Marie-Christine Reinert1, David Pacheu-Grau2, Claudia B Catarino3, Thomas Klopstock3,4,5, Andreas Ohlenbusch6, Michael Schittkowski7, Ekkehard Wilichowski6, Peter Rehling2,8,9, Knut Brockmann10. 1. Division of Pediatric Neurology, Department of Pediatrics and Adolescent Medicine, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany. marie-christine.reinert@med.uni-goettingen.de. 2. Department of Cellular Biochemistry, University Medical Center Göttingen, Göttingen, Germany. 3. Department of Neurology, Friedrich-Baur-Institute, University Hospital, LMU Munich, Munich, Germany. 4. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. 5. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. 6. Division of Pediatric Neurology, Department of Pediatrics and Adolescent Medicine, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany. 7. Department of Ophthalmology, Section for Strabismus, Neuroophthalmology and Oculoplastics, University Medical Center Göttingen, Göttingen, Germany. 8. Cluster of Excellence "Multiscale Bioimaging: From Molecular Machines To Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany. 9. Max Planck Institute for Biophysical Chemistry, Göttingen, Germany. 10. Interdisciplinary Pediatric Center for Children With Developmental Disabilities and Severe Chronic Disorders, University Medical Center Göttingen, Göttingen, Germany.
Abstract
BACKGROUND: Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder and characterized by acute or subacute painless visual loss. Environmental factors reported to trigger visual loss in LHON mutation carriers include smoking, heavy intake of alcohol, raised intraocular pressure, and some drugs, including several carbonic anhydrase inhibitors. The antiepileptic drug sulthiame (STM) is effective especially in focal seizures, particularly in benign epilepsy of childhood with centrotemporal spikes, and widely used in pediatric epileptology. STM is a sulfonamide derivate and an inhibitor of mammalian carbonic anhydrase isoforms I-XIV. RESULTS: We describe two unrelated patients, an 8-year-old girl and an 11-year-old boy, with cryptogenic focal epilepsy, who suffered binocular (subject #1) or monocular (subject #2) visual loss in close temporal connection with starting antiepileptic pharmacotherapy with STM. In both subjects, visual loss was due to LHON. We used real-time respirometry in fibroblasts derived from LHON patients carrying the same mitochondrial mutations as our two subjects to investigate the effect of STM on oxidative phosphorylation. Oxygen consumption rate in fibroblasts from a healthy control was not impaired by STM compared with a vehicle control. In contrast, fibroblasts carrying the m.14484T>C or the m.3460G>A LHON mutation displayed a drastic reduction of the respiration rate when treated with STM compared to vehicle control. CONCLUSIONS: Our observations point to a causal relationship between STM treatment and onset or worsening of visual failure in two subjects with LHON rather than pure coincidence. We conclude that antiepileptic medication with STM may pose a risk for visual loss in LHON mutation carriers and should be avoided in these patients.
BACKGROUND:Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder and characterized by acute or subacute painless visual loss. Environmental factors reported to trigger visual loss in LHON mutation carriers include smoking, heavy intake of alcohol, raised intraocular pressure, and some drugs, including several carbonic anhydrase inhibitors. The antiepileptic drug sulthiame (STM) is effective especially in focal seizures, particularly in benign epilepsy of childhood with centrotemporal spikes, and widely used in pediatric epileptology. STM is a sulfonamide derivate and an inhibitor of mammalian carbonic anhydrase isoforms I-XIV. RESULTS: We describe two unrelated patients, an 8-year-old girl and an 11-year-old boy, with cryptogenic focal epilepsy, who suffered binocular (subject #1) or monocular (subject #2) visual loss in close temporal connection with starting antiepileptic pharmacotherapy with STM. In both subjects, visual loss was due to LHON. We used real-time respirometry in fibroblasts derived from LHON patients carrying the same mitochondrial mutations as our two subjects to investigate the effect of STM on oxidative phosphorylation. Oxygen consumption rate in fibroblasts from a healthy control was not impaired by STM compared with a vehicle control. In contrast, fibroblasts carrying the m.14484T>C or the m.3460G>A LHON mutation displayed a drastic reduction of the respiration rate when treated with STM compared to vehicle control. CONCLUSIONS: Our observations point to a causal relationship between STM treatment and onset or worsening of visual failure in two subjects with LHON rather than pure coincidence. We conclude that antiepileptic medication with STM may pose a risk for visual loss in LHON mutation carriers and should be avoided in these patients.
Authors: C Macmillan; T Kirkham; K Fu; V Allison; E Andermann; D Chitayat; D Fortier; M Gans; H Hare; N Quercia; D Zackon; E A Shoubridge Journal: Neurology Date: 1998-02 Impact factor: 9.910
Authors: E K Nikoskelainen; R J Marttila; K Huoponen; V Juvonen; T Lamminen; P Sonninen; M L Savontaus Journal: J Neurol Neurosurg Psychiatry Date: 1995-08 Impact factor: 10.154
Authors: Julia Zibold; Bettina von Livonius; Hana Kolarova; Günter Rudolph; Claudia S Priglinger; Thomas Klopstock; Claudia B Catarino Journal: Orphanet J Rare Dis Date: 2022-08-09 Impact factor: 4.303