Abstract
The numbers of patients with dementia and patients with epilepsy are increasing in the global population. In fact, these two conditions are related, and it is estimated that at least 5–10% of seizures or epilepsy in older individuals (aged > 60 years) are caused by a neurodegenerative dementia. In the vast majority, one of the four following diseases is involved: Alzheimer’s disease, Lewy body dementia, frontotemporal dementia, or vascular dementia. These diseases cause, not only seizures or epilepsy in affected patients, but cognitive, behavioral, and motor disorders as well. As a result, the challenges of treating seizures in older patients with neurodegenerative disease go beyond the usual limitations associated with this age group (i.e., lower fluid compartment, lower protein binding, increased risk of drug–drug interactions) by imposing other issues and pitfalls. In this setting, the drug-related potential aggravation of neurodegenerative symptoms must be taken into account. As cognition is particularly vulnerable, the prescription of antiseizure medications in dementia must consider the potential neurocognitive impact and limit it as much as possible. Consequently, the choice of a treatment for seizures in this age group is even more demanding than in younger patients, and therefore more restricted. Based on current but limited evidence, it appears that second-generation antiseizure medications are more likely to be appropriate for the management of older patients with epilepsy with neurodegenerative disease given their more favorable pharmacokinetic profiles. Nevertheless, even newer antiseizure medications are not devoid of any risks, which can however be anticipated and corrected.
Similar content being viewed by others
References
Brodie MJ, Elder AT, Kwan P. Epilepsy in later life. Lancet Neurol. 2009;8(11):1019–30. https://doi.org/10.1016/S1474-4422(09)70240-6.
Sen A, Jette N, Husain M, Sander JW. Epilepsy in older people. Lancet. 2020;395(10225):735–48. https://doi.org/10.1016/S0140-6736(19)33064-8.
Tallis R, Hall G, Craig I, Dean A. How common are epileptic seizures in old age? Age Ageing. 1991;20(6):442–8. https://doi.org/10.1093/ageing/20.6.442.
Hesdorffer DC, Logroscino G, Benn EK, Katri N, Cascino G, Hauser WA. Estimating risk for developing epilepsy: a population-based study in Rochester, Minnesota. Neurology. 2011;76(1):23–7. https://doi.org/10.1212/WNL.0b013e318204a36a.
Olafsson E, Ludvigsson P, Gudmundsson G, Hesdorffer D, Kjartansson O, Hauser WA. Incidence of unprovoked seizures and epilepsy in Iceland and assessment of the epilepsy syndrome classification: a prospective study. Lancet Neurol. 2005;4(10):627–34. https://doi.org/10.1016/S1474-4422(05)70172-1.
GBD 2016 Epilepsy Collaborators. Global, regional, and national burden of epilepsy, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016 [published correction appears in Lancet Neurol. 2019 May;18(5):e4]. Lancet Neurol. 2019;18(4):357–75. https://doi.org/10.1016/S1474-4422(18)30454-X.
Faught E, Richman J, Martin R, et al. Incidence and prevalence of epilepsy among older U.S. Medicare beneficiaries. Neurology. 2012;78(7):448–53. https://doi.org/10.1212/WNL.0b013e3182477edc.
Ip Q, Malone DC, Chong J, Harris RB, Labiner DM. An update on the prevalence and incidence of epilepsy among older adults. Epilepsy Res. 2018;139:107–12. https://doi.org/10.1016/j.eplepsyres.2017.11.022.
Beghi E, Giussani G. Aging and the epidemiology of epilepsy. Neuroepidemiology. 2018;51(3–4):216–23. https://doi.org/10.1159/000493484.
GBD 2016 Dementia Collaborators. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(1):88–106. https://doi.org/10.1016/S1474-4422(18)30403-4.
Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia. 1993;34(3):453–68. https://doi.org/10.1111/j.1528-1157.1993.tb02586.x.
Friedman D, Honig LS, Scarmeas N. Seizures and epilepsy in Alzheimer’s disease. CNS Neurosci Ther. 2012;18(4):285–94. https://doi.org/10.1111/j.1755-5949.2011.00251.x.
Stefan H. Epilepsy in the elderly: facts and challenges. Acta Neurol Scand. 2011;124(4):223–7. https://doi.org/10.1111/j.1600-0404.2010.01464.x.
Subota A, Pham T, Jetté N, Sauro K, Lorenzetti D, Holroyd-Leduc J. The association between dementia and epilepsy: a systematic review and meta-analysis. Epilepsia. 2017;58(6):962–72. https://doi.org/10.1111/epi.13744.
