Journal of Neurodegenerative Disorders

ISSN: 2642-4274

Review Article | Volume 3 | Issue 1 | DOI: 10.36959/459/560 Open Access

Epilepsy as a First Symptom of the Alzheimer's Disease: A Narrative Review

Francesco Raudino

  • Francesco Raudino 1*
  • Department of Neurology, Valduce Hospital, Italy

Raudino F (2020) Epilepsy as a First Symptom of the Alzheimer's Disease: A Narrative Review. J Neurodegener Disord 3(1):51-53.

Accepted: February 06, 2020 | Published Online: February 08, 2020

Epilepsy as a First Symptom of the Alzheimer's Disease: A Narrative Review

Abstract


Introduction

Seizures are common in the course of the Alzheimer's disease (AD), but are also described as a first sign of the disease. This work aims at reviewing the literature considering epilepsy as a first sign of the AD.

Methods

Medline search until September 2019.

Results

Seizures precede the cognitive deficits in some animal models of the AD. In humans, some case reports and few series reports describe seizures preceding cognitive impairment, with frequency comprised between 1.7% and 3.1%.

Conclusions

The frequency of seizures as a first sign of the AD is probably underestimated. The physician should be aware that seizures of unknown origin among the elderly could be the first sign of the AD. Besides, if confirmed by wider series, it should be admitted the possibility of an atypical non-cognitive onset of the AD.

Introduction


Memory impairment has long been seen as the first sign of the Alzheimer's disease (AD). However, over time, reports of atypical presentation have increased. In 2011, workgroup defining diagnostic guidelines for Alzheimer's disease [1] added non-amnesic presentations to the more typical amnesic presentations, which include impairments in learning and in recalling recently learned information. These non-amnesic presentations include: 1) Language presentation (mainly deficits in word-finding); 2) Visuospatial presentation (deficits in spatial cognition); 3) Executive dysfunction (mainly impaired reasoning, judgment and problem solving). The literature often described non-cognitive symptoms in the early stages of the AD as atypical presentations. For a long time, epilepsy was considered a late symptom, and only quite recently it has been reported in the early stages of the AD, and in the Mild Cognitive Impairment (MCI) [2]. The aim of this work is to review the literature regarding the epilepsy as a first symptom of the AD.

Method


Medline literature until September 2019 was scanned using "epilepsy", "seizures", "Alzheimer's disease", "model of AD", "dementia" and "mild cognitive impairment", as keywords. Other studies were identified by reviewing relevant bibliography quoted in the original papers.

Results


Animal models

Although there are several animal models of the AD, none of these reproduce exactly the human disease. In the Tg2576 mouse the cognitive impairment appears at the age of 3-5 months [3] whereas interictal spikes are found at the age of 5 weeks, before the β-amyloid deposition, mainly during the REM sleep, spontaneous seizures are observed in older mice [4]. In the same model, Bezzina and Coll [5] found spontaneous interictal spikes and higher seizure susceptibility to systemic injections of GABAa at the age of 1.5 months. The APP23 mice displays spontaneous hypersynchronicity in the hippocampus, beginning at the same age of memory deficits [6]. In the 3xtg-AD mice, higher seizure susceptibility was found at the age of 3 weeks, before amyloid deposition [7], whereas the first cognitive deficit was observed at the age of 3-5 months [3]. Increased sensitivity to pentylenetetrazole was found in the TgCRND8 mice in the pre-plaque stage [8].

Human studies

MCI is regarded as a borderline status between changes of aging and very early dementia. Rao and Coll [9] described unexplained new-onset seizures preceding the cognitive impairment in 10 MCI patients. Vossel and Coll [10] also described 8 MCI patients: In 1 case, the seizures preceded the MCI diagnosis, and in the other 7 the seizures and MCI appeared at the same time. Studying 430 patients with MCI, Cretin and Coll [11], identified 13 patients (3.1%) with seizures: In 10 MCI patients, seizures preceded the cognitive disturbances by 1-10-years, while in other 3 patients the appearance of seizures and cognitive complaints were concomitant. Analysing 1,371 patients with AD, Di Francesco and Coll [12] retrospectively identified 23 patients (1.7%) with adult-onset epilepsy originating from unknown causes; the seizures preceded the cognitive decline by a mean of 4.6-years. Besides, some case-reports have also been published relatively recently [13-15] suggesting that seizures or auras are preceding or concomitant to the initial cognitive deficits.

Epilepsy is frequent in the familial AD, Zarea and Coll [16], investigating 132 patients with dominantly inherited AD, reported 4 (3%) patients where seizures had represented the first sign of the disease. The results are summarized in the Table 1.

Discussion


According to the criteria developed by NINCDS-ADRDA [17] and Dubois [18], seizures at the onset or very early in the course of the AD make the diagnosis uncertain or unlikely. This statement was removed only in 2011 [1]. It is now clear that seizures are present also in the early stages of the AD, although the causes of this relationship are not clear [2].

