“My eyes are turned outside”

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Clinical challenges

“My eyes are turned outside”

Nagham Al-Zubidi, MDa,b, Patricia Chevez-Barrios, MDc,d,Rod Foroozan, MDd,*, M. Tariq Bhatti, MDe,f

aDepartment of Ophthalmology, The Methodist Hospital, Houston, TexasbDepartment of Ophthalmology, Weill Cornell Medical College, Houston, TexascDepartments of Pathology and Genomic Medicine, The Methodist Hospital, Houston, TexasdDepartment of Ophthalmology, Baylor College of Medicine, Houston, TexaseDepartment of Ophthalmology, Duke Eye Center and Duke University Medical Center, Durham, North CarolinafDepartment of Neurology, Duke University Medical Center, Durham, North Carolina

a r t i c l e i n f o

Article history:

Received 30 September 2013

Accepted 1 October 2013

Available online 24 October 2013

Peter Savino and Helen

Danesh-Meyer, Editors

* Corresponding author: Rod Foroozan, MDE-mail address: [email protected] (

0039-6257/$ e see front matter ª 2014 Elsevhttp://dx.doi.org/10.1016/j.survophthal.2013.

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

the end of the article.)

1. Case report

A 78-year-old white woman with a past medical history of

uncontrolled hypertension, hyperlipidemia, bilateral long-

standing optic disk pallor, and fibromyalgia presented with

progressively worsening headache, decreased vision, dizzi-

ness, imbalance, and binocular horizontal and vertical

diplopia of two months duration. Initially she was given the

diagnosis of isolated, ischemic left fourth nerve palsy. Review

of systems was otherwise negative. She had had bilateral

cataract surgery. Her father was said to have optic disk pallor

of uncertain etiology. Her medications included amitriptyline,

duloxetine, valsartan, cyclobenzaprine, and lorazepam. She

denied tobacco, alcohol, or illicit drug use.

When she was seen at an outside institution, her best-

corrected visual acuity fluctuated between 20/80 and 20/100

in both eyes. The pupils were isocoric and symmetric, without

a relative afferent pupillary defect (RAPD). Extraocular move-

ments showed a right hypertropia worse in left gaze and right

, 1977 Butler Boulevard,R. Foroozan).ier Inc. All rights reserve10.001

head tilt. Slit-lamp examination and intraocular pressure

were normal except for bilateral posterior chamber intraoc-

ular lenses (PCIOLs). Dilated fundus examination revealed

bilateral optic disk pallor.

What is the differential diagnosis?

What studies would you suggest?

2. Comments

2.1. Comments by M. Tariq Bhatti, MD

There are two main physical examination findings in this

elderlywoman thatwemust try to reconcile with one another:

1. The right hypertropia

2. The bilateral optic nerve pallor

If we apply Occam’s razor, choosing the simplest expla-

nation (law of parsimony), then we need to find a single

Houston, Texas 77030.

d.

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Fig. 1 e Parks-Bielschowsky three step test based on a right

hypertropia, greater in left gaze and right head tilt. Step

1 [ in primary gaze there is a right hypertropia indicating

either the depressors of the right eye (superior oblique or

inferior rectus muscle) or the elevators of the left eye

(inferior oblique or superior rectusmuscle) are paretic. Step

2 [ the right hypertropia is worse in left gaze compared

with right gaze, indicating dysfunction in the right eye of

the inferior oblique or superior oblique muscle and in the

left eye of the superior rectus or inferior rectus muscle.

Step 3 [ the right hypertropia is worse in right head tilt

compared with left head tilt, indicating dysfunction in the

right eye of the superior rectus or superior oblique muscle

(incyclotorsion), and in the left eye of the inferior oblique or

inferior rectus muscle (excyclotorsion). The only muscle

that is highlighted three times (depicted by the circle) is the

right superior oblique muscle. (Medical illustrator: Rob

Flewell, CMI). IO [ inferior oblique muscle; SO [ superior

oblique muscle; IR [ inferior rectus muscle; SR [ superior

rectus muscle.

s u r v e y o f o p h t h a lm o l o g y 5 9 ( 2 0 1 4 ) 3 5 4e3 6 0 355

anatomical lesion or disease process to link these two

apparently distinct afferent and efferent system findings. We

also must not forget the wise statement made by Dr. John

Hickman: “Patients can have as many diseases as they damn

well please”.

