Abstract

Epilepsy is a common neurological disorder with greatest incidence in older individuals. The bidirectional link between epilepsy and dementia is supported by epidemiological studies, molecular pathology and animal models. The effect of sleep on the interplay between epilepsy and dementia is an area of growing research. Sleep disruption is common in epilepsy with increased seizure activity observed across certain sleep stages, such as slow wave sleep. Dementia is associated with poor sleep and altered circadian rhythms. Recent evidence suggests that sleep may be the critical window when pathological hyperexcitability in both epilepsy and dementia occur. Poor sleep may underpin cognitive dysfunction in both conditions. A better understanding of the underlying mechanisms may, therefore, illuminate new therapeutic avenues to help cognitive difficulties in epilepsy and in dementia.

Introduction

Onset of epilepsy is most common after 55 years [1]. In the context of the ageing global population, the prevalence of epilepsy will increase along with impact on affected individuals, carers and society. There is a bidirectional relationship between epilepsy and dementia as people with epilepsy are at 2-3x greater risk of developing dementia [1] while those with dementia have an up to 10-fold increase incidence of seizures compared to the general older population [2].

Sleep represents a critical intersection between epilepsy and dementia. In this review, we will discuss how sleep and epilepsy are closely intertwined as neuronal hypersynchrony and epileptic activity are heightened during specific stages of sleep [3]. Circadian disruption is common in dementia with mechanistic processes related to poor clearance of neurodegenerative proteins [4]. We will consider how poor sleep may underpin cognitive dysfunction in both epilepsy and dementia and why exploring such mechanisms may lead to new treatment strategies.

Epilepsy and sleep: a tight relationship

As the brain passes through different stages of sleep, there is increased neuronal hypersynchrony and hyperexcitability. Slow-wave sleep, seen during non-rapid eye movement (NREM) sleep stage 3, is a state of maximal physiological synchrony [3] and associated with increased interictal epileptiform discharges [5] (Figure 1). Sleep-related seizures, though, often occur during lighter sleep stages and on arousal from NREM [6] suggesting mechanisms other than purely a hypersynchronous system. Conversely, REM sleep is associated with suppression of epileptic activity and with low seizure incidence [7].

Treating epilepsy is generally associated with improved sleep architecture which may be due to a combination of better controlled seizures or the direct effect of anti-seizure medications. The effect of anti-seizure medications on sleep were recently reviewed by Carvalho and colleagues and are summarised in Table 1 [8]. This updated previous work [9] and complements a meta-analysis into the effects of anti-seizure medications on polysomnography recording. It is important to highlight that the data for these effects are variable, often with small sample size and generally studies are graded as class III evidence. For example, an exploratory, 4-week, double-blind, randomised study of pregabalin in 15 individuals with well controlled focal seizures on anti-seizure medication monotherapy suggested improved sleep continuity [10]. Observational studies of lamotrigine usage have reported improved REM and SWS with add-on therapy whilst other work has suggested no sleep benefit or even a weak association with insomnia [9,11].

Further, disentangling the effects of seizures, improved seizure control and medication side-effects can be challenging. There are also other factors which may confound this picture such as the improved mood, reduced anxiety and social stability associated with good seizure control. Epilepsy is also increasingly associated with obstructive sleep apnoea (OSA). A study of 39 refractory pre-surgical patients identified a 33% prevalence of having OSA on polysomnography, despite no prior history [12], that was significantly higher than population rates (4-11%). OSA, which can contribute to sleep disruption and non-restorative sleep, may be compounded by anti-seizure medication use. Sodium Valproate, for example, can lead to weight gain which is a risk factor for OSA while other medications with sedating or muscle-relaxant effects can reduce upper airway muscle tone during sleep [13].

