SURVEY OF OPHTHALMOLOGY VOLUME 56 � NUMBER 3 � MAY–JUNE 2011

CLINICAL CHALLENGESPETER SAVINO AND HELEN DANESH-MEYER, EDITORS

Syphilis and the MonkAlejandra Decanini-Mancera, MD,1 Simmons Lessell, MD,2 Michael S. Lee, MD,1

and Prem S. Subramanian, MD, PhD3

1Department of Ophthalmology, University of Minnesota, Minneapolis, Minnesota, 2Massachusetts Eye and EarInfirmary, Boston, Massachusetts; and 3Wilmer Eye Institute, Baltimore, Maryland, USA

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

Case Report

A 47-year-old man developed ‘‘foggy vision’’ anda foreign body sensation in the left eye. He deniedphotopsias or pain on touching or moving the eye.His past medical history was notable for a positivetuberculin (PPD) and malaria in 1977, but hedenied any other medical problems and took nomedications. He was born in Vietnam and wasa former monk with a philosophy degree. Heimmigrated to the U.S. in 1980 and worked asa public librarian. He claimed that he had beencelibate prior to his marriage 2 years earlier anddenied high-risk sexual behavior.

His visual acuities were 20/15 OD and 20/200 OS.He identified 10 out of 10 of the Ishihara colorplates OD, but only the control plate OS. A leftrelative afferent pupillary defect (RAPD) was noted.Ocular motility, exophthalmometry, and slit lampbiomicroscopic examinations were normal. Kineticmanual perimetry is shown (Fig. 1). Ophthalmos-copy showed mild edema of the superior aspect ofthe left optic disk.

What is your differential diagnosis? How would youproceed?

267

� 2011 by Elsevier Inc.All rights reserved.

Comments

COMMENTS BY PREM SUBRAMANIAN, MD

The findings of a left RAPD, large cecocentralscotoma OS, and swollen left optic disk indicatea left optic neuropathy as the cause of the patient’svisual symptoms. The patient presents with unilat-eral loss of vision and foreign body sensation. Thetime of onset of the ‘‘foggy vision’’ is not stated, butpatients with sudden vision loss usually do notreport visual fog, but rather complain specifically ofcentral or peripheral vision loss. Thus, the patientmost likely has a chronic process leading to hisvision loss, although an acute event cannot beexcluded. Optic neuritis is a possibility in a man ofthis age, but would be more common in a womanbetween the ages of 20 and 45. Pain on eyemovement is not present here and occurs in 92%of patients with optic neuritis. The clinical pre-sentation is not consistent with either nonarteritic(NAION) or arteritic anterior ischemic optic neu-ropathy. The patient does not have systemic riskfactors for NAION like hypertension and mostimportantly has a large cup in the fellow eye. Hehas no systemic symptoms of an arteritic process.

0039-6257/$ - see front matterdoi:10.1016/j.survophthal.2010.08.004

Fig. 1. Kinetic visual fields show a centrocecal scotoma in the left eye. The right visual field is normal.

268 Surv Ophthalmol 56 (3) May--June 2011 DECANINI-MANCERA ET AL

For a chronic optic neuropathy, first and foremosta compressive lesion must be excluded. The lack ofany orbital symptoms (pain, proptosis, diplopia)would place the potential lesion in the intracranialspace or optic canal. Optic nerve sheath meningi-oma also may present in this manner, although likeoptic neuritis, it is more common in women.Infiltrative optic neuropathies from systemic in-flammatory conditions such as sarcoidosis, fromdisseminated malignancies like CNS lymphoma, ordirect optic nerve metastases are in the differential.Tuberculosis—to which this patient has been ex-posed given his positive PPD, syphilis, and lesscommonly Lyme disease also may cause optic discswelling and a chronic optic neuropathy. HIVinfection may result in optic neuropathy, eitherdirectly or more commonly in association withcytomegalovirus or toxoplasma infection. The pa-tient emigrated from Vietnam many years ago, butwe are not told if he has traveled there recently. Ifso, then unusual parasitic infections such as opticnerve cysticercosis must be considered.

Cecocentral scotomata are classically associatedwith hereditary, toxic, or nutritional optic neurop-athies. Leber hereditary optic neuropathy oftenpresents with unilateral vision loss, but the diskswelling shown here is too severe to support thisdiagnosis. Toxic and nutritional optic neuropathiesare almost never so asymmetric in their presentationand rarely cause optic disk swelling.

