Journal of Neuro-Ophthalmology, March 2010, Volume 30, Issue 1

Letters to the Editor

Another Case of Bisphosphonate-Induced Orbital Inflammation Bisphosphonates are used to inhibit bone absorption as a treatment for hypercalcemia associated with osteo-lytic bone cancer, bony metastasis, Paget disease, and osteoporosis. There have been 7 reported cases of bisphosphonate-induced orbital inflammation (1-7). We describe another case and document MRI abnormalities. An 89-year-old woman was well until 20 minutes after receiving her first dose of 4 mg zoledronic acid intravenously when she developed acute, severe lower extremity arthralgias, followed by ascending arthralgias and a left-sided headache. Three days later she developed bilateral periocular pain associated with intense sharp pain provoked by eye move-ment, blurred vision in the left eye, and binocular horizontal diplopia with image separation greater in lateral gaze. Best-corrected visual acuity was 20/40 in the right eye and 20/50 in the left eye without a relative afferent pupil defect. In primary gaze position, she had 10 prism-diopters (PD) of esotropia which increased to 25 PD in right and left gaze (Fig. 1). Confrontation visual fields were full. Slit-lamp examination showed diffuse conjunctival injection and bullous chemosis with no sign of anterior uveitis. Ophthalmoscopy disclosed no abnormalities. MRI showed diffuse fat stranding, optic nerve sheath enhancement, posterior scleral enhancement, and slight enlargement of extraocular muscles bilaterally (Fig. 2). Bisphosphonate-induced orbital inflammation was diagnosed and treated with 1 g methylprednisolone intravenously per day for 3 days followed by prednisone on a tapered dose regimen. Over the next 3 days, headache, double vision, chemosis, and orbital pain dramatically improved. One month later, ophthalmic abnormalities had largely resolved (Fig. 3). This is the first reported case of orbital inflammation caused by bisphosphonate treatment for osteoporosis. In all reported cases of bisphosphonate-induced orbital inflam-mation, the onset of ocular symptoms has varied from 1 to 6 days after drug administration. The symptoms have included orbital pain, diplopia, and lid swelling. The common signs have been periocular edema, chemosis, conjunctival injection, proptosis, reduced ocular ductions, and minimal anterior chamber inflammation. The treatment of this adverse event has been discontin-uation of the offending drug and use of high-dose systemic corticosteroids. All reported patients have had rapid and complete resolution. Although discontinuation of bisphosphonate alone may be sufficient (1,2,3,4,5), corti-costeroids may hasten the recovery process. The mechanism of orbital inflammation in this setting is unsettled. Inflammatory factors have been implicated, given that augmented levels of tumor necrosis factor- (TNF-), FIG. 1. At initial presentation, the patient displays esotropia, bilateral abduction deficits, and a small upgaze deficit, as well as conjunctival hyperemia and chemosis. 94 Yang et al: J Neuro-Ophthalmol 2010; 30: 94-103 Letters to the Editor interleukin (IL)-1 and IL-6 have been detected in patients after zoledronic acid infusion (8). E. Bo Yang, MD Emily S. Birkholz, MD Departments of Ophthalmology and Visual Sciences, Neurology, and Neurosurgery The University of Iowa Hospitals and Clinics Iowa City, Iowa Andrew G. Lee, MD The Methodist Hospital Weill Cornell Medical College Houston, Texas [e-mail] Addendum: After this letter was accepted for publica-tion, a paper on this subject was published. Procianoy F, Procianoy E. Orbital inflammatory disease secondary to a single-dose administration of zoledronic acid for treat-ment of postmenopausal osteoporosis. Osteoporos Int October 27, 2009 [epub ahead of print]. REFERENCES 1. Russell RG, Xia Z, Dunford JE, et al. Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy. Ann NY Acad Sci 2007;1117: 209-257. 2. Subramanian PS, Kerrison JB, Calvert PC, et al. Orbital inflammatory disease after pamidronate treatment for metastatic prostate cancer. Arch Ophthalmol 2003;121: 1335-1346. 3. Phillips PM, Newman SA. Orbital inflammatory disease after intravenous infusion of zoledronate for treatment of metastatic renal cell carcinoma. Arch Ophthalmol 2008;126: 137-139. 4. Meaney TP, Musadiq M, Corridan PG. Diplopia following intravenous administration of pamidronate. Eye 2004;18: 103-114. 5. Sharma NS, Ooi J, Masselos K et al. Zoledronic acid infusion and orbital inflammatory disease. N Engl J Med 2008;359: 1410-1421. 6. Ghose K, Waterworth R, Trolove P, et al. Uveitis associated with pamidronate. Aust NZ Med 1994;24:320. 