The Challenge of Memory in Epilepsy

Individuals with epilepsy frequently complain of memory impairment. It is challenging to ascertain the degree and nature of memory complaints based only on self or family report, and many factors contribute to this challenge. People with intractable epilepsy are frequently in denial of the severity of their memory impairments and frequently are seen for neuropsychologic testing only at the urging of family and friends. Correlations between self-reported complaints and neuropsychologic test results are low. Frequently, people who report no or minimal memory problems perform poorly on certain neuropsychologic tests, whereas patients with multiple memory complaints might perform at, or above average levels recorded for typical people of the same age and education.

Memory impairment is among the largest contributors to poor quality of life for those with epilepsy.1 Factors that contribute to memory impairments include antiseizure medications (ASM), underlying causes of seizures, psychosocial factors, and effects of recurrent seizures. It is unclear if memory impairments remain stable over time or worsen as seizures become more intractable. In this review, we discuss the possible reasons for memory impairments in people with intractable epilepsy.

Memory Impairment Before Epilepsy Diagnosis

A number of studies indicate that some memory impairment can precede the diagnosis of epilepsy.2-5 A study assessed 155 people with a newly diagnosed and untreated seizure disorder without known neuropathology with a battery of neuropsychologic testing.5 After adjusting for age, sex, and education, people with newly diagnosed epilepsy had worse performance on a finger-tapping task with the dominant hand, poor motor speed on the Adult Memory and Information Processing Battery, poor word recall on the Rey Auditory Verbal Learning Test, and poor story recall. Performance did not significantly differ among those with partial vs generalized vs unclassified epilepsy. These results are consistent with prior studies2-4; however, in all studies, some individuals had experienced 1 or more generalized tonic-clonic seizures before neuropsychologic testing. Although, at the time of diagnosis, people with epilepsy have been shown to exhibit negative mood and anxiety,6 which could contribute to some of the memory deficits observed, 2 studies found no relationship between mood and neuropsychologic test results.5,6 Although patients with abnormal brain imaging findings were excluded in these studies, it is unclear if EEG findings were present prior to neuropsychologic testing.

Interictal Discharges and Memory

People with epilepsy frequently have interictal discharges (IED) or epileptic sharp or spike and slow waves seen on EEG. These pathological discharges are frequently seen in-between seizures and occur in and around the seizure-onset zone. An IED is a large synchronous burst of neuronal activity thought to be preceded by a paroxysmal depolarization shift (PDS) related to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA)- and N-methyl-D-aspartate (NMDA) channel-mediated calcium conductance.7-9 A following hyperpolarization phase, or the after-going slow wave, is thought to be mediated by GABA.10 Although IEDs are classically considered asymptomatic, there is some evidence they are related to brief lapses in cognitive function.11-18 The term transient cognitive impairment (TCI) was created to explain the correlation with lapses of cognition during IED seen on EEG.19 Although earlier work correlated longer generalized 3-Hz spike and slow wave discharges to memory impairment, especially in children and young adults,19,20 IEDs can be shorter in duration and focal in origin and location. The impairments related to focal IEDs appear to be related to duration and location.11,12,21,22

Most work on the relationship between IEDs and memory processing has been performed with scalp EEG,19,23,24 which has spatial limitations when it comes to understanding how deeper brain structures initiating an IED interact with hippocampal memory processes. More recent work in people with intractable epilepsy using intracranial EEG (ie, implanted depth or subdural grid electrodes) has begun to show a clearer picture of the connection between hippocampal cognitive processes and IED impairments.11,12,22 The occurrence of IEDs recorded with intracranial electrodes correlates with impaired working memory performance and delayed free-recall tasks.12,22,25 When IEDs occurred outside a left-hemispheric seizure-onset zone, memory encoding and word retrieval was affected; in contrast, IEDs occurring inside the seizure-onset zone did not affect memory or word retrieval.11 A study of 10 patients who had intracranial implanted EEG showed that right-sided hippocampal discharges significantly reduced memory retrieval in a working memory task, but not memory encoding.22 Although these studies show correlations between IEDs and behavior, it remains unknown why IEDs are indicative of such impairments.