Sarkis RA, Dickerson BC, Cole AJ, Chemali ZN. Clinical and neurophysiologic characteristics of unprovoked seizures in patients diagnosed with dementia. J Neuropsychiatry Clin Neurosci. 2016;28(1):56–61. https://doi.org/10.1176/appi.neuropsych.15060143.
Dementia: not all about Alzheimer’s. Lancet. 2015;386(10004):1600. https://doi.org/10.1016/S0140-6736(15)00672-8.
Hesdorffer DC, Hauser WA, Annegers JF, Kokmen E, Rocca WA. Dementia and adult-onset unprovoked seizures. Neurology. 1996;46(3):727–30. https://doi.org/10.1212/wnl.46.3.727.
Beagle AJ, Darwish SM, Ranasinghe KG, La AL, Karageorgiou E, Vossel KA. Relative incidence of seizures and myoclonus in Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia. J Alzheimers Dis. 2017;60(1):211–23. https://doi.org/10.3233/JAD-170031.
Rao SC, Dove G, Cascino GD, Petersen RC. Recurrent seizures in patients with dementia: frequency, seizure types, and treatment outcome. Epilepsy Behav. 2009;14(1):118–20. https://doi.org/10.1016/j.yebeh.2008.08.012.
Cretin B, Blanc F, Gaultier C, Sellal F. Epileptic amnesic syndrome revealing Alzheimer’s disease. Epilepsy Res. 2012;102(3):206–9. https://doi.org/10.1016/j.eplepsyres.2012.08.002.
Vossel KA, Beagle AJ, Rabinovici GD, et al. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol. 2013;70(9):1158–66. https://doi.org/10.1001/jamaneurol.2013.136.
Lozsadi DA, Larner AJ. Prevalence and causes of seizures at the time of diagnosis of probable Alzheimer’s disease. Dement Geriatr Cogn Disord. 2006;22(2):121–4. https://doi.org/10.1159/000093664.
Cretin B, Sellal F, Philippi N, et al. Epileptic prodromal Alzheimer’s disease, a retrospective study of 13 new cases: expanding the spectrum of Alzheimer’s disease to an epileptic variant? J Alzheimers Dis. 2016;52(3):1125–33. https://doi.org/10.3233/JAD-150096.
Arnaldi D, Donniaquio A, Mattioli P, et al. Epilepsy in neurodegenerative dementias: a clinical, epidemiological, and EEG study. J Alzheimers Dis. 2020;74(3):865–74. https://doi.org/10.3233/JAD-191315.
DiFrancesco JC, Tremolizzo L, Polonia V, et al. Adult-onset epilepsy in presymptomatic Alzheimer’s disease: a retrospective study. J Alzheimers Dis. 2017;60(4):1267–74. https://doi.org/10.3233/JAD-170392.
Costa C, Romoli M, Liguori C, et al. Alzheimer’s disease and late-onset epilepsy of unknown origin: two faces of beta amyloid pathology. Neurobiol Aging. 2019;73:61–7. https://doi.org/10.1016/j.neurobiolaging.2018.09.006.
Hauser WA, Morris ML, Heston LL, Anderson VE. Seizures and myoclonus in patients with Alzheimer’s disease. Neurology. 1986;36(9):1226–30. https://doi.org/10.1212/wnl.36.9.1226.
Sherzai D, Losey T, Vega S, Sherzai A. Seizures and dementia in the elderly: nationwide inpatient sample 1999–2008. Epilepsy Behav. 2014;36:53–6. https://doi.org/10.1016/j.yebeh.2014.04.015.
Zelano J, Brigo F, Garcia-Patek S. Increased risk of epilepsy in patients registered in the Swedish Dementia Registry. Eur J Neurol. 2020;27(1):129–35. https://doi.org/10.1111/ene.14043.
Baker J, Libretto T, Henley W, Zeman A. The prevalence and clinical features of epileptic seizures in a memory clinic population. Seizure. 2019;71:83–92. https://doi.org/10.1016/j.seizure.2019.06.016.
Cretin B, Philippi N, Bousiges O, et al. Do we know how to diagnose epilepsy early in Alzheimer’s disease? Rev Neurol (Paris). 2017;173(6):374–80. https://doi.org/10.1016/j.neurol.2017.03.028.
Vöglein J, Ricard I, Noachtar S, et al. Seizures in Alzheimer’s disease are highly recurrent and associated with a poor disease course. J Neurol. 2020. https://doi.org/10.1007/s00415-020-09937-7.2020(Epub 2 Jun 2020).