The initial evaluation of this patient should thusinclude complete blood count with differential,assessment of inflammatory markers (ESR, CRP,ANA, c-ANCA, ACE), Lyme ELISA, RPR, FTA-ABS,chest x-ray or possibly chest CT, and MRI of the brainand orbits with gadolinium contrast. Lumbar punc-ture with measurement of opening pressure and CSF

analysis for cell count, protein, glucose, VDRL assay,and infectious organisms (fungal, parasitic) shouldbe performed after the MRI if a definitive cause forthe optic neuropathy (such as compressive tumor) isnot identified. I would not order testing for toxins orhereditary diseases at this time.

Case Report (Continued)

Brain MRI showed three non-specific white matterlesions. The left optic nerve had an area of vague T2hyperintensity within the cisternal segment thatenhanced with gadolinium. Angiotensin convertingenzyme levels (ACE), erythrocyte sedimentation rate(ESR), complete blood count (CBC), antinuclearantibodies (ANA), HIV and Bartonella titers were allnormal. However, treponema pallidum particle agglu-tination assay (TP-PA) and fluorescent treponemalantibody absorbed (FTA-ABS) were reactive. Rapidplasma reagin (RPR) titers were positive on twodifferent occasions at a dilution of 1:8.

Three weeks later, his acuity spontaneouslyimproved to 20/40 and color vision to 9/10 OS.At that time his fundi were unchanged and kineticperimetry showed mild improvement of the centralscotoma OS (Fig. 2). The patient complained ofintermittent episodes of occipital headache eachlasting 10 to 15 minutes. At lumbar puncture theopening pressure was 150 mm CSF, and cerebrospi-nal fluid chemistry and cytology were normal. TheCSF Venereal Disease Research Laboratory assay(VDRL) was negative. The patient denied exposureto, or treatment for, syphilis in the past.

Is this patient’s optic neuropathy related to syphilis andwould you treat him for syphilis?

Fig. 2. Kinetic visual field in the left eye showsimprovement in the density of the scotoma compared toFig. 1.

SYPHILIS AND THE MONK 269

Comments (Continued)

COMMENTS BY DR. SUBRAMANIAN

The TP-PA and FTA-ABS tests are both thought tobe highly specific for syphilitic infection, and theirpositivity suggests that syphilitic infection is present,although cross-reactivity with M. tuberculosis andother mycobacteria has been reported. Syphiliticoptic neuropathy can present with optic diskswelling and vision loss; pain may or may not bepresent. This patient’s presentation is more charac-teristic of secondary rather than tertiary syphilis,where optic atrophy is more frequent. The negativeCSF VDRL does not exclude syphilitic optic neu-ropathy, but CNS involvement should be presumedif syphilis is the cause of the optic nerve disease. Thespontaneous improvement in visual acuity and fieldis not characteristic and supports an inflammatoryor other process. However, in the absence of anyother positive diagnostic data, I would treat thepatient with intravenous penicillin G after aninfectious disease consultation to determine theappropriate dose and duration of treatment.

Case Report (Continued)

The patient received a 10-day course of IVpenicillin G (PCNG), four million units (MU) every4 hours, followed by three weekly IM injections ofbenzathine PCN (2.4 MU). Two months later, hisvision improved to 20/25. Despite the visualimprovement, the optic nerve edema worsened OS(Fig. 3) and perimetry showed new inferonasalconstriction (Fig. 4). Over the course of 6 weeks hisvisual function continued to decline. The patientstarted experiencing left retro-orbital pain. A repeat

MRI showed enhancement of the optic nerve andthe adjacent anterior clinoid process (Fig. 5). Nohyperostosis of the left anterior clinoid was noted bycomputed tomography (CT). Over the next severalweeks, the acuity worsened to 20/800.

How would you proceed?

Comments (Continued)

COMMENTS BY PREM SUBRAMANIAN

It is possible that syphilitic infection was re-sponsible for some portion of the vision loss, asthere was significant improvement shortly after theappropriate treatment. Relapse following treatmentis virtually unknown, barring reinfection. Thecurrent clinical and radiographic findings are notconsistent with syphilitic infection, however. En-hancement of the anterior clinoid in addition to theoptic nerve suggests an active, invasive infectious orneoplastic process. Metastatic cancers such asprostate commonly spread to bone, as do lymphoidtumors like myeloma. The apparent local spreadfrom the optic nerve to the clinoid is moresuggestive of infection than malignancy. At thistime, biopsy of the anterior clinoid and surroundingtissues should be performed either by an endo-scopic route or by minimally invasive craniotomy.