Invasive intracranial EEG recording has allowed significant insights into memory processing and sleep.26-28 Preliminary research from our own laboratory using intracranial EEG with implanted depth electrodes in people with intractable epilepsy suggests bilateral hippocampal IEDs can cause TCI by modulating single-neuron activity of putative inhibitory interneurons. Behaviorally, the occurrence of hippocampal IEDs was accompanied by a disruption in recognizing familiar images only if they occurred up to 2 seconds prior to stimulus onset. This is the first time the mechanism of TCI has been studied in humans at the single-neuron level. In conclusion, EEG abnormalities such as generalized spike and slow wave and focal IEDs can be responsible for causing impairment in cognitive processes. The type of impairment depends on the type (generalized vs focal), location (inside vs outside seizure-onset zone or neocortical vs hippocampal), and duration of the IED.

Mesial Temporal Lobe Epilepsy and Memory

Much of our knowledge regarding memory impairments in intractable epilepsy comes from preoperative and postoperative neuropsychologic testing of people being considered for surgery to treat intractable mesial temporal lobe epilepsy. Deficits in visuospatial or verbal memory measured with traditional neuropsychologic testing can help localize dominant or nondominant hemisphere dysfunction.29,30 Hippocampal volume loss (observed on postoperative histopathologic analysis and preoperative functional imaging, or both) has been correlated with verbal memory loss seen in people with dominant hemispheric temporal lobe epilepsy.31,32 Unfortunately, postoperative memory decline is greatest in individuals with higher verbal memory scores on presurgical evaluation.33

The reliability of visual memory deficits as a distinct sign of nondominant hemispheric dysfunction is more complex.34 This is related to visuospatial memory processing in people with chronic mesial temporal lobe epilepsy and the global dysfunction associated with the disease. In some patients intracarotid amobarbital testing (also known as WADA testing) may be needed to confirm lateralization of language and memory and predict postoperative memory change in individuals undergoing mesial temporal lobe resection.35

Worsening Epilepsy and Memory

One of the many questions frequently asked by people with chronic epilepsy is if their memory impairments will worsen as their epilepsy progresses (Box). Could the effects of interictal activity, seizures, and medications predispose a person to long-term memory impairment? Independent cross-sectional studies of global cognitive function in people with chronic mesial temporal lobe epilepsy show the answer is yes.36 The first study investigating the possibility of worsening cognitive decline in 78 people with unilateral mesial temporal lobe intractable epilepsy found a negative correlation with duration of epilepsy and a difference between scores on the Wechsler Adult Intelligence Scale-Revised (WAIS-R) and the estimated passive vocabulary intelligence test (Mehrfachwal-Wortschatz-Test Part B [MWT-B]) that could not be attributed to aging alone. Multiple regression analysis found that age, sex, education, and age at epilepsy onset did not contribute to the variance observed between the test scores. In a much larger study, the same group investigated the Full-Scale Intelligence Quotient (FS-IQ) in 209 people with intractable mesial temporal lobe epilepsy. The study examined multiple covariates including age, sex, mono- and polytherapy with ASM, duration of epilepsy, age of onset, medication levels, and level of education. Epilepsy duration was the only factor to reach statistical significance. Individuals who had epilepsy for more than 30 years performed worse on FS-IQ compared with those who had epilepsy for less than 30 years. For individuals with a higher level of education, FS-IQ scores remained stable for longer periods of epilepsy, compared with those who had less education. It has been suggested that the decline in cognitive functioning in people with more than 30 years of epilepsy might be related to ongoing hippocampal neuronal loss and loss of hippocampal volume.37-41

Antiseizure Medications and Memory

Antiseizure medications are commonly used to control seizures in patients with epilepsy and are effective for approximately 64% of people epilepsy. Often people with epilepsy skip doses, primarily because of side effects.42 Daytime drowsiness and dizziness are among the common complaints associated with ASM. These medications can also affect attention and concentration, which could indirectly affect memory processing.43 Patients on ASM monotherapy have been shown to perform worse compared with those taking no medication on attention, memory, language, motor speed, reading speed, subjective behavioral, and neurophysiologic tests.43-45