7. Ryan PJ, Sampath R. Idiopathic orbital inflammation following intravenous pamidronate. Rheumatology 2001;40:956-967. 8. Dicuonzo G, Vincenzi B, Santini D, et al. Fever after zoledronic acid administration is due to increase in TNF- and IL-6. J Interferon Cytokine Res 2003;23: 649-654. FIG. 2. Postcontrast fat-suppressed T1 axial (A) and coronal (B) MRI studies show enhancement of the sclera, extraocular muscles, and optic nerve sheaths bilaterally. FIG. 3. Four months after corticosteroid treatment, the esotropia and abduction deficits have resolved and the conjunctival hyperemia and chemosis have dissipated. Yang et al: J Neuro-Ophthalmol 2010; 30: 94-103 95 Letters to the Editor Visual Loss Without Papilledema in Idiopathic Intracranial Hypertension Idiopathic intracranial hypertension (IIH) is classically associated with papilledema, which can produce pro-gressive irreversible visual field constriction and blindness if untreated (1,2). It has long been suggested that papilledema is required for visual loss to occur in IIH (3), implying that patients without papilledema are not at risk for visual loss. We report a patient with IIH who developed visual loss due to papilledema in one eye and a progressive optic neuropathy without papilledema in the other. A 32-year-old obese African-American man presented with intermittent headache and transient visual obscura-tions (TVOs) in the right eye. He had no history of hypertension, sleep apnea, or any other obesity-related illnesses, and he was taking no medications. Before referral, he had been evaluated by a neurologist and an ophthal-mologist, both of whom had documented optic disc edema in the right eye and a normal optic disc in the left eye. Because his TVOs were thought to be vascular in origin, retinal fluorescein angiography had been performed, and results for the left eye were normal; there was no leakage to suggest subtle optic disc edema. Results of catheter cerebral angiography were normal. On our examination, his height was 6 feet 2 inches (188 cm) and weight was 266 lb (121 kg), giving a body mass index of 34 kg/m2. Blood pressure was within normal limits. Visual acuity was 20/20 in both eyes. There was chronic optic disc edema in the right eye and a normal optic disc, without signs to suggest resolved optic disc edema, in the left eye. Visual field testing showed a superior arcuate and nasal defect in the right eye and no defect in the left eye. MRI of the brain and orbits was unremarkable. Lumbar puncture showed an opening pressure of 55 cm H2O with normal cerebrospinal fluid (CSF) composition. His headache and TVOs transiently improved after the lumbar puncture. IIH was diagnosed and treatment with acetazol-amide was started. Over the following months, he developed a progressive optic neuropathy in the left eye, with visual acuity decreas-ing to finger counting, a ceco-central scotoma (Fig. 1A), and a left relative afferent pupillary defect. Progressive left optic disc pallor was noted (Fig. 1B-D), but optic disc edema was never observed. Despite a thorough workup for compres-sive, inflammatory, toxic, and hereditary disorders, no cause for the optic neuropathy was identified. Repeat MRI of the brain and orbits was normal, except for posterior scleral flattening and optic nerve sheath dilatation, both greater on the right. He did not return for scheduled lumbar punctures. Despite treatment with acetazolamide, the visual field defect and papilledema in the right eye persisted, as did his headache and TVOs. Therefore, a right optic nerve sheath fenestration (ONSF) was performed. At surgery, there was a gush of CSF upon fenestration. The visual field defect and optic disc edema in the right eye subsequently improved (Fig. 1C). In the left eye, however, the visual acuity deficit and ceco-central scotoma persisted, the optic disc became paler (Fig. 1C), and a dense left relative afferent pupillary defect was noted. Accordingly, a left ONSF was performed 1 month after the right ONSF. At surgery, the optic nerve sheath did not appear distended and no CSF drained upon fenestration. Results of histopathologic examination of a biopsy specimen from the optic nerve sheath were unremarkable. Postoperatively, visual acuity in the left eye did not improve, but the ceco-central scotoma decreased in size (Fig. 1D). Although optic atrophy is a classic complication of papilledema in IIH (2,4), our patient developed a left optic neuropathy and subsequent optic atrophy without ever having had papilledema, as far as we could tell. Given that we were unable to identify an alternative cause for this optic neuropathy, we presume that it resulted from raised intracranial pressure (ICP). Although