New Insights in Vanishing White Matter Disease: Isolated Bilateral Optic Neuropathy in Adult Onset Disease

Vanishing white matter disease (VWMD) is a rare disease affecting cerebral white matter. The adult form is even rarer and manifests with motor symptoms, behavioral problems, and dementia. There is no treatment and progression is inevitable. We describe a case with atypical manifestations and an unusual course. Description of a 42-year-old man with VWMD complaining of progressive visual loss in the right eye. The patient's visual acuity was 20/60, right eye, and 20/25, left eye, with pale optic nerves bilaterally. MRI showed atrophy of the corpus callosum, diffuse rarefaction of cerebral white matter including the anterior and posterior visual pathways. Our patient had no further symptoms besides loss of visual acuity, which is rare in patients with VWMD of the same age and genetic mutation.

Original Contribution New Insights in Vanishing White Matter Disease: Isolated Bilateral Optic Neuropathy in Adult Onset Disease Sandra R. Barros, MD, Sónia C. R. Parreira, MD, Ana F. B. Miranda, MD, Ana M. B. Pereira, MD, Nuno M. P. Campos, MD Background: Vanishing white matter disease (VWMD) is a rare disease affecting cerebral white matter. The adult form is even rarer and manifests with motor symptoms, behavioral problems, and dementia. There is no treatment and progression is inevitable. We describe a case with atypical manifestations and an unusual course. Methods: Description of a 42-year-old man with VWMD complaining of progressive visual loss in the right eye. Results: The patient's visual acuity was 20/60, right eye, and 20/25, left eye, with pale optic nerves bilaterally. MRI showed atrophy of the corpus callosum, diffuse rarefaction of cerebral white matter including the anterior and posterior visual pathways. Conclusion: Our patient had no further symptoms besides loss of visual acuity, which is rare in patients with VWMD of the same age and genetic mutation. Journal of Neuro-Ophthalmology 2018;38:42-46 doi: 10.1097/WNO.0000000000000565 © 2017 by North American Neuro-Ophthalmology Society V anishing white matter disease (VWMD), described in 1966 by Van der Knaap et al (1), is one of the most prevalent hereditary white matter diseases, most commonly autosomal recessive (2). Patients with VWMD exhibit a broad range of symptoms and signs, and 5 clinical variants have been described (Table 1) (3-7). Neuroimaging criteria for the diagnosis of VWM have been reported (8). MRI images show diffuse abnormali- Ophthalmology Department (SRB, SP, AFBM, AMP, NC), Garcia de Orta Hospital, Almada, Portugal. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to: Sandra Rodrigues Barros, Ophthalmology Department, Garcia de Orta Hospital, Av. Torrado da Silva, 2801-951 Almada, Portugal; E-mail: [e-mail] 42 ties on T1 and T2 sequences involving almost all the cerebral white matter, with progressive rarefaction and cystic degeneration that leads to its complete disappearance. These findings are better seen on proton density and fluid-attenuated inversion recovery images, where within the rarified and cystic white matter, a stripe-like pattern can be found, which represents remaining tissue strands. The cerebellar and brainstem white matter can be affected as well, but no cystic degeneration has been reported. Molecular genetic studies confirm up to 90% of affected patients. Five genes (eIF2B1-5) have been implicated in the disease. These genes encode the 5 subunits of eukaryotic translation initiation factor eIF2B (eIF2Ba-e), with the mutations in eIF2B5 being the most frequent in previous reports (4-6). Mutations in the genes encoding eIF2B could affect protein synthesis inhibition, rendering glia cells more vulnerable to stress. These cells are responsible for forming myelin and providing support and protection for neurons; therefore, their vulnerability may produce an alteration of the myelin. In addition, studies in human brain samples and mouse models for VWM indicate that the development of astroglial cells and oligodendrocytes is impaired (1,9,10). Prognosis is variable and recent studies are pointing toward possible correlations between genotype and phenotype (11). Nevertheless, chronic progression is inevitable, and there is no available treatment. We describe a patient with adult VWMD who followed an atypical clinical course. CASE REPORT A 42-year-old man complained of progressive vision loss in his right eye for 3 months. His medical history included the diagnosis of VWM at the age of 30 years with his primary complaint at that time of headaches. Genetic analysis showed homozygosity for the mutation in EIF2B5: Barros et al: J Neuro-Ophthalmol 2018; 38: 42-46 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Clinical types of vanishing white matter disease Type Prenatal (3rd trimester) or congenital Infantile (,2 yr) Clinical Findings Natural History Decreased fetal movements; oligohydramnios; microcephalopathy; cataract; hypotemia; multiple organ involvement; epilepsy; coma Hypotension; seizures; lethargy; spasticity; developmental arrest Cerebellar ataxia; spasticity; mental impairment; seizures; optic atrophy Death within a few months Death by age 2 years Progression often occurs with triggers Early childhood or childhood (infection, fever, heat trauma, and acute ataxia with central fright); survival variable (months to hypomyelination (CACH) (2- decades) 5 yr old) Late childhood (5-15 yr old) Spastic diplegia; mental impairment Slow progression; longer survival (years) Insidious course; less stress-related Adult (.16 yr old) Motor difficulties; behavioral changes; neurologic decline