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Electroretinographic abnormalities associated with pregabalin: a case report

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Abstract

Purpose

Pregabalin binds to the α2–δ1/α2–δ2 subunits of the voltage-gated L-type calcium channel (LTCC), which is expressed in rod/cone photoreceptor terminals. The purpose of this report was to describe electroretinographic abnormalities associated with pregabalin treatment.

Case presentation

This is an observational case report. A 49-year-old female reported photophobia and night blindness in her left eye after 10 months of pregabalin administration. One month after the symptoms, ophthalmic examinations were performed, which revealed good visual acuity and no remarkable fundus findings. However, full-field electroretinography (ERG) of the left eye revealed a decreased b-wave in rod ERG, a slightly decreased a-wave and severely decreased b-wave (negative ERG) in bright flash ERG, decreased a- and b-waves in cone ERG, and decreased b-waves in 30-Hz flicker ERG. These findings are similar to those seen in incomplete congenital stationary night blindness, whereas the right eye ERG showed normal responses, except for a square a-wave in cone ERG. The ERG gradually improved from 1 to 12 months after discontinuing pregabalin. Finally, b-waves in bright flash ERG and cone ERG responses largely recovered, but b-waves in rod ERG and a-waves in bright flash ERG only partially recovered in the left eye. The square a-wave recovered to normal in the right eye.

Conclusions

This is the first report to indicate that ERG abnormalities might be associated with pregabalin treatment. Our results suggest that pregabalin may affect LTCC function via the α2–δ1/α2–δ2 subunits, which leads to defective synaptic transmission from rod/cone photoreceptors to bipolar cells.

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References

  1. Selak I (2001) Pregabalin (Pfizer). Curr Opin Investig Drugs 2:828–834

    CAS  PubMed  Google Scholar 

  2. Dworkin RH, Corbin AE, Young JP Jr, Sharma U, LaMoreaux L, Bockbrader H, Garofalo EA, Poole RM (2003) Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 60:1274–1283. https://doi.org/10.1212/01.wnl.0000055433.55136.55

    Article  CAS  PubMed  Google Scholar 

  3. French JA, Kugler AR, Robbins JL, Knapp LE, Garofalo EA (2003) Dose–response trial of pregabalin adjunctive therapy in patients with partial seizures. Neurology 60:1631–1637. https://doi.org/10.1212/01.wnl.0000068024.20285.65

    Article  CAS  PubMed  Google Scholar 

  4. Dooley DJ, Donovan CM, Pugsley TA (2000) Stimulus-dependent modulation of [(3)H]norepinephrine release from rat neocortical slices by gabapentin and pregabalin. J Pharmacol Exp Ther 295:1086–1093

    CAS  PubMed  Google Scholar 

  5. Fehrenbacher JC, Taylor CP, Vasko MR (2003) Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C. Pain 105:133–141

    Article  CAS  Google Scholar 

  6. Field MJ, Cox PJ, Stott E, Melrose H, Offord J, Su TZ, Bramwell S, Corradini L, England S, Winks J, Kinloch RA, Hendrich J, Dolphin AC, Webb T, Williams D (2006) Identification of the alpha 2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. Proc Natl Acad Sci USA 103:17537–17542. https://doi.org/10.1073/pnas.0409066103

    Article  CAS  PubMed  Google Scholar 

  7. Taylor CP, Angelotti T, Fauman E (2007) Pharmacology and mechanism of action of pregabalin: the calcium channel alpha 2-delta (alpha 2-delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res 73:137–150. https://doi.org/10.1016/j.eplepsyres.2006.09.008

    Article  CAS  PubMed  Google Scholar 

  8. Catterall WA (1991) Functional subunit structure of voltage-gated calcium channels. Science 253:1499–1500. https://doi.org/10.1126/science.1654596

    Article  CAS  PubMed  Google Scholar 

  9. Catterall WA (1998) Structure and function of neuronal Ca2+ channels and their role in neurotransmitter release. Cell Calcium 24:307–323