there was no formal documentation of raised ICP after the initial lumbar puncture, our patient reported ongoing headache and TVOs, and there was persistent papilledema in the right eye, suggesting that ICP was elevated. Although papilledema can be asymmetric, unilateral, or absent in patients with IIH (5-7), it is unclear how visual loss would develop in the absence of papilledema. Others have suggested that the visual loss in such cases is non-organic (7). However, it is possible that raised ICP could produce intracranial or retrobulbar optic nerve compression if there is anatomic compartmentation of the subarachnoid space around the optic nerve. Such compartmentation has been proposed on the basis of histologic, radiologic, and biologic data (8-10). Although functional compartmentation could potentially contribute to the development of papilledema in patients with IIH (10), anatomic compartmentation of the subarachnoid space around the optic nerve could stop the CSF pressure gradient from reaching the retrolaminar portion of the 96 Thurtell et al: J Neuro-Ophthalmol 2010; 30: 94-103 Letters to the Editor nerve, thereby producing retrobulbar optic nerve com-pression without optic disc swelling. In our patient, the operative finding of a nondistended retrolaminar optic nerve sheath, without CSF drainage upon fenestration, supports this hypothesis. A second explanation is that sequestration of CSF con-taining a toxic metabolite could have produced a unilateral toxic optic neuropathy (10). Because many patients with IIH have cerebral venous hypertension (11), a third explanation is that the optic neuropathy could have resulted from posterior optic nerve ischemia due to impaired venous drainage, as has been proposed for optic neuropathy occurring with carotid-cavernous fistulas (12). Despite this unusual case, we advise extreme caution before attributing visual loss in IIH to raised ICP when there is no papilledema. FIG. 1. A. Several months after our initial examination, the right optic disc shows chronic optic disc edema and the left optic disc appears normal. The Humphrey 24-2 visual field of the right eye shows superior arcuate and nasal defects; the Goldmann visual field of the left eye (II4e isopter) shows a ceco-central scotoma. B. Six weeks later, the right optic disc has not changed, but the left optic disc has developed mild pallor. The visual field defect in the right eye has not changed, but the visual field defect in the left eye has enlarged, despite a lumbar puncture and treatment with acetazolamide. C. One week after right optic nerve sheath fenestration, the optic disc edema in the right eye has improved, but the left optic disc has become paler. The visual field defect in the right eye has improved, but the ceco-central scotoma in the left eye persists. D. Two years after left optic nerve sheath fenestration, the right optic disc edema has resolved, but the left optic disc has become paler. The ceco-central scotoma in the left eye has decreased in size. Thurtell et al: J Neuro-Ophthalmol 2010; 30: 94-103 97 Letters to the Editor Matthew J. Thurtell, MBBS, FRACP Department of Ophthalmology Emory University School of Medicine Atlanta, Georgia [e-mail] Nancy J. Newman, MD Vale´rie Biousse, MD Departments of Ophthalmology and Neurology Emory University School of Medicine Atlanta, Georgia This study was supported, in part, by a departmental grant (Department of Ophthalmology) from Research to Prevent Blindness, Inc, New York, New York, and by core grants P30-EY06360 (Department of Ophthalmology) from the National Institute of Health, Bethesda, Maryland. Dr. Newman is a recipient of a Research to Prevent Blindness Lew R. Wasserman Merit Award. Dr. Thurtell was supported by the Department of Veterans Affairs and the Evenor Armington Fund. REFERENCES 1. Friedman DI, Jacobson DM. Diagnostic criteria for idiopathic intracranial hypertension. Neurology 2002;59:1492-5. 2. Corbett JJ, Savino PJ, Thompson HS, et al. Visual loss in pseudotumor cerebri: follow-up of 57 patients from five to 41 years and a profile of 14 patients with permanent severe visual loss. Arch Neurol 1982;39:461-74. 3. Digre KB, Corbett JJ. Diagnosis and management of idiopathic intracranial hypertension (pseudotumor cerebri). In: Tusa RJ, Newman SA, eds. Neuro-Ophthalmological Disorders: Diagnostic Work-up and Management. New York: Marcel Dekker, 1995:55-64. 4. Golnik KC, Devoto TM, Kersten RC, et al. Visual loss in idiopathic intracranial hypertension after resolution of papilledema. Ophthalmic Plast Reconstr Surg 1999;15: 442-4. 5. Marcelis J, Silberstein SD. Idiopathic intracranial hypertension without papilledema. Arch Neurol 1991;48: 392-9. 