seizures; dementia; behavioral problems with cognitive decline (may precede other neurologic symptoms); acute transient neurologic events (optic neuritis, complicated migraine, hemiparesis, ovarian failure; ovarioleukodystrophy) c.338G.A/p.Arg113His in chromosome locus 3q27. Family history was unremarkable. His parents did not have a consanguineous marriage. The visual acuity was 20/60, right eye and 20/25, left eye. Pupils were slowly reactive to light with no relative afferent pupillary defect. Anterior biomicroscopy, intraocular pressures, and ocular motility were normal. Funduscopy revealed bilaterally pale optic discs (Fig. 1) with a normal retinal examination. Optical coherence tomography showed decreased retinal nerve fiber layer bilaterally, particularly in the superior and inferior quadrant of the right eye and sparing the nasal quadrant of the left eye (Fig. 2). Automated perimetry revealed superior and inferior defects and cecocentral scotoma in the right eye and a superior scotoma in the left eye. MRI demonstrated diffuse loss of white matter in both cerebral hemispheres with atrophy of the corpus callosum (Fig. 3). Neurological testing showed no evidence of pyramidal signs or cerebellar ataxia. Neuropsychological evaluation of memory, oral and written language, and calculations were impaired. Testing was intact for attention, visuospatial skills, and executive functioning. DISCUSSION Adulthood-onset VWM represents 15% of reported cases. A milder and more insidious clinical course characterizes this variant with presenting signs including behavioral changes, dementia, seizures (12,13), ovarian failure (14- 16), or, rarely, complicated migraines (17). Typical stressrelated acute neurological deteriorations are less frequent in this variant (18). P.Arg113His in EIF2B5 is the most frequent genetic mutation. In the homozygous state, it is almost always associated with adulthood onset and milder disease course (11). Published case reports of adult patients with VWMD homozygous for mutation in EIF2B5: c.338 G.A/p.Arg113His, and case series of adult patients with VWMD FIG. 1. Optic discs are pale bilaterally. Barros et al: J Neuro-Ophthalmol 2018; 38: 42-46 43 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Optical coherence tomography shows decrease retinal nerve fiber layer thickness in both eyes. are summarized in Supplemental Digital Content (see Table E1, http://links.lww.com/WNO/A244) (12-14,16,19-22). None of them presented phenotypical similarities to our patient. Adult VWMD is the least common form of VWMD despite being associated with the most frequent genetic mutation. This paradox may result in an underestimation of the diagnosis in adulthood-onset disease. In particular, there is lack of the classic symptoms of VWMD including ataxia, spasticity, and seizures. Other possible contributing factors are an incomplete understanding of the mechanism of this 44 disease, mutations of still unidentified regulatory genes, and the existence of environmental factors that could affect the expression of eIF2B (21). Optic atrophy in VWMD is rare and only has been reported in the pediatric age group. Hanefeld et al (23) described 3 patients with VWMD. One of these, an 11year-old boy, developed optic atrophy during follow-up, but details of visual function were not reported. It is unclear why VWMD had a predilection for the optic nerves in our patient. To our knowledge, there are no reports specifically addressing visual function in patients Barros et al: J Neuro-Ophthalmol 2018; 38: 42-46 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 3. A. Axial fluid-attenuated inversion recovery (FLAIR) MRI reveals confluent frontal and parietal subcortical hyperintensities with periventricular cystic formation. B. Sagittal FLAIR image shows marked atrophy of the corpus collosum. with the adult variant of VWMD. Hopefully, future studies will address this issue. In the largest reported cohort of 184 patients with VWMD by van der Lei et al (11), age at onset in individuals homozygous for p. Arg113His was approximately 19.2 years (±14.1), age at loss of unsupported walking was 21.9 years (±10.7), and age at death was 33 years (±4.2). Yet, patients with this particular mutation have longer survival and longer ability to walk independently compared to patients with other genotypes. Our patient, who carries the same mutation, had a later onset, with a slowly evolving clinical course, and no new symptoms until he was 42 years, when visual loss was reported due to bilateral optic nerve involvement. He is still independent in his daily life activities. These findings may indicate that other factors, such as genetic or environmental, may contribute to a more benign disease course. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: S. R. Barros, S. Parreira; b. acquisition of data: S. R. Barros, S. Parreira, A. F. Bebiano Miranda; c. analysis and interpretation of data: S. R. Barros, A. M. Pereira. Category 2: a. Drafting the manuscript: S. R. Barros, N. Campos; b. revising it for intellectual content: S. R. Barros, A. F. Bebiano Miranda. Category 3: a. Final approval of the completed manuscript: S. R. Barros ACKNOWLEDGMENTS Dr. Paulo Saraiva, Hospital Garcia de Orta, Almada. REFERENCES 1. Van Der Knaap MS, Pronk JC, Scheper GC. Vanishing white matter disease. Lancet Neurol. 2006;5:413-423. 2. Bugiani M, Boor I, Powers JM, Scheper GC, van der Knaap MS. Leukoencephalopathy with vanishing white matter: a review. J Neuropathol Exp Neurol. 2010;69:987-996. 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Barros et al: J Neuro-Ophthalmol 2018; 38: 42-46 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.