    Article  CAS  Google Scholar 

  10. Arroyo S, Anhut H, Kugler AR, Lee CM, Knapp LE, Garofalo EA, Messmer S, Group P-IS (2004) Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose–response study in adults with partial seizures. Epilepsia 45:20–27. https://doi.org/10.1111/j.0013-9580.2004.31203.x

    Article  CAS  PubMed  Google Scholar 

  11. Lee BI, Yi S, Hong SB, Kim MK, Lee SA, Lee SK, Shin DJ, Kim JM, Song HK, Heo K, Lowe W, Leon T (2009) Pregabalin add-on therapy using a flexible, optimized dose schedule in refractory partial epilepsies: a double-blind, randomized, placebo-controlled, multicenter trial. Epilepsia 50:464–474. https://doi.org/10.1111/j.1528-1167.2008.01954.x

    Article  CAS  PubMed  Google Scholar 

  12. Aktaş S, Tetikoğlu M, İnan S, Aktaş H, Özcura F (2017) Unilateral hemorrhagic macular infarction associated with marijuana, alcohol and antiepileptic drug intake. Cutan Ocul Toxicol 36:88–95. https://doi.org/10.3109/15569527.2016.1141420

    Article  PubMed  Google Scholar 

  13. Tanyıldız B, Kandemir B, Mangan MS, Tanyıldız A, Göktaş E, Şimşek Ş (2018) Bilateral serous macular detachment after attempted suicide with pregabalin. Turk J Ophthalmol 48:254–257. https://doi.org/10.4274/tjo.70923

    Article  PubMed  PubMed Central  Google Scholar 

  14. McCulloch DL, Marmor MF, Brigell MG, Hamilton R, Holder GE, Tzekov R, Bach M (2015) ISCEV standard for full-field clinical electroretinography (2015 update). Doc Ophthalmol 130:1–12. https://doi.org/10.1007/s10633-014-9473-7

    Article  PubMed  Google Scholar 

  15. Robson AG, Nilsson J, Li S, Jalali S, Fulton AB, Tormene AP, Holder GE, Brodie SE (2018) ISCEV guide to visual electrodiagnostic procedures. Doc Ophthalmol 136:1–26. https://doi.org/10.1007/s10633-017-9621-y

    Article  PubMed  PubMed Central  Google Scholar 

  16. Katagiri S, Hayashi T, Kondo M, Tsukitome H, Yoshitake K, Akahori M, Ikeo K, Tsuneoka H, Iwata T (2016) RPE65 mutations in two Japanese families with Leber congenital amaurosis. Ophthalmic Genet 37:161–169. https://doi.org/10.3109/13816810.2014.991931

    Article  CAS  PubMed  Google Scholar 

  17. Katagiri S, Hosono K, Hayashi T, Kurata K, Mizobuchi K, Matsuura T, Yoshitake K, Iwata T, Nakano T, Hotta Y (2018) Early onset flecked retinal dystrophy associated with new compound heterozygous RPE65 variants. Mol Vis 24:286–296

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Schubert G, Bornschein H (1952) Analysis of the human electroretinogram. Ophthalmologica 123:396–413. https://doi.org/10.1159/000301211

    Article  CAS  PubMed  Google Scholar 

  19. Miyake Y, Yagasaki K, Horiguchi M, Kawase Y, Kanda T (1986) Congenital stationary night blindness with negative electroretinogram. A new classification. Arch Ophthalmol 104:1013–1020. https://doi.org/10.1001/archopht.1986.01050190071042

    Article  CAS  PubMed  Google Scholar 

  20. Mansergh F, Orton NC, Vessey JP, Lalonde MR, Stell WK, Tremblay F, Barnes S, Rancourt DE, Bech-Hansen NT (2005) Mutation of the calcium channel gene Cacna1f disrupts calcium signaling, synaptic transmission and cellular organization in mouse retina. Hum Mol Genet 14:3035–3046. https://doi.org/10.1093/hmg/ddi336