6. Lepore FE. Unilateral and highly asymmetric papilledema in pseudotumor cerebri. Neurology 1992;42: 676-8. 7. Digre KB, Nakamoto BK, Warner JE, et al. A comparison of idiopathic intracranial hypertension with and without papilledema. Headache 2009;49:185-93. 8. Liu D, Kahn M. Measurement and relationship of subarachnoid pressure of the optic nerve to intracranial pressure in fresh cadavers. Am J Ophthalmol 1993;116: 548-56. 9. Killer HE, Laeng HR, Flammer J, et al. Architecture of arachnoid trabeculae, pillars, and septa in the subarachnoid space of the human optic nerve: anatomy and clinical considerations. Br J Ophthalmol 2003;87: 777-81. 10. Killer HE, Jaggi GP, Flammer J, et al. Cerebrospinal fluid dynamics between the intracranial and the subarachnoid space of the optic nerve: is it always bidirectional? Brain 2007;130:514-20. 11. King JO, Mitchell PJ, Thomson KR, et al. Manometry combined with cervical puncture in idiopathic intracranial hypertension. Neurology 2002;58:26-30. 12. Hedges TR III, Debrun G, Sokol S. Reversible optic neuropathy due to carotid-cavernous fistula. J Clin Neuroophthalmol 1985;5:37-40. Monocular Embolic Retinal Arteriolar Occlusions After Ipsilateral Intraoral Triamcinolone Injection We describe multiple branch retinal artery occlusions, mydriasis, and iritis after triamcinolone injection into an intraoral fibrous scar. A 36-year-old year old woman underwent multiple oral maxillofacial procedures to correct jaw asymmetry. At the time of a subsequent irrigation and drainage procedure, 1 mL of triamcinolone was injected submucosally intraorally into a fibrous scar in the left mandibular retromolar pad. After the procedure, the patient complained of blurred vision in her left eye. The following morning an oral surgeon reported a fixed and dilated left pupil. Three hours later, ophthalmologic examination revealed the patient's visual acuity to be 20/25 in the right eye and counting fingers at 3 feet in the left eye. Ocular motility and alignment were normal in both eyes. There was no ptosis. The right pupil measured 2.5 mm in dim illumination and the left measured 5.5 mm; the right pupil constricted normally to direct light and the left pupil did not constrict. There was a left afferent pupillary defect. The left pupil did not demonstrate light-near dissociation. Slit lamp exami-nation revealed 2+ white blood cells and flare in the anterior chamber in the left eye. Intraocular pressure was 17 mm Hg in the right eye and 12 mm Hg in the left eye. Humphrey visual field protocol (30-2 SITA) were normal in the right eye and demonstrated a dense paracentral scotoma in the left eye. Dilated ophthalmoscopy demonstrated multiple white emboli within the retinal vasculature of the left eye; fluorescein angiography confirmed blockage of multiple retinal arterioles (Fig. 1). The patient declined therapeutic paracentesis, but digital massage was performed. After other embolic sources were ruled out, the occlusion was attributed to the triamcinolone injection. One month later the patient's visual acuity was unchanged. The pupils measured 4 mm in dim illumination and reacted adequately to light, but a mild relative afferent 98 McEwan et al: J Neuro-Ophthalmol 2010; 30: 94-103 Letters to the Editor pupillary defect persisted in the left eye. The anterior chamber of the left eye was free of cells and flare and the retinal emboli had disappeared. There are reports of various ophthalmic complications after intraoral anesthetic injection of common dental anesthetics such as lidocaine, mepivacaine, and procaine (1). In our patient, intraoral injection of triamcinolone resulted in an ocular ischemic syndrome manifested by branch retinal artery occlusions, mydriasis, and iritis. We are unaware of previous reports documenting these ocular complications in this setting. Retinal artery occlusions have occurred after intralesional injection of corticosteroids for eyelid hemangiomas and after retrobulbar injections and other procedures near the orbit (2-4). Corticosteroid particles can reach the ophthalmic system through retrograde flow and through anastomotic connections between the external carotid and ophthalmic arteries (2-4). We believe that corticosteroid particle embolization also caused temporary loss of pupillary sphincter function and iritis in our patient's left eye. Anterior segment inflammation as a result of ciliary ischemia has been demonstrated in other cases of ocular ischemic syndrome and frequently after muscle surgery (5); however, there are no reported cases of orbital vascular occlusion by corticosteroid emboli. Mydriasis and iritis may have occurred in other cases of corticosteroid orbital vascular occlusion but were overlooked or underreported in the face of retinal pathologic lesions. Gavin McEwan, MD Elizabeth Hofmeister, MD Kenneth Kubis, MD Kent Blade, MD Department of Ophthalmology Naval Medical Center San Diego, California [e-mail] REFERENCES 1. Horowitz J, Almog Y, Wolf A, et al. Ophthalmic complications of dental anesthesia: three new cases. J Neuroophthalmol 2005;25;95-100. 