Case Report (Continued)

He underwent ethmoidectomy, sphenoidectomy,and a trans-sphenoidal biopsy of the left orbitalapex. The surgeon noted purulent material aroundthe posterior left optic nerve. Histologic sectionsdemonstrated fibrosis and chronic, polyclonal in-flammatory cells. Multiple acid fast bacillus, trepo-nemal, fungal stains, and cultures were all negative.Chest and abdomen CT were also normal. A PPDwas positive. Postoperatively, he complained ofnumbness in the first division of the left trigeminalnerve, his acuity declined to 2/200 OS, and he wasstarted on oral prednisone (1 mg/kg) and isoniazidprophylaxis. Four weeks later, his acuity remainedunchanged, and his examination revealed new leftupper lid ptosis and reduced elevation OS. Predni-sone was immediately tapered.

Repeat lumbar puncture opening pressure, CSFcytology, and chemistry were all normal. An MRIshowed, in addition to postoperative changes withinthe left sphenoid sinus, an enhancing lesionextending from the orbital apex into the cavernoussinus (Fig. 6). At a left fronto-temporal craniotomya 5-mm nodule at the orbital apex above theentrance of the optic canal and thickened opticnerve dura mater were found. A yellowish material

Fig. 3. The left optic disk shows moderate edema and hyperemia.

270 Surv Ophthalmol 56 (3) May--June 2011 DECANINI-MANCERA ET AL

medial to the optic nerve was sent for cultures andpathology.

The final diagnosis was orbital aspergillosis(Aspergillus fumigatus) (Fig. 7). The patient was begunon intravenous amphotericin B therapy, but devel-oped postoperative fever and CSF leukocytosis. Cas-pofungen was added to his regimen. A mycoticaneurysm developed in his posterior fossa. Emboliza-tion led to an infarction of the left cerebellum, whichrequiredsurgicaldecompression.Despite theadditionof voriconazole, he developed multiple mycoticaneurysms, with subarachnoid hemorrhage requiringemergent surgery. He was discharged to hospice.

Discussion

Aspergillus is a ubiquitous fungus foundparticularlyin soil and decaying vegetation. Aspergillosis may beseen inhealthy individuals, but ismuchmorecommonin immunocompromised patients. A. fumigatus and A.

Fig. 4. The left kinetic visual field shows a persistentcentral scotoma and a new inferonasal defect.

flavus are the most common fungal contaminants ofthe sinuses and thus have the potential to infect theorbit7,11 secondarily, causing sino-orbital aspergillo-sis.3,23 Primary orbital aspergillus infection withoutsinus involvement is, however, reported.19 Primaryorbital aspergillosis may present with unilat-eral2,5,9,17,21 or bilateral optic neuropathy,13 ophthal-moplegia,8,13,15,20 proptosis,4 and pain,4,10,20 witha typical insidious, uncontrollable progression. Pri-mary orbital infection represents a diagnostic chal-lenge for clinicians because of nonspecificneuroimaging findings, frequently negative bloodcultures, and a low yield of tissue histopathology.14,23

Our immunocompetent patient initially mani-fested clinical and radiological signs of an isolatedunilateral optic neuropathy. After an extensiveworkup to exclude demyelinating, infectious, ische-mic, infiltrative, and inflammatory etiologies, thepresumptive diagnosis was optic neuropathy second-ary to syphilis based on positive serology.16 Di-agnostic ‘‘confirmation’’ was obtained by a positiveTP-PA, in addition to RPR and FTA-ABS, and high-dose penicillin was given. After he worsenedclinically, a transphenoidal biopsy of the orbitalapex was performed. Faced with negative fungal andacid fast stains along with histopathologic findingsof chronic inflammation and fibrosis, corticoste-roids were begun.

The literature on orbital aspergillosis reveals thatclinicians involved in these cases frequently encoun-ter diagnostic problems, and aspergillus infection isnot considered until other infectious causes such aspyogenic organisms and tuberculosis inflammatorydiseases such as sarcoidosis or Wegener’s granulo-matosis and neoplasia have been ruled out.11,12,14

More severe diagnostic problems arise when nosinus disease is seen on imaging studies, and there isno evidence of an orbital apex mass initially. Ifa vasculitic or a granulomatous condition is di-

Fig. 5. Postgadolinium, coronal T1 MRI shows persistentenhancement of the left optic nerve (black arrowhead). Theanterior clinoid also enhances with gadolinium (whitearrowhead).

SYPHILIS AND THE MONK 271

agnosed and corticosteroids are administered, clin-ical deterioration is not uncommon, as was the casein our patient.

