Skip to main content

Advertisement

Log in

Diagnosis and Management of Seizures in Neurodegenerative Diseases

  • Dementia (J Pillai, Section Editor)
  • Published:
Current Treatment Options in Neurology Aims and scope Submit manuscript

Abstract

Purpose of Review

This review presents a critical appraisal of epileptic seizures in common neurodegenerative diseases related to proteinopathy, including Alzheimer’s disease (AD), dementia with Lewy bodies, frontotemporal dementias, and prion diseases. Studies on prevalence, seizure type, and treatment are reviewed, and tentative management recommendations made. Gaps in the evidence base are indicated.

Recent Findings

Epidemiological studies show that patients with AD are at increased risk of epileptic seizures. Cumulative seizure frequency of > 10% is reported and may be higher if subtle seizure features are sought by means of a proforma. Seizures may be associated with more rapid cognitive decline. The evidence base for treatment with anti-epileptic drugs in AD is weak, and potential benefits must be weighed against the risk of adverse events. Animal studies indicate that the abnormal protein species, amyloid peptides and tau, accumulating in AD brain may be implicated in epileptogenesis. Fewer data are available for the other neurodegenerative diseases, meaning that seizure treatment is largely empirical.

Summary

Epileptic seizures may be an integral part of many proteinopathies of the brain, rather than epiphenomena. Symptomatic treatment of seizures is currently largely empirical. The hope for the future is that seizures, like cognitive impairment, may be susceptible to disease-modifying treatments targeting aberrant protein species.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Larner AJ. Epileptic seizures in neurodegenerative dementia syndromes. J Neurol Neurosci. 2010;1(1):3.

    Google Scholar 

  2. 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;58:962–72.

    Article  PubMed  Google Scholar 

  3. Keret O, Hoang TD, Xia F, Rosen HJ, Yaffe K. Association of late-onset unprovoked seizures of unknown etiology with the risk of developing dementia in older veterans. JAMA Neurol. 2020;77:710–5.

    Article  PubMed  Google Scholar 

  4. Alzheimer A. Über eigenartige Krankheitsfalle des sapteren Alters. Z Gesamte Neurol Psychiatr. 1911;4:356–85.

  5. Vossel KA, Tartaglia MC, Nygaard HB, Zeman AZ, Miller BL. Epileptic activity in Alzheimer’s disease: causes and clinical relevance. Lancet Neurol. 2017;16:311–22.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Giorgi FS, Guida M, Vergallo A, Bonuccelli U, Zaccara G. Treatment of epilepsy in patients with Alzheimer’s disease. Expert Rev Neurother. 2017;17:309–18.

    Article  CAS  PubMed  Google Scholar 

  7. Cretin B. Pharmacotherapeutic strategies for treating epilepsy in patients with Alzheimer’s disease. Expert Opin Pharmacother. 2018;19:1201–9.

    Article  CAS  PubMed  Google Scholar 

  8. Sen A, Capelli V, Husain M. Cognition and dementia in older patients with epilepsy. Brain. 2018;141:1592–608.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Asadollahi M, Atazadeh M, Noroozian M. Seizure in Alzheimer’s disease: an underestimated phenomenon. Am J Alzheimers Dis Other Dement. 2019;34:81–8.

    Article  Google Scholar 

  10. Powell G, Ziso B, Larner AJ. The overlap between epilepsy and Alzheimer’s disease and the consequences for treatment. Expert Rev Neurother. 2019;19:653–61.

    Article  CAS  PubMed  Google Scholar 

  11. 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;54:700–7.

    Article  CAS  PubMed  Google Scholar 

  12. Cheng CH, Liu CJ, Ou SM, Yeh CM, Chen TJ, Lin YY, et al. Incidence and risk of seizures in Alzheimer’s disease: a nationwide population-based cohort study. Epilepsy Res. 2015;115:63–6.

    Article  PubMed  Google Scholar 

  13. Cook M, Baker N, Lanes S, Bullock R, Wentworth C, Arrighi HM. Incidence of stroke and seizure in Alzheimer’s disease dementia. Age Ageing. 2015;44:695–9.

    Article  PubMed  Google Scholar 

  14. Lyou HJ, Seo KD, Lee JE, Pak HY, Lee JH. Association of Alzheimer’s disease with risk of developing epilepsy: a 10-year nationwide cohort study. Dement Neurocogn Disord. 2018;17:156–62.

    Article  PubMed  Google Scholar 

  15. • 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;60:211–23. Although a retrospective study, this is currently the best available evidence on the frequency of seizures in DLB and FTD.