Figure 1. Sleep hypnogram and occurrence of epileptic activity. Schematic representation of overnight sleep involving shift across light to deep sleep as well as rapid eye movement (REM, bold red line). Colour shading indicates sleep stages which are associated with seizure occurrence (light sleep; pink), hypersynchrony and epileptiform activity (deep sleep; lilac) and reduced occurrence of epileptic activity (REM; green). REM – rapid eye movement/tab
Anti-seizure MedicationMechanism of ActionEffect on Sleep Architecture
Carbamazepine (CBZ)Blocks voltage-gated sodium channels; enhances GABAergic inhibitionIncreases SWS, reduces REM sleep, improves sleep continuity
Reduces awakenings, increases REM and SWS
Gabapentin (GBP)Binds to α2δ subunit of voltage-gated calcium channelsIncreases REM, reduces stage shifts, slight reduction in SWS.
Lamotrigine (LTG)Inhibits sodium channels; reduces glutamate releaseWeak link to insomnia.
Increases N2 stage, reduces REM, improves sleep efficiency
Levetiracetam (LEV)Binds synaptic vesicle protein SV2A; modulates neurotransmitter release
May increase daytime somnolence, unknown effects on sleep stages
Perampanel (PER)Non-competitive AMPA receptor antagonistIncreases arousals, reduces REM sleep, increases SWS (short-term use)
Phenytoin (PHT)Blocks sodium channels; affects calcium channelsReduction in sleep latency, reduces REM and SWS.
Phenobarbital (PB)Positive allosteric modulator of GABAA receptorsAssociated with somnolence.
Increases SWS, reduces awakenings, improved sleep continuity
Pregabalin (PGB)Binds to α2δ subunit of voltage-gated calcium channelsIncreases SWS, reduces awakenings, improved sleep continuity
Topiramate (TPM)Blocks sodium channels; enhances GABA activity; inhibits AMPA/kainate receptors; exhibits weak carbonic anhydrase inhibitionMinimal impact on sleep architecture
Valproate (VPA)Increases GABA availability; modulates NMDA receptors; blocks voltage‐gated sodium channelsSleep-stabilising, may increase arousals in some patients
Table 1. Summary of common anti-seizure medication effects on sleep architecture. REM – rapid eye movement; SWS – slow wave sleep, GABA – Gamma-aminobutyric acid, NMDA – N-methyl-D-aspartate

Sleep and cognition

Good sleep is essential for healthy brain and cognitive function. Physiologically, cortical-cortical and hippocampal-cortical oscillatory activity seem crucial to memory encoding and consolidation. Slow wave sleep oscillations are important for declarative memory with a study using direct current stimulation studies able to enhance activity and performance on a word-pair retention task [14]. Similarly, other neurophysiological phenomena such as neocortical sleep spindles during stage 2 sleep appear to couple with activity in the hippocampus and are implicated in episodic memory formation [15].

Early experimental work showed that a single night of sleep deprivation was associated with poor declarative memory, despite controlling for alertness with caffeine [16]. Population and large cohort studies commonly focus on self-reported sleep duration and observe an ‘inverted-U’ relationship whereby an optimal amount of sleep – around seven hours – is associated with better cognitive metrics [17]. This likely represents two different processes, for sleeping too few hours may lead to disruption in memory consolidation whereas individuals who report sleeping many hours are likely to have disrupted sleep or not actually be asleep for that whole reported duration. Co-morbidities which may affect cognition, including depression, are also linked to prolonged but poor periods spent sleeping. Other sleep metrics are less well studied but may be more informative. Objective sleep quality analysis suggest that time spent in different sleep stages and the presence of sleep fragmentation may associate worse with cognitive function compared with overall sleep duration [18].

Taking a brief sleep history is a standard feature of memory clinics and is advisable for clinicians seeing any individual with memory difficulties. A simple structured interview about pre-bedtime routine, time of going to bed, any overnight waking such as trips to the toilet, and time of morning waking provides a wealth of information that may identify factors affecting poor memory and simple measures to improve upon.

Long term effects of sleep disruption on cognition and dementia risk

Chronic sleep disruption is associated with increased dementia risk. Analysis of data from almost 8000 participants from the Whitehall II study indicated that short sleep-duration in mid-life was related to incident dementia in later years [19] while other studies indicate that both long and short sleep duration were associated with increased rates of dementia [20]. Sleep structure is also observed to be disrupted early in those with mild cognitive impairment and dementia [21] with specific reduction in both SWS and REM sleep. This parallels the reciprocal relationship seen in sleep and epilepsy.

How, then, may poor sleep lead to dementia? Recent evidence highlights the potential role for the glymphatic system, the ‘lymphatic drainage of the brain’ as a single night of sleep deprivation in humans is associated with increased levels of amyloid-β in cerebrospinal fluid [4]. This suggests disruption in diurnal glymphatic drainage of neurodegenerative proteins through brain interstitial-cerebrospinal fluid kinetics during sleep. Tau is slightly harder to study in human sleep deprivation studies owing to a longer physiological turnover rate. Animal models, however, have identified a role for aquaporin-4 facilitated exchange of interstitial-cerebrospinal fluid with reduced tau pathology clearance in knockout models alongside increased deposition of phosphorylated tau [22]. Sleep disruption is prominent years prior to the diagnosis of AD and, therefore, may be a driver for amyloid-β and tau pathophysiology and related cognitive impairment. 

Sleep and the interplay between epilepsy and Alzheimer’s disease

Although EEG data in people with AD is relatively limited, epileptiform discharges in this population are far more common in sleep than in wake. More recent work using foramen ovale electrodes showed that inter-ictal discharges on invasive recordings were most abundant during slow wave sleep (SWS) and NREM sleep stage 2 followed by NREM sleep stage 1 and are least frequent during wakefulness and REM sleep [23]. Furthermore, there is evidence of abnormal sleep functional networks in AD reflected by reduced delta connectivity during sleep stage 2 which associates with worse cognition [24].  A study of individuals with AD highlighted how one hour of sleep EEG recording had the same sensitivity as eight hours of awake EEG data in terms of detecting epileptiform discharges [25].

A stereo-encephalopgraphy (sEEG) study of 20 epilepsy surgery candidates tested visual and verbal memory consolidation at immediate, 30-minute and one-week delays to investigate long term memory consolidation in relation to sleep metrics [26]. Verbal memory performance at one week correlated with the number of hippocampal interictal spikes during NREM sleep suggesting that epileptiform activity interferes with hippocampal-neocortical transfer and memory consolidation [26]. There was no significant correlation between interictal spikes during wake and long-term performance although there was a correlation with 30-minute memory scores. Importantly, the authors controlled for the number of seizures in their model. Anti-seizure medications may complicate this picture as a study of pre-surgical epilepsy patients identified that polytherapy of anti-seizure medications was associated with reduced coupling of spindle-slow wave [27]. From a mechanistic perspective, however, an animal model of temporal lobe epilepsy highlighted how interictal epileptiform discharges originating from the hippocampus may disrupt neocortical ripple-spindle coupling during NREM sleep leading to impaired memory consolidation [28].

Evidence therefore implicates epileptiform activity, particularly in sleep, as a key disruptor of cognitive cortico-cortical and cortico-hippocampal oscillatory activity.  Poor sleep can also associate with accumulation of neurodegenerative proteins in epilepsy and Alzheimer’s disease, further destabilising neuronal networks (Figure 2).

Figure 2. Schematic representation of the complex interplay between epilepsy, dementia and sleep.

Underlying shared mechanisms of cognitive dysfunction between epilepsy and dementia include deposition of neurodegenerative proteins, such as tau and amyloid-β. Pathological hyperexcitability manifesting as epileptic phenomena, including interictal epileptic spikes, can also contribute. Taken together, these changes may disrupt cortico-cortical and hippocampo-cortical networks. Sleep may represent the critical window within which such pathological mechanisms may accelerate.

Future directions and discussion

Impaired sleep causing accumulation of neurodegenerative proteins and abnormal neuronal activity, potentially underpins cognitive dysfunction in both epilepsy and Alzheimer’s disease. Detecting and suppressing pathological hyperexcitability is an enticing avenue of inquiry given the preliminary evidence suggesting that sleep disruption worsens pathological hyperexcitability. Several questions remain.

Non-invasive scalp EEG is limited in detecting sub-clinical epileptiform activity while invasive recordings are understandably restricted to a small subset of individuals. In particular, better spatial and temporal resolution are needed for non-invasive detection of pathological hyperexcitability. Magnetoencephalography (MEG), for example, is non-invasive and offers improved spatial resolution and source localisation over scalp EEG [29]. MEG may be a useful modality to examine pathological hyperexcitability at a larger scale than invasive techniques. Longitudinal tracking of hyperexcitability and objective sleep quality is another avenue for advancement with newer long-term home EEG devices, including wireless patch electrodes, more discreet inside-the-ear devices or subcutaneous EEG, that can record for months in some instances [30]. Limitations around reduced spatial EEG coverage and substantial muscle artifact may be outweighed by the ability to capture long term data and overcome by newer quantitative analytical methods.

Possible therapeutic avenues from better understanding of underlying neurobiology may emerge. This could include suppression of epileptic activity using anti-seizure medications as a novel treatment for individuals with dementia to mitigate cognitive impairment. Conversely, the shared pathological mechanisms around amyloid-β and tau suggests that recent FDA-approved immunotherapy to remove pathological proteins in Alzheimer’s disease may have a potential future application in epilepsy.

Improving sleep to reduce dementia risk is another exciting prospect. Clinicians should begin with simple but effective sleep hygiene measures. Use of medications to aid sleep is not routinely advised as these often promote the sleep state but disrupt underlying sleep architecture. While there are no international guidelines on prescribing anti-seizure medications to address sleep disruption and seizures, we recommend a holistic approach (outlined in Figure 3). Newer medications are being considered, although randomised studies are required prior to making clinical recommendations. For example, there is interest in pharmacological modulation of orexin-neuron activity to reduce the orexin hyperexcitability and sleep fragmentation seen in AD [31]. Few trials have examined whether sleep interventions have a long-term effect on cognition or dementia risk with unclear or pending results. This reflects the costly nature and need for long follow-up for such trials and the complex interplay between sleep, dementia and aberrant epileptic activity. Nevertheless, improving sleep may be a very worthwhile pursuit to improve cognition in people with epilepsy and dementia.

Figure 3. Practical approach to sleep difficulties in epilepsy.

A detailed seizure and sleep history is key. We recommend investigating and optimising any ongoing seizure activity. The clinician may then focus on sleep hygiene discussion, clinical factors and consider potential management on an individual basis.

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