Equally, the relationship between the development pace of cognitive impairments and seizures is poorly understood. Indeed patients with seizures in the early stages of the AD have a more rapid cognitive decline [10,12]. The data in the literature are scanty and often obtained from series carried out for other purposes [9,10,16] as a consequence, the frequency of the seizures at the beginning of the AD is probably underestimated, and wider series are needed. Instead, a better understanding of the relationship between epilepsy and AD could provide more insights into the pathogenesis of both diseases, the use of antiepileptic drugs in these patients, and even contribute to the development of new drugs.

These remarks have a twofold value. From a diagnostic point of view, the appearance of seizures of unknown origin in elderly people should raise the doubt of being in the presence of an initial AD. From an analytical point of view, the possibility of an atypical non-cognitive onset, different from those accepted in the guidelines, should be now foreseen, and particularly if the figures below will be confirmed by wider series. This may also apply to other non-cognitive symptoms such as behavioural disorders [19] or eye disorders [20].

References


  1. Mc Khann GM, Knopman DS, Chertkow H, et al. (2011) The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 7: 263-269.
  2. Raudino F (2017) Alzheimer's disease and epilepsy: A literature review. Arch Neurosci 4: e39578.
  3. Webster SJ, Bachstetter AD, Nelson PT, et al. (2014) Using mice to model Alzheimer's dementia: An overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. Front Genet 5: 88.
  4. Kam K, Duffy AM, Moretto J, et al. (2016) Interictal spikes during sleep are an early defect in the Tg2576 mouse model of β-amyloid neuropathology. Sci Rep 6: 20119.
  5. Bezzina C, Verret L, Juan C, et al. (2015) Early onset of hypersynchronous network activity and expression of a marker of chronic seizures in the Tg2576 mouse model of Alzheimer's disease. PLoS One 10: e0119910.
  6. Ittner AA, Gladbach A, Bertz J, et al. (2014) p38 MAP kinase-mediated NMDA receptordependent suppression of hippocampal hypersynchronicity in a mouse model of Alzheimer's disease. Acta Neuropathol Commun 2: 149.
  7. Kazim SF, Chuang SC, Zhao W, et al. (2017) Early-onset network hyperexcitability in presymptomatic alzheimer's disease transgenic mice is suppressed by passive immunization with anti-human app/aβ antibody and by mglur5 blockade. Front Aging Neurosci 9: 71.
  8. Del Vecchio RA, Gold LH, Novick SJ, et al. (2004) Increased seizure threshold and severity in young transgenic CRND8 mice. Neurosci Lett 367: 164-167.
  9. Rao SC, Dove G, Cascino GD, et al. (2009) Recurrent seizures in patients with dementia: frequency, seizure-types and treatment outcome. Epilepsy Behav 14: 118-120.
  10. Vossel KA, Beagle AJ, Rabinovici GD, et al. (2013) Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol 70: 1158-1166.
  11. Cretin B, Sellal F, Philippi N, et al. (2016) Epileptic prodromal Alzheimer's disease, a retrospective study of 13 new cases: Expanding the spectrum of Alzheimer's disease to an epileptic variant? J Alzheimer's Dis 52: 1125- 1133.
  12. DiFrancesco JC, Tremolizzo L, Polonia V, et al. (2017) Adult-onset epilepsy in presymptomatic Alzheimer's disease: A retrospective study. J Alzheimers Dis 60: 1267-1274.
  13. Picco A, Archetti S, Ferrara M, et al. (2011) Seizures can precede cognitive symptoms in late-onset Alzheimer's disease. J Alzheimers Dis 27: 737-742.
  14. Cretin B, Di Bitonto L, Blanc F, et al. (2015) Left temporal lobe epilepsy revealing left posterior cortical atrophy due to Alzheimer's disease. J Alzheimers Dis 45: 521-526.
  15. Sarkis RA, Willment KC, Gale SA, et al. (2017) Recurrent epileptic auras as a presenting symptom of Alzheimer's disease. Front Neurol 8: 360.
  16. Zarea A, Charbonnier C, Rovelet-Lecrux A, et al. (2016) Seizures in dominantly inherited Alzheimer disease. Neurology 87: 912-919.
  17. McKhann G, Drachman D, Folstein M, et al. (1984) Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA work group under the auspices of department of health and human services task force on Alzheimer's disease. Neurology 34: 939-944.
  18. Dubois B, Feldman HH, Jacova C, et al. (2007) Research criteria for the diagnosis of Alzheimer's disease: Revising the NINCDS–ADRDA criteria. Lancet Neurol 6: 734-746.
  19. Taragano FE, Allegri RF, Heisecke SL, et al. (2018) Risk of conversion to dementia in a mild behavioral impairment group compared to a psychiatric group and to a mild Cognitive Impairment Group. J Alzheimers Dis 62: 227-238.
  20. Raudino F (2019) Ocular and Visual manifestation of Alzheimer's disease: A literature review II Part: Clinical studies. Arch Neurosci 6: e74239.

