MRI of the Optic Nerves and Chiasm in Patients With Leber Hereditary Optic Neuropathy

The aim of this study was to characterize brain and orbital MRI features of patients with Leber hereditary optic neuropathy (LHON), with particular attention to the optic nerves and chiasm. We studied a patient cohort with genetically confirmed LHON followed at 2 ophthalmologic hospitals in France between 2013 and 2015. High-resolution brain and orbital MRI studies were analyzed for each patient during the first 12 months after the onset of visual loss was analyzed. Our study included 20 men and 8 women with a mean age of 38.3 years at diagnosis, and all had genetic mutations for LHON. Nineteen patients (67.9%) had T2 hyperintensity in the posterior portion of both optic nerves and in the optic chiasm, and enlargement of the chiasm was found in 16 patients (59.3%). No enhancement of the optic nerves or chiasm was detected. The T2 hyperintensity lesions were not associated with the time between symptom onset and obtaining MRI, the mutation type, or sex of the patient. Nonspecific T2 white matter lesions were found in MRI of 6 patients, but without the characteristics of those found in patients with multiple sclerosis. Involvement of the posterior portions of the optic nerves has been described previously in case reports of patients with LHON. Our results support this observation with neuroimaging performed within 1 year of onset of visual loss. Enlargement of the optic chiasm also may occur in patients with LHON. The pathophysiology of the MRI changes is not yet understood.

Original Contribution MRI of the Optic Nerves and Chiasm in Patients With Leber Hereditary Optic Neuropathy Christelle Blanc, MD, Françoise Heran, MD, Christophe Habas, MD, Yannick Bejot, MD, PHD, José Sahel, MD, PHD, Catherine Vignal-Clermont, MD Background: The aim of this study was to characterize brain and orbital MRI features of patients with Leber hereditary optic neuropathy (LHON), with particular attention to the optic nerves and chiasm. Method: We studied a patient cohort with genetically confirmed LHON followed at 2 ophthalmologic hospitals in France between 2013 and 2015. High-resolution brain and orbital MRI studies were analyzed for each patient during the first 12 months after the onset of visual loss was analyzed. Results: Our study included 20 men and 8 women with a mean age of 38.3 years at diagnosis, and all had genetic mutations for LHON. Nineteen patients (67.9%) had T2 hyperintensity in the posterior portion of both optic nerves and in the optic chiasm, and enlargement of the chiasm was found in 16 patients (59.3%). No enhancement of the optic nerves or chiasm was detected. The T2 hyperintensity lesions were not associated with the time between symptom onset and obtaining MRI, the mutation type, or sex of the patient. Nonspecific T2 white matter lesions were found in MRI of 6 patients, but without the characteristics of those found in patients with multiple sclerosis. Conclusions: Involvement of the posterior portions of the optic nerves has been described previously in case reports of patients with LHON. Our results support this observation with neuroimaging performed within 1 year of onset of visual loss. Enlargement of the optic chiasm also may occur in patients with LHON. The pathophysiology of the MRI changes is not yet understood. Journal of Neuro-Ophthalmology 2018;38:434-437 doi: 10.1097/WNO.0000000000000621 © 2017 by North American Neuro-Ophthalmology Society Department of Neurology (CB, YB), CHU de DIJON, Dijon, France; Department of Neuro-radiology (FH), Fondation Ophtalmologique Adolphe de Rothschild, Paris, France; Department of Neuroradiology (CH), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris, France; Clinical Center of Investigations (JS, CV-C), Centre Hospitalier National d'Ophtalmologie des QuinzeVingts, Paris, France; and Department of Neuro-Ophthalmology (JS, CV-C), Fondation Ophtalmologique Adolphe de Rothschild, Paris, France. The authors report no conflicts of interest. Address correspondence to Christelle Blanc, MD, Neurology Unit 1, 14 rue Paul Gaffarel, 21000 Dijon, France; E-mail: [e-mail] 434 L eber hereditary optic neuropathy (LHON) is characterized by subacute, bilateral visual loss that typically occurs in young men (1,2) and is most often caused by 3 mitochondrial DNA mutations (11778G.A, 3460G.A, and 14484T.C) (3-6). In rare pathological studies, axonal and myelin loss within the optic nerve has been reported (7-9). The objective of our study was to determine the MRI features of the optic nerve and chiasm in patients with a recent diagnosis of LHON. We also wanted to determine whether there were differences between MRI findings according to sex, mutation type, and duration