Although some newer ASMs have fewer cognitive adverse effects compared with the older ones,45 many people with medically refractory epilepsy are frequently on polytherapy, which can have a significant deleterious effect on attention, executive function, and memory.46

People with medically refractory epilepsy (seizure duration > 10 years) on ASM polytherapy (ie, a combination of newer and older medication such as lamotrigine, clonazepam, carbamazepine, gabapentin, primidone, phenytoin, topiramate, levetiracetam, and phenobarbital) performed worse on the Dementia Rating Scale (DRS), the Wechsler Memory Scale (WMS III) logical memory subtest, and CFL word fluency test compared to individuals with mild cognitive impairment (MCI).47

Future Directions

Memory-related complaints and deficits are a common contributor to poor quality of life in people with epilepsy, especially intractable temporal lobe epilepsy. This shouldn’t be surprising since the hippocampus and amygdala, which are involved in memory processes, are also central to epileptogenesis. In recent years significant progress has been made using functional brain imaging and intracranial EEG to understand the mechanism of seizure generation48,49 and memory processing in humans.50-52 Despite these advancements, as yet there are no therapies to improve memory in people with epilepsy; managing comorbid conditions such as mood disorders or switching to newer antiseizure medications may be helpful for some. Other fortunate individuals may find a surgical cure for chronic seizures to be an ideal remedy for
memory complaints.53

There is emerging evidence that treatment with brain stimulation may also help address memory concerns in people with chronic epilepsy. In a recent study of 10 people with epilepsy, transcranial direct current cathodal stimulation resulted in a 56.2% improvement in working memory and a decrease in seizure frequency when applied directly to the seizure onset zone. This study did not have a control group, however, so a placebo effect cannot be ruled out.54 Transmagnetic stimulation has had mixed results in enhancing memory in people with chronic epilepsy.55-57 Chronic intracranial stimulation using deep brain stimulation (DBS) of the thalamic anterior nucleus or responsive neurostimulation (RNS) of either bilateral hippocampi or to the ipsilateral to the seizure onset zone has shown promising results.58-62 It is unclear, however, if these improvements could be related to the improvements in mood or better seizure control. In contrast to chronic brain stimulation, which aims to improve memory over a long period of time, task-related acute stimulation aims to enhance task-specific memory.63,64 The latter provides an interesting therapeutic option for memory enhancement for those with epilepsy in which a person with epilepsy uses a magnet to provide closed-loop stimulation before a particular task to facilitate recall of the task at a later date.

Conclusions

Memory impairments are a common complaint for people with chronic intractable epilepsy. Medications, psychosocial comorbidities, IEDs, and the pathologic disturbances caused by seizures are believed to contribute to the impairments. Some of these cognitive problems can precede epilepsy diagnosis and worsen as the disease progresses. Recent studies on memory enhancement using extracranial and intracranial acute or chronic brain stimulation show promise. Until then, neurologists can help people with memory complaints by switching to medications with fewer side effects or treating comorbid mood disorders.

1. Fisher RS, Vickrey BG, Gibson P, et al. The impact of epilepsy from the patient’s perspective I. Descriptions and subjective perceptions. Epilepsy Res. 2000;41(1):39-51.

2. Aikia M, Kalviainen R, Riekkinen PJ. Verbal learning and memory in newly diagnosed partial epilepsy. Epilepsy Res. 1995;22:157-164.

3. Aikia M, Salmenpera T, Partanen K, Kalviainen R. Verbal memory in newly diagnosed patients and patients with chronic left temporal lobe epilepsy. Epilepsy Behav. 2001;2(1):20-27.

4. Pulliainen V, Kuikka P, Jokelainen M. Motor and cognitive functions in newly diagnosed adult seizure patients before antiepileptic medication. Acta Neurol Scand. 2000;101(2):73-78.

