Vision Loss and Symmetric Basal Ganglia Lesions in Leber Hereditary Optic Neuropathy

A 30-year-old woman with progressive vision loss was found to have asymptomatic, bilateral, and symmetric basal ganglia lesions on MRI and was later diagnosed with Leber hereditary optic neuropathy (LHON). The rare occurrence of basal ganglia changes on MRI in patients with LHON is discussed.

Clinical Observation Vision Loss and Symmetric Basal Ganglia Lesions in Leber Hereditary Optic Neuropathy Matthew A. Mercuri, MD, Halina White, MD, Cristiano Oliveira, MD Abstract: A 30-year-old woman with progressive vision loss was found to have asymptomatic, bilateral, and symmetric basal ganglia lesions on MRI and was later diagnosed with Leber hereditary optic neuropathy (LHON). The rare occurrence of basal ganglia changes on MRI in patients with LHON is discussed. Journal of Neuro-Ophthalmology 2017;37:411-413 doi: 10.1097/WNO.0000000000000524 © 2017 by North American Neuro-Ophthalmology Society L eber hereditary optic neuropathy (LHON) is a maternally inherited disease caused by point mutations in mitochondrial DNA (mtDNA). Three primary mutations cause up to 90% of cases worldwide, located at mtDNA nucleotide positions 11778, 3460, and 14484 (1-2). MRI is most often normal (3). Enhancement of the optic nerves and/or chiasm has been infrequently described (4-6). Gray matter lesions are rare and have been reported almost exclusively in LHON patients with movement disorders (7). We report the case of a woman with the 14484 LHON mutation, who developed painless sequential vision loss and was found on MRI to have bilateral and symmetric putaminal hyperintensities. After a short period of partial visual recovery, she re-experienced visual decline in both eyes associated with radiographic involvement of the anterior visual pathways and simultaneous improvement in putaminal lesions. CASE REPORT A 30-year-old woman reported a 2 month history of progressive, painless vision loss in her right eye, followed Departments of Neurology (MAM, HW) and Ophthalmology (CO), Weill Cornell Medical College, New York, New York. Supported by a Research to Prevent Blindness (RPB) unrestricted grant to the Weill Cornell Department of Ophthalmology. The authors report no conflicts of interest. Address correspondence to Cristiano Oliveira, MD, 1305 York Avenue 11th Floor, New York, NY 10021; E-mail: [e-mail] Mercuri et al: J Neuro-Ophthalmol 2017; 37: 411-413 by left eye involvement 10 days before her examination. She had been evaluated within a week of symptom onset and diagnosed with right optic neuritis. No optic nerve abnormality was detected on MRI. Her only medications were venlafaxine taken for anxiety and oral contraceptive pills. On examination, visual acuity was counting fingers, right eye, and 20/20, left eye. There was a right relative afferent pupillary deficit. Visual field testing revealed a central scotoma in the right and the left visual field was intact. Fundus appearance was normal in each eye. To reassess the patient for possible optic neuritis, a contrastenhanced MRI brain/orbits was obtained. The scan showed bilateral symmetric posterior putaminal T2 hyperintensities (Fig. 1A). The anterior visual pathways were normal in appearance. The MRI finding raised concern for a toxic-metabolic process. In further discussion, the patient reported regular alcohol consumption including self-made wine, restrictive eating habits, and abuse of tetrahydrolipstatin for weight loss (body mass index: 16 kg/m2). She had no symptoms suggestive of a movement disorder, and no signs of such were found on her examination. Approximately 1 week later, the patient experienced visual decline in her left eye with acuity of 20/70. She was admitted to hospital and received intravenous methylprednisolone. Laboratory included serologies for vitamin levels (B1, B2, B6, B12, A, D, E, and K), folate, heavy metals, zinc, copper, ammonia, rapid plasma reagin test, antineutrophil cytoplasmic antibodies, antinuclear antibody, HIV, as well as serum and cerebrospinal fluid testing for Epstein-Barr virus, CMV, HHV-6, West Nile Virus, angiotensin converting enzyme, immunoglobulin index, oligoclonal bands, antiaquaporin-4 antibody, lactate, pyruvate, and paraneoplastic antibodies. Genetic testing for mitochondrial diseases was obtained. MRI brain/orbits failed to reveal abnormalities of the visual pathways but showed unchanged bilateral putaminal lesions. Contrast-enhanced MRI of the cervical and thoracic spine was unremarkable. There was no visual improvement in either eye 411 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 1. A. Axial fluid-attenuated inversion recovery MRI shows bilateral, symmetric posterior putaminal hyperintensities (arrows). B. There is a decrease in the putaminal hyperintensities (arrows) at the time of recurrent vision loss. and the patient was discharged on supplements of vitamins B12, B2, and D, coenzyme Q10, and with the recommendation to stop drinking alcohol. One month later, vision acuity had improved to 