O’Toole et al presented two cases of orbitalaspergillosis with late stage diagnoses. A patientpresented with dyschromatopsia and RAPD, followedby signs of a sixth and partial third nerve cranialneuropathies. Imaging, CSF studies, and temporalartery biopsy were negative, and Tolosa Huntsyndrome was diagnosed. Corticosteroids were given,followed by severe deterioration, and an orbital massappeared on further imaging.14 Choi et al also

Fig. 6. Coronal postgadolinium T1 weighted images show en

describe a patient with presumed optic neuritis anda negative CTwho received corticosteroid treatment,followed by clinical deterioration, who was thendiagnosed on histopathology as having aspergillosis.2

Thus, suspecting orbital aspergillosis is particularlyimportant when corticosteroids are a possible ther-apy, as with presumed optic neuritis or idiopathicorbital inflammation, as steroid therapy may provefatal in a patient harboring aspergillosis.

Many individuals with orbital aspergillosis haveunfortunate clinical courses, and ours was noexception. Marcet et al and Suzuki et al reportedorbital aspergillosis complicated by subarachnoidhemorrhage from ruptured mycotic aneurysms.12,18

Clancy et al reviewed 29 cases of sino-orbital diseaseand found a mortality rate of 60% for patients whosetreatment commencedmore than 6months after theonset of symptoms, compared to 36% for patientswho started treatment within 6 months.3 In addition,the need for invasive procedures to make a definitivediagnosis increases morbidity and mortality. Ap-proaches for obtaining tissue include orbitotomy,trans-sphenoidal, craniotomy, and fine-needle aspi-ration biopsy. Open craniotomy has a high mortalityrate and is frequently complicated by the spread ofinfection to meningoencephalitis or cerebral vascu-litis.14 When the orbital lesion is associated withsinus disease, and the tissue sample is acquired byendoscopic approach, surgical morbidity andmortality are markedly reduced.1 Ultrasound-guided fine-needle aspiration biopsy has been usedin the diagnosis of an optic nerve lesion caused byAspergillus fumigatus with good results.6

Defining optimal treatment for this condition iscomplicated as the result the small number of casesand the different approaches taken. In addition,many of the studies include patients with sino-

largement of the enhancing lesion in the left orbital apex.

Fig. 7. Giemsa stain demonstrates nonseptate branchinghyphae consistent with Aspergillus.

272 Surv Ophthalmol 56 (3) May--June 2011 DECANINI-MANCERA ET AL

orbital aspergillosis, which is known to differ fromprimary orbital disease in many ways. In general,intravenous anti-fungals and aggressive surgicalresection are the cornerstones of therapy.3,14 Al-though IV antifungals are the treatment of choice,Browning et al reported a patient with opticneuropathy and ophthalmoplegia from sino-orbitalaspergillosis in whom a two-year course of oralitraconazole led to a complete resolution of imagingabnormalities and clinical stabilization. Successfuloutcome is dependant on preventing further in-tracranial extension, which has a high mortality. Inone survey 62% of patients with complete surgicalresections showed either resolution or stabilization,compared to only 31% of patients with incompleteresection.3 Dortzbach et al treated a 40-year-old manwith orbital aspergillosis with limited orbital exen-teration and adjunctive amphotericin B. Forty-twomonths later the patient was alive without recur-rence. Whitehurst et al also reported a child inwhom exenteration followed by a 6-week therapywith amphotericin B resulted in no recurrence aftera two-year follow-up.22

In conclusion, orbital aspergillosis in an immu-nocompetent individual without paranasal sinusinvolvement is often diagnosed only late in thecourse of the disease. A high index of suspicion mayresult in more aggressive diagnostic testing, avoidingcorticosteroid use, and prompt institution of anti-fungal therapy.

Disclosure

The authors reported no proprietary or commer-cial interest in any product mentioned or conceptdiscussed in this article. Publication of this articlewas supported by unrestricted grants from Research

to Prevent Blindness, New York, NY, and the LionsClub of Minnesota.