of visual loss. PATIENTS AND METHODS Our study included patients with genetically confirmed LHON, recruited from 2 medical institutions in France, Adolphe de Rothschild Ophthalmological Foundation and the National Ophthalmological Center of the Quinze-Vingts Hospital, between January 2013 and December 2015. Demographic data, including age, sex, and family history of LHON, were obtained retrospectively. Clinical data, including age at onset of the visual loss, funduscopic examination, final visual acuity, and mitochondrial mutation type, were also collected. Inclusion criteria consisted of a diagnosis of LHON based on the clinical presentation and genetic studies. The 3 most common LHON pathogenic mutations were screened for and, if negative, complete mitochondrial DNA sequencing was performed. Orbital and brain MRI had to be obtained within the first 12 months after the onset of the visual loss. Patients were excluded from the study if orbital and brain MRIs were obtained beyond 1 year of onset of vision loss or if the diagnosis of LHON was uncertain. The MRI protocol for each patient (1.5 T in 14 patients and 3 T in 14 patients) included the following: Blanc et al: J Neuro-Ophthalmol 2018; 38: 434-437 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution T1 with contrast (gadolinium), T2 fast spin echo, and fluid-attenuated inversion recovery (FLAIR). Other sequences such as fat suppression or short tau inversion recovery (STIR) were used in imaging of the orbit, if necessary. We used 2-mm slices in the coronal plane and 3-mm slices in the axial plane to study the optic nerves and chiasm. MRI was considered abnormal if 2 neuroradiologists were in agreement with one of the following criteria: 1. A T2 or T2 STIR hyperintense signal (HS) in any part of the optic nerve (orbital, canalicular, or intracranial portion) and/or of the chiasm. 2. Contrast enhancement. 3. T2 HS in brain white matter. T2 HS was classified according to its location along the anterior visual pathways: level 0, no HS; level 1, T2 HS of orbital optic nerves (ON) segments; level 2, T2 HS of canalicular ON segments; level 3, T2 HS of the canalicular and intracranial ON segments; and level 4, T2 HS of both the canalicular and the intracranial ON segments with extension to the chiasm. Statistical analyses were performed using the Fisher exact test and the 1-sided Fisher exact test. RESULTS Thirty-three patients with LHON were screened between 2013 and 2015. Five were excluded because MRI was not performed. Among the 28 remaining patients enrolled, there were 20 men and 8 women. The mean age was 38.3 years, with women older than the men (mean age 46.5 years and 35.05 years, respectively). A family history of LHON was found in 15 patients (64.3%). Twenty-one patients (75%) harbored the 11778 mutation, 4 the 3460 mutation, 2 the 14484 mutation, and 1 a rare 14487 mutation. The final visual acuity was worse than 20/200 bilaterally in all but 2 eyes; 1 had the 14484 mutation and 1 the 3460 mutation. Final acuities in these 2 patients were 20/40 and 20/50, respectively. With all levels combined, HS appeared in 19/28 patients (67.9%), and an extensive T2 HS to the chiasm was seen in 16/28 patients (57%) (Figs. 1 and 2). This HS was present in 10/14 patients who underwent 1.5 T MRI and in 9/14 patients who underwent 3 T MRI. The locations of HS among the various levels were as follows: level 0, 9/28 patients (32%); level 1 and 2, no patients; level 3, 3/28 patients (11%); and level 4, 16/28 patients (57%). Of the 16 patients with T2 HS in the chiasm, all had qualitative enlargement of the chiasm as well (Fig. 2). No patients demonstrated enhancement of the optic nerves or chiasm. There was no difference in the prevalence of the T2 hyperintense lesions in the anterior visual Blanc et al: J Neuro-Ophthalmol 2018; 38: 434-437 FIG. 1. MRI performed in a 17-year-old boy 2 months after the onset of bilateral visual loss, occurring 2 weeks apart. He had a family history of Leber hereditary optic neuropathy. Coronal T2 image shows hyperintense signal (arrows) in the intracranial portion of both optic nerves. pathway according to the mutation type (P . 0.05, Table 1). We divided our patients into 2 groups (,3 months and 3-12 months) depending on the time interval from the onset of visual loss to performance of MRI. In 18 patients, MRI was performed within 3 months of onset, and in 10, it was obtained between 3 and 12 months. A T2 HS of the intracranial portion of both optic nerves was present in 13/ 18 patients with early MRI and in 6/10 patients who had their MRI later with no significant difference between both FIG. 2. MRI in a 52-year-old man with bilateral visual loss who had the 17778 mitochondrial mutation. Coronal T2 scan reveals the hyperintense signal (arrows) and enlargement of the optic chiasm. 