5. Taylor J, Kolamunnage-Dona R, Marson AG, et al. Patients with epilepsy: cognitively compromised before the start of antiepileptic drug treatment? Epilepsia 2010;51(1):48-56.

6. Pulliainen V, Kuikka P, Kalska H. Are negative mood states associated with cognitive function in newly diagnosed patients with epilepsy? Epilepsia. 2000;41:421-425.

7. Johnston D, Brown TH. The synaptic nature of the paroxysmal depolarizing shift in hippocampal neurons. Ann Neurol. 1984;16(Suppl):S65-S71.

8. Traub RD, Wong RK. Cellular mechanism of neuronal synchronization in epilepsy. Science. 1982;216(4547):745-747.

9. Trevelyan AJ, Sussillo D, Watson BO, Yuste R. Modular propagation of epileptiform activity: evidence for an inhibitory veto in neocortex. J Neurosci. 2006;26(48):12447-12455.

10. Cohen I, Navarro V, Clemenceau S, Baulac M, Miles R. On the origin of interictal activity in human temporal lobe epilepsy in vitro. Science. 2002;298:1418-1421.

11. Ung H, Cazares C, Nanivadekar A, et al. Interictal epileptiform activity outside the seizure onset zone impacts cognition. Brain. 2017;140(8):2157-2168.

12. Horak PC, Meisenhelter S, Song Y, et al. Interictal epileptiform discharges impair word recall in multiple brain areas. Epilepsia. 2017;58(3):373-380.

13. Aldenkamp AP, Arends J. Effects of epileptiform EEG discharges on cognitive function: is the concept of “transient cognitive impairment” still valid? Epilepsy Behav. 2004;5(Suppl1):S25-S34.

14. Aldenkamp AP, Arends J, Verspeek S, Berting M. The cognitive impact of epileptiform EEG-discharges; relationship with type of cognitive task. Child Neuropsychol. 2004;10(4):297-305.

15. Binnie CD. Cognitive impairment during epileptiform discharges: is it ever justifiable to treat the EEG? Lancet Neurol 2003;2(12):725-730.

16. Binnie CD, Kasteleijn-Nolst Trenite DG, Smit AM, Wilkins AJ. Interactions of epileptiform EEG discharges and cognition. Epilepsy Res. 1987;1(4):239-245.

17. Binnie CD, Marston D. Cognitive correlates of interictal discharges. Epilepsia. 1992;33(Suppl 6):S11-S17.

18. Browne TR, Penry JK, Proter RJ, Dreifuss FE. Responsiveness before, during, and after spike-wave paroxysms. Neurology. 1974;24(7):659-665.

19. Aarts JH, Binnie CD, Smit AM, Wilkins AJ. Selective cognitive impairment during focal and generalized epileptiform EEG activity. Brain. 1984;107(Pt 1):293-308.

20. Stores G. Electroencephalographic parameters in assessing the cognitive function of children with epilepsy. Epilepsia. 1990;31(Suppl 4):S45-S49.

21. Rugland AL. Neuropsychological assessment of cognitive functioning in children with epilepsy. Epilepsia. 1990;31(Suppl 4):S41-S44.

22. Kleen JK, Scott RC, Holmes GL, et al. Hippocampal interictal epileptiform activity disrupts cognition in humans. Neurology. 2013;81(1):18-24.

23. Schwab RS. Method of measuring consciousness in attacks of petit mal epilepsy. Arch Neurol Psychiatry. 1939;41:215-217.

24. Rausch R, Lieb JP, Crandall PH. Neuropsychologic correlates of depth spike activity in epileptic patients. Arch Neurol. 1978;35(11):699-705.

25. Krauss GL, Summerfield M, Brandt J, Breiter S, Ruchkin D. Mesial temporal spikes interfere with working memory. Neurology. 1997;49(4):975-980.

26. Rutishauser U, Schuman EM, Mamelak AN. Online detection and sorting of extracellularly recorded action potentials in human medial temporal lobe recordings, in vivo. J Neurosci Methods. 2006;154(1-2):204-224.