References

1. Browning AC, Sim KT, Timms JM, et al. Successful treatmentof invasive cavernous sinus aspergillosis with oral itracona-zole monotherapy. J Neuroophthalmol. 2006;26:103--6

2. Choi MY, Bae IH, Lee JH, et al. Aspergillosis presenting as anoptic neuritis. Korean J Ophthalmol. 2002;16:119--23

3. Clancy CJ, Nguyen MH. Invasive sinus aspergillosis inapparently immunocompetent hosts. J Infect. 1998;37:229--240

4. Dortzbach RK, Segrest DR. Orbital aspergillosis. OphthalmicSurg. 1983;14:240--4

5. Fernando SS, Lauer CS. Aspergillus fumigatus infection ofthe optic nerve with mycotic arteritis of cerebral vessels.Histopathology. 1982;6:227--34

6. Garcia-Asensio S, Artigas JM, Barrena R. Optic nerveaspergillosis: report of a case diagnosed by fine-needleaspiration biopsy. Eur Radiol. 2000;10:573--5

7. Green WR, Font RL, Zimmerman LE. Aspergillus of theorbit. Arch Ophthalmol. 1969;82:302--13

8. Hedges TR, Leung LS. Parasellar and orbital apex syndromecaused by aspergillosis. Neurology. 1976;26:117--20

9. Hutnik CML, Nicolle DA, Munoz DG. Orbital aspergillosis:a fatal masquerader. J Neuroophthalmol. 1997;17:257--61

10. Larsen SA, Steiner BM, Rudolph AH. Laboratory diagnosisand interpretation of tests for syphilis. Clin Microbiol Rev.1995;8:1--21

11. Levin LA, Avery R, Shore JW, et al. The spectrum of orbitalaspergillosis: a clinicopathological review. Surv Ophthalmol.1996;41:142--54

12. Marcet MM, Yang W, Albert DM, et al. Aspergillus infectionof the orbital apex masquerading as Tolosa-Hunt syndrome.Arch Ophthalmol. 2007;125:563--6

13. Matsuo T, Notohara K, Yamadori I. Aspergillosis causingbilateral optic neuritis and later orbital apex syndrome. JpnJ Ophthalmol. 2005;49:430--1

14. O’Toole L, Acheson JA, Kidd D. Orbital apex lesion due toaspergillosis presenting in immunocompetent patientswithout apparent sinus disease. J Neurol. 2008;255:1798--801

15. Slavin ML. Primary aspergillosis of the orbital apex. ArchOphthalmol. 1991;109:1502--3

16. Smith GT, Goldmeier D, Migdal C. Neurosyphilis with opticneuritis: an update. Postgrad Med J. 2006;82:36--9

17. Spoor TC, Hartel WC, Harding S, et al. Aspergilluspresenting as a corticosteroid responsive optic neuropathy.J Clin Neuroophthalmol. 1982;2:103--7

18. Suzuki K, Iwabuchi N, Kuramochi S, et al. Aspergillusaneurysm of the middle cerebral artery causing a fatalsubarachnoid hemorrhage. Intern Med. 1995;34:550--3

19. Townes DE. Orbital aspergilloma. Surv Ophthalmol. 1967;12:337--43

20. Weinstein JM, Morris GL, ZuRhein GM, et al. Posteriorischemic optic neuropathy due to aspergillus fumigatus.J Clin Neuro-ophthalmol. 1989;9:7--13

21. Weinstein JM, Sattler FA, Towfighi J, et al. Optic neuropathyand paratrigeminal syndrome due to aspergillus fumigatus.Arch Neurol. 1982;39:582--5

22. Whitehurst FO, Liston TE. Orbital aspergillosis: report ofa case in a child. J Ped Ophthalmol Strab. 1981;18:50--4

23. Willermain F, Bradstreet C, Kampouridis S, et al. Differentpresentations of ophthalmic aspergillosis. Eur J Ophthal-mol. 2008;18:827--30

Reprint address: Michael S. Lee, MD, University of MinnesotaDepartment of Ophthalmology, MMC 493, 420 Delaware StreetS.E., Minneapolis, MN 55455-0501.

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Abstract. Primary orbital aspergillus infection may occur in immunocompetent individuals. Itfrequently represents a diagnostic challenge for clinicians due to nonspecific clinical presentations andneuroimaging signs. We present a 47-year-old otherwise healthy man with an isolated unilateral opticneuropathy secondary to primary orbital aspergillosis. He had a remote history of tuberculosis andpositive syphilis serologies. After he worsened despite intravenous penicillin therapy, a biopsy showedchronic inflammation. Corticosteroids treatment was followed by further deterioration of his clinicalcondition. Finally, a repeat biopsy revealed the aspergillus infection. Despite antifungal therapy, theoutcome was unfavorable. A high index of suspicion should result in aggressive diagnostic testing andprompt institution of antifungal therapy in patients with primary orbital aspergillosis. (SurvOphthalmol 56:267--273, 2011. � 2011 Elsevier Inc. All rights reserved.)

Key words. antifungal therapy � Aspergillus infection � corticosteroids � primary orbitalAspergillosis