Let’s begin by analyzing the ocular motility abnormality.

We are told only that this elderly lady has a right hypertropia

that is worse in left gaze and right head tilt. Based on the

Parks-Bielschowsky three step test, she would appear to have

a right superior oblique or fourth nerve palsy (Fig. 1); the test is

not infallible, however, and may falsely implicate the fourth

cranial nerve when in fact the problem ismyasthenia gravis, a

restrictive strabismus such as thyroid eye disease, multiple

vertical muscle paresis, or a skew deviation.14 In differenti-

ating a fourth nerve palsy from a skew deviation, it is helpful

to do an additional fourth step to determine if there is a

torsional component to the strabismus. Patients with a fourth

nerve palsymay have excyclotorsion of the hypertropic eye. In

contrast, patients with a skew deviation will have incyclo-

torsion of the hypertropic eye.

A lesion affecting the fourth nerve can be anatomically

divided into nuclear, fascicular, or peripheral (Fig. 2). Most

nuclear and fascicular lesions are associated with signs or

symptoms of brainstem dysfunction (contralateral Horner

syndrome, hemiparesis, etc.). Peripheral fourth nerve palsy

may be either congenital or acquired. The most common

cause of acquired fourth nerve palsy is trauma, but in an

elderly patient with vascular risk factors, microvascular

ischemia is a possibility. An intracranial process must be

considered in any patient with an ocular motor cranial neu-

ropathy.20 Unlike the third nerve, the fourth nerve does not

travel near major branching points of the circle of Willis;

therefore, aneurysmal compression is not a major concern.

Her other major finding is optic nerve pallor. The differ-

ential diagnosis is extensive, but broadly can be divided into

idiopathic, vascular, inflammatory, toxic, metabolic, nutri-

tional, inflammatory, traumatic, and hereditary etiologies.

The most common cause of optic nerve pallor in an elderly

patient is the sequelum of non-arteritic anterior ischemic

optic neuropathy (NAION). Without a previously documented

swollen optic nerve, however, NAION is a diagnosis of exclu-

sion. In this patient we are provided with an interesting his-

tory of optic nerve pallor in her father, raising the possibility of

a hereditary optic neuropathy such as autosomal dominant

optic atrophy completely unrelated to her double vision; for

this diagnosis to be considered, however, we need more

details.

Getting back to Occam’s razor, the one anatomical area

that could explain a fourth nerve palsy and bilateral optic

nerve pallor is the region of the sella because this is where the

fourth nerve is in close proximity to the visual apparatus.

I would recommend a complete blood count (CBC),

comprehensive metabolic panel (CMP), and hemoglobin A1c.

Because she is complaining of a headachedalthough appar-

ently she has no other symptoms of giant cell arteritis such as

jaw claudication or scalp tendernessdI would add an eryth-

rocyte sedimentation rate (ESR). In addition, I would perform

magnetic resonance imaging (MRI) of the brain and orbits with

contrast and fat suppression with special attention to the

parasellar region and the course of the fourth nerve.

3. Case report (continued)

Her headache increased in frequency and severity, with

nausea and blurred vision. CBC and CMP were normal except

for normocytic, normochromic anemia with a hemoglobin



Fig. 2 e Illustration of the course of the fourth nerve from its origin in the midbrain to its destination, the superior oblique

muscle. Several interesting facts regarding the anatomy of the fourth nerve are: 1) The fourth nerve nucleus innervates the

contralateral superior obliquemuscle; 2) The fascicular portion of the fourth nerve is very short; 3) The fourth nerve exits the

brainstem dorsally; 4) The right and left fourth nerves cross each other in the superior medullary velum; 5) The fourth nerve

travels between the posterior cerebral and superior cerebellar arteries, but unlike the third nerve, is some distance away

from the posterior communicating artery and other arterial branching points. (Medical illustrator: Rob Flewell, CMI).


of 10.4 g/dL Platelet count was normal at 246.2 K/mm3. Anti-

nuclear antibody was negative, and Westergren ESR was

55 mm/hr. MRI showed mild white matter changes consistent

with small vessel disease with no acute infarction, hemor-

rhage, or intracranial mass.

