Statins in Neuro-Ophthalmology
All content on Eyewiki is protected by copyright law and the Terms of Service. This content may not be reproduced, copied, or put into any artificial intelligence program, including large language and generative AI models, without permission from the Academy.
Medical Therapy
Statins are one of the most prescribed medicines in the United States, and use of statins has significantly increased in recent years [1]. According to the Centers for Disease Control and Prevention (CDC), more than 25% of adults over 40 years of age in the United States use statins [2]. Statins are a class of cholesterol-lowering agents used for dyslipidemia treatment and for reduction of atherosclerotic cardiovascular disease (ASCVD) risk [5]. They have been shown to decrease morbidity as well as mortality in patients who have an increased risk of ASCVD [5]. Although statins are safe for the vast majority of patients to use, they are associated with some adverse effects [6]. In this article, we will discuss adverse effects of statins in both a general context and in the context of neuro-ophthalmology. In addition, we will discuss potential therapeutic benefits of statins in neuro-ophthalmologic conditions.
Indications and Contraindications
Statins are used adjunctively with diet and exercise to lower total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) concentrations while also increasing high-density lipoprotein cholesterol (HDL-C) concentration[7]. They are used in primary prevention as well as secondary prevention of ASCVD events. In addition, statins are useful for the management of various dyslipidemias such as familial hypercholesterolemia, familial combined hyperlipidemia, familial dysbetalipoproteinemia, and familial hypertriglyceridemia. [7]. Selection of a stain should be based on pharmacokinetic profiles, patient-specific characteristics, and the AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. [8].
Contraindications to statins may include hypersensitivity to medication and acute liver failure or decompensated cirrhosis [7].
Clinical Pharmacology
Statins have been reported to reduce cardiovascular events and mortality in patients at low, intermediate, and high cardiovascular risk [3] and act by inhibiting HMG-CoA reductase, an enzyme that catalyzes a crucial step of cholesterol biosynthesis called the mevalonate pathway [4]. Inhibition of HMG-CoA reductase limits biosynthesis of cholesterol and decreases hepatic cholesterol concentrations [4]. This decrease in hepatic cholesterol concentration results in increased expression of LDL receptors in liver cell membranes which allows for enhanced clearance of circulating LDL cholesterol from the blood [4]. Statins primarily target the liver, however, they are also associated with pleiotropic effects [9]. These pleiotropic effects are a result of the ability of statins to inhibit the biosynthesis of isoprenoid intermediates in the mevalonate pathway. Isoprenoids are lipid attachments for intracellular proteins involved in signal transduction and cell growth. [10]. Inhibition of isoprenoid intermediate biosynthesis leads to altered production of pro-inflammatory cytokines and reactive oxygen species, atherosclerotic plaque stability, platelet reactivity, expression of endothelial nitric oxide synthase, and development of cardiac hypertrophy and fibrosis.
Statins are metabolized by enzymes in cytochrome P450--mediated metabolism. The majority of statins such as atorvastatin, simvastatin, and lovastatin are substrates of CYP3A4, and numerous interactions involving CYP3A4-mediated metabolism have been reported [12]. Fluvastatin is uniquely metabolized by CYP2C29 [13] and pravastatin and rosuvastatin are not susceptible to drug-drug interactions mediated by P450 metabolism [12, 14, 15].
Adverse Reactions
Neuromuscular Symptoms
After the use of statins, some patients have reported neuromuscular symptoms including cramps, myalgia, immune-mediated necrotizing myopathy, and rhabdomyolysis [16]. Statin-associated muscle symptoms (SAMS) are the primary statin side effects associated with discontinuation of therapy [17,18]. 10 to 25% of patients on statin therapy report SAMS [18]. Numerous mechanisms such as gene regulation and polymorphisms, mitochondrial dysfunction, the HMG-CoA Reductase pathway, protein prenylation and coenzyme Q10, and atrogin-1 calcium signaling and glycine amidinotransferase have been proposed, however, none of them have been proven as a direct underlying cause [18].