Imfeld P, Bodmer M, Schuerch M, Jick SS, Meier CR. Seizures in patients with Alzheimer’s disease or vascular dementia: a population-based nested case-control analysis. Epilepsia. 2013;54(4):700–7. https://doi.org/10.1111/epi.12045.
Gasparini S, Ferlazzo E, Beghi E, et al. Epilepsy associated with Leukoaraiosis mainly affects temporal lobe: a casual or causal relationship? Epilepsy Res. 2015;109:1–8. https://doi.org/10.1016/j.eplepsyres.2014.10.012.
Johnson EL, Krauss GL, Lee AK, et al. Association between white matter hyperintensities, cortical volumes, and late-onset epilepsy. Neurology. 2019;92(9):e988–95. https://doi.org/10.1212/WNL.0000000000007010.
Choi H, Pack A, Elkind MS, Longstreth WT Jr, Ton TG, Onchiri F. Predictors of incident epilepsy in older adults: the Cardiovascular Health Study. Neurology. 2017;88(9):870–7. https://doi.org/10.1212/WNL.0000000000003662.
Cretin B, Philippi N, Dibitonto L, Blanc F. Epilepsy at the prodromal stages of neurodegenerative diseases. Geriatr Psychol Neuropsychiatr Vieil. 2017;15(1):75–82. https://doi.org/10.1684/pnv.2017.0652.
Ukai K, Watanabe M. Transient epileptic amnesia accompanied by prodromal symptoms of dementia with Lewy bodies: the second case report in the literature. Psychogeriatrics. 2019;19(6):622–3. https://doi.org/10.1111/psyg.12434.
Marawar R, Wakim N, Albin RL, Dodge H. Seizure occurrence and related mortality in dementia with Lewy bodies. Epilepsy Behav. 2020;111:107311. https://doi.org/10.1016/j.yebeh.2020.107311(Epub 18 Jul 2020).
Morris M, Sanchez PE, Verret L, et al. Network dysfunction in α-synuclein transgenic mice and human Lewy body dementia. Ann Clin Transl Neurol. 2015;2(11):1012–28. https://doi.org/10.1002/acn3.257.
Bang J, Spina S, Miller BL. Frontotemporal dementia. Lancet. 2015;386(10004):1672–82. https://doi.org/10.1016/S0140-6736(15)00461-4.
Beghi E, Carpio A, Forsgren L, et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia. 2010;51(4):671–5. https://doi.org/10.1111/j.1528-1167.2009.02285.x.
Gaxatte C, Puisieux F, Derambure P. Does the epileptic threshold change with age? Psychol Neuropsychiatr Vieil. 2007;5(1):5–9. https://doi.org/10.1684/pnv.2007.0096.
Romanelli MF, Morris JC, Ashkin K, Coben LA. Advanced Alzheimer’s disease is a risk factor for late-onset seizures. Arch Neurol. 1990;47(8):847–50. https://doi.org/10.1001/archneur.1990.00530080029006.
Mendez MF, Catanzaro P, Doss RC, Arguello R, Frey WH 2nd. Seizures in Alzheimer’s disease: clinicopathologic study. J Geriatr Psychiatry Neurol. 1994;7(4):230–3. https://doi.org/10.1177/089198879400700407.
Giorgi FS, Saccaro LF, Busceti CL, Biagioni F, Fornai F. Epilepsy and Alzheimer’s disease: potential mechanisms for an association. Brain Res Bull. 2020;160:107–20. https://doi.org/10.1016/j.brainresbull.2020.04.009.
Palop JJ, Mucke L. Epilepsy and cognitive impairments in Alzheimer disease. Arch Neurol. 2009;66(4):435–40. https://doi.org/10.1001/archneurol.2009.15.
Villemagne VL, Burnham S, Bourgeat P, et al. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 2013;12(4):357–67. https://doi.org/10.1016/S1474-4422(13)70044-9.
Lam AD, Deck G, Goldman A, Eskandar EN, Noebels J, Cole AJ. Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer’s disease. Nat Med. 2017;23(6):678–80. https://doi.org/10.1038/nm.4330.
Vossel KA, Ranasinghe KG, Beagle AJ, et al. Incidence and impact of subclinical epileptiform activity in Alzheimer’s disease. Ann Neurol. 2016;80(6):858–70. https://doi.org/10.1002/ana.24794.
Roberson ED, Halabisky B, Yoo JW, et al. Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer’s disease. J Neurosci. 2011;31(2):700–11. https://doi.org/10.1523/JNEUROSCI.4152-10.2011.
Sanchez PE, Zhu L, Verret L, et al. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc Natl Acad Sci USA. 2012;109(42):E2895–903. https://doi.org/10.1073/pnas.1121081109.