27. Kornblith S, Quian Quiroga R, Koch C, Fried I, Mormann F. Persistent single-neuron activity during working memory in the human medial temporal lobe. Curr Biol. 2017;27(7):1026-1032.

28. Reed CM, Birch KG, Kaminski J, et al. Automatic detection of periods of slow wave sleep based on intracranial depth electrode recordings. J Neurosci Methods. 2017;282:1-8.

29. Jones-Gotman M. Memory for designs: the hippocampal contribution. Neuropsychologia. 1986;24(2):193-203.

30. Milner B. Disorders of learning and memory after temporal lobe lesions in man. Clin Neurosurg 1972;19:421-446.

31. Sawrie SM, Martin RC, Gilliam F, Knowlton R, Faught E, Kuzniecky R. Verbal retention lateralizes patients with unilateral temporal lobe epilepsy and bilateral hippocampal atrophy. Epilepsia. 2001;42:651-659.

32. Trenerry MR, Jack CR, Jr., Cascino GD, Sharbrough FW, So EL. Bilateral magnetic resonance imaging-determined hippocampal atrophy and verbal memory before and after temporal lobectomy. Epilepsia. 1996;37:526-533.

33. Hermann BP, Wyler AR, Somes G, Dohan FC, Jr., Berry AD 3rd, Clement L. Declarative memory following anterior temporal lobectomy in humans. Behav Neurosci. 1994;108(1):3-10.

34. Ivnik RJ, Sharbrough FW, Laws ER, Jr. Anterior temporal lobectomy for the control of partial complex seizures: information for counseling patients. Mayo Clin Proc. 1988;63:783-793.

35. Trenerry MR, Loring DW. Intracarotid amobarbital procedure. The Wada test. Neuroimaging Clin N Am. 1995;5(4):721-728.

36. Jokeit NaE, A. Effects of chronic epilepsy on intellectual functions. Prog Brain Res. 2002135:455-463.

37. Mathern GW, Babb TL, Pretorius JK, Melendez M, Levesque MF. The pathophysiologic relationships between lesion pathology, intracranial ictal EEG onsets, and hippocampal neuron losses in temporal lobe epilepsy. Epilepsy Res. 1995;21:133-147.

38. Mathern GW, Babb TL, Vickrey BG, Melendez M, Pretorius JK. The clinical-pathogenic mechanisms of hippocampal neuron loss and surgical outcomes in temporal lobe epilepsy. Brain. 1995;118 ( Pt 1):105-118.

39. Mathern GW, Pretorius JK, Babb TL, Quinn B. Unilateral hippocampal mossy fiber sprouting and bilateral asymmetric neuron loss with episodic postictal psychosis. J Neurosurg. 1995;82(2):228-233.

40. Barr WB, Ashtari M, Schaul N. Bilateral reductions in hippocampal volume in adults with epilepsy and a history of febrile seizures. J Neurol Neurosurg Psychiatry. 1997;63:461-467.

41. Breier JI, Mullani NA, Thomas AB, et al. Effects of duration of epilepsy on the uncoupling of metabolism and blood flow in complex partial seizures. Neurology. 1997;48:1047-1053.

42. McAuley JW, Passen N, Prusa C, Dixon J, Cotterman-Hart S, Shneker BF. An evaluation of the impact of memory and mood on antiepileptic drug adherence. Epilepsy Behav. 2015;43:61-65.

43. Smith ME, Gevins A, McEvoy LK, Meador KJ, Ray PG, Gilliam F. Distinct cognitive neurophysiologic profiles for lamotrigine and topiramate. Epilepsia. 2006;47(4):695-703.

44. Chung SS, McEvoy LK, Smith ME, Gevins A, Meador K, Laxer KD. Task-related EEG and ERP changes without performance impairment following a single dose of phenytoin. Clin Neurophysiol. 2002;113(6):806-814.

45. Salinsky MC, Binder LM, Oken BS, Storzbach D, Aron CR, Dodrill CB. Effects of gabapentin and carbamazepine on the EEG and cognition in healthy volunteers. Epilepsia. 2002;43(5):482-490.