Myasthenia Gravis
Myasthenia gravis is a chronic autoimmune condition that involves antibodies against acetylcholine receptors or other neuromuscular junction targets. The main symptom is fatigable weakness, however, involvement of extraocular muscles and the levator palpebrae are typically seen at some point throughout the disease course [24]. A recent disproportionality analysis of 184,284 cases of adverse effects related to statins from a World Health Organization-associated pharmacovigilance global database found 169 suspected cases of statin-induced myasthenia gravis from 3967 reports mentioning myasthenia gravis [25]. Case reports have also documented ocular myasthenia gravis including both de novo seropositive cases as well as disease relapse from long-term remission [25]. Although the exact pathogenesis is unknown, one proposed mechanism is believed to be related to the immunomodulatory effects of statins. In experimental animal studies, statins have been shown to upregulate Th2 secretion of cytokines that stimulate the anti-acetylcholine receptor response [26, 27].
Insulin Resistance
Studies have suggested that statins can increase the risk of type 2 diabetes [19]. Meta-analyses of statin trials report an increased risk of diabetes by 9-12% and large population studies report an even higher risk [19, 20, and 21]. Statins have been found to contribute to development of type 2 diabetes in mice [23]. A meta-analysis found that when effects of all statin types are pooled together, HbA1c was significantly increased in individuals with normal HbA1c [22]. This meta-analysis also found that in individuals with high HbA1c levels above 6.5%, only atorvastatin was associated with a significant increase [22]. Numerous studies have published findings of an association between statins with insulin resistance in adipose tissue, skeletal muscle, and the liver however the mechanism by which this occurs is unknown [19].
Potential Therapeutic Benefits
Multiple Sclerosis
Multiple sclerosis (MS) is a central nervous system disorder characterized by inflammatory demyelinating lesions that affect grey and white matter. Afferent and efferent visual pathways can become involved, and optic neuritis is the most common ocular symptom [25]. Although there is limited evidence, some trials have shown that statin therapy may reduce visual symptoms of MS. Treatment with 80 mg of simvastatin per day for six months significantly decreased visual evoked potential latency and increased amplitude. In addition, this treatment was found to improve contrast sensitivity, color perception, and self-evaluated visual function, which suggests that simvastatin is both well tolerated and possibly beneficial for patients experiencing acute optic neuritis [29]. Another trial has reported that 80 mg of simvastatin significantly decreased the yearly rate of whole-brain atrophy in patients with secondary progressive MS as compared to the placebo group [30]. However, other trials have found that statin therapy did not significantly change brain atrophy rates or the number of gadolinium-enhancing lesions [25]. Although evidence is limited and varied, the literature suggests that statins may be a beneficial treatment for individuals with MS.
Migraine
Migraine is characterized by severe, throbbing unilateral headaches with associated nausea, vomiting, photophobia, and phonophobia [31]. About ⅓ of patients with migraines experience aura before the headache. In patients who experience aura, over 90% experience visual aura in particular that is characterized by spark photopsia, scotoma, or teichopsia [32]. Other visual symptoms experienced by patients with migraines that are not diagnostic of aura include undulations, shimmering, or heat waves [33]. The mechanism behind migraine is not clear, and treatments are limited, however, it may be influenced by dyslipidemia and genetic factors [34]. Evidence suggests that individuals migraineurs have increased cardiovascular risk profiles with elevated total cholesterol levels and increased total/high-density lipoprotein C ratio [35]. Studies have suggested that three months of statin therapy can potentially be effective in migraine prophylaxis [25, 36]. However, statin therapy has also been implicated in migraine pathogenesis due to its ability to reduce circulating CoQ10 concentrations and induce mitochondrial dysfunction [37]. Overall, statins show potential but lack evidence for migraine management. However, a recent Mendelian Randomization analysis was able to offer causal insight into genetically predicted lipid traits, drug targets, and migraine association risk and found that the use of genetic proxies for HMG-CoA reductase inhibition resulted in a significant association with decreased migraine risk [34]. Further investigation needs to be done, however, this finding indicates that statins may be a promising drug target for migraine treatment.