    Article  PubMed  PubMed Central  Google Scholar 

  16. 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.

    Article  PubMed  Google Scholar 

  17. • Baker J, Libretto T, Henley W, Zeman A. A longitudinal study of epileptic seizures in Alzheimer’s disease. Front Neurol. 2019;10:1266. Two reports from the prospective Presentation of Epileptic Seizures in Dementia (PrESIDe) study found evidence of seizures in up to 25% of AD patients and more rapid cognitive decline over 12 months in this group.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Cumbo E, Ligori LD. Levetiracetam, lamotrigine, and phenobarbital in patients with epileptic seizures and Alzheimer’s disease. Epilepsy Behav. 2010;17:461–6.

    Article  PubMed  Google Scholar 

  19. • Liu J, Wang LN, Wu LY, Wang YP. Treatment of epilepsy for people with Alzheimer’s disease. Cochrane Database Syst Rev. 2018;12:CD011922. The most recent iteration of the Cochrane review of the treatment of epilepsy in AD, highlighting the significant shortcomings of the available evidence base: no randomized double-blind placebo-controlled study has been reported.

    PubMed  Google Scholar 

  20. Sarycheva T, Lavikainen P, Taipale H, Tiihonen J, Tanskanen A, Hartikainen S, et al. Antiepileptic drug use and mortality among community-dwelling persons with Alzheimer disease. Neurology. 2020;94:e2099–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Larner AJ, Marson AG. Epileptic seizures in Alzheimer’s disease: another fine MESS? J Alzheimers Dis. 2011;25:417–9.

    Article  PubMed  Google Scholar 

  22. Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblended randomised controlled trial. Lancet. 2007;369:1000–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Vossel KA, Beagle AJ, Rabinovici GD, Shu H, Lee SE, Naasan G, et al. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol. 2013;70:1158–66.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Cretin B, Sellal F, Philippi N, Bousiges O, di Bitonto L, Martin-Hunyadi C, 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;52:1125–33.

    Article  PubMed  Google Scholar 

  25. Sarkis RA, Dickerson BC, Cole AJ, Chemali ZN. Clinical and neurophysiologic characteristics of unprovoked seizures in patients diagnosed with dementia. J Neuropsychiatr Clin Neurosci. 2016;28:56–61.

    Article  Google Scholar 

  26. Belcastro V, Costa C, Galletti F, Pisani F, Calabresi P, Parnetti L. Levetiracetam monotherapy in Alzheimer patients with late-onset seizures: a prospective observational study. Eur J Neurol. 2007;14:1176–8.

    Article  CAS  PubMed  Google Scholar 

  27. Sanchez MP, Garcia-Cabrero AM, Sanchez-Elexpuru G, Burgos DF, Serratosa JM. Tau-induced pathology in epilepsy and dementia: notions from patients and animal models. Int J Mol Sci. 2018;19(4):E1092.

    Article  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed  Google Scholar 

  29. Larner AJ. Presenilin-1 mutation Alzheimer’s disease: a genetic epilepsy syndrome? Epilepsy Behav. 2011;21:20–2.

    Article  CAS  PubMed  Google Scholar 

  30. Zarea A, Charbonnier C, Rovelet-Lecrux A, Nicolas G, Rousseau S, Borden A, et al. Seizures in dominantly inherited Alzheimer disease. Neurology. 2016;87:912–9.

    Article  PubMed  Google Scholar 

  31. Ryan NS, Nicholas JM, Weston PS, et al. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series. Lancet Neurol. 2016;15:1326–35.

    Article  PubMed  Google Scholar 

  32. Vöglein J, Noachtar S, McDade E, Quaid KA, Salloway S, Ghetti B, et al. Seizures as an early symptom of autosomal dominant Alzheimer’s disease. Neurobiol Aging. 2019;76:18–23.

    Article  PubMed  Google Scholar 

  33. Tang M, Ryman DC, McDade E, Jasielec MS, Buckles VD, Cairns NJ, et al. Neurological manifestations of autosomal dominant familial Alzheimer's disease: a comparison of the published literature with the Dominantly Inherited Alzheimer Network Observational Study (DIAN-OBS). Lancet Neurol. 2016;15:1317–25.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, et al. Aberrant excitatory neuronal activity and compensatory remodelling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron. 2007;55:697–711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Palop JJ, Mucke L. Amyloid beta induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci. 2010;13:812–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gschwind T, Lafourcade C, Gfeller T, Zaichuk M, Rambousek L, Knuesel I, et al. Contribution of early Alzheimer’s disease-related pathophysiology to the development of acquired epilepsy. Eur J Neurosci. 2018;47:1534–62.

