Although substantial evidence suggests that cognitive impairments can emerge or worsen with acute and progressive neurologic changes in epilepsy, experts are also increasingly recognizing that comorbidity does not indicate causality. Indeed, cognitive impairments warrant distinct assessment and mitigation from the diagnosis and treatment of epilepsy.

Christoph Helmstaedter, PhD, and Juri-Alexander Witt, PhD, both of the Department of Epileptology at the University of Bonn in Germany, and others have suggested that a bidirectional relationship between cognitive and behavioral problems and epilepsy can exist. They have acknowledged, however, the difficulty in untangling the etiologies of cognitive problems in epilepsy and noted the need to consider these within multifactorial and neurodevelopmental models.

“Cognitive problems in epilepsy can have multiple causes, which, when viewed individually or in combination, determine the course of cognitive development and, when taken as symptoms, are not disease specific,” Helmstaedter and Witt wrote.1

The proposition of a bidirectional nature of epilepsy comorbidities represents a paradigm shift in the neuropsychology of epilepsy, according to David Loring, PhD, director of neuropsychology in the Department of Neurology and a professor of neurology and pediatrics at the Emory University School of Medicine in Atlanta, Georgia, and colleagues.2 “The paradigm shift that we described addressed the proposition that both the behavioral—particularly depression—as well as some of the cognitive issues are not necessarily the result of active epilepsy but in fact can predate and actually be associated with factors prior to the seizures emerging,” Loring explained to NeurologyLiveTM.

Investigations into mechanisms of epilepsy and comorbidities including cognitive impairment have identified alterations in both signaling pathways and neuronal network function, as well as indications that comorbidity can occur without shared causality, according to Gregory L. Holmes, MD, of the Department of Neurological Sciences at the Larner College of Medicine at the University of Vermont in Burlington. In his review of the roles of network abnormalities in cognitive impairment with epilepsy, Holmes acknowledged that current understanding of processes underlying comorbidities lags behind knowledge about the mechanisms of epilepsy.3 He found, however, that “the biological underpinnings of cognitive impairment can be distinct from the pathophysiological processes that cause seizures.”

Identify Common Comorbidities

Helmstaedter and Witt estimated that about 70% to 80% of patients with chronic epilepsies have cognitive deficits, and they noted that mood and behavioral problems are also common, with depression found in up to 60%.1 Cognitive impairments are prevalent in children with epilepsy, with one large population study finding intellectual disability in 17% of pediatric patients, disorders in psychological development in 21.3%, and unspecified developmental delay in 7.5%.4

“The causal relationship between epilepsy and its behavioral comorbidities was first challenged in epidemiological studies showing that psychiatric comorbidities may well precede the onset of epilepsy and that they may even be viewed as a biomarker for developing epilepsy,” observed Helmstaedter and Witt.1

The most recent epidemiologic evidence of a bidirectional association emerged from the first longitudinal investigation of an association between early-life cognitive ability and risk of incident epilepsy, conducted by Merete Osler, MD, PhD, DMSc, of the Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, and the Department of Public Health at the University of Copenhagen in Denmark, and colleagues.5

This large, population-based cohort study included records for over 1 million men from 3 Danish databases, including 22,364 patients (1.9%) who had developed epilepsy. A supplementary analysis with approximately 14,000 female patients corroborated the initial findings across gender.

The investigators ascertained cognitive ability using the Børge Priens Prøve intelligence test, which they indicated correlates well with the full-scale Wechsler Adult Intelligence Scale. They obtained the diagnosis of epilepsy from Danish hospital patient registers.

Osler and colleagues found that cognitive ability in young adulthood was inversely associated with the risk of epilepsy. Also, an epilepsy diagnosis during childhood and adolescence was associated with an approximately 0.25 SD lower cognitive ability in young adulthood. A limitation of the study was that the cognitive measure had not been repeated, leaving the investigators unable to determine whether a lower cognitive ability had been present before disease onset or had decreased because of the e ect of epileptic seizures or treatment.