435 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. MRI findings in patients with LHON according to their mutation type Male Family history Visual acuity in right eye Visual acuity in left eye Optic nerve HS Optic chiasm HS Level 0 Level 1 Level 2 Level 3 Level 4 HS, hyperintense neuropathy. 11778 Positive Mutation, n = 21 11778 Negative Mutation, n=7 P 16 15 20/200 4 3 20/125 0.31 0.18 0.55 20/600 14 12 7 0 0 2 12 20/125 5 4 2 0 0 1 4 0.41 0.60 0.62 0.60 - - 0.59 0.67 signal; LHON, Leber hereditary optic groups (P = 0.68). In addition, the distribution of T2 HS in the optic nerves and chiasm was not significantly different between both groups (Table 2) or according to the sex of the individual. FLAIR HS of the brain was detected in 6 patients. These lesions were considered nonspecific because of their location (subcortical but not periventricular, or juxtacortical distribution) and their size (less than 3 mm) and appeared related to cardiovascular risk factors (hypertension in 5 patients, tobacco use and diabetes in 1 patient). No patient had T2 lesions meeting the Swanton criteria for multiple sclerosis (10). DISCUSSION In our study, we evaluated the findings on MRI performed within 1 year of onset of visual loss in 28 TABLE 2. MRI features according to the time from onset of vision loss to obtaining MRI in patients with LHON Optic Optic Level Level Level Level Level nerve HS chiasm HS 0 1 2 3 4 MRI ,3 mo, N = 18 MRI Between 3 and 12 mo, N = 10 P 13 10 5 0 0 3 10 6 6 4 0 0 0 6 0.68 1.00 0.68 - - 0.53 1.00 HS, hyperintense signal; LHON, Leber hereditary optic neuropathy; mo, months. 436 patients with LHON. Areas of HS on T2 images were detected frequently in the posterior portion of the optic nerves and optic chiasm. These signal changes within the chiasm, coupled with chiasmal enlargement, were detected in 16 patients (59%). There was no difference in the MRI changes if the patient was scanned within the first 3 months after the onset of vision loss compared with those imaged between 4 and 12 months. None of the areas of HS in the anterior visual pathway demonstrated contrast enhancement. Neither the sex of the patient nor the genetic mutation had any effect on the neuroimaging findings. There are a number of case reports and small case series describing the MRI changes in the anterior visual pathway of patients with LHON. In 1989, Kermode et al (11) demonstrated HS on T2 MRI in the posterior optic nerves in 8 of 13 patients with LHON. Scans were obtained between 3 months and 16 years after the onset of vision loss. Spatial resolution on MRI was inadequate to evaluate the optic chiasm. Detection of HS on T2 images of the optic nerves was reported in a minority of patients with LHON in a number of studies (12-20). Scans were performed at variable times up to 1 year after the onset of visual symptoms, and the abnormalities were also found in more anterior locations of the optic nerves. More recently, with highresolution MRI, Van Westen et al (17) demonstrated HS on T2 images involving the prechiasmal optic nerves, chiasm, and optic tracts in 2 patients with LHON. This was confirmed by Vaphiades (18). The findings of enlargement of the optic chiasm support the observation by Phillips et al (19). Although we did not find evidence of contrast enhancement of the anterior visual pathways, a number of studies did demonstrate enhancement of the optic nerves with weeks of vision loss (19,21-24). The precise cause of the T2 changes observed in patients with LHON is unknown. We speculate that with axonal degeneration and demyelination seen in the optic nerves of patients with LHON (25,26), there is also damage to astrocytes and oligodendrocytes, cells dependent on functioning mitochondria. The HS found in the optic nerves and chiasm of patients with LHON is because of gliosis, which appears days to weeks after the onset of vision loss (27) and may persist chronically (12,13,16). The findings of contrast enhancement in some patients early in the course of visual failure suggest an inflammatory component with disruption of the blood-brain barriers (24). A major limitation of our study was its retrospective and descriptive design. Our patient cohort was too small to enable any meaningful statistical analysis. Nevertheless, the findings of our report may indicate that MRI of the anterior visual pathway can play a role in establishing the diagnosis of LHON and help provide insight into the pathophysiology of this optic neuropathy. Blanc et al: J Neuro-Ophthalmol 2018; 38: 434-437 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution REFERENCES 1. Newman NJ, Biousse V. 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