    Article  PubMed  Google Scholar 

  37. Costa C, Romoli M, Liguori C, Farotti L, Eusebi P, Bedetti 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.

    Article  CAS  PubMed  Google Scholar 

  38. Möller HJ, Graeber MB. The case described by Alois Alzheimer in 1911. Historical and conceptual perspectives based on the clinical record and neurohistological sections. Eur Arch Psychiatry Clin Neurosci. 1998;248:111–22.

    Article  PubMed  Google Scholar 

  39. Fortea J, Vilaplana E, Carmona-Iragui M, Benejam B, Videla L, Barroeta I, et al. Clinical and biomarker changes of Alzheimer’s disease in adults with Down syndrome: a cross-sectional study. Lancet. 2020;395:1988–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lott IT, Doran E, Nguyen VQ, Tournay A, Movsesyan N, Gillen DL. Down syndrome and dementia: seizures and cognitive decline. J Alzheimers Dis. 2012;29:177–85.

    Article  PubMed  PubMed Central  Google Scholar 

  41. McCarron M, McCallion P, Reilly E, Dunne P, Carroll R, Mulryan N. A prospective 20-year longitudinal follow-up of dementia in persons with Down syndrome. J Intellect Disabil Res. 2017;61:843–52.

    Article  CAS  PubMed  Google Scholar 

  42. Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, et al. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron. 2005;48:913–22.

    Article  CAS  PubMed  Google Scholar 

  43. 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 U S A. 2012;109:E2895–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Shi JQ, Wang BR, Tian YY, Xu J, Gao L, Zhao SL, et al. Antiepileptics topiramate and levetiracetam alleviate behavioral deficits and reduce neuropathology in APPswe/PS1dE9 transgenic mice. CNS Neurosci Ther. 2013;19:871–81.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Wu JW, Hussaini SA, Bastille IM, Rodriguez GA, Mrejeru A, Rilett K, et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat Neurosci. 2016;19:1085–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tábuas-Pereira M, Durães J, Lopes J, Sales F, Bento C, Duro D, et al. Increased CSF tau is associated with a higher risk of seizures in patients with Alzheimer’s disease. Epilepsy Behav. 2019;98:207–9.

    Article  PubMed  Google Scholar 

  47. Sperfeld AD, Collatz MB, Baier H, Palmbach M, Storch A, Schwarz J, et al. FTDP-17: an early-onset phenotype with parkinsonism and epileptic seizures caused by a novel mutation. Ann Neurol. 1999;46:708–15.

    Article  CAS  PubMed  Google Scholar 

  48. Garcia-Cabrero AM, Guerrero-Lopez R, Giraldez BG, et al. Hyperexcitability and epileptic seizures in a model of frontotemporal dementia. Neurobiol Dis. 2013;58:200–8.

    Article  CAS  PubMed  Google Scholar 

  49. DeVos SL, Goncharoff DK, Chen G, et al. Antisense reduction of tau in adult mice protects against seizures. J Neurosci. 2013;33:12887–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Rahimi J, Kovacs GG. Prevalence of mixed pathologies in the aging brain. Alzheimers Res Ther. 2014;6:82.

    Article  PubMed  PubMed Central  Google Scholar 

  51. • Cretin B, Blanc F. How does epilepsy impact the pharmacotherapeutic management of patients with dementia with Lewy bodies? Expert Opin Pharmacother. 2020;21:377–9. A careful consideration of the treatment options for seizures in DLB.

    Article  PubMed  Google Scholar 

  52. Morris M, Sanchez PE, Verret L, Beagle AJ, Guo W, Dubal D, et al. Network dysfunction in alpha-synuclein transgenic mice and human Lewy body dementia. Ann Clin Transl Neurol. 2015;2:1012–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Mackenzie IR, Neumann M, Bigio EH, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol. 2010;119:1–4.

    Article  PubMed  Google Scholar 

  54. Mackenzie IRA, Neumann M, Baborie A, Sampathu DM, du Plessis D, Jaros E, et al. A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol. 2011;122:111–3.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Baiardi S, Capellari S, Bartoletti Stella A, Parchi P. Unusual clinical presentations challenging the early clinical diagnosis of Creutzfeldt-Jakob disease. J Alzheimers Dis. 2018;64:1051–65.