Giant Cell Arteritis
Giant cell arteritis [GCA] is an ophthalmic emergency that can cause irreversible vision loss. It is an immune-mediated systemic granulomatous vasculitis that affects medium and large-sized arteries [38]. Statins may benefit GCA patients due to their ability to modulate immune responses [25] and have been shown to lower erythrocyte sedimentation rate and downregulate IL-16 and IL-17. However, they do not impact vision-related outcomes [39, 25]. In comparison to patients who don’t use statins, statin users do not exhibit significant reductions in acute visual ischemic complications [40]. Stroke Prevention Recently, the literature has reported that statins may significantly reduce cerebrovascular event occurrence [41], but preventative effects of statins are still uncertain. In a meta-analysis that looked at mortality rate, incidence, and recurrence rate of patients in a prevention group and control group, it was found that statins could possibly reduce the risk of stroke recurrence, but there were no significant correlations with mortality and morbidity of stroke patients [41]. Another meta-analysis that analyzed 11 RCTs and 12 cohort studies independently found that statins were associated with significantly reduced stroke recurrence risk of any stroke subtype [42].
Subarachnoid Hemorrhage
Aneurysmal subarachnoid hemorrhage (aSAH) is characterized by infiltration of blood into the subarachnoid space as the result of an intracranial aneurysm [45]. Complications of aSAH include cerebral ischemia, bacterial meningitis, cephaledema, seizure, hydrocephalus, and vasospasm [46, 47]. Because of their pleiotropic effects, it has been hypothesized that statins may aid in alleviating vasospasm and improving outcomes post-aSAH. A study retrospectively compared the frequency and severity of vasospasm, outcomes, and fatigue post-aSAH in patients with pre-ictal and continued statin use and found that patients with pre-ictal and continued statin use show a reduced occurrence of radiological/sonological and symptomatic vasospasm, shorter lengths of stay, more favorable functional outcomes, and lower fatigue levels. However, mortality levels were similar to the non-statin group [47]. A meta-analysis evaluated the efficacy of statins in aSAH-induced vasospasm, delayed cerebral ischemia, mortality, disability, neurological prognosis, and adverse events. The findings from this meta-analysis show that statins reduced cerebral vasospasm, mortality, delayed cerebral ischemia, and delayed ischemic neurologic deficit in patients post-aSAH. [48]. The mechanisms behind these beneficial effects are not clear, and more studies need to be done in order to better understand the potential benefits of statins in relation to aSAH outcomes.
Alzheimer’s Disease
Alzheimer’s disease is a neurodegenerative disorder that causes progressive memory loss, personality changes, and decreased ability to perform activities of daily functioning [49]. Visual symptoms of Alzheimer’s may include visual field defects, depressed contrast sensitivities, prolonged VEP, abnormal eye movement recordings, problems with color and stereoacuity, constructional and visuoperceptual abnormalities, visual agnosia, spatial agnosia and Balint’s syndrome, visual hallucinations, environmental disorientation, and facial identification problems [25]. It is postulated that statins may be effective in the treatment of Alzheimer’s due to their ability to lower cholesterol and/or their pleiotropic functions. Some proposed mechanisms include activation of the heme oxygenase/biliverdin reductase system in the brain [49] as well as modulation of the phosphorylation of tau and Aβ [25]. Effects of statins pertaining to visual-motor function in Alzheimer’s Disease is currently lacking and has only been studied in at-risk individuals [25].
Parkinson’s Disease
Parkinson’s disease (PD) is a neurodegenerative disease that develops as a result of dopaminergic neuron loss in the substantia nigra as well as subsequent dopamine deficiency in the putamen and caudate nucleus [51]. Visual symptoms can occur as a part of the sensory dysfunction caused by PD, and it is likely that these symptoms are due to a combination of motor disorders of ocular motility with disorders of visual perception and dopaminergic denervation of amacrine retinal cells [52]. The notion that statin therapy may be neuroprotective in PD is controversial, for although the literature contains findings that point to statins protecting against the development of PD, other findings show that they may be harmful and actually increase the risk of PD development [51]. A review that aimed to further clarify the role of statins in PD and analyzed the pros and cons of statins in PD states that a protective role could be present as the result of modulation of inflammatory, lysosomal signaling pathways, and microglia activation [51], however it also states that long-term statin use may increase risk of developing PD by mechanisms such as reduction of CoQ10. The effects of statins on visual symptoms associated with PD have not been studied at this time [25].
