Increased Levels of Endothelin-1 in Cerebrospinal Fluid Are a Marker of Poor Visual Recovery after Optic Neuritis in Multiple Sclerosis Patients

Hindawi Disease Markers Volume 2019, Article ID 9320791, 5 pages https://doi.org/10.1155/2019/9320791 Research Article Increased Levels of Endothelin-1 in Cerebrospinal Fluid Are a Marker of Poor Visual Recovery after Optic Neuritis in Multiple Sclerosis Patients Massimiliano Castellazzi ,1,2,3 Giuseppe Lamberti,4 Maria Vittoria Resi,5 Eleonora Baldi,2,3 Luisa Maria Caniatti,2,3 Giuditta Galante,1 Paolo Perri,1,4 and Maura Pugliatti1,2,3 1 Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy Interdepartmental Research Center for the Study of Multiple Sclerosis and Inflammatory and Degenerative Diseases of the Nervous System, University of Ferrara, Ferrara, Italy 3 Department of Neuroscience and Rehabilitation, S. Anna University Hospital, Ferrara, Italy 4 Department of Specialty Surgery, S. Anna University Hospital, Ferrara, Italy 5 School of Medicine, University of Ferrara, Italy 2 Correspondence should be addressed to Massimiliano Castellazzi; Received 16 April 2019; Revised 8 August 2019; Accepted 30 August 2019; Published 10 September 2019 Academic Editor: Hubertus Himmerich Copyright © 2019 Massimiliano Castellazzi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Multiple sclerosis (MS), a chronic inflammatory and degenerative disease of the central nervous system, typically features immune-mediated focal demyelination and secondary axonal degeneration. Cerebral hypoperfusion of the normalappearing white matter (NAWM) has been reported in MS patients and may be mediated by elevated levels of endothelin-1 (ET-1), a most potent vasoconstrictive peptide released from reactive astrocytes in MS focal lesions. Optic neuritis (ON) is one of the most frequent manifestations of MS and also shows peripapillary vascular hypoperfusion in combination with disc swelling. Aims. We aimed to compare serum and cerebrospinal fluid (CSF) levels of ET-1 as a potential prognostic marker of MS-ON in two groups of patients differing for severity of MS-ON clinical presentation. Materials and Methods. A crosssectional study to compare serum and CSF levels of ET-1 between patients with clinically aggressive MS-ON (A-MS-ON) and nonaggressive MS-ON (NA-MS-ON) according to conventional ophthalmological criteria, including optical coherence tomography. CSF and serum concentrations of ET-1 were measured using a commercially available ELISA method. Results. Sixteen patients consecutively referred to the Units of Neurology for visual disturbances attributable to MS were recruited, 11 (69%) patients with A-MS-ON and 5 (31%) with NA-MS-ON. Median CSF ET-1 levels and CSF/serum ET-1 quotient were significantly higher in patients with A-MS-ON (0.30 vs. 0.56 ng/ml) as compared to NA-MS-ON (0.16 vs. 0.16). Conclusions. Severity and failure in the recovery from ON in MS patients may depend from vascular hypoperfusion of the optic nerve induced by high intrathecally produced ET-1, a potential prognostic marker of ON recovery in MS. The detection of CSF ET-1 levels may allow identifying groups of ON patients potentially benefitting from treatment with ET-1 antagonists (e.g., bosentan). 1. Introduction Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS) and the most frequent cause of neurological disability in young adulthood. Immune-mediated focal demyelination and secondary axonal degeneration with T-cell-mediated inflam- matory response against CNS myelin are the disease pathological hallmark. More recently, cerebral hypoperfusion of the normalappearing white matter (NAWM) at perfusion-weighted magnetic resonance imaging (MRI) studies has been reported in patients with both relapsing-remitting and progressive MS at an early stage of the disease [1, 2] and in 2 association with cognitive decline and fatigue [3]. By promoting mitochondrial dysfunction, oxidative stress, and axonal loss [4], blood perfusion of the gray matter is found significantly decreased in MS patients as compared with control subjects, and hypoperfusion is directly associated with degeneration and atrophy [5]. Cerebral hypoperfusion in MS has been hypothesized to be mediated by elevated levels of endothelin-1 (ET-1), a potent vasoconstrictive peptide released in the cerebral circulation from reactive astrocytes in MS focal lesions [6] and actively implicated in modulating activities of neurons and glia [7, 8]. ET-1-related reactive astrogliosis has been reported for neurodegeneration in Alzheimer’s disease [9], traumatic brain injury [10], and stroke [11]. Optic neuritis (ON) is one of the most frequent manifestations of MS (Optic Neuritis Study Group 2008). Among the typical MS-ON manifestations are subacute monocular visual loss associated with pain during eye movement, visual loss or blurring, and dyschromatopsia. Acute MS-ON also shows peripapillary vascular hypoperfusion in combination with disc swelling [12]. Persistent demyelination [13] and axonal loss account for incomplete or poor visual recovery in MS-ON. We assessed the levels of ET-1 in the cerebrospinal fluid (CSF) and in serum with a special focus on ON which occurred in MS patients as a potential prognostic marker of visual outcome. 2. Materials and Methods We designed a cross-sectional study to compare serum and CSF levels of ET-1 between patients with clinically aggressive MS-ON (A-MS-ON) and patients with nonaggressive MSON (NA-MS-ON). For the study purposes, subjects with a diagnosis of ON were regarded as “aggressive”(A-MS-ON) if at least one of the following criteria was met: (i) visual acuity of 5/10 or less, (ii) visual acuity greater than 5/10 but possible through residual receptive fields, (iii) paracentral scotoma with 1 point less than 10 dB or at least 3 contiguous points less than 4 dB according to Heijl-Krakau criteria, (iv) a deep and wide defect of the papillomacular bundle at optical coherence tomography (OCT) (structural criterion), (v) concomitant inflammatory and ischemic changes of postchiasmatic visual pathways, and (iv) impairment of oculomotor pathways with diplopia concomitant with visual deficit onset. MS-ON presentation which did not meet any of the above criteria was defined “nonaggressive” (NA-MS-ON). A history of comorbidity with special regard to cardiovascular disorders and metabolic syndromes was collected from the study participants. The study was approved by the local Committee for Medical Ethics in Research (Protocol no. 151197, 21 January 2016), and written informed consent was obtained from all participants. 2.1. Sample Handling. Paired CSF and serum samples were collected as a part of the diagnostic workup and measured under the same conditions. Cell-free CSF and serum were Disease Markers (i) obtained after centrifugation at 2,000 g at 20°C for 15 minu (...truncated)