BILATERAL PRESUMED ISCHEMIC OPTIC NEUROPATHY SECONDARY TO CEREBRAL AUTOSOMAL DOMINANT ARTERIOPATHY WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY Lucy E. Barker, MBChB, Graham M. Thompson, MBBS

Purpose: To report a case of bilateral ischemic optic neuropathy (ION) secondary to hypoperfusion of the optic nerve because of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, an uncommon condition causing stepwise subcortical small vessel infarcts because of arterial wall rigidity, loss of autoregulation, and hypoperfusion. Methods: We describe the ophthalmological presentation of this case including fluorescein angiography and kinetic perimetry. Results: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is an increasingly recognized condition with significant neurological sequelae. This case demonstrates the potential for secondary visual loss because of optic nerve hypoperfusion, and the literature confirms this mechanism of injury for both the optic nerve and retina. Retinal screening may add evidence toward the diagnosis in visually asymptomatic patients. Because there is no treatment for the condition, management is symptomatic only but involves psychological support and genetic counseling. Conclusion: We propose that cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy be added to the list of potential differential diagnoses for ION in young patients. RETINAL CASES & BRIEF REPORTS 6:95–98, 2012

1991.1 The responsible gene was identified in 1993 as the notch3 receptor gene on chromosome 19p.2 Genetic mutation causes accumulation of the extracellular receptor domain and secondary fibrosis of the arterial wall, reducing the vascular capacity for autoregulation.3 We describe a case of bilateral sequential anterior ischemic optic neuropathy in a known case of CADASIL where hypoperfusion of the optic nerve is the proposed mechanism of injury.

From the St George’s University Hospital, Tooting, London, United Kingdom.

C

erebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant nonatherosclerotic nonamyloid arteriopathy affecting the small arteries of the cerebral vasculature, first described in L. E. Barker was supported by Roy Harfitt Eye Unit, Epsom and St Helier NHS Trust and G. M. Thompson was supported by St George’s University Hospital NHS Trust. The authors have no proprietary interests and received no funding for this work. Reprint requests: Dr Lucy E. Barker, MBChB, Department of Ophthalmology, Sutton Hospital, Cotswold Road, Sutton SM2 5NF; e-mail: [email protected]

Case Report A 44-year-old man was referred from the neurology department with visual disturbance. He was normotensive, had a normal body mass index, and was a lifelong nonsmoker. His only medical history was of migraine. He was known to have CADASIL having been diagnosed by genetic screening because of early-onset lacunar

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Fig. 1. Fundus photographs showing bilateral optic disk pallor.

stroke. There was no family history of the condition. In keeping with his condition, he was mildly cognitively impaired, emotionally labile, and dysarthric. He experienced ataxia and hypertonia and walked with a spastic gait. He was a poor historian but gave a vague history of impaired vision over the last year, worse in the last 3 months. His best-corrected visual acuity was 6/24 in the right eye and 6/36 in the left. Colour vision was markedly impaired with only the test plate being seen in the right eye (Ishihara, 1/17 right and 0/17 left). Anterior segment examination was unremarkable, and intraocular pressures were within the normal range. There was no relative afferent papillary defect. Examination showed bilateral superotemporal pallor of the right optic disk and temporal pallor of the left optic disk (Figure 1). Findings of fundus fluorescein angiography was unremarkable. Kinetic perimetry revealed a bilateral inferior hemifield defect (Figure 2). Recent magnetic resonance imaging of the brain showed white matter changes consistent with his diagnosis (Figure 3, A–C). The retrospective diagnosis of bilateral nonarteritic ischemic optic neuropathy secondary to hypoperfusion of the optic nerves because of the underlying diagnosis of CADASIL was made.

Discussion The incidence of CADASIL is unknown. In 1 study, screening for the 4 most common genetic mutations in

Fig. 2. Kinetic perimetry demonstrating bilateral inferior hemifield defects.

patients presenting with lacunar stroke showed an overall incidence of ,0.05%, which increased to 2% in patients younger than 65 years and further increased to 11% in those younger than 50 years.4 The autosomal dominant nature of the condition, as described in its name, ordinarily generates a strong family history, although sporadic cases can occur as in the patient described here. The responsible gene was identified in 1993 as the Notch3 gene on chromosome 19p.2 Notch3 is a transmembrane receptor protein with a large extracellular component, which accumulates in CADASIL because of disruption of the disulfide bonds.3 This leads to adventitial fibrosis and stiffening of the vessel wall with a resultant reduction in capacity for blood pressure autoregulation.5 The effects of loss of autoregulation are seen most dramatically on the T2-weighted magnetic resonance