Abstract


Introduction

Seizures are common in the course of the Alzheimer's disease (AD), but are also described as a first sign of the disease. This work aims at reviewing the literature considering epilepsy as a first sign of the AD.

Methods

Medline search until September 2019.

Results

Seizures precede the cognitive deficits in some animal models of the AD. In humans, some case reports and few series reports describe seizures preceding cognitive impairment, with frequency comprised between 1.7% and 3.1%.

Conclusions

The frequency of seizures as a first sign of the AD is probably underestimated. The physician should be aware that seizures of unknown origin among the elderly could be the first sign of the AD. Besides, if confirmed by wider series, it should be admitted the possibility of an atypical non-cognitive onset of the AD.

References

  1. Mc Khann GM, Knopman DS, Chertkow H, et al. (2011) The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 7: 263-269.
  2. Raudino F (2017) Alzheimer's disease and epilepsy: A literature review. Arch Neurosci 4: e39578.
  3. Webster SJ, Bachstetter AD, Nelson PT, et al. (2014) Using mice to model Alzheimer's dementia: An overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. Front Genet 5: 88.
  4. Kam K, Duffy AM, Moretto J, et al. (2016) Interictal spikes during sleep are an early defect in the Tg2576 mouse model of β-amyloid neuropathology. Sci Rep 6: 20119.
  5. Bezzina C, Verret L, Juan C, et al. (2015) Early onset of hypersynchronous network activity and expression of a marker of chronic seizures in the Tg2576 mouse model of Alzheimer's disease. PLoS One 10: e0119910.
  6. Ittner AA, Gladbach A, Bertz J, et al. (2014) p38 MAP kinase-mediated NMDA receptordependent suppression of hippocampal hypersynchronicity in a mouse model of Alzheimer's disease. Acta Neuropathol Commun 2: 149.
  7. Kazim SF, Chuang SC, Zhao W, et al. (2017) Early-onset network hyperexcitability in presymptomatic alzheimer's disease transgenic mice is suppressed by passive immunization with anti-human app/aβ antibody and by mglur5 blockade. Front Aging Neurosci 9: 71.
  8. Del Vecchio RA, Gold LH, Novick SJ, et al. (2004) Increased seizure threshold and severity in young transgenic CRND8 mice. Neurosci Lett 367: 164-167.
  9. Rao SC, Dove G, Cascino GD, et al. (2009) Recurrent seizures in patients with dementia: frequency, seizure-types and treatment outcome. Epilepsy Behav 14: 118-120.
  10. Vossel KA, Beagle AJ, Rabinovici GD, et al. (2013) Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol 70: 1158-1166.
  11. Cretin B, Sellal F, Philippi N, et al. (2016) Epileptic prodromal Alzheimer's disease, a retrospective study of 13 new cases: Expanding the spectrum of Alzheimer's disease to an epileptic variant? J Alzheimer's Dis 52: 1125- 1133.
  12. DiFrancesco JC, Tremolizzo L, Polonia V, et al. (2017) Adult-onset epilepsy in presymptomatic Alzheimer's disease: A retrospective study. J Alzheimers Dis 60: 1267-1274.
  13. Picco A, Archetti S, Ferrara M, et al. (2011) Seizures can precede cognitive symptoms in late-onset Alzheimer's disease. J Alzheimers Dis 27: 737-742.
  14. Cretin B, Di Bitonto L, Blanc F, et al. (2015) Left temporal lobe epilepsy revealing left posterior cortical atrophy due to Alzheimer's disease. J Alzheimers Dis 45: 521-526.
  15. Sarkis RA, Willment KC, Gale SA, et al. (2017) Recurrent epileptic auras as a presenting symptom of Alzheimer's disease. Front Neurol 8: 360.
  16. Zarea A, Charbonnier C, Rovelet-Lecrux A, et al. (2016) Seizures in dominantly inherited Alzheimer disease. Neurology 87: 912-919.
  17. McKhann G, Drachman D, Folstein M, et al. (1984) Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA work group under the auspices of department of health and human services task force on Alzheimer's disease. Neurology 34: 939-944.
  18. Dubois B, Feldman HH, Jacova C, et al. (2007) Research criteria for the diagnosis of Alzheimer's disease: Revising the NINCDS–ADRDA criteria. Lancet Neurol 6: 734-746.
  19. Taragano FE, Allegri RF, Heisecke SL, et al. (2018) Risk of conversion to dementia in a mild behavioral impairment group compared to a psychiatric group and to a mild Cognitive Impairment Group. J Alzheimers Dis 62: 227-238.
  20. Raudino F (2019) Ocular and Visual manifestation of Alzheimer's disease: A literature review II Part: Clinical studies. Arch Neurosci 6: e74239.