocu- the retina, with 10 mm thickness and probable The patient is now being treated for a lar tumours.1 episcleral infiltration. Her left eye was enucle- second breast tumour (at the remnant of the They appear sporadically in the absence of ated on January 1995. Histopathological find- right breast). clear predisposing genetic factors. However, ings were that of a mixed cell malignant uveal melanoma, with predominance of epithelioid the family history of some patients suggests COMMENT that there could be a genetic basis.2 Some type, with significant scleral invasion. In November 1997 a right breast nodule The family presented includes not only three cases of family uveal melanoma have been individuals aVected with this unusual pathol- described in the literature, and they point to a was found, measuring 2 cm in diameter. The mammography showed the right breast lump ogy but they are also three siblings belonging dominant autosomal hereditary transmis- to the same generation, which is even more sion.34 compatible with a primary breast tumour and the biopsy was positive for malignancy. It was unusual. The family uveal melanoma accounts for All the cases corresponded to mixed uveal only 0.6% of patients with uveal melanoma. finally resected in December 1997. The histopathological report confirmed a breast melanomas; in one of these cases (case 3) the Considering the low incidence of uveal patient also had a malignant breast tumour melanoma in the general population, the metastasis of a malignant uveal melanoma which was diagnosed 2 years before the ocular possibility of developing uveal melanoma in a with axillary ganglion metastases. tumour; in this same case, even though the family context is very low. Since the first Systemic treatment with polichemotherapy clinical findings and the imaging tests were description by Silcock in 1892 of the case of a was started in February 1998, based on suspicious of a choroidal metastasis, the mother and her two daughters aVected with cisplatin, dacarbazide, and tamoxifen, five history of two ocular melanomas in her this illness, only 51 families had been reported series were completed by July 1998. In August siblings led to the enucleation of the eye, with until 1996.45 1998 the patient suVered a right coxofemoral the subsequent diagnosis of ocular melanoma; Unidentified mutations on the germinal line pain irradiated to the ipsilateral knee. Pelvic x the patient is still alive but is being treated for might be involved in its pathogenesis.46There rays showed multiple lytic lesions in the pelvis. a new breast lump. are several reports of simultaneous occurrence Bone scintigraphy (September 1998) noted Case 2 shows another peculiarity: the of uveal melanoma and breast cancer. Some of hyperactive areas in the anterior arc of the them are related to one of the genes already third rib, pelvic bones, iliac wing, and superior patient had been enucleated in January 1995 known as predisposing to breast and ovary third of the right femoral bone. because of a mixed choroidal melanoma; cancer, the “BRCA2.” 78 She was evaluated because of the risk of a almost 3 years later she was operated because Even though there is no demonstration of local bone fracture and a surgical fixation was of a probable primary breast tumour, and the an implicated gene, many studies suggest that then implemented. Histopathological bone mastectomy specimen showed a breast and the occurrence of family uveal melanoma is biopsy (November 1998) confirmed bone axillary compromise of the formerly enucle- not just a coincidence.9 metastases of a melanocytic tumour, in ated ocular melanoma. Nine months later,

Three clinical cases of histopathologically accordance with the primary ocular bone metastases of the primary choroidal http://bjo.bmj.com/ proved intraocular malignant melanoma in- melanoma. She died in December 1998 with a melanoma were diagnosed and histologically volving first generation members of the same progressive disease. confirmed. The patient died a few months family (siblings) are analysed, and their evolu- later. tion is reported. Case 3 The first case (case 1) was another unusual A 38 year old female patient, who was one: at the diagnosis, the patient had an exter- operated on her left breast (modified radical nalised ocular melanoma with extrascleral CASE REPORTS mastectomy) in September 1998 because of a invasion allowing a preoperative diagnosis Case 1 30 × 33 mm ductal infiltrating carcinoma through a biopsy, even though this procedure

A 40 years old male patient, with a history of on September 24, 2021 by guest. Protected copyright. (DIC), with 40% of in situ carcinoma, is diYcult to achieve in most of the ocular ocular trauma 2 years earlier, presented with histological grade II, 0/6 negative axillary melanomas. In this patient an orbital ex- progressive loss of vision in the right eye, being nodes. She then received polichemotherapy enteration was done owing to its extension admitted to hospital in March 2000. The ear- with four cycles of doxorubicin and cyclo- beyond the eye itself. The histopathological lier examination showed an ulcerated tumour phosphamide (AC) followed by radiotherapy, report was that of a mixed melanoma (with in the right eye that protruded over the lower completing the treatment with tamoxifen epithelioid component). Seven months later eyelid, round in shape, 1 cm diameter, because of high positive oestrogen receptors. the patient developed progressive liver metas- pigmented and painful. He underwent a com- In March 2000 she suVered a trauma in her tasis with general deterioration, while under puted tomography (CT) scan of the orbit right eye. An ocular ultrasound scan showed a palliative care. which showed an external ocular melanoma with extrascleral invasion. Studies for stratifi- cation were negative for malignancy. Given the accessibility of the tumour, a biopsy con- I:1 I:2 firmed a malignant melanoma. An exentera- tion of the right orbit was performed in April 2000. The histopathological report was of a mixed type (spindle B and epithelioid) malignant melanoma, with perineural and perive- II:1 II:2 II:3 II:4 II:5 II:13 II:6 II:14 II:7 II:15 II:16II:8 II:17 II:9 II:18 II:10 II:11II:19II:20 II:12 LC BC LC 46y nular scleral infiltration. A liver ultrasound Dg/De59y De49y De57y Dg/De 40y BCDg 43y performed in November 2000 showed multiple, solid, round-shaped hypoechogenic im- ages in both hepatic lobes, compatible with secondary metastasis in the liver, confirmed III:1 III:2 III:3 III:4III:5 III:6III:7 III:8 III:9 III:10 III:11 III:13 III:15 III:17 III:19 III:21 III:22 III:23 by CT scan, leading to plan a chemotherapeu- 40y UM 38y III:12 III:14 III:16 III:18 III:20 UM Dg40y Dg39y De40y BC Dg35y tic treatment with hepatic intra-arterial cispla- UM Dg38y tin. Because of the clear tumour progression in Figure 1 Genealogical family tree. UM = uveal melanoma, LC = lung cancer, BC = breast cancer, Dg = diagnostic age, De = dead age, Dg/De = diagnostic and dead age, y = years, I = first generation, such a short time, a painful hepatomegaly and II = second generation, III third generation.