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Fig. 3. Magnetic resonance imaging of the patient. A. Sagittal T2-weighted magnetic resonance imaging demonstrating confluent subcortical white matter lesions. B. Axial T2-weighted magnetic resonance imaging demonstrating confluent subcortical white matter lesions in the frontal and parietal lobes. C. Axial T2-weighted magnetic resonance imaging demonstrating confluent subcortical white matter lesions in the anterior temporal lobes.

imaging of patients with CADASIL where white matter watershed zone infarcts occur because of hypoperfusion (Figure 3, A–C). Multiple symmetrical white matter lesions are seen early in the disease, which become confluent over time and predominantly affect the frontal and temporal lobes, basal ganglia, internal and external capsules, and the brainstem.6 The propensity for the frontal and temporal lobes to be affected early accounts for the classical features of the disease. Chabriat et al7 described the stepwise progression of the disease from migraine, with aura in early adulthood, to mood disorders, particularly depression, and multiple subcortical infarcts in the middle age. The resulting stepwise deterioration of both cognitive and neurological function ultimately leads to dementia, pseudobulbar palsy, and death in the seventh decade. Laboratory studies have documented reduced blood flow and volume in the optic nerve head8 and peripapillary retina of patients with CADASIL by means of scanning laser doppler flowmetry.9 The latter study also showed no significant difference in vessel caliber compared with controls and added evidence to the proposed mechanism of injury as loss of autoregulatory capacity rather than narrowing of the lumen as occurs in atherosclerosis.9 Retinal screening reveals that 39% of visually asymptomatic, nondiabetic, normotensive patients with CADASIL have retinal abnormalities, with 17% showing cotton wool spots and 22% demonstrating significant nerve fiber layer thinning.10 Like the magnetic resonance imaging signs, the cotton wool spots were visible in young patients before any symptoms of CADASIL became manifest.

There is currently no treatment for CADASIL. Tight control of vascular risk factors, particularly smoking, seems important, although anticoagulation seems unnecessary. Experimental work continues to try and identify alternative treatment strategies; however, at present, management is supportive only, consisting of symptom control, genetic counseling, and psychological support. This case highlights an unusual, if increasingly recognized, cause for a relatively common condition. CADASIL is a relentlessly progressive disease with a terrible prognosis and severe emotional and psychological implications. Although the family history will provide significant diagnostic clues in this autosomal dominant condition, sporadic cases (including ours) are reported, and therefore, we believe that CADASIL should be added to the more infrequent end of the list of potential differential diagnoses for patients, particularly those younger than 50 years, with ION and/or otherwise unexplainable cotton wool spots. Key words: CADASIL, cotton wool spots, optic neuropathy, subcortical infarcts. References 1. Tournier-Lasserve E, Iba-Zizen MT, Romero N, Bousser MG. Autosomal dominant syndrome with strokelike episodes and leukoencephalopathy. Stroke 1991;22:1297–1302. 2. Tournier-Lasserve E, Joutel A, Melki J, et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat Genet 1993;3:256–259. 3. Joutel A, Andreux F, Gaulis S, et al. The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. J Clin Invest 2000;105:597–605.

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4. Dong Y, Hassan A, Zhang Z, Huber D, Dalageorgou C, Markus HS. Yield of screening for CADASIL mutations in lacunar stroke and leukoaraiosis. Stroke 2003;34:203–206. 5. Lacombe P, Oligo C, Domenga V, Tournier-Lasserve E, Joutel A. Impaired cerebral vasoreactivity in a transgenic mouse model of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke 2005;36:1053–1058. 6. Yousry TA, Seelos K, Mayer M, et al. Characteristic MR lesion pattern and correlation of T1 and T2 lesion volume with neurological and neuropsychological findings in CADASIL. Am J Neuroradiol 1999;20:91–100.

7. Chabriat H, Vahedi K, Iba-Zizen MT, et al. Clinical spectrum of CADASIL: a study of 7 families. Lancet 1995;7:934–939. 8. Rufa A, Dotti MT, Frezzotti P, De Stefano N, Caporossi A, Federico A. Hemodynamic evaluation of the optic nerve head in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Arch Neurol 2004;61:1230–1233. 9. Harju, M, Tuominen S, Summanen P, et al. Scanning laser doppler flowmetry shows reduced retinal capillary blood flow in CADASIL. Stroke 2004;35:2449–2452. 10. Cumurcuic R, Massin P, Paques M, et al. Retinal abnormalities in CADASIL: a retrospective study of 18 patients. J Neurol Neurosurg Psychiatry 2004;75:1058–1060.

Bilateral presumed ischemic optic neuropathy secondary to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

To report a case of bilateral ischemic optic neuropathy (ION) secondary to hypoperfusion of the optic nerve because of cerebral autosomal dominant art...
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