Noebels J. A perfect storm: converging paths of epilepsy and Alzheimer’s dementia intersect in the hippocampal formation. Epilepsia. 2011;52 Suppl. 1(Suppl. 1):39–46. https://doi.org/10.1111/j.1528-1167.2010.02909.x.
Lin R, Jones NC, Kwan P. Unravelling the role of glycogen synthase kinase-3 in Alzheimer’s disease-related epileptic seizures. Int J Mol Sci. 2020;21(10):3676. https://doi.org/10.3390/ijms21103676.
Palop JJ, Mucke L. Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat Rev Neurosci. 2016;17(12):777–92. https://doi.org/10.1038/nrn.2016.141.
Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging [published correction appears in Lancet Neurol. 2013;12(6):532]. Lancet Neurol. 2013;12(5):483–97. https://doi.org/10.1016/S1474-4422(13)70060-7.
Prins ND, Scheltens P. White matter hyperintensities, cognitive impairment and dementia: an update. Nat Rev Neurol. 2015;11(3):157–65. https://doi.org/10.1038/nrneurol.2015.10.
Ivens S, Kaufer D, Flores LP, et al. TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain. 2007;130(Pt 2):535–47. https://doi.org/10.1093/brain/awl317.
Vezzani A, Aronica E, Mazarati A, Pittman QJ. Epilepsy and brain inflammation. Exp Neurol. 2013;244:11–21. https://doi.org/10.1016/j.expneurol.2011.09.033.
De Reuck J, Nagy E, Van Maele G. Seizures and epilepsy in patients with lacunar strokes. J Neurol Sci. 2007;263(1–2):75–8. https://doi.org/10.1016/j.jns.2007.06.004.
Arvanitakis Z, Capuano AW, Leurgans SE, Bennett DA, Schneider JA. Relation of cerebral vessel disease to Alzheimer’s disease dementia and cognitive function in elderly people: a cross-sectional study. Lancet Neurol. 2016;15(9):934–43. https://doi.org/10.1016/S1474-4422(16)30029-1.
van der Zande JJ, Gouw AA, van Steenoven I, Scheltens P, Stam CJ, Lemstra AW. EEG characteristics of dementia with Lewy bodies, Alzheimer’s disease and mixed pathology. Front Aging Neurosci. 2018;10:190. https://doi.org/10.3389/fnagi.2018.00190.
García-Cabrero AM, Guerrero-López R, Giráldez BG, et al. Hyperexcitability and epileptic seizures in a model of frontotemporal dementia. Neurobiol Dis. 2013;58:200–8. https://doi.org/10.1016/j.nbd.2013.06.005.
Kuroda M, Matsuwaki T, Tanaka Y, Yamanouchi K, Nishihara M. Convulsive responses to seizure-inducible drugs are exacerbated in progranulin-deficient mice. NeuroReport. 2020;31(6):478–83. https://doi.org/10.1097/WNR.0000000000001425.
Vatsavayai SC, Yoon SJ, Gardner RC, et al. Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia. Brain. 2016;139(Pt 12):3202–16. https://doi.org/10.1093/brain/aww250.
Spires-Jones TL, Attems J, Thal DR. Interactions of pathological proteins in neurodegenerative diseases. Acta Neuropathol. 2017;134(2):187–205. https://doi.org/10.1007/s00401-017-1709-7.
Desmarais P, Miville C, Milán-Tomás Á, et al. Age representation in antiepileptic drug trials: a systematic review and meta-analysis. Epilepsy Res. 2018;142:9–15. https://doi.org/10.1016/j.eplepsyres.2018.03.005.
Lezaic N, Gore G, Josephson CB, Wiebe S, Jetté N, Keezer MR. The medical treatment of epilepsy in the elderly: a systematic review and meta-analysis. Epilepsia. 2019;60(7):1325–40. https://doi.org/10.1111/epi.16068.
Lattanzi S, Trinka E, Del Giovane C, Nardone R, Silvestrini M, Brigo F. Antiepileptic drug monotherapy for epilepsy in the elderly: a systematic review and network meta-analysis. Epilepsia. 2019;60(11):2245–54. https://doi.org/10.1111/epi.16366.
Cumbo E, Ligori LD. Levetiracetam, lamotrigine, and phenobarbital in patients with epileptic seizures and Alzheimer’s disease. Epilepsy Behav. 2010;17(4):461–6. https://doi.org/10.1016/j.yebeh.2010.01.015.