2. Digre KB, Corbett JJ. Amaurosis fugax and not so fugax-vascular disorders of the eye. In: Digre KB, Corbett JJ. Practical Viewing of the Optic Disc. Burlington, MA: Butterworth Heinemann, 2003:269-344. 3. Morgan CM, Schatz H, Vine AK, et al. Ocular complications associated with retrobulbar injections. Ophthalmology 1988; 95:660-5. 4. Egbert JE, Schwartz GS, Walsh AW. Diagnosis and treatment of an ophthalmic artery occlusion during an intralesional injection of corticosteroid into an eyelid capillary hemangioma. Am J Ophthalmol 1996;121:638-42. 5. Jacobs NA, Ridgway EA. Syndrome of ischaemic ocular inflammation: six cases and a review. Br J Ophthalmol 1985; 69:681-7. Protracted Cortical Visual Loss in a Child With Ornithine Transcarbamylase Deficiency We describe a 5-year-old girl with ornithine trans-carbamylase deficiency (OTCD) who presented with headache and cortical visual loss in the absence of other neurologic signs. Serum ammonia levels were found to be elevated and vision recovered slowly over several weeks with protein restriction. To our knowledge, isolated cortical visual loss has not been reported as a presenting feature of this condition, although visual loss has been described as a complication of hyperammonemic encephalopathy. FIG. 1. Fundus photography and fluorescein angiography performed one day after intraoral triamcinolone injection. A. Fundus of the right eye is normal. B. Fundus of the left eye demonstrates white particulate emboli, a partial cherry-red spot, ischemic retinal whitening, and cotton wool spots. C. Fluorescein angiography demonstrates dark areas of dye cutoff corresponding to blockage of dye flow in the retinal circulation. Anderson and Brodsky: J Neuro-Ophthalmol 2010; 30: 94-103 99 Letters to the Editor Two weeks prior to her presentation to us, OCTD had been diagnosed in a 5-year-old girl after she presented to the hospital with acute lethargy and ataxia. She had started a school program that included meals containing a greater protein load than she had eaten at home. Her parents had noted that she generally avoided high-protein foods such as meat. On her initial admission to the hospital at that time, her serum ammonia level had been elevated to 226 mmol/L (normal range 29-57 mmol/L). She was started on a restricted protein diet and treated with phenylbutyrate and citrulline, which produced normalization of mental status and of serum ammonia levels over a period of 2 days. DNA analysis, performed at the time of admission and 2 days after onset of symptoms, showed a frameshift mutation in the OTC gene at position 287 in exon 8, because of insertion of 2 nucleotides (ACA-ACACA). Results of genetic testing for mutations in the CACNA1A and ATP1A2 genes for familial hemiplegic migraine were negative. Two weeks after her initial admission, while still taking phenylbutyrate and citrulline, she presented to us with a 3-day history of blindness, headaches, and ataxia. On our examination, she was unable to detect the presence of bright light shined into either eye. Both pupils reacted briskly to light without afferent pupillary defect. Extraocular move-ments were full, and there was no nystagmus or strabismus. Slit lamp biomicroscopy and retinal examination showed no abnormalities. Blood pressure, measured throughout her hospitalization, was repeatedly normal. Lumbar pressure measurement, performed on the first day of admission, showed a normal opening pressure with no neurochemical abnormalities (glutamine levels were not measured). Results of electroencephalography were normal. Serum ammonia levels had normalized to 22 mmol/L. Brain MRI, performed on day 5 of her visual loss, showed no abnormalities on precontrast studies (Fig. 1A), even on diffusion imaging. Postcontrast studies showed mild bilateral enhancement confined to the occipital lobes (Fig. 1B). Results of magnetic resonance angiography and venography were normal. Over a 2-week period, she was treated with verapamil (for migraine) and oral corticosteroids (for an inflammatory component). Ataxia improved during the first 3 days of treatment, but severe headache and visual loss persisted. Several neuro-ophthalmologic examinations over the fol-lowing 2 weeks showed no papilledema. Over a 6-week period, the patient