Neuromyelitis Optica
Neuromyelitis optica spectrum disorder (NMOSD) is a severe autoimmune disease of the CNS secondary to pathogenic autoantibodies to aquaporin-4, the most abundant water channel in the CNS [25, 53]. Although no RCTs have been done to investigate statin usage in NMOSD, potential pleiotropic benefits have recently been investigated in vitro pertaining to vasculocentric deposition of activated complement in human tissues affected by NMOSD [25]. This investigation has shown that atorvastatin, simvastatin, lovastatin, and fluvastatin increase expression of complement regulator protein CD55 in primary cultures [54]. However, there are also potential risks of statin therapy in NMOSD patients, for they could potentially lead to remyelination inhibition due to their effects on cholesterol biosynthesis [25, 55].
Ocular Disorders
A recent systematic review of RCTS assessed the association of ocular disorders such as cataracts, glaucoma, age-related macular disease, glaucoma, diabetic retinopathy, dry eye, and uveitis with statin therapy [43]. Because statins are able to reduce pro-inflammatory cytokines, it is believed that they may be able to minimize inflammation-mediated tissue damage in wet AMD, dry eye disease, uveitis, and diabetic retinopathy. Results of this systematic review also support the idea that statins may be able to minimize complications of diabetic retinopathy by interfering with retinal vessels and/or by reducing hard exudates [43]. Another meta-analysis showed that statin therapy was associated with a reduced risk of proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, and diabetic macular edema [44]. However, additional research needs to be done to provide more robust conclusions and definite answers regarding the role statins may play in the treatment of ocular disorders.
Conclusion
In addition to effectively treating dyslipidemia and lowering ASCVD risk, increasing evidence suggests that statins may be beneficial to specific neuro-ophthalmological conditions [25]. However, more research needs to be done in order to better establish potential benefits and to better understand effects on visual outcomes. Although further studies need to be conducted, providers should be aware that co-existing benefits for neuro-ophthalmological conditions may exist when prescribing statins. In addition, providers should be aware of possible adverse effects and continue to be cautious when prescribing statins to patients who have neuromuscular disorders.
References
1. Salami JA, Warraich H, Valero-Elizondo J, et al. National Trends in Statin Use and Expenditures in the US Adult Population From 2002 to 2013: Insights From the Medical Expenditure Panel Survey. JAMA Cardiol. 2017;2(1):56-65. doi:10.1001/jamacardio.2016.4700
2. Gu Q, Paulose-Ram R, Burt VL, Kit BK. Prescription cholesterol-lowering medication use in adults aged 40 and over: United States, 2003-2012. NCHS Data Brief. 2014;(177):1-8.
3. Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380(9841):581-590. doi:10.1016/S0140-6736(12)60367-5
4. Sirtori CR. The pharmacology of statins. Pharmacological Research. 2014;88:3-11. doi:https://doi.org/10.1016/j.phrs.2014.03.002
5. Sadowska A, Osiński P, Roztocka A, et al. Statins-From Fungi to Pharmacy. Int J Mol Sci. 2023;25(1):466. Published 2023 Dec 29. doi:10.3390/ijms25010466
6. Ramkumar S, Raghunath A, Raghunath S. Statin Therapy: Review of Safety and Potential Side Effects. Acta Cardiol Sin. 2016;32(6):631-639. doi:10.6515/acs20160611a
7. Bansal AB, Cassagnol M. HMG-CoA Reductase Inhibitors. PubMed. Published 2022. https://www.ncbi.nlm.nih.gov/books/NBK542212/#article-22953.s2
8. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published correction appears in Circulation. 2019 Jun 18;139(25):e1182-e1186. doi: 10.1161/CIR.0000000000000698] [published correction appears in Circulation. 2023 Aug 15;148(7):e5. doi: 10.1161/CIR.0000000000001172]. Circulation. 2019;139(25):e1082-e1143. doi:10.1161/CIR.0000000000000625
9. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation. 2004;109(23 Suppl 1):III39-III43. doi:10.1161/01.CIR.0000131517.20177.5a
10. Campbell WW. Statin myopathy: the iceberg or its tip?. Muscle Nerve. 2006;34(4):387-390. doi:10.1002/mus.20603
11. Oesterle A, Laufs U, Liao JK. Pleiotropic Effects of Statins on the Cardiovascular System [published correction appears in Circ Res. 2018 Sep 28;123(8):e20. doi: 10.1161/RES.0000000000000228]. Circ Res. 2017;120(1):229-243. doi:10.1161/CIRCRESAHA.116.308537
12. Shitara Y, Sugiyama Y. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: Drug–drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacology & Therapeutics. 2006;112(1):71-105. doi:https://doi.org/10.1016/j.pharmthera.2006.03.003
13. Transon C, Leemann T, Dayer P. In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors. European Journal of Clinical Pharmacology. 1996;50(3):209-215. doi:https://doi.org/10.1007/s002280050094
14. White CM. A Review of the Pharmacologic and Pharmacokinetic Aspects of Rosuvastatin. The Journal of Clinical Pharmacology. 2002;42(9):963-970. doi:https://doi.org/10.1177/009127000204200902
15. Hatanaka T. Clinical pharmacokinetics of pravastatin: mechanisms of pharmacokinetic events. Clinical Pharmacokinetics. 2000;39(6):397-412. doi:https://doi.org/10.2165/00003088-200039060-00002
16. Attardo S, Musumeci O, Velardo D, Toscano A. Statins Neuromuscular Adverse Effects. Int J Mol Sci. 2022;23(15):8364. Published 2022 Jul 28. doi:10.3390/ijms23158364
17. Alonso R, Cuevas A, Cafferata A. Diagnosis and Management of Statin Intolerance. J Atheroscler Thromb. 2019;26(3):207-215. doi:10.5551/jat.RV17030
18. Vinci P, Panizon E, Tosoni LM, et al. Statin-Associated Myopathy: Emphasis on Mechanisms and Targeted Therapy. Int J Mol Sci. 2021;22(21):11687. Published 2021 Oct 28. doi:10.3390/ijms222111687
19. Laakso M, Fernandes Silva L. Statins and risk of type 2 diabetes: mechanism and clinical implications. Front Endocrinol (Lausanne). 2023;14:1239335. Published 2023 Sep 19. doi:10.3389/fendo.2023.1239335
20. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735-742. doi:10.1016/S0140-6736(09)61965-6
21. Thakker D, Nair S, Pagada A, Jamdade V, Malik A. Statin use and the risk of developing diabetes: a network meta-analysis. Pharmacoepidemiol Drug Saf. 2016;25(10):1131-1149. doi:10.1002/pds.4020
22. Alvarez-Jimenez L, Morales-Palomo F, Moreno-Cabañas A, Ortega JF, Mora-Rodríguez R. Effects of statin therapy on glycemic control and insulin resistance: A systematic review and meta-analysis. Eur J Pharmacol. 2023;947:175672. doi:10.1016/j.ejphar.2023.175672