What should be done at this point?

4. Comments (continued)

4.1. Comments by Dr. Bhatti

Her ESR is slightly elevated at 55mm/hr, with the upper limit of

normal for a 78-year-oldwomanbeing 44mm/hr ([ageþ10]/2). I

would consider a temporal artery biopsy (TAB), but not

recommend it at this time. I think it would be helpful to know

the C-reactive protein (CRP) level. If both the CRP and ESR are

elevated, that would heighten my concern for giant cell arter-

itis (GCA).17 I would consider performing a lumbar puncture

with cytologic examination of the cerebrospinal fluid for ma-

lignant cells. The patient needs to be followed closely to see if

the double vision resolves or if she develops any new

ophthalmological, neurological, or systemic signs or symptoms

that would suggest a diagnosis other than a microvascular

ischemic fourth nerve palsy.


The patient was referred to our institution for further man-

agement. At that time she was still experiencing headache.

The headache was moderate to severe and over both temples.

In addition she reportedweight loss, dizziness, and imbalance

as well as worsening of binocular diplopia that she described

as vertical and horizontal with her “eyes turned outside”.

There was no variability or fatigability of the diplopia. She

denied any history of a thyroid problem in the past, stra-

bismus, or a history of patching. Visual acuities were 20/100

OD and 20/80 OS. The pupils were equal, sluggishly reactive,

and without a RAPD. Color plates were 3/10 OD and 2/10

OS. Extraocular movements showed right abduction and

adduction deficits with a left adduction deficit and right

hypertropia. She had a 40 prism diopter exotropia in primary

position with alternate cover testing (Fig. 3). Slit-lamp



Fig. 3 e Extraocular movements revealed right abduction and adduction deficits with a left adduction deficit. An exotropia of

40 prism diopters was present in primary position.


examination was normal except for PCIOLs. The intraocular

pressure was normal, and dilated funduscopic examination

revealed diffuse optic disk pallor bilaterally.

What should be done at this point?



I am not sure if the temporal artery was abnormal on physical

examination, but with the persistent headache involving the

temple regions, I must place GCA high on my differential

diagnosis. Because of the emergent nature of GCA, I immedi-

ately start corticosteroid therapy (oral or intravenous

depending on the absence of presence of visual loss) and

obtain a TAB within 1 to 2 weeks.


She was started on empiric prednisone 60 mg per day, and a

TAB was performed. The initial biopsy result was interpreted

as “no evidence of giant cell arteritis.” (The intima showed

moderate-to-severe fibromuscular hyperplasia. Focal breaks

of the elastic lamina were noted. The muscle layer and

adventitia were unremarkable). Her ophthalmoplegia was

unchanged one week after empiric steroid therapy.

What is your interpretation of this biopsy?

What would you do next?



It is imperative that the TAB specimen be processed properly.

At Duke University Medical Center all TABs are cut into six to

ten cross-sections (depending on the vessel length) and then

the cross-sections are prepared as ten slides containing 5 mm

histological sections of every cross-section. Each slide repre-

sents a “level” or “step section” with 50 mm between slides.

Thus, 500 mm of each of the multiple artery cross-sections is

evaluated to minimize the possibility of a skip lesion. Seven

slides are stained with hematoxylin and eosin. One slide is

stained with elastic stain to evaluate the internal elastic

lamina, one slide is stained with Masson trichrome stain to

highlight scarring, and one slide is stained with Congo red to

evaluate for amyloid deposition.