    Article  CAS  PubMed  Google Scholar 

  21. Chang B, Heckenlively JR, Bayley PR, Brecha NC, Davisson MT, Hawes NL, Hirano AA, Hurd RE, Ikeda A, Johnson BA, McCall MA, Morgans CW, Nusinowitz S, Peachey NS, Rice DS, Vessey KA, Gregg RG (2006) The nob2 mouse, a null mutation in Cacna1f: anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses. Vis Neurosci 23:11–24. https://doi.org/10.1017/S095252380623102X

    Article  PubMed  PubMed Central  Google Scholar 

  22. Zeitz C, Robson AG, Audo I (2015) Congenital stationary night blindness: an analysis and update of genotype–phenotype correlations and pathogenic mechanisms. Prog Retin Eye Res 45:58–110. https://doi.org/10.1016/j.preteyeres.2014.09.001

    Article  PubMed  Google Scholar 

  23. Bech-Hansen NT, Naylor MJ, Maybaum TA, Sparkes RL, Koop B, Birch DG, Bergen AA, Prinsen CF, Polomeno RC, Gal A, Drack AV, Musarella MA, Jacobson SG, Young RS, Weleber RG (2000) Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness. Nat Genet 26:319–323. https://doi.org/10.1038/81619

    Article  CAS  PubMed  Google Scholar 

  24. Chang TS, Aylward W, Clarkson JG, Gass JD (1995) Asymmetric canthaxanthin retinopathy. Am J Ophthalmol 119:801–802. https://doi.org/10.1016/s0002-9394(14)72791-6

    Article  CAS  PubMed  Google Scholar 

  25. Browning DJ (2014) Clinical examples in managing patients taking 4-aminoquinolines. In: Browning DJ (ed) Hydroxychloroquine and chloroquine retinopathy. Springer, New York, pp 247–286

    Chapter  Google Scholar 

  26. Mack HG, Fuzzard DRW, Symons RCA, Heriot WJ (2018) Asymmetric hydroxychloroquine macular toxicity with aphakic fellow eye. Retin Cases Brief Rep. https://doi.org/10.1097/ICB.0000000000000750

    Article  PubMed  Google Scholar 

  27. Goetgebuer G, Kestelyn-Stevens AM, De Laey JJ, Kestelyn P, Leroy BP (2008) Cancer-associated retinopathy (CAR) with electronegative ERG: a case report. Doc Ophthalmol 116:49–55. https://doi.org/10.1007/s10633-007-9074-9

    Article  PubMed  Google Scholar 

  28. Ueno S, Nakanishi A, Nishi K, Suzuki S, Terasaki H (2015) Case of paraneoplastic retinopathy with retinal ON-bipolar cell dysfunction and subsequent resolution of ERGs. Doc Ophthalmol 130:71–76. https://doi.org/10.1007/s10633-014-9470-x

    Article  PubMed  Google Scholar 

  29. Ueno S, Inooka D, Nakanishi A, Okado S, Yasuda S, Kominami T, Sayo A, Morimoto T, Kondo M, Katagiri S, Hayashi T, Terasaki H (2019) Clinical course of paraneoplastic retinopathy with anti-TRPM1 autoantibody in Japanese cohort. Retina. 39:2410–2418

    Article  Google Scholar 

  30. Dolphin AC (2013) The alpha2delta subunits of voltage-gated calcium channels. Biochim Biophys Acta 1828:1541–1549. https://doi.org/10.1016/j.bbamem.2012.11.019

    Article  CAS  PubMed  Google Scholar 

  31. Klugbauer N, Marais E, Hofmann F (2003) Calcium channel alpha2delta subunits: differential expression, function, and drug binding. J Bioenerg Biomembr 35:639–647