23. Wang HJ, Park JY, Kwon O, et al. Chronic HMGCR/HMG-CoA reductase inhibitor treatment contributes to dysglycemia by upregulating hepatic gluconeogenesis through autophagy induction. Autophagy. 2015;11(11):2089-2101. doi:10.1080/15548627.2015.1091139
24. Estephan EP, Baima JPS, Zambon AA. Myasthenia gravis in clinical practice. Arq Neuropsiquiatr. 2022;80(5 Suppl 1):257-265. doi:10.1590/0004-282X-ANP-2022-S105
25. Tan A, Fraser C, Khoo P, Watson S, Ooi K. Statins in Neuro-ophthalmology. Neuroophthalmology. 2020;45(4):219-237. Published 2020 Jun 24. doi:10.1080/01658107.2020.1755872
26. Youssef S, Stüve O, Patarroyo JC, et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature. 2002;420(6911):78-84. doi:10.1038/nature01158
27. Conti-Fine BM, Milani M, Wang W. CD4+ T cells and cytokines in the pathogenesis of acquired myasthenia gravis. Ann N Y Acad Sci. 2008;1132:193-209. doi:10.1196/annals.1405.042
28. Travers BS, Tsang BK, Barton JL. Multiple sclerosis: Diagnosis, disease-modifying therapy and prognosis. Aust J Gen Pract. 2022;51(4):199-206. doi:10.31128/AJGP-07-21-6103
29. Tsakiri A, Kallenbach K, Fuglø D, Wanscher B, Larsson H, Frederiksen J. Simvastatin improves final visual outcome in acute optic neuritis: a randomized study. Mult Scler. 2012;18(1):72-81. doi:10.1177/1352458511415452
30. Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet. 2014;383(9936):2213-2221. doi:10.1016/S0140-6736(13)62242-4
31. Khan J, Asoom LIA, Sunni AA, et al. Genetics, pathophysiology, diagnosis, treatment, management, and prevention of migraine. Biomed Pharmacother. 2021;139:111557. doi:10.1016/j.biopha.2021.111557
32. Russell MB, Olesen J. A nosographic analysis of the migraine aura in a general population. Brain. 1996;119 ( Pt 2):355-361. doi:10.1093/brain/119.2.355
33. Dodick DW. Migraine. Lancet. 2018;391(10127):1315-1330. doi:10.1016/S0140-6736(18)30478-1
34. Bi Y, Zhu Y, Tang S, Huang Y. Lipids, lipid-modifying drug target genes and migraine: a Mendelian randomization study. J Headache Pain. 2023;24(1):112. Published 2023 Aug 18. doi:10.1186/s10194-023-01633-x
35. Scher AI, Terwindt GM, Picavet HS, Verschuren WM, Ferrari MD, Launer LJ. Cardiovascular risk factors and migraine: the GEM population-based study. Neurology. 2005;64(4):614-620. doi:10.1212/01.WNL.0000151857.43225.49
36. Medeiros FL, Medeiros PL, Valença MM, Dodick D. Simvastatin for migraine prevention. Headache. 2007;47(6):855-856. doi:10.1111/j.1526-4610.2007.00824.x
37. Qu H, Meng YY, Chai H, et al. The effect of statin treatment on circulating coenzyme Q10 concentrations: an updated meta-analysis of randomized controlled trials. Eur J Med Res. 2018;23(1):57. Published 2018 Nov 10. doi:10.1186/s40001-018-0353-6
38. Hayreh SS. Giant cell arteritis: Its ophthalmic manifestations. Indian J Ophthalmol. 2021;69(2):227-235. doi:10.4103/ijo.IJO_1681_20
39. Hegg R, Lee AG, Tagg NT, Zimmerman MB. Statin or nonsteroidal anti-inflammatory drug use is associated with lower erythrocyte sedimentation rate in patients with giant cell arteritis. J Neuroophthalmol. 2011;31(2):135-138. doi:10.1097/WNO.0b013e31820c4421
40. García-Martínez A, Hernández-Rodríguez J, Grau JM, Cid MC. Treatment with statins does not exhibit a clinically relevant corticosteroid-sparing effect in patients with giant cell arteritis. Arthritis Rheum. 2004;51(4):674-678. doi:10.1002/art.20541
41. San X, Lv Z, Xu P, Wang J, Lan T. The prevention of stroke by statins: A meta-analysis. Medicine (Baltimore). 2022;101(38):e30606. doi:10.1097/MD.0000000000030606