46. Piazzini A, Canevini MP, Turner K, Chifari R, Canger R. Elderly people and epilepsy: cognitive function. Epilepsia. 2006;47(Suppl 5):82-84.

47. Griffith HR, Martin RC, Bambara JK, Marson DC, Faught E. Older adults with epilepsy demonstrate cognitive impairments compared with patients with amnestic mild cognitive impairment. Epilepsy Behav. 2006;8(1):161-168.

48. Keller CJ, Truccolo W, Gale JT, et al. Heterogeneous neuronal firing patterns during interictal epileptiform discharges in the human cortex. Brain. 2010;133(Pt 6):1668-1681.

49. Schevon CA, Weiss SA, McKhann G, Jr., et al. Evidence of an inhibitory restraint of seizure activity in humans. Nat Commun. 2012;3:1060.

50. Rutishauser U, Mamelak AN, Schuman EM. Single-trial learning of novel stimuli by individual neurons of the human hippocampus-amygdala complex. Neuron. 2006;49(6):805-813.

51. Rutishauser U, Schuman EM, Mamelak AN. Activity of human hippocampal and amygdala neurons during retrieval of declarative memories. Proc Natl Acad Sci U S A. 2008;105(1):329-334.

52. Rutishauser U, Ye S, Koroma M, et al. Representation of retrieval confidence by single neurons in the human medial temporal lobe. Nat Neurosci. 2015;18(7):1041-1050.

53. McAuley JW, Elliott JO, Patankar S, et al. Comparing patients’ and practitioners’ views on epilepsy concerns: a call to address memory concerns. Epilepsy Behav. 2010;19(4):580-583.

54. Karvigh SA, Motamedi M, Arzani M, Roshan JH. HD-tDCS in refractory lateral frontal lobe epilepsy patients. Seizure 2017;47:74-80.

55. Blumenfeld RS, Lee TG, D’Esposito M. The effects of lateral prefrontal transcranial magnetic stimulation on item memory encoding. Neuropsychologia. 2014;53:197-202.

56. Kahn I, Pascual-Leone A, Theoret H, Fregni F, Clark D, Wagner AD. Transient disruption of ventrolateral prefrontal cortex during verbal encoding affects subsequent memory performance. J Neurophysiol. 2005;94(1):688-698.

57. Kohler S, Paus T, Buckner RL, Milner B. Effects of left inferior prefrontal stimulation on episodic memory formation: a two-stage fMRI-rTMS study. J Cogn Neurosci. 2004;16(2):178-188.

58. Loring DW, Kapur R, Meador KJ, Morrell MJ. Differential neuropsychological outcomes following targeted responsive neurostimulation for partial-onset epilepsy. Epilepsia. 2015;56(11):1836-1844.

59. Oh YS, Kim HJ, Lee KJ, Kim YI, Lim SC, Shon YM. Cognitive improvement after long-term electrical stimulation of bilateral anterior thalamic nucleus in refractory epilepsy patients. Seizure. 2012;21(3):183-187.

60. Troster AI, Meador KJ, Irwin CP, Fisher RS, SANTE Study Group. Memory and mood outcomes after anterior thalamic stimulation for refractory partial epilepsy. Seizure. 2017;45:133-141.

61. Suthana N, Fried I. Deep brain stimulation for enhancement of learning and memory. Neuroimage. 2014;85(Pt 3):996-1002.

62. Suthana N, Haneef Z, Stern J, et al. Memory enhancement and deep-brain stimulation of the entorhinal area. N Engl J Med. 2012;366(6):502-510.

63. Ezzyat Y, Wanda PA, Levy DF, et al. Closed-loop stimulation of temporal cortex rescues functional networks and improves memory. Nat Commun. 2018;9(1):365.

64. Inman CS, Manns JR, Bijanki KR, et al. Direct electrical stimulation of the amygdala enhances declarative memory in humans. Proc Natl Acad Sci U S A. 2018;115(1):98-103.

CR reports no disclosures.