experienced a gradual visual recovery to 20/25 in both eyes, with normal color vision and normal visual fields to confrontation. Her parents reported a milder episode of reduced vision 2 months later, which lasted for 2 days and was not associated with hyperammonemia. No examination occurred during that event, so the visual loss could not be medically confirmed. A brain MRI performed 6 weeks after this reported episode of visual loss was entirely normal, showing no residual enhancement. With an incidence of 1 case per 14,000 births, OTCD is the most common inborn error of metabolism of the urea cycle (1,2). OTCD is an X-linked disorder characterized by the accumulation of precursors of urea, principally ammonia and glutamine (1). The presenting signs of OTCD are largely due to cerebral edema caused by elevated levels of ammonia (1). The most severe clinical form of OTCD occurs in full-term infants who appear healthy for FIG. 1. A. Precontrast T1 axial MRI shows no abnormalities. B. Postcontrast T1 axial MRI shows selective enhancement of the striate cortex bilaterally. 100 Anderson and Brodsky: J Neuro-Ophthalmol 2010; 30: 94-103 Letters to the Editor 24-48 hours and then exhibit signs of progressive lethargy, hypothermia, and apnea (2).Milder forms of OTCD, which include vomiting, abnormal mental status, ataxia, seizures, or developmental delay, may become evident at any age from infancy to adulthood (2). Late-onset OTCD occurs commonly in women who have a mutation at the OTC locus on one of the X chromosomes (2). Hyperammonemic attacks can be trig-gered by a high-protein diet, infections, valproic acid and other medications, and the postpartum state (3). In hetero-zygous females, the clinical phenotype can range from complete absence of symptoms to severe hyperammonemic episodes (4). This striking phenotypic variability may reflect genetic heterogeneity as well as the random pattern of X inactivation that occurs within hepatocytes (5). Treatment with medications that activate new pathways of nitrogen waste excretion can reduce the number of hyperammonemic episodes and the long-term risk of cognitive decline in young girls with symptomatic OTCD (6). In some young women, OTCD causes recurrent stroke-like episodes (4,5). Reports of late-onset OTCD described neuroimaging findings that resemble those of ischemic stroke (7-10). The basis of hyperammonemic encephalop-athy in OTCD has not been established (1,2). One theory attributes the manifestations to the intracerebral accumu-lation of glutamine due to high levels of ammonia in astrocytes, which promotes the conversion of glutamate to glutamine via glutamine synthetase (1,2). According to this proposed mechanism, the accumulation of glutamine pro-duces changes in intracellular osmolality, leading to swelling of astrocytes, cerebral edema, intracranial hypertension, and cerebral hypoperfusion. In support of this mechanism is the fact that the cerebral edema associated with hyperammo-nemia can be prevented by reducing glutamine accumula-tion in the brain, suggesting that hyperammonemia alone does not produce cerebral edema (1,2). In patients with OTCD, cerebrospinal glutamine concentrations are extremely elevated during hyperammonemic encephalo-pathy (11,12). Proton magnetic resonance spectroscopy has also demonstrated high glutamine concentrations in patients with hyperammonemic encephalopathy (11,12). Brain MRI generally demonstrates injury to the cingulate gyrus and insular cortex, with sparing of the perirolandic and occipital cortex (2). These perisulcal white matter lesions may reflect diminished cerebral perfusion in the face of elevated intracranial pressure (13,14). It has been suggested that the occipital cortex is particularly resistant to hyperammonemic-hyperglutaminergic encephalopathy (2,15). Our patient had newly diagnosed OTCD associated with isolated protracted cortical blindness. This episode began shortly after treatment of her hyperammonemia and persisted over a 6-week period. Typically, neurologic manifestations of hyperammonemia occur quite rapidly- within 24 hours of elevated ammonia levels. Usually these manifestations resolve as the ammonia level falls. Because our patient's serum ammonia levels were normal at the time of visual loss, its cause remains unclear. The differential diagnosis includes migraine, stroke, seizure, or inflamma-tory infectious or a metabolic disorder (16). Although we treated her presumptively for migraine and epilepsy, the protracted nature of the event is inconsistent with these causes, and it is doubtful that our treatment influenced her recovery. This unusual clinical history demonstrates that OTCD can relatively selectively injure the occipital cortex to produce protracted blindness. Jennifer M. Anderson, MD Department of Ophthalmology University of Arkansas for Medical Sciences Little Rock, Arkansas Michael C. Brodsky, MD Mayo Clinic and Mayo Foundation Rochester, Minnesota [e-mail] REFERENCES 1. Brusilow SW, Horwich AL. Urea cycle enzymes. In: Scriver CR, Beaudet AL, Sly WS, et al., eds. The Metabolic and Molecular Basis of Inherited Disease. 