42. Yin Y, Zhang L, Marshall I, Wolfe C, Wang Y. Statin Therapy for Preventing Recurrent Stroke in Patients with Ischemic Stroke: A Systematic Review and Meta-Analysis of Randomized Controlled Trials and Observational Cohort Studies. Neuroepidemiology. 2022;56(4):240-249. doi:10.1159/000525672
43. Lymperopoulou C, Kandarakis SA, Tzanaki I, Mylona I, Xanthos T, Agouridis AP. The Effect of Statins on Ocular Disorders: A Systematic Review of Randomized Controlled Trials. Pharmaceuticals (Basel). 2023;16(5):711. Published 2023 May 7. doi:10.3390/ph16050711
44. Ooi KG, Khoo P, Vaclavik V, Watson SL. Statins in ophthalmology. Surv Ophthalmol. 2019;64(3):401-432. doi:10.1016/j.survophthal.2019.01.013 44. Pranata R, Vania R, Victor AA. Statin reduces the incidence of diabetic retinopathy and its need for intervention: A systematic review and meta-analysis. Eur J Ophthalmol. 2021;31(3):1216-1224. doi:10.1177/1120672120922444
45. Chen TF, Chen KW, Chien Y, et al. Dental Pulp Stem Cell-Derived Factors Alleviate Subarachnoid Hemorrhage-Induced Neuroinflammation and Ischemic Neurological Deficits. Int J Mol Sci. 2019;20(15):3747. Published 2019 Jul 31. doi:10.3390/ijms20153747
46. He J, Zhang L, Yu Y, et al. Effects of clazosentan, cilostazol, and statins on aneurysmal subarachnoid hemorrhage: A protocol for systematic review and meta-analysis. Medicine (Baltimore). 2020;99(17):e19902. doi:10.1097/MD.0000000000019902
47. Andersen S, Western E, Sorteberg W, Sorteberg A. The impact of pre-ictal statin use on vasospasm and outcome in aneurysmal subarachnoid hemorrhage. Acta Neurochir (Wien). 2023;165(11):3325-3338. doi:10.1007/s00701-023-05812-2
48. Shen J, Shen J, Zhu K, Zhou H, Tian H, Yu G. Efficacy of Statins in Cerebral Vasospasm, Mortality, and Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. World Neurosurg. 2019;131:e65-e73. doi:10.1016/j.wneu.2019.07.016
49. Barone E, Di Domenico F, Butterfield DA. Statins more than cholesterol lowering agents in Alzheimer disease: their pleiotropic functions as potential therapeutic targets. Biochem Pharmacol. 2014;88(4):605-616. doi:10.1016/j.bcp.2013.10.030
50. Al-Kuraishy HM, Al-Gareeb AI, Alexiou A, et al. Pros and cons for statins use and risk of Parkinson's disease: An updated perspective [published correction appears in Pharmacol Res Perspect. 2024 Jun;12(3):e1221. doi: 10.1002/prp2.1221]. Pharmacol Res Perspect. 2023;11(2):e01063. doi:10.1002/prp2.1063
51. Poewe W, Seppi K, Tanner CM, et al. Parkinson disease. Nat Rev Dis Primers. 2017;3:17013. Published 2017 Mar 23. doi:10.1038/nrdp.2017.13
52. Sauerbier A, Ray Chaudhuri K. Parkinson’s disease and vision. Basal Ganglia. 2013;3(3):159-163. doi:https://doi.org/10.1016/j.baga.2013.05.002
53. Kümpfel T, Giglhuber K, Aktas O, et al. Update on the diagnosis and treatment of neuromyelitis optica spectrum disorders (NMOSD) - revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part II: Attack therapy and long-term management [published correction appears in J Neurol. 2024 Jun;271(6):3702-3707. doi: 10.1007/s00415-024-12288-2]. J Neurol. 2024;271(1):141-176. doi:10.1007/s00415-023-11910-z
54. Tradtrantip L, Duan T, Yeaman MR, Verkman AS. CD55 upregulation in astrocytes by statins as potential therapy for AQP4-IgG seropositive neuromyelitis optica. J Neuroinflammation. 2019;16(1):57. Published 2019 Mar 9. doi:10.1186/s12974-019-1448-x
55. Klopfleisch S, Merkler D, Schmitz M, et al. Negative impact of statins on oligodendrocytes and myelin formation in vitro and in vivo. J Neurosci. 2008;28(50):13609-13614. doi:10.1523/JNEUROSCI.2765-08.2008