20/100, right eye, and 20/30, left eye. The optic discs remained normal in appearance. Two months later, approximately 4 months after symptom onset, the patient noted progressive painless vision loss in both eyes. Visual acuity was 20/400 in the right eye and 20/100 in the left eye, with bilateral central scotomas and mild temporal pallor of the right optic disc. At that time, MRI brain/orbits demonstrated enlargement and enhancement of the prechiasmatic optic nerves and chiasm (Fig. 2). There also was interval decrease in the bilateral putaminal hyperintensities (Fig. 1B). The new findings were suspicious for an inflammatory disorder; therefore, intravenous steroid treatment was repeated, but without visual improvement. A few weeks later, the results of genetic testing sent at the time of her hospitalization revealed the MT-ND6 (TI14484C) pathogenic mutation of LHON and a secondary MT-ND1 (T3394C) mutation. Idebenone, an analog of coenzyme Q10 reported to potentially promote visual recovery, had been empirically started 1 month before the LHON diagnosis and was continued at a daily dose of 900 mg/d (8). Her visual function remained unchanged in both eyes. DISCUSSION Our patient's presentation was initially thought to represent an inflammatory optic neuropathy. However, the absence of a clinical response to steroids and the presence of bilateral putaminal hyperintensities required a broader differential diagnosis, including toxic insults (methanol, carbon monoxide, and cyanide), systemic metabolic disorders (Leigh disease, Wilson disease, osmotic myelinolysis, and Wernicke encephalopathy), and neurodegenerative diseases (Huntington disease, neurodegeneration with brain iron accumulation, Creutzfeldt-Jakob disease, and Fahr disease) (9). In patients with LHON, brain MRI is typically normal (3). However, there are infrequent reports of T2 hyperintense white matter lesions, which can occur in any region of FIG. 2. Postcontrast coronal T1 images show enlargement and enhancement (arrows) of the prechiasmal optic nerves (A) and optic chiasm (B). 412 Mercuri et al: J Neuro-Ophthalmol 2017; 37: 411-413 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation the brain or spinal cord and can be radiographically indistinguishable from those occurring in multiple sclerosis (10-12). Enlargement and enhancement of the optic tracts, chiasm, and optic radiations also have been described in LHON patients (4,5). In at least one patient, radiographic involvement of the anterior pathways coincided with clinical decline (6), as in our patient. Gray matter lesions in LHON are extremely rare and seen primarily in cases associated with dystonia, implicating the G11696A, G14459A, and T14596A mutations (12,13). To the best of our knowledge, there is only one other case report of an asymptomatic gray matter abnormality associated with LHON; however, this patient had unilateral basal ganglia involvement and a different mutation (G14459A) (7). Unlike LHON, other mitochondrial disorders such as Leigh syndrome, Kearns-Sayre syndrome, and Alpers syndrome are often associated with T2 abnormalities in the deep gray matter (14). The basal ganglia are selectively vulnerable to injury in mitochondrial disorders because of high metabolic demand, rich vascularity, and high concentrations of ionic elements leading to the formation of oxygen free radicals (15,16). We suspect that alcohol consumption and malnutrition may have unmasked our patient's underlying disease via toxic-metabolic stress on the retinal ganglion cells (17). The oxidative stress from these factors might have also increased her susceptibility to the gray matter damage observed on MRI. It is important to note that the basal ganglia lesions shrank in the months following her presentation possibly, in part, because of alcohol cessation and improved nutrition. Our patient had an atypical radiographic presentation of a rare disease and harbored a mutation that carries a much smaller risk of clinical symptomatology in women than men (18). Given the combination of gray and white matter changes observed in our patient, it is possible that she might develop additional neurological findings in the future. Although the significance of gray matter changes in LHON remains uncertain, the evolution of neuroimaging abnormalities in our patient suggests that LHON may have stages of disease activity affecting different neuronal pathways, perhaps influenced by the level of oxidative stress to which the cells are exposed and their degree of metabolic resilience. Alternatively, the disease may have variable patterns of neuronal involvement determined by associated mitochondrial mutations and/or environmental factors. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: C. Oliveira, M. A. Mercuri, and H. White; b. Acquisition of data: C. Oliveira, M. A. Mercuri, and H. White; c. Analysis and interpretation of data: C. Oliveira, M. A. Mercuri, and H. White. Category 2: a. Drafting the manuscript: C. Oliveira, M. A. 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