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Once again this case denotes the aggressive- 1 Sahel Jo, Steeves R, Albert D. Intraocular Br J Ophthalmol: first published as 10.1136/bjo.85.8.1007d on 1 August 2001. Downloaded from ness of this tumour in this family. melanoma. In: DeVita V, Hellmann S, Rosen- berg SA, eds. Cancer: principles and practice of The genealogical family tree (Fig 1) shows oncology. Philadelphia: Lippincott-Raven, that the siblings’ parents developed malignant 1997;1995–2012. tumours: the father was diagnosed with lung 2 Singh AD, Shields CL, Shields JA, et al. Uveal melanoma in young patients. Arch Ophthalmol cancer at the age of 59 dying a few months 2000;118:918–23. later and the mother had breast cancer 3 Young LH, Egan KN, Walsh SM, et al. Familial diagnosed at the age of 49 dying at the age of uveal melanoma. Am J Ophthalmol 1994;117: 57. Also a maternal aunt was diagnosed with 516–20. 4 Singh AD, Wang MX, Donoso LA, et al. Genetic lung cancer at the age of 38 and died 2 years aspects of uveal melanoma: a brief review. Sem later, while another maternal aunt is still alive Oncol 1996;23:768–72. with breast cancer diagnosed when she was 5 Singh AD, Shields CL, De Potter P, et al. Famil- ial uveal melanoma. Clinical observations on 56 43. The paternal family history was irrelevant patients. Arch Ophthalmol 1996;114:392–9. with no malignancies in any of the first or sec- 6 Canning CR, Hungerford J. Familial uveal ond generation members. melanoma. Br J Ophthalmol 1988;72:241–3. Figure 1 Dendritic ulcer of the right eye. 7 Sinilnikova OM, Egan KM, Quinn JL, et al. The family tree shows, in the same genera- Germline brca2 sequence variants in patients tion as the aVected patients, five more siblings, with ocular melanoma. Int J Cáncer 1999;82: all of them aged less than 40 years who are 325–8. currently healthy but may eventually be 8 Houlston RS, Damato BE. Genetic predisposition to ocular melanoma: Eye 1999;13:43–6. aVected with ocular melanoma or another 9 Singh AD, Wang MX, Donoso LA, et al. Familial malignancy; are there any kind of preventive uveal melanoma, III. Is the occurrence of famil- measures we can take for these patients?. ial uveal melanoma coincidental? Arch Ophthal- mol 1996;114:1101–4. Anecdotal reports of cases of ocular 10 Walker J, Weiter J, Albert D, et al. Uveal melanoma occurring in families with inherited malignant melanoma in three generations of the susceptibility to breast cancer owing to brca2 same family. Am J Ophthalmol 1979;88:723–6. germ line mutations have been previously reported.7 Herpes simplex dendritic keratitis after Although germ line brca2 mutations may treatment with latanoprost for primary account for a small proportion of all ocular melanoma cases, there may be additional loci open angle glaucoma contributing to family aggregation of uveal EDITOR,—Medications used to treat glaucoma melanoma and to the family association 7 can cause side eVects such as irritation, between ocular melanoma and breast cancer. redness, foreign body sensation, and pain in Based on the limited data available, an the eye.1 There are reports that latanoprost autosomal dominant mode of inheritance with has almost no serious side effects. incomplete penetration has been postulated to We present two patients treated with explain the family involvement in uveal 5 latanoprost for primary open angle glaucoma Figure 2 Immunofluorescence demonstrates the melanoma. who developed herpes keratitis. presence of herpes simplex virus. In order to determine some genetic altera- tion that could account for this family uveal melanoma, blood samples were recently taken CASE REPORTS treatment, trabeculectomy was carried out in from diVerent members of the family (apart Case 1 the right eye, when latanoprost treatment was from the aVected patients still alive). A 68 year old female patient presented to the continued in the left eye. After a small period The family predisposition to uveal cornea department of the eye clinic, Univer- of time, in the right eye—without latanoprost melanoma can be a component of a wider sity of Athens, in January 1997. She was being treatment—there was no herpetic infection, predisposition syndrome to cancer, which treated for primary open angle glaucoma with while in the left eye—with latanoprost http://bjo.bmj.com/ could explain the high number of tumours latanoprost drops once daily for the past 3 treatment—herpetic infection presented aVecting these families, with multiple organs months. Visual acuity in the right eye was again. involved and the appearance at younger ages 20/40 and in the left 20/20. The intraocular than those observed in the general popula- pressure of the left eye was 16 mm Hg. Exam- COMMENT tion.10 ination with a slit lamp demonstrated a Both patients presented with herpes keratitis Because of no previous evidence of family dendritic ulcer in the right eye (Fig 1). during latanoprost treatment. After discon- members with uveal melanoma in the genea- Immunofluorescence studies of the cornea tinuing the latanoprost treatment, there was epithelium from the ulcer demonstrated the logical tree (Fig 1), either an environmental no recurrence of the keratitis. on September 24, 2021 by guest. Protected copyright. factor that remains undisclosed might be sus- presence of herpes simplex virus. Latanoprost Latanoprost is a prostaglandin analogue.34 pected or a new mutation may have arisen. treatment was discontinued and the patient It is an esterified predrug inactivate until its Either way careful monitoring of the remain- was placed on antiviral treatment. Two weeks enzymatic hydrolysis in the cornea, where it ing siblings would be of great interest. later the keratitis had resolved. The patient becomes a biologically active acid.5 Owing to was treated again with latanoprost drops once the biochemical disturbance in the cornea, GKRYGIER daily in the right eye. Three months later she K LOMBARDO and the keratopathy confirmed with staining, developed the same problems in the right eye. we can suppose that the presence of latano- C VARGAS Latanoprost treatment was discontinued Medical Oncology Department; Universitary Hospital prost predisposes the appearance of herpes de Clinicas, Montevideo, Uruguay again and antiviral treatment with aciclovir keratitis. ointments was recommended. There has been More cases must be studied before we can I ALVEZ no recurrence of the herpetic infection. R COSTA reach more specific conclusions. M ROS PANTELIS EKATOMATIS 2 Ophthalmology Department; Universitary Hospital de Case Eye Clinic, University of Athens, Greece Clinicas, Montevideo A 65 year old female presented to the cornea department of the eye clinic, University of Correspondence to: Eye Clinic, University of Ath- M ECHENIQUE ens, 89 Kifisias Avenue, GR-115 23 Athens, Greece Pathology Department; Universitary Hospital de Athens, in March 1997. Examination detected Accepted for publication 27 February 2001 Clinicas, Montevideo epithelial lesions in the centre of the cornea in V NAVARRO the right eye (Fig 2) and at 11 clock hours in 2 L DELGADO the periphery of the left eye. The patient had 1 Weinred RN. Compliance with medical treat- A VIOLA had treatment with latanoprost once daily for ment of glaucoma. J Glaucoma 1992;1:134–6. I MUSÉ primary open angle glaucoma during the past 2 Wilhelmus KR, Falcon MG, Jones BR. Bilateral herpetic keratitis. Br J Ophthalmol 1981;65:385- Medical Oncology Department; Universitary Hospital 2 months. There was no history of herpes 7. de Clinicas, Montevideo keratitis. Latanoprost treatment was discon- 3 CuiVre G. The eVects of prostaglandin F2á in Correspondence to: Gabriel Krygier, MD, Blanca tinued. The samples of the corneal epithelium the human eye. Graefes Arch Clin Exp Ophthal- del Tabare 2964, Montevideo, Uruguay CP 11300 from the ulcerated area of both eyes demon- mol 1985;222:1339–41. 4 Rácz P, Ruzsonyi MR, Nagy ZT, et al. Main- [email protected] strated the presence of herpes simplex virus, tained intraocular pressure reduction with once- Accepted for publication 16 April 2001 using immunofluorescence. After antiviral a-day application of a new prostaglandin F2á

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analogue (PhXA41). An in-hospital, placebo- Br J Ophthalmol: first published as 10.1136/bjo.85.8.1007d on 1 August 2001. Downloaded from controlled study. Arch Ophthalmol 1993;111: Wild type Mutant 657–61. T TGCATGCA T 5 Basu S, Sjoquist B, Stjernschantz J, et al. Corneal A A A A permeability to and ocular metabolism of A A phenyl substituted prostaglandin esters in vitro. A A Prostaglandins Leukot Essent Fatty Acids 1994;50: A A A A 161–8. AVal Ala G C C T T A A Optic neuropathy and cerebellar ataxia T T T T associated with a rare missense variation A A (A14510G) of mitochondrial DNA A A

EDITOR,—Mitochondrial diseases manifest a U C C C variety of syndromic signs. Skeletal muscle, 1 2 3 central nervous system, heart, eye, ear, liver, Wild type kidney, pancreas, bone marrow, and colon are the common target organs in mitochondrial diseases. The mitochondrial DNA (mtDNA) Figure 1 Magnetic resonance imaging of the is responsible for the mitochondrial diseases brain in the patient with A14510G mutation of mtDNA. A 52 year old Japanese man with through molecular defect of oxidative phos- bilateral optic neuropathy and cerebellar ataxia. Mutant phorylation enzymes in conjunction with the T1 weighted imaging shows cerebellar atrophy nuclear genome.1 Optic neuropathy and cere- with dilatation of the fourth ventricle. bellar ataxia are a frequent association in mitochondrial diseases. We report a sporadic we could not dismiss the diagnosis of a mito- case of bilateral optic neuropathy, cerebellar chondrial disease subtype because of the bilat- Figure 2 Identification of A14510G mutation ataxia, and peripheral neuropathy associated eral optic neuropathy accompanied by cer- of mtDNA. (Top) Sequencing result of ND6 in with a rare missense variation at np 14510 ebellar ataxia. Peripheral blood was obtained mtDNA in the patient. An A to G substitution at which replaced Val by Ala in the ND 6 coding after informed consent and examined for np 14510 replaces Val by Ala in the ND 6 coding sequence of mtDNA (arrow). (Bottom) sequence of mtDNA. common pathogenic mtDNA point mutations PCR restriction detection for A14510G by polymerase chain reaction (PCR) restric- mutation. U = untreated amplicon; C1, C2, and 2 CASE REPORT tion methods described elsewhere. The nu- C3 = negative controls; n = A14510G variant. A 52 year old Japanese man first noted writing cleotide sequences of sense and antisense The amplicon (243 bp) spanning from np 14429 disturbance, tremor of hands, and mild gait strands of ND1, ND4, and ND6 genes of to 14671 of mtDNA is treated with Alu I which mtDNA from the patient were evaluated by recognises allele G and the mutant fragment is disturbance at the age of 49 years. The patient digested into 82 bp and 161 bp. The patient (n) had a 30 year history of drinking (daily alcohol autocycle sequencing methods. In the patient, no major pathological mutation was found by has homoplasmic A14510G mutation. C1, C2, consumption 125 g) and smoking (daily 20 and C3 show only the wild type fragments. cigarettes). Physical examination revealed a PCR restriction detection at np 3243 for complex of neurological signs including cere- mitochondrial myopathy, encephalopathy, lac- healthy individuals. Thus, grouped with previ- bellar ataxia and peripheral neuropathy. The tic acidosis, and stroke-like episodes ous data in other populations, the frequency of gait was broad based and ataxic. There was (MELAS), 3460 for Leber’s hereditary optic A14510G is estimated to be two in 1413, or mild ataxia of the lower extremities on heel to neuropathy (LHON), 8344 for myoclonic epi- approximately one in 700. Noticeably, this knee test. Deep tendon reflexes were hyperac- lepsy and ragged red fibres (MERRF), 8993 frequency is remarkably rare compared with tive with normal plantar responses. Peripheral for neurogenic weakness, ataxia, and retinitis commonly found mtDNA polymorphisms nerve conduction velocity studies revealed pigmentosa, 11778 for LHON, or 14484 for that are innocent or not pathogenic. Although sensory polyneuropathy in the upper and LHON. There was no known mutation in clinical information from the Australian with lower limbs. Muscular strength and volume of ND1, ND4, or ND6 gene of mtDNA by A14510G is not available, it is possible to http://bjo.bmj.com/ the limbs were normal. Magnetic resonance nucleotide sequencing. Instead, nucleotide assume that the mtDNA plays a part in the imaging showed cerebellar atrophy with dila- sequencing and Alu I restriction detection aetiology of a syndromic clinical disorder. We tation of the fourth ventricle (Fig 1). The cere- confirmed a homoplasmic missense mutation could not confirm maternal inheritance or brospinal fluid was normal without any at np 14510 (A14510G) that replaced Val by heteroplasmy of the A14510G mutation in inflammatory signs. Peripheral blood exam- Ala in the ND 6 gene of mtDNA (Fig 2). The our family. According to the statements from ination showed mild macrocytic anaemia. The DNA samples reserved by us were examined the patient, the family members had normal serum levels of vitamin B-1, vitamin B-12, and for the relevant mtDNA mutation. The vision but clinical and molecular genetic A14510G mutation was not detected in 468 folic acid were within the normal range. Red assessments in them may give significant on September 24, 2021 by guest. Protected copyright. blood cell folate level was also normal. The Japanese individuals, including 39 LHON information for the genotype phenotype cor- patient also had suVered from insidious, patients with 11778 mutation, 24 healthy car- relation of the A14510G mutation. progressive loss of central vision in both eyes riers with 11778 mutation, one LHON Mutational eVect of A14510G is unknown. since 51 years of age. At presentation, best patient with 3460 mutation, one LHON Two of the primary mtDNA mutations, corrected visual acuity was 0.1 in the right eye patient with 14484 mutation, 78 patients with G14459A (Ala72Val) for LHON plus dysto- and 0.08 in the left. Pupils were round, isoco- aetiology undefined bilateral optic neu- nia and T14484C (Met64Val) for LHON, ric, and sluggish to light. There was no ropathy, 239 patients with spinocerebellar have been verified near A14510G (Val55Ala) blepharoptosis. Ocular motility was normal. ataxias who did not carry any abnormal in the ND6 gene.3 Another missense mutation Anterior segments and media were clear. Fun- trinucleotide repeats in the genes of spinocere- (A14495G, Leu60Ser) has recently been duscopy disclosed dilatation of small retinal bellar ataxia type 1, 2, 3, 6, 7, or 8, and 86 found in the same gene in two LHON vessels neighbouring the optic nerve head in unrelated healthy individuals. families, suggesting that the ND6 gene is a hot both eyes. Optic nerve heads were not spot for LHON mutations.6 The amino acid hyperaemic but slightly atrophic with tempo- COMMENT sequence relevant to A14510G (VFLI- ral pallor. Static and kinetic visual field testing The nucleotide at np 14510 of mtDNA is YLGGMMVVFGYTTA; letters in bold are showed central scotomas. Farnsworth’s panel most usually adenine (14510A). A literature replaced by the mutations) is highly conserved D-15 test showed red-green colour vision survey reveals that 153 individuals in east in mammalia including human, bovine, and defects. Full field scotopic electroretinograms Asia, 411 in an aboriginal Siberian popula- mouse, but not strictly conserved in xenopus, and visual evoked cortical potentials were nor- tion, 60 in a native American population, and sea urchin, or drosophila. This region is a part mal. The patient was the fourth of five siblings 173 in a white population all had 14510A.3 of hydrophobic transmembrane helices of the of non-consanguineous parents. Because of Only one Australian among 147 individuals of ND enzyme. Mutations in the ND6 gene may the alcoholism, he was divorced and lived African, Asian, white, aboriginal Australian, disturb the enzymatic stability of NADH CoQ alone. Family members were not accessible, and aboriginal New Guinean was reported to reductase. but according to his statement, there was no have guanine at np 14510 (14510G).45 The Optic neuropathy is the predominant sign relative having similar disease. A14510G mutation in the present patient was of LHON and may also be developed in Although the clinical signs in this patient found in none of 468 Japanese patients with patients with other mitochondrial disorders were not inconsistent with the eVects of genetically proved LHON, unexplained bilat- such as chronic progressive external ophthal- chronic alcoholism and tobacco abuse alone, eral optic neuropathy, cerebellar ataxia, or moplegia, MELAS, and MERRF, occasionally

www.bjophthalmol.com 1010 Letters characterised by insidious, chronic progressive 5 Cann RL, Stoneking M, Wilson AC. Mitochon- by a microlymphocytoxicity test and DNA Br J Ophthalmol: first published as 10.1136/bjo.85.8.1007d on 1 August 2001. Downloaded from optic nerve disease.1 Our patient developed a drial DNA and human evolution. Nature typing techniques, respectively.4 As a control 1987;325:31–6. late onset, insidious bilateral optic neuropathy 6 Chinnery PF, Brown DT, Andrews RM, et al. group, 176 unrelated healthy individuals from with mildly atrophic optic nerve heads and The mitochondrial ND6 gene is a hot spot for Madrid were also HLA typed. tortuous retinal vessels, being compatible with mutations that cause Leber’s hereditary optic The distribution of the frequencies of HLA features of LHON.7 Cerebellar ataxia and/or neuropathy. Brain 2001;124:209–18. alleles in both groups was compared using the 7 Nikoskelainen E, Hoyt WF, Nummelin K, et al. cerebellar atrophy are caused by mutations of Fundus findings in Leber’s hereditary optic Fisher test. The aetiological fraction (ä) and mtDNA—for example, large scale deletions or neuroretinopathy. III. Fluorescein angiographic the odds ratio (OR) value with the corre- tRNA mutations.3 An extensive review of the studies. Arch Ophthalmol 1984;102:981–9. sponding 95% confidence intervals (CI) was literature demonstrates a variety of neurologi- 8 Went LN. Leber disease and variations. In: calculated. Handbook of clinical neurology. Amsterdam: cal abnormalities in LHON patients, includ- North Holland, 1972:94–110. ing cerebellar ataxias and peripheral nerve 9 Funakawa I, Kato H, Terao A, et al. Cerebellar COMMENT 8 disorders. Our patient had cerebellar ataxia ataxia in patients with Leber’s hereditary optic In our series, HLA-A24 is found in 67% of the and sensory polyneuropathy, with evidence of neuropathy. J Neurol 1995;242:75–7. 10 Kerrison JB, Miller NR, Hsu F, et al. A patients, compared with 14% in the Spanish cerebellar atrophy on magnetic resonance case-control study of tobacco and alcohol control population (p >0.05, Fisher test). No imaging. Similar neurological complications consumption in Leber hereditary optic neu- other HLA class I allele shows a remarkable ropathy. 2000; :803–12. were rarely found in a LHON family with Am J Ophthalmol 130 deviation from the control population. Re- 9 G11778A mutation. garding HLA class II alleles, HLA-DR14 (a Although epigenic factors have been con- The tubulointerstitial nephritis and HLA-DR6 subtype) is found in two of our sidered for the disease expression and visual patients, whereas it appears in eight of our outcome of LHON patients in association uveitis (TINU) syndrome is associated with HLA-DR14 in Spanish patients control individuals (67% v 4%, p=0.006; OR with mtDNA mutations, it has yet to be 48.2 (95% CI 5.5–258)). This finding would proved. A retrospective analysis of LHON sib- lend further support to the HLA-DR6 associ- ships has failed to demonstrate a significant EDITOR,—An uncommon association between tubulointerstitial nephritis and anterior uveitis ation previously reported in other popula- deleterious association between tobacco or tions.3 The frequency of other HLA class II alcohol consumption and vision loss among was described in two adolescent female patients with non-caseating granulomas in alleles is also increased in the diseased group individuals at risk with the major mtDNA when compared with the control group, mutations.10 In the present clinical isolate, it both bone marrow and lymph nodes by Dobrin1 and is referred to as TINU syndrome. although statistical significance is not reached: remains unknown whether the malnutritional HLA-DQ5 (100% v 40%, p >0.05, Fisher condition provided a potential risk factor in Since then, some 50 cases (35 paediatric patients and 15 adults) have been described. test) and HLA-DR52 (100% v 56%, p>0.05) the clinical manifestation associated with the When the aetiological fraction (ä) is consid- underlying mtDNA defect. The A14510G Its distribution is typically in young girls aged 10–14 years. The kidneys are aVected by ered, HLA-DR52 and HLA-DQ5 show the mutation of mtDNA is expected to be found highest value (ä=1), followed by HLA-DR14 in other independent patients especially with tubulointerstitial nephritis with predominant mononuclear infiltrate in the majority of cases. (ä=0.74) and HLA-A24 (ä=0.71). unknown optic neuropathy and cerebellar These data point to HLA class II antigens ataxia. The ocular lesion invariably consists of anterior uveitis and, exceptionally, panuveitis. rather than HLA class I as the main TINU Although the aetiology is still unknown, the susceptibility markers. It may be worth recall- No proprietary interest. ing that HLA class II molecules are expressed This work was supported by grants in aid for laboratory findings reported suggest that 2 in renal epithelial cells or in the uvea when scientific research (12877279, 12671715) from the TINU is a cell mediated immune disease. inflamed. Thus, genetically predisposed indi- Japanese Ministry of Education, Science and Cul- Genetic markers (HLA alleles) have also been viduals (that is, HLA-DR14) would be more ture. implicated as susceptibility risk factors.3 YASUSHI ISASHIKI prone to producing the lesions observed in the Center for Chronic Viral Diseases, Kagoshima TINU syndrome upon activation of the University Faculty of Medicine, Kagoshima-shi CASE REPORT immune system. 890-8520, Japan We describe the cases of three further female We are aware of the limited value of the sta-

adult patients of Spanish origin who devel- http://bjo.bmj.com/ NORIO OHBA tistical analysis carried out given the small Department of Ophthalmology oped acute renal insuYciency secondary to number of patients studied, but this is idiopathic acute tubulointerstitial nephritis, inherent to the pathology itself, since scarcely MASANORI NAKAGAWA and who, several months later, suVered a 50 TINU patients have been described world- Department of Medicine bilateral acute anterior uveitis. In all three wide since its first description in 1975. We SHUJI IZUMO patients, similar laboratory findings were thus would use HLA phenotyping in future Center for Chronic Viral Diseases found including slight anaemia, increase of the patients to assess the role of these HLA class Correspondence to: Yasushi Isashiki, MD, PhD, serum creatinine, blood urea nitrogen, and II antigens in TINU susceptibility. Division of Molecular Pathology and Genetic Epide- erythrocyte sedimentation rate. Glycosuria miology, Center for Chronic Viral Diseases, Ka- and proteinuria were found in the urinalysis. on September 24, 2021 by guest. Protected copyright. goshima University Faculty of Medicine, Sakura- Hantavirus or hepatitis B, C antibodies were We are grateful to Dr A Annaiz-Villena (Immuno- gaoka 8-35-1, Kagoshima 890-8520, Japan logia Hospital “12 de Octubre,” Madrid) for HLA [email protected] not found. Tuberculin and Bengal rose were typing of patients. Accepted for publication 27 March 2001 negative. ANA, anti-DNA, anti-Sm Anti- RNP, anti-SSA, anti-SSB, and ANCA autoan- MARINA B GORROÑO-ECHEBARRÍA MIGUEL A CALVO-ARRABAL tibodies, detected by indirect immunofluores- 1 Chinney PF, Tumbull DM. Mitochondrial DNA FERNANDO ALBARRÁN and disease. Lancet 1999;354(suppl I):17–21. cence (IFI) or counterimmunoelectrophoresis MELCHOR ALVAREZ-MON 2 Isashiki Y, Nakagawa M, Ohba N, et al. Retinal (CIE), were all negative. RPR, antistreptolysin Departments of Ophthalmology and Diseases of the manifestations in mitochondrial diseases associ- O, PCR, and rheumatoid factor were also Immune system, Hospital Universitario “Príncipe de ated with mitochondrial DNA mutation. Acta Asturias” (Alcalá de Henares) Ophthalmol Scand 1998;76:6–13. negative. Thyroid function was normal, as 3 A human mitochondrial genome database: http:// were the chest and abdomen x rays and renal Correspondence to: Dr M B Gorroño-Echebarría, www.gen.emory.edu/mitomap.html ultrasonography. Finally, polyclonal hyper- Department Oftalmología, Hospital Universitario 4 Cann RL, Brown WM, Wilson AC. Polymorphic gammaglobulinaemia was found. Further de- “Príncipe de Asturias,” Carretera Alcalá-Meco s/n sites and the mechanism of evolution in human Alcalá de Henares, 28805 Madrid, Spain mitochondrial DNA. Genetics 1984;106:479– tails are given in Table 1.The HLA class I and 99. class II phenotype of patients was carried out [email protected]

Table 1 Main clinical manifestations of the patients. Their HLA phenotype is also shown

Case 1 Case 2 Case 3 Sex Female Female Female Age 69 51 49 First symptoms Nausea and anorexia Upper respiratory infection Asymptomatic, coincidental ﬁnding Uveitis Bilateral AAU Bilateral AAU with papillitis Bilateral AAU with retinal vasculitis Onset of uveitis 4 months after the nephritis Unknown, at the time or possibly prior to the nephitis 5 months after the nephritis HLA phenotype A24, A32, B62, B39, Bw6, Cw7, Cw3, A28, B57, Bw4, DR11, DR14, DR52, DQ5 A3, A24, B35, B7, Bw6, Cw4, DR103, DR14, DR8, DR52, DQ5 DR3, DR52, DQ5

AAU = acute anterior uveitis.

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Accepted for publication 28 March 2001 fingers in the left eye. On fundus examination was applied to polypoidal vessels. The param- Br J Ophthalmol: first published as 10.1136/bjo.85.8.1007d on 1 August 2001. Downloaded from of the right eye diVuse soft confluent drusen, eters used were a laser power of 200 mW, an 1 Dobrin RS, Vernier RL, Fish AL. Acute eosi- some calcified, and geographic atrophy (GA) exposure time of 0.2 seconds, and a spot size nophilic interstitial nephritis and renal failure were detected (Fig 1A). In the left, the most of 200 µm. This resulted in resolution of the with bone marrow-lymph node granulomas and striking feature was the presence of marked CMO and PED (Fig 2D) on FA, closure of anterior uveitis. A new syndrome. Am J Med and diVuse cystoid macular oedema (CMO), the choroidal vascular network on ICG (Fig 1975;59:325–33. 2 Manjon MT, Sanchez-Burson J, Montero R, et and a serosanguineous pigment epithelial 2B, E), and on a subjective improvement in al.Two cases of acute tubulointerstitial nephritis detachment (PED) associated with large vision 2 weeks following laser treatment. associated with panuveitis (TINU syndrome). J amounts of hard exudates (Fig 1B). Soft and Rheumatol 1999;26:234–6. 3 Gafter U, Kalechman Y, Zevin D, et al. calcified drusen and GA were also present. COMMENT Tubulointerstitial nephritis and uveitis: associ- Fluorescein angiography (FA) disclosed dif- IPCV is characterised by the presence of ation with suppressed cellular immunity. Neph- fuse pooling of dye in the macula in the left recurrent serosanguineous PEDs and neuro- rol Dial Transplant 1993;821–6. 1–5 4 Martinez-Laso J, De Juan D, Martinez-Quiles N, eye, and an area of hyperfluorescence corre- sensory retinal detachments (NSRD). The et al.The contribution of the HLA-A, -B, -C and sponding to the PED (Fig 2A). Window vascular abnormality underlying the disorder -DR, -DQ DNA typing to the study of the defects corresponding to areas of atrophy were appears to be in the inner choroid. Dilated origins of Spaniards and Basques. Tissue Anti- gens 1995;45:237–45. detected in both eyes. On indocyanine green networks of vessels terminating in aneurysmal angiography (ICG) a choroidal vascular net- dilatations or “polyps” can be observed on work of polypoidal structures was observed in ICG angiography.2–5 Polypoidal lesions may Idiopathic polypoidal choroidal the left eye (Fig 2B, C). arise from the peripapillary region,12macula,5 vasculopathy in a patient with atrophic After informed consent was obtained, focal or peripheral areas.4 Histopathological evalua- age related macular degeneration laser photocoagulation using an argon laser tion of a case of IPCV showed extensive

EDITOR,—Since the initial description by Stern and colleagues in 1985,1 the clinical entity now known as idiopathic polypoidal choroidal vasculopathy (IPCV)2 has been increasingly recognised. Although it was initially described in black, middle aged, hypertensive women,1 it is now widely accepted that IPCV can aVect men and women of any race, and may represent a signiﬁcant proportion of patients with age related macular degeneration (AMD).34 In this report, the case of a patient with atrophic AMD and evidence of IPCV is presented. To my knowledge, the co-existence of IPCV and atrophic AMD has not been previously reported.

CASE REPORT An 80 year old white woman presented complaining of sudden deterioration in vision in her left eye. Her ocular history was remarkable for atrophic AMD. Visual acuity was measured at 6/6 in the right eye and counting http://bjo.bmj.com/ on September 24, 2021 by guest. Protected copyright.

Figure 2 On fluorescein angiography pooling of dye at the macula was observed in late phases (A). An area of bright hyperfluorescence with late staining, corresponding to the serosanguineous pigment Figure 1 Fundus examination of both eyes epithelial detachment, was also present (A). On indocyanine green angiography, a network of dilated disclosed soft confluent and calcified drusen and channels terminating in aneurysmal dilations was observed in early frames of the angiogram (B), and areas of geographic atrophy (A and B). In the leakage from this vascular network was detected in late frames (C). Laser photocoagulation was left eye, a neurosensory detachment of the macula applied to cover the vascular network shown in B (inset). Following laser treatment, resolution of the and a serosanguineous pigment epithelial neurosensory detachment of the macula and pigment epithelial detachment was noted on fundus detachment surrounded by extensive hard examination and on fluorescein angiography (D). Closure of the polypoidal vessels was confirmed by exudation were also present (B, arrowheads). indocyanine green angiography (E).

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fibrovascular proliferation in the subretinal Br J Ophthalmol: first published as 10.1136/bjo.85.8.1007d on 1 August 2001. Downloaded from space and within Bruch’s membrane, and a marked lymphocytic infiltration with both B and T cells.6 Although laser photocoagulation appears to be very eVective in preserving visual acuity in patients with IPCV, spontaneous resolution of PEDs and NSRDs can also occur.5 The patient described in this report had evidence of atrophic AMD. However, the diagnosis of IPCV was suspected by the presence of a marked NSRD, extensive and diVuse hard exudates, and a serosanguineous PED. Since it was not clear whether GA was involv- ing the fovea in the left eye, laser treatment was applied in an attempt to achieve resolution of subretinal fluid and hard exudates and in the hope that an associated visual improvement will occur. Rapid resolution of all subretinal fluid was noted and, more spec- tacularly, resolution of the serosanguineous PED, distantly located from the treated area, was also observed 2 weeks after laser treatment. Although no objective improvement in visual acuity was measured, the patient perceived a gain in vision after the treatment. Although probably rare, IPCV can occur in Figure 2 MRI scans showing retrobulbar patients with atrophic AMD. A high index of haemorrhage not compressing optic nerve. suspicion may be required to establish the Figure 1 Deviation of globe and left exophthalmos. (Reproduced with patient’s diagnosis in these cases. permission.) ReoPRo (abciximab) a recent glycoprotein NOEMI LOIS GP IIib/IIIa antagonist, which has marked ReoPRo (abciximab), a glycoprotein GP IIib/ Retina Service, Ophthalmology Department, Aberdeen antithrombolytic eVects.5 Further, as well as IIIa antagonist. There was no ocular history of Royal Infirmary, Foresterhill, Aberdeen, AB25 2ZN, aspirin and subcutaneous heparin, she was Scotland, UK note but she was known to have had treatment also receiving clopidrogel—a P2 receptor Correspondence to: [email protected] for hypertension and hypercholestolaemia. Accepted for publication 20 April 2001 Her medication before angioplasty included antagonist, which inhibits platelet aggrega- subcutaneous heparin, aspirin, and tion.6 We might speculate that one of these newer agents or combinations of these agents 1 Stern RM, Zakov ZN, Zegarra H, et al. Multiple clopidrogel—a P2 receptor antagonist. recurrent serosanguineous retinal pigment epi- On examination, her best corrected visual may have been responsible. Against this thelial detachments in black women. Am J Oph- acuity was 6/9 left 6/6 right. There was no evi- evidence, however, was the finding of a normal thalmol 1985;100:560–9. dence of a relative aVerent pupillary defect. platelet count and clotting screen. In this par- 2 Yannuzzi LA, Sorenson J, Spaide RF, et al. Idiopathic polypoidal choroidal vasculopathy There was no desaturation on field examina- ticular case, the patient made a complete (IPCV). Retina 1990;10:1–8. tion with a red target in either eye. The left eye recovery probably as a result of venous bleed. 3 Yannuzzi LA, Wong DWK, Sforzolini BS, et al. was proptosed by 4 mm (Fig 1). There was Polypoidal choroidal vasculopathy and neovas- However, many cases of spontaneous orbital cularized age-related macular degeneration. evidence of limitation in elevation and dextro- haemorrhage reported have required surgical Arch Ophthalmol 1999;117:1503–10. version giving vertical and horizontal diplopia intervention with variable prognoses.78 Oph- http://bjo.bmj.com/ 4 Ahuja RM, Stanga PE, Vingerling JR, Poly- et al. in those positions of gaze. Anterior segment thalmologists need to be vigilant and carefully poidal choroidal vasculopathy in exudative and was entirely normal but for slight chemosis haemorrhagic pigment epithelial detachments. monitor these rare cases. Br J Ophthalmol 2000;84:479–84. (Fig 1) and the posterior segment examina- 5 Moorthy RS, Lyon AT, Rabb MF, et al. tion including funduscopy did not reveal any PETROS ANDREOU Idiopathic polypoidal choroidal vasculopathy of abnormality. An MRI scan of the orbit (Fig 2) RICHARD WINTLE the macula. Ophthalmology 1998;105:1380–5. JOHN BRAZIER 6 MacCumber MW, Dastgheib K, Bressler NM, et revealed an intraorbital extraconal acute al. Clinicopathologic correlation of the multiple haemorrhage measuring 1.7 cm and lying University College Hospital, recurrent serosanguineous retinal pigment epi- superior and lateral to the superior rectus Eye Department, The Middlesex Hospital,

thelial detachments syndrome. Retina 1994;14: Outpatient Department, Cleveland Street, on September 24, 2021 by guest. Protected copyright. 143–52. muscle and displacing it. There was no evidence of optic nerve compression. She had London W1N 8AA, UK a normal platelet count and clotting screen. Correspondence to: Mr Petros Andreou Spontaneous orbital haemorrhage She was managed conservatively and made a Accepted for publication 26 March 2001 following cardiac angioplasty complete recovery with 6/6 vision in each eye at 4 months after haemorrhage. 1 Krohel GB, Wright JE. Orbital haemorrhage. EDITOR,—Orbital haemorrhage occurs most Br 1971; :556–8. commonly following trauma, retrobulbar in- J Ophthalmol 55 COMMENT 2 Wright JE. Orbital vascular anomalies. Trans Am jection, or orbital surgery. Spontaneous orbital This case represents a rare case of spontane- Acad Ophthalmol Otolaryngol 1974;78:606–16. haemorrhage is a rare condition usually ous orbital haemorrhage. Most cases of 3 Rubenstein RA, Albert DM, Sheie HG. Ocular associated with vascular anomalies, lym- reported spontaneous orbital haemorrhage complications of haemophilia. Arch Ophthalmol 1966;76:230–2. phangiomas, or systemic haematological appear to have a cause to which the haemor- disorders.1–3 Rarely, it has been reported in 4 Chang WJ, Nowinski TS, Repke CS, et al. Spon- rhage could be referred to like venous anoma- taneous orbital haemorrhage in pregnant pregnant females being treated with subcutan- lies of the orbit such as lymphangiomas, women treated with subcutaneous heparin. Am 4 eous heparin. In this case report, we describe haemangiomas or carotid cavernous ﬁstulas.12 J Ophthalmol 1996;122:907–8. a woman who developed a spontaneous Other predisposing factors include blood dys- 5 Hayes R, Chesebro JH, Fuster V, et al. Am J Car- orbital haemorrhage in the perioperative diol 2000;85:1167–72. crasias such as Von Willebrand’s disease or 6 Erlinge D. Cardiovascular treatment potentials. period following cardiac angioplasty. 3 haemophilia. Heparin has been implicated in P2 receptors important for future drugs. Lakar- two cases of pregnant women treated with tidnigen 1999;96:2586–9. CASE REPORT subcutaneous heparin and hypertension, and 7 Chorich LJ, Derick RJ, Chambers RB, et al. A 48 year old woman awoke with blurred Valsalva manoeuvres have also been impli- Haemorrhagic ocular complications associated 4 with the use of systemic thrombolytic agents. vision and diplopia in her left eye 1 day after cated as possible causes. In this particular Ophthalmology 1998;105:428–31. percutaneous coronary angioplasty for coron- case, it is not clear what the predisposing fac- 8 Brooks AM, Finkelstein E. Spontaneous orbital ary stenosis. Before angioplasty she received tor may be. This woman was receiving haemorrhage. Br J Ophthalmol 1984;68:838–40.