There are a couple of key points to consider before

accepting a negative TAB report as excluding the diagnosis of

giant cell arteritis. First, I recommend obtaining at least a 2 cm

length of artery because a short specimen lengthmay result in

a false negative result. Second, several studies have shown

that approximately 3% of TABs are negative on one side, but

positive on the other.3

In this patient, the TAB was negative for inflammation and

only showed moderate to severe fibromuscular hyperplasia

with focal breaks of the elastic lamina, which are nonspecific

findings that can be age related or associated with hyperten-

sive disease. Ultimately, I rely on the pathologist to tell me

whether there is confirmatory evidence of GCA or not on

the TAB.

If my suspicion for GCA is high despite a negative TAB in

the setting of an adequate specimen length and proper his-

topathological sectioning and analysis, I recommend a TAB of

the contralateral side.


Despite the negative TAB, she was continued on prednisone.

The decision was made to proceed with a contralateral TAB

which was positive for changes consistent with treated/heal-

ing GCA. The pathologist’s report described a medium-sized

artery that showed irregular moderate to severe intimal




hyperplasia. The elastic lamina, better seen with a Movat

pentachrome stain, was focally absent. In the area of absent

elastic lamina, there was associated fibrosis and thinning of

themuscle layer. The adventia contained small arterioles, one

of which was surrounded by lymphocytes. A CD68 stain

showed a few macrophages and multinucleated giant cells at

the level of elastic lamina (Fig. 4).

Four weeks later she reported resolution of all symptoms,

includingdiplopia,dizziness, andheadache, and improvement

of visual acuity. Visual acuities were 20/80�2 OD and 20/50�2

OS, and color vision remained unchanged. Extraocular move-

ments were full, and she was orthotropic in all positions of

gaze. Dilated fundus examination revealed bilateral diffuse

optic disk pallor (Fig. 5). Automated perimetry showed few re-

sponses with a suggestion of a cloverleaf pattern OS.

Why was there a delay in improvement of the ophthalmoplegia

after steroids were started?


10.1. Comments by Dr Bhatti

Histopathological observation of TAB specimens have shown

luminal narrowing of the vessel from transmural inflamma-

tion and intimal hyperplasia.23 Based on this, I feel that the

delayed improvement in the ophthalmoplegia is the result of

the slow reestablishment of blood flow and function to the

extraocular muscles as the luminal vessel inflammation

decreased and the intraluminal diameter increased. Hayreh

et al reviewed visual improvement in 84 patients with giant

Fig. 4 e A: Temporal artery biopsy specimen showed irregular

highlights the segmentally absent inner elastic lamina (arrows

hyperplastic intima. (Movat pentachrome stain, 103 original m

macrophages showed a few scattered macrophages (darkly stai

(Immunohistochemistry using CD68 antibody and DAB chromo

cell arteritis and found some who achieved their best final

vision as long as 2months after the initiation of corticosteroid

treatment.9

11. Case report (concluded)

Three months later she was stable and asymptomatic. Repeat

ESR was 3 mm/hr, and the prednisone dose was tapered to

50 mg per day.

12. Discussion

Giant cell arteritis, the most common chronic immune-

mediated vasculitis that affects large to medium-sized ves-

sels, should be suspected in any patient over 50 years of age

with headache, transient or fixed visual loss, and transient or

fixed diplopia. Ocular findings of GCA include visual loss,

transient monocular blindness, eye pain, anterior and poste-

rior ischemic optic neuropathy, central and cilioretinal artery

occlusion, and ocular ischemia.7,19 In one series diplopia was

present in 5 of 170 patients with biopsy-proven GCA.8 Diplopia

may be the presenting symptom of GCA in the absence of

vision loss. In a review of 81 patients with diplopia from GCA,

21 (26%) patients had no other symptoms.16

Ophthalmoplegia and multiple cranial nerves palsies are

infrequent manifestations of GCA. In 2010, Warburton et al

reported a 72- year-old woman with bilateral multiple cranial

nerve palsies that resolved with treatment with cyclophos-

phamide. Fisher et al and Lazaridis et al reported two

intimal hyperplasia with narrow lumen (*). B: Elastic stain

at edges) and the duplication of elastic lamina in the

agnification.) C and D: Immunohistochemistry for

ned cells) at the level of the residual elastic lamina (arrows).

gen, 403 original magnification.)