8th ed. Baltimore: McGraw-Hill; 2001:1909-63. 2. Takanashi J, Barkovich AJ, Cheng SF, et al. Brain MR imaging in acute hyperammonemic encephalopathy arising from late-onset ornithine transcarbamylase deficiency. AJNR Am J Neuroradiol 2003;24:390-3. 3. Schwab S, Schwartz S, Mayatepak E, et al. Recurrent brain edema in ornithine transcarbamylase deficiency. J Neurol 1999;246:609-11. 4. Christodoulou J, Qureshi IA, McInnes RR, et al. Ornithine transcarbamylase deficiency presenting with stroke-like episodes. J Pediatr 1993;122:423-5. 5. Wraith JE. Ornithine carbamoyltransferase deficiency. Arch Dis Child 2001;84:84-8. 6. Maestri NE, Brusilow SW, Clissold DB, et al. Long-term treatment of girls with ornithine-transcarbamylase deficiency. N Engl J Med 1996;335:855-9. 7. de Grauw TJ, Smit LM, Brockstedt M, et al. Acute hemiparesis as the presenting sign in a heterozygote for ornithine transcarbamylase deficiency. Neuropediatrics 1990;21:133-5. 8. Mirowitz SA, Sartor K, Prensky AJ, et al. Neurodegenerative diseases of childhood: MR and CT evaluation. J Comput Assist Tomog 1991;15:210-22. 9. Mamourian AC, du Plessis A. Urea cycle defect: a case with MR and CT findings resembling infarct. Pediatr Radiol 1991; 21:594-605. 10. Connelly A, Cross JH, Gadian DG, et al. Magnetic resonance spectroscopy shows increased brain glutamine in ornithine carbamoyl transferase deficiency. Pediatr Res 1993;33: 77-81. 11. Bajaj SK, Kurlemann G, Schuierer G, et al. CT and MRI in a girl with late-onset ornithine transcarbamylase deficiency: case report. Neuroradiology 1996;38: 796-9. 12. Takanashi J, Kurihara A, Tomita M, et al. Distinctly abnormal brain metabolism in late-onset ornithine transcarbamylase deficiency. Neurology 2002;59: 210-4. Anderson and Brodsky: J Neuro-Ophthalmol 2010; 30: 94-103 101 Letters to the Editor 13. Janzer RC, Friede RL. Perisulcal infarcts: lesions caused by hypotension during increased intracranial pressure. Ann Neurol 1979;6:399-404. 14. Kurihara A, Takanashi J, Tomita M, et al. Magnetic resonance imaging in late-onset transcarbamylase deficiency. Brain Dev 2003;25:40-4. 15. Arnold SM, Els T, Spreer J, et al. Acute hepatic encephalopathy with diffuse cortical lesions. Neuroradiology 2001;43:551-4. 16. Afshari MA, Afshari NA, Fulton AB. Cortical visual impairment in infants and children. Int Ophthalmol Clin 2001;41:159-69. Third Cranial Nerve Palsy as the Presenting Neuro- Ophthalmic Feature of Nasopharyngeal Carcinoma Nasopharyngeal carcinoma, the most common carci-noma to involve the skull base, may present with neuro-ophthalmic features. Most patients have multiple cranial nerve dysfunction, the fifth and sixth cranial nerves being most often affected (1-3). We report a case that presented with third cranial nerve palsy as the only neuro-ophthalmic feature. A 48-year-old man with no significant past medical history presented to our clinic with a complaint of diplopia and ipsilateral periocular pain of 3 days duration. The patient also reported having noticed a mass in the left submandibular area 6 months earlier. Neurologic examination revealed partial right ptosis and complete absence of adduction, supraduction, and infraduc-tion of the right eye. The pupils in low illumination were equal at 4 mm and symmetrically reactive to light and near targets. Visual acuity, ophthalmoscopy, and cranial nerve and motor examination results were normal. Results of the remaining physical examination were within normal limits except for a painless mass over the left submandibular area. All laboratory values and were within the normal ranges. MRI of the brain and nasopharynx showed a large mass centered at the clivus region and spreading into the nasopharynx, invading the basis of the occipital bone, both sphenoid and posterior ethmoid sinuses, the medial part of the right cavernous sinus, and the petrous apex (Fig. 1A-B). The mass enhanced heterogeneously. The superior and inferior orbital fissures, optic nerves, and other intraorbital structures were spared. Significant bilateral lymphadenop-athy of the neck was evident and some lymph nodes showed hypodense centers indicative of necrosis. A digital sub-traction angiogram revealed no vascular abnormalities. FIG. 1. A. T2 axial MRI shows a tumor with mixed signal intensity that is invading the sphenoid and posterior ethmoid sinuses. B. Postcontrast coronal MRI shows an enhancing tumor centered at the clivus with partial right cavernous sinus invasion (arrow). FIG. 2. Histopathology of a nasopharyngeal punch biopsy shows fibrous connective tissue with infiltrating cords of anaplastic cells (hematoxylin and eosin, 340). 