    Article  CAS  Google Scholar 

  32. Yoshida S, Yashar BM, Hiriyanna S, Swaroop A (2002) Microarray analysis of gene expression in the aging human retina. Investig Ophthalmol Vis Sci 43:2554–2560

    Google Scholar 

  33. Klugbauer N, Lacinová L, Marais E, Hobom M, Hofmann F (1999) Molecular diversity of the calcium channel alpha2delta subunit. J Neurosci 19:684–691

    Article  CAS  Google Scholar 

  34. Barclay J, Balaguero N, Mione M, Ackerman SL, Letts VA, Brodbeck J, Canti C, Meir A, Page KM, Kusumi K, Perez-Reyes E, Lander ES, Frankel WN, Gardiner RM, Dolphin AC, Rees M (2001) Ducky mouse phenotype of epilepsy and ataxia is associated with mutations in the Cacna2d2 gene and decreased calcium channel current in cerebellar Purkinje cells. J Neurosci 21:6095–6104

    Article  CAS  Google Scholar 

  35. Huang J, Zhou L, Wang H, Luo J, Zeng L, Xiong K, Chen D (2013) Distribution of thrombospondins and their neuronal receptor α2δ1 in the rat retina. Exp Eye Res 111:36–49. https://doi.org/10.1016/j.exer.2013.03.012

    Article  CAS  PubMed  Google Scholar 

  36. Nag TC, Wadhwa S (2001) Differential expression of syntaxin-1 and synaptophysin in the developing and adult human retina. J Biosci 26:179–191

    Article  CAS  Google Scholar 

  37. Bech-Hansen NT, Naylor MJ, Maybaum TA, Pearce WG, Koop B, Fishman GA, Mets M, Musarella MA, Boycott KM (1998) Loss-of-function mutations in a calcium-channel alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness. Nat Genet 19:264–267. https://doi.org/10.1038/947

    Article  CAS  PubMed  Google Scholar 

  38. Strom TM, Nyakatura G, Apfelstedt-Sylla E, Hellebrand H, Lorenz B, Weber BH, Wutz K, Gutwillinger N, Rüther K, Drescher B, Sauer C, Zrenner E, Meitinger T, Rosenthal A, Meindl A (1998) An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness. Nat Genet 19:260–263. https://doi.org/10.1038/940

    Article  CAS  PubMed  Google Scholar 

  39. Zeitz C, Kloeckener-Gruissem B, Forster U, Kohl S, Magyar I, Wissinger B, Mátyás G, Borruat FX, Schorderet DF, Zrenner E, Munier FL, Berger W (2006) Mutations in CABP4, the gene encoding the Ca2+-binding protein 4, cause autosomal recessive night blindness. Am J Hum Genet 79:657–667. https://doi.org/10.1086/508067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wycisk KA, Zeitz C, Feil S, Wittmer M, Forster U, Neidhardt J, Wissinger B, Zrenner E, Wilke R, Kohl S, Berger W (2006) Mutation in the auxiliary calcium-channel subunit CACNA2D4 causes autosomal recessive cone dystrophy. Am J Hum Genet 79:973–977. https://doi.org/10.1086/508944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wycisk KA, Budde B, Feil S, Skosyrski S, Buzzi F, Neidhardt J, Glaus E, Nurnberg P, Ruether K, Berger W (2006) Structural and functional abnormalities of retinal ribbon synapses due to Cacna2d4 mutation. Investig Ophthalmol Vis Sci 47:3523–3530. https://doi.org/10.1167/iovs.06-0271

    Article  Google Scholar 

  42. Qin N, Yagel S, Momplaisir ML, Codd EE, D’Andrea MR (2002) Molecular cloning and characterization of the human voltage-gated calcium channel alpha(2)delta-4 subunit. Mol Pharmacol 62:485–496. https://doi.org/10.1124/mol.62.3.485