Fig. 5 e Fundus photographs revealed diffuse optic disk pallor bilaterally.


patients with bilateral cranial nerve palsies in biopsy-proven

GCA. Others have reported third nerve palsies, bilateral

internuclear ophthalmoplegia, and bilateral sixth nerve

palsies.1,2,4,5,10,16,18,21,22

The pathogenesis of ophthalmoplegia and transient or

persistent diplopia in GCA is still debated. Competing theories

have included ischemia affecting the extraocular muscles

and ischemia to the ocular motor nerves. Fisher et al sug-

gested that ischemia of the vasa nervorum of the third nerve

following cerebral artery inflammation was the cause of

the bilateral oculomotor nerve palsy. A third mechanism

may occur in patients with orbital inflammation, similar to

that in idiopathic orbital inflammation.11,12 A fourth possi-

bility, emboli, seems less likely. Whatever the underlying

pathogenesis, the ocular motility fully recovered after steroid

treatment in most reported patients, suggesting there was no

necrosis.1,5,10,13,15,21,22 It is important to recognize the histo-

pathologic features of healing/treated temporal arteritis in the

absence of the typical transmural lymphocytic and giant-cell

infiltrate. In these cases there is scarring of the media with

segmental absence of the elastic lamina better appreciated

with an elastic stain such as the Movat pentachrome, which

also highlights areas of fibrosis. In addition, there is no

transmural infiltrate and only increased cellularity at the level

of the intima/media. Immunohistochemistry using anti-

macrophage antibodies such as CD68 may disclose histio-

cytes attached to the elastic lamina. CD68-positive cells in

other areas, such as the adventitia or the intima near the

lumen, may be seen in other pathologic processes such as

artherosclerosis.6,11,24

13. Literature Search

The literature search was performed using MEDLINE (OvidSP,

EBSCO), UpToDate, and PubMed and the following search

terms: ophthalmoplegia, diplopia, nerve palsy, unusual presenta-

tion of giant cell arteritis, internuclear ophthalmoplegia, abducens

nerve palsy and giant cell arteritis, oculomotor nerve palsy, and

giant cell arteritis. The search included papers in English only.

Case reports were only included if they provided relevant in-

formation about characteristics and diagnosis of the disease.

14. Disclosure

The authors report no proprietary or commercial

interest in any productmentioned or concept discussed in this

article.

Acknowledgments

Supported in part by a Duke Eye Center departmental grant

from Research to Prevent Blindness, Inc.

r e f e r e n c e s

1. Barricks ME, Traviesa DB, Glaser JS, et al. Ophthalmoplegia incranial arteritis. Brain. 1977;100:209e21

2. Bondeson J, Asman P. Giant cell arteritis presentingwith oculomotor nerve palsy. Scand J Rheumatol.1997;26:327e8

3. Boyev LR, Miller NR, Green WR. Efficacy of unilateral versusbilateral temporal artery biopsies for the diagnosis of giantcell arteritis. Am J Ophthalmol. 1999;128:211e5

4. Davies GE, Shakir RA. Giant cell arteritis presenting asoculomotor nerve palsy with pupillary dilatation. PostgradMed J. 1994;70:298e9

5. Fisher CM. Ocular palsy in temporal arteritis. Minn Med.1959;42:1258e68

6. Font RL, Prabhakaran VC. Histological parameters helpful inrecognizing steroid-treated temporal arteritis: an analysis of35 cases. Br J Ophthalmol. 2007;91:204e9

7. Gonzalez-Gay MA, Blanco R, Rodrıguez-Valverde V, et al.Permanent visual loss and cerebrovascular accidents in giantcell arteritis: predictors and response to treatment. ArthritisRheum. 1998;41:1497e504