102 Beckmann et al: J Neuro-Ophthalmol 2010; 30: 94-103 Letters to the Editor Biopsy of the nasopharyngealmass revealed a nonkeratinizing differentiated carcinoma (Fig. 2). The patient was referred to the oncology department for radiotherapy and chemotherapy. The third cranial nerve paralysis remained stable without improvement, and no other neurologic symptoms had occurred after 3 months. A retrospective study of 79 patients with nasopharyngeal carcinomas (4) disclosed that one quarter of these patients have neuro-ophthalmic manifestations. In a group of 564 patients with nasopharyngeal carcinomas (1), cranial nerve dysfunction was present in 12%. In 92% of the patients, neurologic deficits were confined exclusively to cranial nerves. Another study (5) showed that the most frequently affected cranial nerves were the fifth and sixth. Our patient is unusual in that the third cranial nerve was the only one involved. The extent of the tumor on MRI fails to indicate why the third cranial nerve was the only affected cranial nerve. Yesim Yetimalar Beckmann, MD Benian Deniz, MD Department of Neurology Atatu¨rk Training and Research Hospital Izmir, Turkey [e-mail] Fazil Gelal, MD Department of Radiology AtatU¨rk Training and Research Hospital Izmir, Turkey Yaprak Secxil, MD Department of Neurology Atatu¨rk Training and Research Hospital Izmir, Turkey REFERENCES 1. Leung SF, Tsao SY, Teo P, et al. Cranial nerve involvement by nasopharyngeal carcinoma: response to treatment and clinical significance. Clin Oncol 1990;2:138-41. 2. Bradley WG, Daroff RB, Fenichel G, et al. Neurology in Clinical Practice. 5th ed. Burlington, MA: Butterworth-Heinemann; 2008. 3. Celebisoy N, Bayam FE, Cag˘ ırgan S, et al. Primary central nervous system leukemia presenting with an isolated oculomotor palsy. J Clin Neurosci 2008;15: 1144-55. 4. Ogunleye AO, Nwaorgu OG, Adaramola SF. Ophthalmo-neurologic manifestation of nasopharyngeal carcinoma. West Afr J Med 1999;18:106-9. 5. Turgman J, Braham J, Modan B, et al. Neurological complications in patients with malignant tumors of the nasopharynx. Eur Neurol 1978;17:149-54. Randot Stereoacuity Test and Multiple Sclerosis In a recent publication in this journal, Sobaci et al (1) concluded that patients with multiple sclerosis (MS) without optic neuritis had considerable abnormalities in stereopsis and that the Randot stereoacuity (RSA) test might be a useful marker of subclinical disease activity in MS. Several conditions can lead to impaired performance on the RSA test. In addition, it is not clear whether optic nerve or retinal diseases are likely to have a big impact on stereoacuity performance (2). The clinical usefulness of the RSA still needs further validation (2,3). Although the sensitivity and specific of the test are acceptable for screening of strabismus (4), it has never been proved for optic neuritis. Viroj Wiwanitkit, MD Wiwanitkit House Bangkhae Bangkok, Thailand [e-mail] REFERENCES 1. Sobaci G, Demirkaya S, Gundogan FC, et al. Stereoacuity testing discloses abnormalities in multiple sclerosis without optic neuritis. J Neuroophthalmol 2009;29:197-202. 2. Shah MB, Fishman GA, Alexander KR, et al. Stereoacuity testing in patients with retinal and optic nerve disorders. Doc Ophthalmol 1995-1996;91:265-71. 3. Fu VL, Birch EE, Holmes JM. Assessment of a new Distance Randot stereoacuity test. J AAPOS 2006;10:419-23. 4. Yang JW, Son MH, Yun IH. A study on the clinical usefulness of digitalized random-dot stereoacuity test. Korean J Ophthalmol 2004;18:154-60. Author's Reply Dr. Viroj Wiwanitkit has made meaningful comments on our article. In this study, we showed that patients with multiple sclerosis (MS) without optic neuritis (ON) had significantly worse Randot stereoacuity (RSA) levels compared with age-matched and sex-matched healthy control subjects. This finding, as indicated in the Discussion, may indicate some structural and/or functional abnormalities or dysfunctional processing in the visual pathways of patients with MS who had no ON attacks. We agree that the diagnostic value of RSA in ON has never been proven. Gungor Sobaci, MD, COL Gulhane Askeri Tip Akademisi Goz Hastaliklari, A.D. Etlik-Ankara, Turkey [e-mail]/[e-mail] Wiwanitkit and Sobaci: J Neuro-Ophthalmol 2010; 30: 94-103 103 Letters to the Editor