Cretin B. Pharmacotherapeutic strategies for treating epilepsy in patients with Alzheimer’s disease. Expert Opin Pharmacother. 2018;19(11):1201–9. https://doi.org/10.1080/14656566.2018.1496237.
Villanueva V, Giráldez BG, Toledo M, De Haan GJ, Cumbo E, Gambardella A, et al. Lacosamide monotherapy in clinical practice: a retrospective chart review. Acta Neurol Scand. 2018;138(3):186–94. https://doi.org/10.1111/ane.12920.
Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, et al. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc Natl Acad Sci USA. 2012;109(42):E2895–903. https://doi.org/10.1073/pnas.1121081109.
Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR, Stark CE, et al. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron. 2012;74(3):467–74. https://doi.org/10.1016/j.neuron.2012.03.023.
Arnold S, Laloyaux C, Schulz AL, Elmoufti S, Yates S, Fakhoury T. Long-term safety and efficacy of brivaracetam in adults with focal seizures: results from an open-label, multinational, follow-up trial. Epilepsy Res. 2020;166:106404. https://doi.org/10.1016/j.eplepsyres.2020.106404.
Nygaard HB, Kaufman AC, Sekine-Konno T, Huh LL, Going H, Feldman SJ, et al. Brivaracetam, but not ethosuximide, reverses memory impairments in an Alzheimer’s disease mouse model. Alzheimers Res Ther. 2015;7(1):25. https://doi.org/10.1186/s13195-015-0110-9.
Ferlazzo E, Gasparini S, Beghi E, et al. Epilepsy in cerebrovascular diseases: review of experimental and clinical data with meta-analysis of risk factors. Epilepsia. 2016;57(8):1205–14. https://doi.org/10.1111/epi.13448.
Brigo F, Lattanzi S, Zelano J, et al. Randomized controlled trials of antiepileptic drugs for the treatment of post-stroke seizures: a systematic review with network meta-analysis. Seizure. 2018;61:57–62. https://doi.org/10.1016/j.seizure.2018.08.001.
Liu J, Wang LN, Wu LY, Wang YP. Treatment of epilepsy for people with Alzheimer’s disease. Cochrane Database Syst Rev. 2018;12(12):CD011922. https://doi.org/10.1002/14651858.CD011922.pub3.
Cretin B, Blanc F. How does epilepsy impact the pharmacotherapeutic management of patients with dementia with Lewy bodies? Expert Opin Pharmacother. 2020;21(4):377–9. https://doi.org/10.1080/14656566.2019.1707185.
Lezaic N, Roussy J, Masson H, Jetté N, Keezer MR. Epilepsy in the elderly: unique challenges in an increasingly prevalent population. Epilepsy Behav. 2020;102:106724. https://doi.org/10.1016/j.yebeh.2019.106724.
Vu LC, Piccenna L, Kwan P, O’Brien TJ. New-onset epilepsy in the elderly. Br J Clin Pharmacol. 2018;84(10):2208–17. https://doi.org/10.1111/bcp.13653.
Wechsler RT, Radtke RA, Smith M, et al. Serum sodium levels and related treatment-emergent adverse events during eslicarbazepine acetate use in adults with epilepsy. Epilepsia. 2019;60(7):1341–52. https://doi.org/10.1111/epi.16069.
Safahani M, Aligholi H, Asadi-Pooya AA. Management of antiepileptic drug-induced nutrition-related adverse effects. Neurol Sci. 2020. https://doi.org/10.1007/s10072-020-04573-5(Epub 14 Jul 2020).
Zaccara G, Lattanzi S. Comorbidity between epilepsy and cardiac arrhythmias: implication for treatment. Epilepsy Behav. 2019;97:304–12. https://doi.org/10.1016/j.yebeh.2019.05.038.
Roberti R, Palleria C, Nesci V, et al. Pharmacokinetic considerations about antiseizure medications in the elderly. Expert Opin Drug Metab Toxicol. 2020. https://doi.org/10.1080/17425255.2020.1806236(Epub 6 Aug 2020).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
No funding was received for the preparation of this article.
Conflict of interest
Benjamin Cretin reports fees and honorarium from UCB-Pharma, Eisai-Pharma, and Advicenne-Pharma.
Ethics approval
Not applicable.
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Availability of data and material
Not applicable.
Author contributions
BC designed and conceptualized study, analyzed the data, drafted the manuscript for intellectual content, and read and approved the final version of the manuscript.
Rights and permissions
About this article
Cite this article
Cretin, B. Treatment of Seizures in Older Patients with Dementia. Drugs Aging 38, 181–192 (2021). https://doi.org/10.1007/s40266-020-00826-2
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40266-020-00826-2