Memory Deficits Associated With Mesial Temporal Lobe Epilepsy

Of patients who suffer from epilepsy, memory impairment is one of the most pronounced cognitive deficits associated with the temporal lobe, which inevitably debilitates normal life activities. Whereas there have recently been increasing evidence of correlation between the frontal lobes, which are responsible for higher-level cognitive processes, and memory deficits in temporal lobe epilepsy (TLE), significantly more is known regarding the relationship between the medial temporal lobe and inadequacy of working memory.[1] Biologically, memory impairment has been found to be associated with neuronal loss and volume reduction of certain areas of the brain. [1] [2]
Magnetic resonance imaging of left hippocampal sclerosis
Magnetic resonance imaging of left hippocampal sclerosis

Specifically, it has been observed that patients with hippocampal sclerosis suffer with severe memory impairment, in which this cognitive loss is related with a reduced volume of the postcentral gyrus. In addition, other factors such as treatment and psychological impact also cause changes in neurocognition in epileptic patients.

Depending on the lateralization of epilepsy, drug interactions with various ligands, receptors, respective substrate concentrations or focal lesions greatly contribute to the development of retrograde or anterograde amnesia .As antiepileptic drugs act to reduce the excitability of neurons, cognitive impairment is a common side effect due to the slowing of functioning motors within the brain; however, the effects on neurocognitive behaviour depends greatly upon the choice of anticonvulsant, dosage, age, and duration of use. [8] Whether depression arises as a result of this cognitive limitation, or if the cognitive limitations are a result of depression are unknown; however, depression has been found to be more severe in cases where epilepsy has been resistant to drug therapy. [8] Although a precise correlation between specific focal lateralization of epilepsy in the temporal lobe and memory deficits has not been established, ongoing research notes that epileptic patients with memory impairments are at a much higher risk of developing major depressive disorder.

1 Temporal Lobe Epilepsy (TLE)

Damage to the mesial temporal lobes is commonly associated with cognitive deficits relating to the formation and consolidation of long-term episodic memories. Two types of seizures are known to originate from within the mesial temporal lobe structures, identified as either mesial-temporal lobe sclerosis with or without an atrophied hippocampus. [1] Of the patients with mesial temporal lobe epilepsy, many frequently perform normally on standard neuropsychological tests. Also associated with memory impairment in epileptic patients is transient epileptic amnesia (TEA) which classifies a form of epilepsy in which there are frequent recurring brief occurrences of selective memory loss. [1] [3] Recently, two new subtypes of TEA have been introduced; accelerated long-term forgetting (ALF) and remote autobiographical memory impairment (RMI)[3] . In both cases, there are profound deficits of declarative memory. In ALF, new memories are rapidly lost over a span of days or weeks. In RMI, memories of autobiographical events which happened within decades are lost over time. Hippocampal atrophy has been found to correlate with poorer memory recollection; however, no correlation has been found between the atrophy and ALF or RMI suggesting that aside from structural lesions of the hippocampus, other physiological factors are also accountable for memory impairment.[4]

1.1 Neurocognitive impairments associated with Right TLE and Left TLE

The type of memory affected is highly associated with the localization of the seizure. In regards to working or short-term memory, localization of the seizure originating from the right or left temporal lobe has been found to induce different effects on verbal and spatial memory. Patients with left TLE display more distinct deficits in storage of short term verbal memory than those with right TLE; whereas patients with right TLE perform worse on spatially coordinated memory tasks. [1] [3] In a study done by Wagner et al. (2009), it was found that in comparison with right and left TLE, right TLE patients experienced a lower than normal visualspatial span while left TLE patients exhibited more severe cognitive deficits in verbal memory span than the former group.[5] In all cases of mesial temporal epilepsy, the severity of memory deficit relies not only on the localization of the seizure, but on a number of other factors also such as the age of onset, the frequency and duration of seizures, associated brain structures and loss of neuronal mass.

1.2 Characterization of Mesial Temporal Lobe Epilepsy

One of the most prominent symptoms of Mesial Temporal Lobe Epilepsy (MTLE) is the
Difference in activation within each hemisphere of patients with Right and Left TLE during tests of verbal fluency as observed by method of functional magnetic resonance imaging
Difference in activation within each hemisphere of patients with Right and Left TLE during tests of verbal fluency as observed by method of functional magnetic resonance imaging

faltering of declarative memory, more specifically in episodic memory. MTLE is characterized by the finding of seizures to originate from the mesial temporal lobe. Of the two types of MTLE, mesial-temporal lobe sclerosis (TLE-MTS) is distinguished by the presence of hippocampal atrophy, where there is a prominent decrease in volume and damage of the tissues of the hippocampus. [2] To detect hippocampal atrophy byhistological examination, there must be a pronounced loss of neurons observed by magnetic resonance imaging (MRI), and signal abnormalities must be prevalent. The other type of MTLE without hippocampal atrophy presents a typical-appearing hippocampus with no abnormalities in MRI signalling and little to no loss of neurons.[2]

Patients with hippocampal atrophy are found to have more severe memory deficits than those without. Although MTLE has been long associated with cognitive deficits in declarative memory, recent studies show that cortical thinning in extratemporal structures on both contralateral and ipsilateral sides of the seizure origination contribute significantly to cognitive impairment.[3] This structural correlate suggests that pathological trademarks of memory impairments extend outside the boundaries of the temporal structures.

2 Hippocampal Sclerosis (MTLE-HS)

Hippocampal sclerosis, a pathological hallmark of mesial temporal lobe epilepsy (MTLE-HS) is one of the most common subsets of TLE. It is one of the most surgically treated and refractory types of epilepsy affiliated with an early onset of febrile seizures in which a silent or normal period follows before more prevalent symptoms emerge.[6] Of the adult patients with HS, it has been noted that they often have had experienced trauma to the brain or an infection of the nervous system within very early years of childhood. MTLE-HS appears to have some hereditary component but no genetic relationship has been found as yet. Hippocampal sclerosis is characterized by the presence of an atrophied hippocampus, abnormal magnetic resonance (MR) signals, and epilepsy-like discharges within the temporal structures which occur between occurrences of seizures. [6] Once the localization of the seizure has been clearly identified, it is possible to treat it by surgically removing the zone causing the epilepsy.

2.1 Volume of the hippocampus, extratemporal structures and memory impairment

In recent studies, there have been found to be associations of temporal lobe epilepsy and the prevalence of extratemporal damage. It is speculated that the reduction of solely the hippocampus size may not be sufficient to cause such distinguished memory deficits in MTLE-HS. Of patients with hippocampal sclerosis, there is often significant degradation of the postcentral gyrus.[7] Whereas a reduction in size of the left postcentral gyrus is associated with poorer egocentric memory, a reduction of the right hippocampus is associated with poorer allocentric memory. [5] Regarding other cortical structures, positive correlation has been identified between the reduction of the ipsilateral hippocampus and the reduction of the ipsilateral and contralateral size reduction of the parietal cortices. [5] Through functional imaging, it has been observed that smaller volumes of the parietal cortices and precuneus both negatively affect egocentric memory.

2.2 Effects on egocentric and allocentric memory

The existence of damage in other cortical areas in addition to hippocampal sclerosis is best accounted for by the propagation of seizures. Rendering of spatial cues is often a problematic task for patients with hippocampal sclerosis; however, whether the memory processes affected are allocentric or egocentric depends on the localization of the extratemporal damage. [5]

  • Allocentric memory: Spatial and environmental memory cues which are not dependent on the individual. Cues may act as navigational landmarks directing the individual towards the retrieval of memory.
  • Egocentric memory: Memory cues that are dependent on the observer, adopting sensorimotor perspectives of head and body movements, and temporal and spatial information relative to the self.
Navigation efficiency through virtual park (a,b) and virtual maze (c,d) by Weniger et al., as a determinant of capability in allocentric and egocentric memory (adapted from Weniger et al., 2012)
Navigation efficiency through virtual park (a,b) and virtual maze (c,d) by Weniger et al., as a determinant of capability in allocentric and egocentric memory (adapted from Weniger et al., 2012)

Patients with temporal lobe epilepsy but without hippocampal sclerosis do not display cognitive deficits of allocentric or egocentric memory. In an experiment conducted by Weniger et al., it was found that patients with hippocampal sclerosis were more impaired in successfully navigating through a virtual maze in which learning was associated with egocentric memory. [5] However, when navigating through a virtual park in which learning the surroundings required allocentric memory, patients with hippocampal sclerosis were more successful than in the maze setting. Only patients with extensive hippocampal sclerosis along with damages to the parahippocampal area amongst other forms of subcortical deterioration displayed prominent allocentric memory deficits, suggesting that secondary to hippocampal damage, other cortical areas must be affected to cause negative changes in allocentric memory. Using functional magnetic resonance imaging techniques, it was observed in normal subjects that during the processing of egocentric memory, there is an increase in activity in structures such as the precuneus and postcentral gyrus. [5] Therefore, damage to such extratemporal areas would result in the impairment of egocentric memory.

2.3 Upregulation of Type 1 cannabinoid receptor (CB1R)

Type 1 cannabinoid receptors (CB1R) are most prevalently found on presynaptic nerve endings as part of the endocannabinoid system which act to regulate the excitability of neurons and protect against hyperexcitability through mechanisms which aid in the restraint of both excitatory and inhibitory neurotransmitters’ release.[8] As part of the processes of molecular changes that occur during episodes of seizures, it was found in a study conducted by Goffin et al., that there was an increase of CB1R abundance within the ipsilateral temporal lobe and a decrease of CB1R abundance in the insular cortex. [7]

Because there is a dramatic decrease in volume of the hippocampus in patients with hippocampal sclerosis,it is difficult to determine the change in CB1R levels pre and post epileptic seizure; however, following surgical treatment of the epileptogenic zone, there is a significant decrease in the abundance of CB1R. Although the role of CB1R is unknown in regards to whether it serves to protect against excitability or act as a signature for a hyperexcitable zone, its upregulation within epileptogenic zones conveys that modifications of the endocannabinoid system is likely responsible for epileptic onset. [7]

3 Anticonvulsants

Memory impairment in patients with temporal lobe epilepsy is perpetually multifactorial. Aside from the biological component, choice in treatment greatly influences cognitive deterioration. Drugs used to control and treat epilepsy; known as anticonvulsants or antiepileptic drugs (AEDs) are of high culpability in causing cognitive deficits. AEDs act to decrease the amount of neuronal activity at the epileptogenic sites, which inadvertently affects normal rates of neuronal firing, attentiveness, and the analysis and storage of incoming information amongst other neurocognitive processes.[9] It has been suggested that the negative effects on memory from AEDs are more prevalent at the extremes on the age scale. [8]

Epileptic patients whose therapy includes only one type of anticonvulsant generally experience less extensive memory impairments than those whose treatments involve multiple anticonvulsants or whose therapy entails higher dosages. Older antiepileptic drugs have a more pronounced negatively associated cognitive profile than newer antiepileptic drugs; however, many confounding factors are present in claiming so as the subjective perception of memory retention is often affected by mood, in which epileptic patients tend to grasp more negatively. [8] [9] Depending on the drug of choice, withdrawal from the treatment may improve memory function. Ongoing studies suggest that AEDs may interact directly with epileptogenic zones or more specifically focal lesions.

3.1 Benzodiazepine in relation to anterograde amnesia

Chemical structures of common benzodiazepines
Chemical structures of common benzodiazepines

Benzodiazepines such as diazepam, lorazepam are a common subset of widely used antiepileptic drugs. Benzodiazepine receptors are found to be situated on GABA-A receptors; pentameric proteins that span the membrane and are Cl- gated.[10]
Benzodiazepines are known to be associated with anterograde amnesia; the loss of memories post-administration of the drug.[11] The severity of amnesia is related to the dosage and the pharmacokinetic properties of different benzodiazepines. [10] Often, the loss of memories before the administration of the drug is not due to retrograde amnesia, but rather due to a disruption in the consolidation of the memories at that period in time. Benzodiazepines more commonly affect the acquiring of new memories, the stage before consolidation.

3.2 Phenobarbital in relation to the impairment of short term memory and attention deficit

Phenobarbital is a common antiepileptic drug therapy chosen for children. The most prominent neurocognitive effects are memory and attention deficits.[12] Recall of short term memory is most affected and negatively correlates with an increase in dosage.[13]
Chemical Structure of phenobarbital
Chemical Structure of phenobarbital
These deficits are particularly harmful for children as a decrease in attentiveness dramatically hinders the acquisition of new information which is required for memory consolidation to occur. However, in a study conducted by Riva and Devoti, it was noted that the negative therapeutic effects of Phenobarbital is reversible following the discontinuation of its use. [11] Within the study, children who have withdrawn from the treatment exemplified similar or improved scores on intelligence tests with no further impairment of memory or attentiveness thereon after.

3.3 Topiramate in relation to verbal inarticulateness

Another common paediatric antiepileptic drug is topiramate. Topiramate functions by inhibiting gated Ca2+ channels, regulating Cl- channels and decreasing excitatory neuronal firing.[14] As opposed to Phenobarbital, Topiramate is a relatively more novel drug.
Chemical structure of topiramate
Chemical structure of topiramate

With less detrimental cognitive impairment, topiramate does not significantly impair attentiveness, reflex or motor coordination.[15] Despite having a less destructive profile, topiramate is known to be associated with deficits in language fluency and short term memory, specifically verbal memory. [13] However, much like Phenobarbital, cessation of topiramate drug therapy returns cognitive functionality to normal. [14]

4 Major Depressive Disorder

Depression is a substantially distinguished psychosocial factor affiliated with temporal lobe epilepsy. This condition is most common particularly in cases of epilepsy that pharmacoresistant or non-responsive to drug therapy.[16] A neurobiological basis has not been explicitly underlined yet. It may be a psychological factor which exhorts deficits of subjective memory or it may be certain mechanisms within cortical structures which give rise to the state of depressed mood. More generally, it is not uncommon that cognitive disorders other than memory impairment have been associated with depressed mood. Although there may be an underlying pathological relationship between the epileptogenic zone and depressed mood, it has been noted that depression dramatically alleviates following a successful surgical treatment of TLE in which seizures cease.[15]

4.1 Serotonin 1A Receptor (5HT 1A receptor)

In temporal lobe epilepsy, it has been found that there is a decrease in 5HT 1A receptor binding within the left hippocampus and mesial temporal cortical structures. While diminishing levels of 5HT 1A receptors are associated with memory impairment, there have recently been studies that suggest a correlation with depressive mood.[17] In cases of depression non-related to TLE, 5HT 1A receptor levels have also been observed to exhibit a decrease in binding within the mesial temporal structures, much like in TLE. In such cases of TLE where there is a decrease of binding of 5HT 1A receptors, treatment with antidepressants alleviated mood and decreased memory impairment. [16]

4.2 Depression and Lesion Localization

A correlation between the localization of the lesion and the presence of depression is still a topic of ongoing research. [14] [15] No solid evidence of any pathological mechanisms between the epileptogenic zone and the regulation of mood has yet been found. Perhaps extratemporal damage to the limbic system (which moderates emotions) due to seizure projection may possibly contribute to the prevalence of depression; however, it does not account for patients with depression without lesions in that particular extratemporal area.[18] Anticipated research in the near future may yield greater clarity of a pathological relationship between depression and lesion localization, if any.

See also


  1. ^ Stretton J, Thompson P.J,. Frontal lobe function in temporal lobe epilepsy. Epilepsy Research (2012) 98:1-13.
  2. ^ Mueller S.G, et al. Different Structural Correlates for Verbal Memory Impairment in Temporal Lobe Epilepsy with and without Mesial Temporal Lobe Sclerosis. Human Brain Mapping (2102) 33:489-499.
  3. ^ Butler C.R, and Zeman A.Z. Recent insights into the impairment of memory in epilepsy: transient epileptic amnesia, accelerated long-term forgetting and remote memory impairment. Brain (2008) 131:2243-2263.
  4. ^ Butler C.R, et al. Transient epileptic amnesia: regional brain atrophy and its relationship to memory deficits. Brain (2009) 132:357-368.
  5. ^ Weniger G, Ruhleder M, Lange C, and Irle E. Impaired egocentric memory and reduced somatosensory cortex size in temporal lobe epilepsy with hippocampal sclerosis. Behavioural Brain Research (2012) 227:116-124.
  6. ^ Cersosimo R, et al. Mesial temporal lobe epilepsy with hippocampal sclerosis: Study of 42 children. Seizure (2011) 20:131-137.
  7. ^ Weniger G, Ruhleder M, Lange C, and Irle E. Impaired egocentric memory and reduced somatosensory cortex size in temporal lobe epilepsy with hippocampal sclerosis. Behavioural Brain Research (2012) 227:116-124.
  8. ^ Goffin K, Paesschen W.V, Laere K.V.In vivo activation of endocannabinoid system in temporal lobe epilepsy with hippocampal sclerosis. Brain (2011) 134:1033-1040.
  9. ^ Motamedi G.K, Meador K.J. Antiepileptic drugs and memory. Epilepsy and Behaviour (2004) 5:435-439.
  10. ^ Beracochea D. Anterograde and retrograde effects of benzodiazepines on memory. The scientific world journal (2006) 6:1460-1465.
  11. ^ Roth T, Roehrs T, Wittig R, Zorick F. Benzodiazepines and memory. Br. J. Clin. Pharmac. (1984) 18:45S-49S.
  12. ^ Riva D and Devoti M. Discontinuation of Phenobarbital in Children: Effects on Neurocognitive Behaviour. Pediatr Neutrol (1996) 36-40.
  13. ^ Macleod C, Dekaban A, and Hunt E. Memory impairment in epileptic patients: Selective effects of Phenobarbital concentration. Science (1978) 202(8): 1102-1104.
  14. ^ Fritz N, et al. Efficacy and cognitive side effects of tiagabine and topiramate in patients with epilepsy. Epilepsy and Behaviour (2005) 6:373-381.
  15. ^ Brandl U, Kurlemann G, Neubauer B, Rettig K, Schauble B, and Schreiner A. Seizure and Cognitive outcomes in children and adolescents with epilepsy treated with topiramate. Neuropediatrics (2010) 41:113-120.
  16. ^ Helmstaedter C, Sonntag- Dillender M, Hoppe C, Elger C.E. Depressed mood and memory impairment in temporal lobe epilepsy as a function of focus lateralization and localization. Epilepsy and behaviour (2004) 5:696-701.
  17. ^ Theodore W.H, et al. Serotonin 1A receptors, depression, and memory in temporal lobe epilepsy. Epilepsia (2012) 53(1): 129-133.
  18. ^ Sanchez-Gistau V. Is major depressive disorder specifically associated with mesial temporal lobe sclerosis? Epilepsia (2012) 53(2):386-392.