    Article  CAS  PubMed  Google Scholar 

  43. Haeseleer F, Imanishi Y, Maeda T, Possin DE, Maeda A, Lee A, Rieke F, Palczewski K (2004) Essential role of Ca2+-binding protein 4, a Cav1.4 channel regulator, in photoreceptor synaptic function. Nat Neurosci 7:1079–1087. https://doi.org/10.1038/nn1320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Morgans CW (2001) Localization of the alpha(1F) calcium channel subunit in the rat retina. Investig Ophthalmol Vis Sci 42:2414–2418

    CAS  Google Scholar 

  45. Ba-Abbad R, Arno G, Carss K, Stirrups K, Penkett CJ, Moore AT, Michaelides M, Raymond FL, Webster AR, Holder GE (2016) Mutations in CACNA2D4 cause distinctive retinal dysfunction in humans. Ophthalmology 123(668–671):e662. https://doi.org/10.1016/j.ophtha.2015.09.045

    Article  Google Scholar 

  46. Vergult S, Dheedene A, Meurs A, Faes F, Isidor B, Janssens S, Gautier A, Le Caignec C, Menten B (2015) Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability. Eur J Hum Genet 23:628–632. https://doi.org/10.1038/ejhg.2014.141

    Article  CAS  PubMed  Google Scholar 

  47. Edvardson S, Oz S, Abulhijaa FA, Taher FB, Shaag A, Zenvirt S, Dascal N, Elpeleg O (2013) Early infantile epileptic encephalopathy associated with a high voltage gated calcium channelopathy. J Med Genet 50:118–123. https://doi.org/10.1136/jmedgenet-2012-101223

    Article  CAS  PubMed  Google Scholar 

  48. Pippucci T, Parmeggiani A, Palombo F, Maresca A, Angius A, Crisponi L, Cucca F, Liguori R, Valentino ML, Seri M, Carelli V (2013) A novel null homozygous mutation confirms CACNA2D2 as a gene mutated in epileptic encephalopathy. PLoS ONE 8:e82154. https://doi.org/10.1371/journal.pone.0082154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Butler KM, Holt PJ, Milla SS, da Silva C, Alexander JJ, Escayg A (2018) Epileptic encephalopathy and cerebellar atrophy resulting from compound heterozygous CACNA2D2 variants. Case Rep Genet 2018:6308283. https://doi.org/10.1155/2018/6308283

    Article  PubMed  PubMed Central  Google Scholar 

  50. Punetha J, Karaca E, Gezdirici A, Lamont RE, Pehlivan D, Marafi D, Appendino JP, Hunter JV, Akdemir ZC, Fatih JM, Jhangiani SN, Gibbs RA, Innes AM, Posey JE, Lupski JR (2019) Biallelic CACNA2D2 variants in epileptic encephalopathy and cerebellar atrophy. Ann Clin Transl Neurol 6:1395–1406. https://doi.org/10.1002/acn3.50824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Ophthalmology, The Jikei University School of Medicine, Tokyo, Japan

    Wakana Ninomiya, Kei Mizobuchi, Takaaki Hayashi, Sachiyo Okude, Satoshi Katagiri, Akiko Kubo & Tadashi Nakano

  2. Department of Ophthalmology, Katsushika Medical Center, The Jikei University School of Medicine, 6-41-2 Aoto, Katsushika-ku, Tokyo, 125-8506, Japan

    Takaaki Hayashi

  3. Department of Ophthalmology, Chigasaki Municipal Hospital, Chigasaki, Kanagawa, Japan

    Nami Masuhara

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  1. Wakana Ninomiya
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Correspondence to Takaaki Hayashi.

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Ninomiya, W., Mizobuchi, K., Hayashi, T. et al. Electroretinographic abnormalities associated with pregabalin: a case report. Doc Ophthalmol 140, 279–287 (2020). https://doi.org/10.1007/s10633-019-09743-1

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