8. Hayreh SS, Podhajsky PA, Zimmerman B. Ocularmanifestations of giant cell arteritis. Am J Ophthalmol.1998;125:509e20

9. Hayreh SS, Zimmerman B, Kardon RH. Visual improvementwith corticosteroid therapy in giant cell arteritis. Report of alarge study and review of literature. Acta Ophthalmol Scand.2002;80:355e67

10. Hughes TA, Wiles CM, Hourihan M. Cervical radiculopathyand bilateral internuclear ophthalmoplegia caused by

http://refhub.elsevier.com/S0039-6257(13)00236-1/oref1a



http://refhub.elsevier.com/S0039-6257(13)00236-1/sref1






































temporal arteritis. J Neurol Neurosurg Psychiatry.1994;57:764e5

11. Islam N, Asaria R, Plant GT, et al. Giant cell arteritismimicking idiopathic orbital inflammatory disease. Eur JOphthalmol. 2003;13:392e4

12. Lee AG, Tang RA, Feldon SE, et al. Orbital presentations ofgiant cell arteritis. Graefes Arch Clin Exp Ophthalmol.2001;239:509e13

13. Jay WM, Nazarian SM. Bilateral sixth nerve pareses withtemporal arteritis and diabetes. J Clin Neuroophthalmol.1986;6:91e5

14. Kushner BJ. Errors in the three-step test in the diagnosis ofvertical strabismus. Ophthalmology. 1989;96:127e32

15. Lazaridis C, Torabi A, Cannon S. Bilateral third nerve palsyand temporal arteritis. Arch Neurol. 2005;62:1766e8

16. Lee AG, Brazis PW. Clinical Pathways in Neuro-ophthalmology: An Evidence-based Approach. foreword byNeil R. New York, Miller Thieme; second ed., 2003

17. Parikh M, Miller NR, Lee AG, et al. Prevalence of a normal C-reactive protein with an elevated erythrocyte sedimentationrate in biopsy-proven giant cell arteritis. Ophthalmology.2006;113:1842e5

18. Rush JA, Kramer LD. Biopsy-negative cranial arteritis withcomplete oculomotor nerve palsy. Ann Ophthalmol.1979;11:209e13

19. Salvarani C, Cimino L, Macchioni P, et al. Risk factors forvisual loss in an Italian population-based cohort of patientswith giant cell arteritis. Arthritis Rheum. 2005;53:293e7

20. Tamhankar MA, Biousse V, Ying GS, et al. Isolated third,fourth, and sixth cranial nerve palsies from presumedmicrovascular versus other causes: a prospective study.Ophthalmology. 2013;120:2264e9

21. Trend P, Graham E. Internuclear ophthalmoplegia ingiant-cell arteritis. J Neurol Neurosurg Psychiatry.1990;53:532e3

22. Warburton KL, Austen E, Gough A, et al. An unusual cause ofbilateral ophthalmoplegia. BMJ Case Rep. 2010. http://dx.doi.org/10.1136/bcr.09.2010.3353

23. Weyand CM, Ma-Krupa W, Goronzy JJ. Immunopathways ingiant cell arteritis and polymyalgia rheumatica. AutoimmunRev. 2004;3:46e53

24. Zhou L, Luneau K, Weyand CM, et al. Clinicopathologiccorrelations in giant cell arteritis: a retrospective study of 107cases. Ophthalmology. 2009;116:1574e80

Keywords:

ophthalmoplegia

giant cell arteritis

diplopia

exotropia

fourth nerve palsy

a b s t r a c t

A 78-year-old white woman noted progressively worsening headache, fluctuating

decreased vision, dizziness, and binocular horizontal and vertical diplopia of two months

duration. She had a 40 prism diopter exotropia and bilateral ophthalmoplegia. An initial

temporal artery biopsy (TAB) was negative for findings of giant cell arteritis (GCA). Empiric

prednisone was continued, and a second TAB was positive for GCA. In time there was

complete resolution of the ophthalmoplegia.ª 2014 Elsevier Inc. All rights reserved.






































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http://dx.doi.org/10.1136/bcr.09.2010.3353

http://dx.doi.org/10.1136/bcr.09.2010.3353











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