“The cognitive impairment seen in adult patients with epilepsy may reflect combined effects of epileptic processes and lower premorbid cognitive ability, which might be a marker of brain dysfunction inherited or acquired early in life,” Osler and colleagues opined.5

Characterize Cognitive Impairment Early

Although the epilepsy-centric view of cognitive changes has held that cumulative neurologic damage in chronic epilepsy contributes to poorer cognitive status over time, Helmstaedter and Witt pointed out that such decline is relatively slow, with not more than 1 SD over a period of approximately 30 years.1

A possible alternative to an accumulating negative effect, they suggested, is that an initial impairment negatively affects mental development or that it interacts with normal aging. “Accordingly, it is essential to examine cognition at the time of epilepsy onset in order to understand when the problems occur and what effects the course of the disease and its treatment will have on cognition,” they advised.1

Performing cognitive screening in new-onset epilepsies in children and adults, they indicated, “enables the physician to monitor the course of the disease and to attribute the potential changes [that] may occur to either the treatment’s success or failure, AED [antiepileptic drug] [adverse] effects [AEs], and the dynamics of the underlying pathology.”1

Loring and colleagues agree with the importance of such screening at the time of new-onset epilepsy, noting that adults with new onset often display a pattern of mild diffuse cognitive impairment at diagnosis and prior to AED treatment. They pointed out that children often have elevated rates of behavioral problems, including attention-deficit/hyperactivity disorder, and early-life histories of academic struggles, with a pattern of distributed cognitive anomalies.2

Screening is important for many neurologic conditions and certainly for epilepsy and particularly for the younger patient, Loring emphasized. “Identifying some cognitive issues that can be addressed while [patients are] still in the school system can enable some compensatory remediation and other sorts of special services to be provided, to maximize their developmental and cognitive outcomes,” Loring said.

Although clinicians have traditionally used clinical neuropsychology to guide epilepsy surgery, Helmstaedter and Witt argued that it is past time to more fully integrate it into the routine care of patients with epilepsy.6 Experts generally agree on the functional domains that should be assessed, but Helmstaedter and Witt noted that clinicians agree far less on the particular tests that should be used.

“No standardized protocols for dominance assessment and [surgical] outcome prediction are in sight,” Helmstaedter and Witt observed, “and the choice of particular tests in epilepsy is still very much determined by general neuropsychological considerations and individual preferences rather than by published evidence in epilepsy.” 6

A recent report from a European pilot network of reference centers, also based at the Department of Epileptology at the University of Bonn, identified 186 different tests in use throughout the 26 participating epilepsy centers.7 The investigators also discovered, however, a smaller “core” set of tests that are frequently chosen based on the clinicians’ experience as well as on published evidence.

In lieu of recommending particular tests for “an evidence-based diagnostic toolbox for use in epilepsy,” Helmstaedter and Witt offered in the following list what they described as a question-guided and modular diagnostic approach (excerpted and edited for brevity and omitting surgery-specific testing)6:

The approach that Loring takes is to offer screening widely to clinicians, before the more time-intensive and specialist-applied neuropsychological testing is considered. “We can do a screen for cognition with a collection of tests that are designed to take on the order of 1 hour, and it includes the NIH [National Institutes of Health] cognition toolbox,” he said.

“The toolbox was developed by the NIH,8 as different tests and measures were being used and it was hard to get a common metric across different studies,” Loring noted. “The NIH battery is in the public domain, so it does not have to be paid for, in contrast with a lot of the neuropsychological tests that are proprietary and have a per-use fee.”

Loring pointed out that the NIH cognition assessment battery is also designed for use by staff who are not formally trained to administer neuropsychological testing. “We give it on an iPad platform that takes about 30 minutes, and supplement it with tests of processing speed and other attention measures that can be applied in clinics,” