You're Too Old for That

CLINICAL CHALLENGESPETER SAVINO AND HELEN DANESH-MEYER, EDITORS

You’re Too Old for ThatVinay A. Shah, MD,1 Sandeep Randhawa, MD,1 Thomas Mizen, MD,4

Andrew G. Lee, MD,1,2,3 and Rod Foroozan, MD5

Departments of 1Ophthalmology, 2Neurology, and 3Neurosurgery at the University of Iowa Hospitals and Clinics,Iowa City, Iowa, USA; the 4H. Stanley Thompson Neuro-ophthalmology Clinic, and Departments of Ophthalmology,Neurology and Neurosurgery, Rush University Medical Center, Chicago, Illinois, USA; and 5Baylor College of Medicine,Houston, Texas, USA

(In keeping with the format of a clinical pathologic conference,the abstract and key words appear at the end of the article.)

SURVEY OF OPHTHALMOLOGY VOLUME 53 � NUMBER 4 � JULY–AUGUST 2008

Case Report. A 72-year-old man presented with visualloss. Eighteen months prior to presentation hecomplained of mild decreased visual acuity OU. Hewas seen by an ophthalmologist and diagnosed withcataracts and subsequently underwent cataract sur-gery OD and then OS. Postoperatively, he requiredsurgical repositioning of the intraocular lens OD. Hethen complained of painless progressive loss of visionOD 1 month after his cataract surgery. The left eye wasnormal. A retina specialist found no abnormalities.The patient subsequently was referred to a neuro-ophthalmologist in September 2004. Visual acuity wasnow count fingers OD and 20/30 OS. He could notread the color plates OD and correctly read 14 out of14 Ishihara color plates OS. The pupils were equaland reactive bilaterally but he had a right relativeafferent pupillary defect (RAPD). Ophthalmoscopyshowed moderate pallor of the right optic nerve, butthe left optic nerve was normal. Kinetic and staticperimetry revealed a cecocentral scotoma OD anda normal visual field OS (Fig. 1).

The past medical history was significant forhypertension, diabetes, hypercholesterolemia, and

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coronary artery disease. He had had a gross totalresection of a melanoma from his right arm severalyears prior to presentation without recurrence ormetastatic disease. His medications were simvastatin,finasteride, tamsulosin, amantadine, lisinopril, babyaspirin, metformin, clopidogrel, hydrochlorothia-zide, multivitamins, and glucosamine/chondroitin.Social history was negative for alcohol or tobaccouse.

What is the differential diagnosis?What further testing should be performed at this time?

Comments

Comments by Rod Foroozan, MDSlowly progressive decreased vision one month

after cataract surgery is most suggestive of retinop-athy (cystoid macular edema), especially witha history of a second procedure to reposition theintraocular lens. We are not told if fluoresceinangiography or optical coherence tomography(OCT) was performed at the time the patient was

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0039-6257/08/$--see front matterdoi:10.1016/j.survophthal.2008.04.003

Fig. 1. Goldmann visual field (GVF) testing demonstrating cecocentral scotoma OD and OS full field in September2004.

404 Surv Ophthalmol 53 (4) July--August 2008 SHAH ET AL

seen by the retina specialist. We also do not havedetails of the examination or know what level ofvisual dysfunction was present at that time. However,by September 2004 the findings reduced visualacuity, visual field defect, RAPD, and optic diskpallor are suggestive of an optic neuropathy.Although these findings may occur from retinopa-thy, I would expect to see an abnormality in theretina during funduscopy to account for this level ofvisual dysfunction.

A general classification of optic neuropathyincludes inflammatory, ischemic, compressive, trau-matic, toxic, and hereditary. The history is key indetermining the type of optic neuropathy. Unilat-eral, painless loss of vision in a 72-year-old man isstatistically most likely to be caused by ischemicoptic neuropathy. Ischemic optic neuropathy wouldbe expected to produce an acute deficit followedwithin weeks by relative stability. However, we donot know the clinical course from the time thepatient was seen until the examination in Septem-ber 2004. Therefore, we cannot exclude compres-sive optic neuropathy, which we would most oftenexpect to cause a gradually progressive loss ofvision. In addition this patient has a history ofmalignancy and melanoma not infrequently mayinvolve the central nervous system. Because detailsof the course of visual loss are unclear I wouldsuggest magnetic resonance imaging of the brainand orbits with contrast and fat suppression. Thereis no history of trauma, no family history of visualloss, and none of his current medications aretypically associated with toxic optic neuropathyor suspected of precipitating an opticneuropathy.7,11,14,22,25,29

Case Report (Continued)

Fundus fluorescein angiography (FA) and mag-netic resonance imaging (MRI) of the brain werenormal. A presumptive diagnosis of ischemic opticneuropathy OD was made. The patient then de-veloped painless visual loss in the fellow eye and wasreferred to the University of Iowa neuro-ophthal-mology clinic for a second opinion in May 2005. Hedenied any photopsias and had no other neurologicsigns or symptoms. Visual acuity was count fingers at3 feet with eccentric fixation OD and 20/30 OS. Thepupils were isocoric but he had a 0.9 log unit RAPDOD. Motility examination, intraocular pressuremeasurements, and slit-lamp biomicroscopy werenormal OU. Kinetic perimetry finding are seen inFig. 2. Ophthalmoscopy showed a normal macula,vessels, and periphery in each eye. The right opticnerve had moderate temporal pallor but the leftoptic nerve was normal (Fig. 3). Optical coherencetomography revealed temporal thinning of theretinal nerve fiber layer (RNFL) OD with normalRNFL OS (Figure 3). Because of the history ofmelanoma both a multifocal electroretinogram(MERG) and a full-field ERG were performed andshowed no evidence of paraneoplastic retinopathy.Repeat MRI of the head and orbit with fatsuppression and gadolinium administration re-vealed questionable T1-weighted enhancement ofthe intracranial optic nerve and high T2 signalintensity of the right optic nerve (Fig. 4). Basedupon the clinical findings and the possible en-hancement of the optic nerve on the MRI thepatient was empirically started on prednisone 60mg/day for a presumptive diagnosis of bilateral

Fig. 2. GVF in May 2005 revealing a dense central scotoma OD with breakout to the superior and inferior nasalperiphery. There was absence of the I1E isopter OS with inferior and superior constriction.

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sequential inflammatory optic neuropathy. Autoim-mune optic neuropathy was considered in thedifferential diagnosis but direct immunofluorescentstudy of a nonexposed skin biopsy did not reveal

deposition of IgM and C3 in the basementmembrane. The patient’s vision continued to de-teriorate centrally OS and on June 17, 2005, thevision was counting fingers OU with bilateral optic

Fig. 3. The optic disk OD shows moderate temporal pallor and a normal optic disk OS. OCT reveales temporal thinningof RNFL OD (mean thickness 105m) with normal nerve fiber layer OS (mean thickness 70m) in May 2005.

406 Surv Ophthalmol 53 (4) July--August 2008 SHAH ET AL

Fig. 4. Coronal T2-weighted cranial MRI showing mild hyperintense signal (long arrow) intensity in the right opticnerve in May 2005. T1 post contrast MRI shows mild enhancement of the right intracranial optic nerve (short arrow).

nerve pallor. The visual field testing now revealedbilateral central scotomas.

What is the differential diagnosis now?What further work up should be done?

Comments (Continued)

Comments by Dr. ForoozanA normal MERG helps exclude retinopathy as the

cause of visual loss. The findings are now suggestiveof an optic neuropathy on each side. If this was fromischemic optic neuropathy it would have to be fromposterior ischemic optic neuropathy because newvisual loss occurred in the absence of optic diskedema on the left side. Posterior ischemic opticneuropathy typically occurs in the setting ofhypotension following general or back surgery orfollowing blood loss or in patients with vasculitissuch as giant cell arteritis (GCA). Furthermore,ischemic optic neuropathy would be unlikely tocause gradually progressive loss in vision. Neverthe-less, symptoms and signs suggestive of GCA shouldbe noted and an erythrocyte sedimentation rateconsidered.

The findings on neuroimaging, with enhancementof the optic nerve, are more suggestive of an

inflammatory optic neuropathy, although enhance-ment may less commonly be seen in ischemic andhereditary (Leber) optic neuropathies. I would haveexpected stability or visual improvement with corti-costeroids in a patient with an inflammatory opticneuropathy and not further deterioration in vision.

I would again review the list of medications fora potential toxic cause and ask questions such aswork history for possible environmental toxins.Urine for heavy metals and blood levels of B12and folate might be helpful for a possible nutri-tional optic neuropathy.

Given the initial visual field findings of a cecocen-tral scotoma and the sequential optic neuropathyover several months, hereditary optic neuropathyfrom Leber hereditary optic neuropathy (LHON)can be considered. Often there are characteristicfunduscopic findings with very mild optic diskedema, but the optic disks may look normal. I havebeen surprised by one 68-year-old man who de-veloped a bilateral gradually progressive loss ofvision over 2--3 months and was initially thought tohave non-physiologic visual loss was found to havea positive blood test for the 11778 mutation. Mostpatients with LHON will have one of three primarymutations; however, in some patients additional

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blood tests may be necessary to exclude othermutations.

At this point the clinical findings and tempo ofvisual loss are atypical for the most common opticneuropathies. Antibodies for autoimmune opticneuropathy can be ordered through the laboratoryat the University of California, Davis. Although theyield is likely to be low in the absence of othersymptoms, other screening blood tests can beconsidered including: RPR, FTA-Abs, angiotensinconverting enzyme, anti-nuclear antibody (ANA),c-ANCA, p-ANCA. A lumbar puncture with analysisof cerebrospinal fluid may help exclude malignantcells within the cerebrospinal fluid.

Case Report (Continued)

Testing for LHON was sent from the outsideacademic institution and was negative for the threecommon LHON mutations. Because of his priorhistory of melanoma and the mild enhancement ofthe optic nerve on the MRI, his primary carephysicians ordered a positron emission tomography(PET) scan that showed nonspecific decreasedmetabolic activity in the parietal lobes and slightincreased activity in the caudate nuclei, which was ofuncertain significance. There was some increasedmetabolic activity in one lymph node in the left axilla,which appeared to be due to benign lymphadenitis.There was some nonspecific increased activity in thesmall and large intestine but no evidence forsarcoidosis or an underlying neoplastic process.Serum C-reactive protein (CRP), rheumatoid factor(RF), ANA, and complement levels were all negative.Cerebrospinal fluid (CSF) analysis (i.e., CSF protein,cell count, glucose, and cytology) was normal. He was

empirically treated with oral corticosteroids forpresumptive inflammatory optic neuropathy.

On August 29, 2005, the visual acuity was countfingers at 4 feet OD and 20/400 with eccentricfixation OS. Kinetic perimetry revealed a cecocentralscotoma OU (Fig. 5). Ophthalmoscopy revealedbilateral temporal optic disk pallor and there wascorresponding thinning of the retinal nerve fiberlayer (RNFL) in both eyes on the OCT (Fig. 6). Thepatient was evaluated by neurology for a foot drop,which was thought to be unrelated. Rheumatologicevaluation for underlying inflammatory diseaseincluding antiphospholipid antibody, antineutro-phil antibodies, rheumatoid factor, serum proteinelectrophoresis, ribonucleoprotein antibody, Sjog-ren antibodies, double-stranded DNA, purifiedequine anti-p-azophenyl-ß-lactoside antibody, com-plete blood count, thyroid stimulating hormone,erythrocyte sedimentation rate, C-reactive protein,B12 level, folate, chest x-ray, compliment levels,reactive plasma reagent and angiotensin convertingenzyme were all negative. Paraneoplastic antibodiessent were negative (antineuronal nuclear antibodytype 1, 2, and 3, Purkinje cell cyto antibody type 1, 2,and TR, amphiysin antibody, striational antibody,calcium channel binding antibody, and acetycholinereceptor binding antibody). He was continued onimmunosuppressive therapy with a tapering dose ofprednisone 25 mg and methotrexate.

What further work-up should be done?

Comments (Continued)

Comments by Dr. ForoozanGiven the results of testing I do not have a cause

for the bilateral optic neuropathy. Had this been

Fig. 5. GVF demonstrating a cecocentral scotoma in both eyes in August 2005.

Fig. 6. Bilateral temporal optic disk pallor with thinning on RNFL in both eyes on OCT mean RNFL thickness 58 m ODand 92 m OS in August 2005.

408 Surv Ophthalmol 53 (4) July--August 2008 SHAH ET AL

from metastatic melanoma or a paraneoplastic pro-cess I would have expected the vision to worsen,perhaps even with the immunosuppressive therapy.As noted previously, some patients with LHON donot have one of the three primary mutations, whichare tested within commercial laboratories. Addi-tional testing for other LHON mutations (which isnot commercially available and requires samples tobe sent to specific laboratories) could beconsidered.

In the absence of other symptoms and withoutabnormal inflammatory blood tests to help monitora potential systemic cause of the optic neuropathy Iwould suggest a gradual taper of the immunosup-pressive medication and follow-up MRI of the brainand orbits to ensure that there is resolution and noprogression of the optic nerve enhancement.

Case Report (Continued)

The patient was seen in follow-up at the Universityof Iowa neuro-ophthalmology clinic in August 2005.Because of the bilateral optic atrophy and cecocen-tral scotomas OU, a second specimen was sent, butthis time to the University of Iowa Carver Labora-tory. One month later this specimen was reported as

positive for the 14484 mitochondrial mutation andthe immunosuppressive therapy was tapered. Be-cause of the conflicting laboratory testing for LHONbetween the first academic institution and theUniversity of Iowa, a third blood sample for LHONwas sent and confirmed the 14484 mutationconsistent with LHON.

Discussion

LHON was initially described as a distinctiveclinical entity in 1871 by a German ophthalmologistTheodore Leber.13 He described the pattern of visualloss among members of four families.8,24,27 LHON isa common mitochondrial genetic disease with anestimated prevalence of approximately 1: 25,000 innortheast England.3 The mechanism of visual loss ishypothesized to be an additional impairment ofoxidative respiration within an optic nerve which isalready compromised by the biochemical effects ofthe mitochondrial gene defect. Various triggers havebeen reported including a disturbance in cvanidemetabolism, metabolic compromise secondary todiabetes, and chronic anemia.2,4,5 Over 95% ofLHON cases are primarily the result of one of threemitochondrial DNA (mt DNA) point mutations,

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G11778A (50--76% of families), G3460A (7--30%)and T14484C (10--31%).15,16,19

In approximately 70% of affected individualsvisual loss begins in the second or third decade oflife and 95% of patients lose their vision by theirfifth decade of life.16,21 To our knowledge, theoldest reported patient with LHON to date is73 years old and was also reported from ourinstitution.1 This patient had the 11778 mt DNA.Our patient was 72 years old when he started havingvisual loss; however, to our knowledge he is one ofthe oldest patients if not the oldest reported patientwith LHON harboring the 14484 mt DNA. It hasbeen noted that this and other atypical late onsetcases are associated with a poorer prognosis forvisual recovery.

Johns et al described the clinical features of theLHON with the 14484 mutation and compared itsclinic features with the other known mutations.They found that the 14484 mitochondrial DNAmutation may have a better prognosis for visualrecovery.9 In their study of 19 visually symptomaticpatients with 14484 mutations, the average age ofonset was 27 years (range 10 to 56 years). Theclinical presentation of these patients as is similar toother known LHON mutations. However the au-thors found a higher incidence of visual recovery(37%, improved to 20/60 or better) in thesepatients as compared with the 11778 (4%), 3460(28%) and 15257 (28%) mutations.10,26

Although MRI of the brain and orbits is usuallynormal in patients with LHON,18 there have beena few cases with enhancement in the opticnerve.17,20,28 In our patient, cranial MRI showeda mild amount of enhancement on T1 postcontrast and increased optic nerve signal on theT2-weighted imaging that prompted more aggres-sive evaluation for inflammatory and autoimmuneoptic neuropathies. There have been a few neuro-pathological studies of LHON. These consistentlyshow degeneration of the retinal ganglion layer andoptic nerve with axonal loss, occasionally with mildinflammation.6,12,23 This may be the basis of opticnerve enhancement on MRI seen in some cases ofLHON.

This patient had undergone testing for LHONearly in his evaluation that was negative. A repeatLHON test at our institution, however, provedpositive for the 14484 mutation. Variability inlaboratory testing, as with any test can, producefalse positive and false negative results and thiscase emphasizes the importance of clinical corre-lation and repeat testing if necessary in specificsituations.

LHON should be considered in the differentialdiagnosis of any bilateral and sequential optic

neuropathy regardless of age. LHON may presentwith a stuttering course and may show mild opticnerve enhancement on MRI that might be mistakenfor an inflammatory optic neuropathy. Spontaneousimprovement, especially in the 14484 mutation, maybe misinterpreted (as was presumed in our patient)as evidence of steroid responsiveness.

References

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2. Berninger TA, von Meyer L, Siess E, et al: Leber’s hereditaryoptic atrophy: further evidence for a defect of cyanidemetabolism? Br J Ophthalmol 73:314--6, 1989

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10. Johns DR, Smith KH, Miller NR: Leber’s hereditary opticneuropathy. Clinical manifestations of the 3460 mutation.Arch Ophthalmol 110:1577--81, 1992

11. Kerrison JB, Miller NR, Hsu F, et al: A case-control study oftobacco and alcohol consumption in Leber hereditary opticneuropathy. Am J Ophthalmol 130:803--12, 2000

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14. Mackey DA, Fingert JH, Luzhansky JZ, et al: Leber’shereditary optic neuropathy triggered by antiretroviraltherapy for human immunodeficiency virus. Eye 17:312--7,2003

15. Mackey DA, Oostra RJ, Rosenberg T, et al: Primarypathogenic mtDNA mutations in multigeneration pedigreeswith Leber hereditary optic neuropathy. Am J Hum Genet59:481--5, 1996

16. Man PY, Turnbull DM, Chinnery PF: Leber hereditary opticneuropathy. J Med Genet 39:162--9, 2002

17. Mashima Y, Oshitari K, Imamura Y, et al: Orbital highresolution magnetic resonance imaging with fast spin echoin the acute stage of Leber’s hereditary optic neuropathy. JNeurol Neurosurg Psychiatry 64:124--7, 1998

18. Newman NJ: Leber’s hereditary optic neuropathy. Newgenetic considerations. Arch Neurol 50:540--8, 1993

19. Nikoskelainen EK, Huoponen K, Juvonen V, et al: Ophthal-mologic findings in Leber hereditary optic neuropathy, withspecial reference to mtDNA mutations. Ophthalmology 103:504--14, 1996

20. Phillips PH, Vaphiades M, Glasier CM, et al: Chiasmalenlargement and optic nerve enhancement on magnetic

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resonance imaging in leber hereditary optic neuropathy.Arch Ophthalmol 121:577--9, 2003

21. Riordan-Eva P, Sanders MD, Govan GG, et al: The clinicalfeatures of Leber’s hereditary optic neuropathy defined bythe presence of a pathogenic mitochondrial DNA mutation.Brain 118:319--37, 1995

22. Rizzo JF: Adenosine triphosphate deficiency: a genre ofoptic neuropathy. Neurology 45:11--6, 1995

23. Saadati HG, Hsu HY, Heller KB, et al: A histopathologic andmorphometric differentiation of nerves in optic nervehypoplasia and Leber hereditary optic neuropathy. ArchOphthalmol 116:911--6, 1998

24. Seedorff T: Leber’s disease. Acta Ophthalmol (Copenh) 46:4--25, 1968

25. Shaikh S, Ta C, Basham AA, et al: Leber hereditary opticneuropathy associated with antiretroviral therapy for humanimmunodeficiency virus infection. Am J Ophthalmol 131:143--5, 2001

26. Stone EM, Newman NJ, Miller NR, et al: Visual recoveryin patients with Leber’s hereditary optic neuropathy and

the 11778 mutation. J Clin Neuroophthalmol 12:10--4,1992

27. Van Senus AHC: Lebers disease in the Netherlands. DocOphthalmol 17:1--162, 1963

28. Vaphiades MS, Newman NJ: Optic nerve enhancementon orbital magnetic resonance imaging in Leber’shereditary optic neuropathy. J Neuroophthalmol 19:238--9, 1999

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The authors reported no proprietary or commercial interest inany product mentioned or concept discussed in this article.

Reprint address: Andrew G. Lee, MD, Department ofOphthalmology, University of Iowa Hospitals and Clinics, 200Hawkins Dr., PFP Iowa City, IA 52242-1091. e-mail: [email protected].

Abstract. Leber hereditary optic neuropathy (LHON) produces a subacute and typically bilateral butsequential optic neuropathy. LHON is a mitochondrial disease and the most common mutations are atpositions 11778, 14484 and 3460. LHON typically presents in young (age 20--40), healthy men but mayoccur in either sex and at any age. We report a case of LHON in a 72-year-old man and we emphasizethe importance of testing for LHON in all cases of unexplained bilateral and sequential opticneuropathy with a ceco-central or central scotoma. (Surv Ophthalmol 53:403--410, 2008. � 2008Elsevier Inc. All rights reserved.)

Key words. central scotoma � Leber hereditary optic neuropathy