    Article  CAS  PubMed  Google Scholar 

  56. Mead S, Rudge P. CJD mimics and chameleons. Pract Neurol. 2017;17:113–21.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Wieser HG, Schindler K, Zumsteg D. EEG in Creutzfeldt-Jakob disease. Clin Neurophysiol. 2006;117:935–51.

    Article  PubMed  Google Scholar 

  58. Appel S, Chapman J, Cohen OS, Rosenmann H, Nitsan Z, Blatt I. Seizures in E200K familial and sporadic Creutzfeldt-Jakob disease. Acta Neurol Scand. 2015;131:152–7.

    Article  CAS  PubMed  Google Scholar 

  59. Meiner Z, Gabizon R, Prusiner SB. Familial Creutzfeldt-Jakob disease. Codon 200 prion disease in Libyan Jews. Medicine. 1997;76:227–37.

    Article  CAS  PubMed  Google Scholar 

  60. Brown P, Goldfarb LG, Gibbs CJ Jr, Gajdusek DC. The phenotypic expression of different mutations in transmissible familial Creutzfeldt-Jakob disease. Eur J Epidemiol. 1991;7:469–76.

    Article  CAS  PubMed  Google Scholar 

  61. Vallabh SM, Vallabh Minikel E, Schreiber SL, Lander ES. Towards a treatment for genetic prion disease: trials and biomarkers. Lancet Neurol. 2020;18:361–8.

    Article  Google Scholar 

  62. Walz R, Castro RM, Velasco TR, et al. Cellular prion protein: implications in seizures and epilepsy. Cell Mol Neurobiol. 2002;22:249–57.

    Article  CAS  PubMed  Google Scholar 

  63. Ng MC, Westover MB, Cole AJ. Treating seizures in Creutzfeldt-Jakob disease. Epilepsy Behav Case Rep. 2014;2:75–9.

    Article  PubMed  PubMed Central  Google Scholar 

  64. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease. Report of the NINCDS-ADRDA work group under the auspices of the Department of Health and Human Service Task forces on Alzheimer’s disease. Neurology. 1984;34:939–44.

    Article  CAS  PubMed  Google Scholar 

  65. Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol. 2014;13:614–29 [Erratum Lancet Neurol. 2014;13:757].

  66. Lozsadi DA, Larner AJ. Prevalence and causes of seizures at the time of diagnosis of probable Alzheimer’s disease. Dement Geriatr Cogn Disord. 2006;22:121–4.

    Article  CAS  PubMed  Google Scholar 

  67. McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology. 2017;89:88–100.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134:2456–77.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Zerr I, Kallenberg K, Summers DM, et al. Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Brain. 2009;132:2659–68 [Erratum Brain. 2012;135:1335].

  70. Mutoh T, Eguchi K, Yamamoto S, Yasui N, Taki Y. Arterial spin labeling magnetic resonance imaging in the assessment of non-convulsive status epilepticus in Alzheimer's disease: a report of two cases. Am J Case Rep. 2019;20:1883–7.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Valls-Carbó A, Gajate V, Romeral M, Gutiérrez-Viedma Á, Parejo-Carbonell B, Cabrera-Martín MN, et al. Non-convulsive status epilepticus in behavioral variant frontotemporal dementia. J Alzheimers Dis. 2020;77:in press:985–91.

    Article  PubMed  Google Scholar 

  72. Ford E, Greenslade N, Paudyal P, Bremner S, Smith HE, Banerjee S, et al. Predicting dementia from primary care records: a systematic review and meta-analysis. PLoS One. 2018;13(3):e0194735.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Horvath A, Kiss M, Szucs A, Kamondi A. Precuneus-dominant degeneration of parietal lobe is at risk of epilepsy in mild Alzheimer’s disease. Front Neurol. 2019;10:878.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Vossel KA, Ranasinghe KG, Beagle AJ, Mizuiri D, Honma SM, Dowling AF, et al. Incidence and impact of subclinical epileptiform activity in Alzheimer’s disease. Ann Neurol. 2016;80:858–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 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;23:678–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Note Added in Proof

Further data on epilepsy risk in dementia and AD have been published since acceptance of this article by Mahamud et al. (Seizure. 2020;82:118-24) and Vöglein et al. (J Neurol. 2020;267:2941-8).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A. J. Larner PhD.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Dementia

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Adan, G., Mitchell, J.W., Ziso, B. et al. Diagnosis and Management of Seizures in Neurodegenerative Diseases. Curr Treat Options Neurol 23, 1 (2021). https://doi.org/10.1007/s11940-020-00656-y

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11940-020-00656-y

Keywords

Navigation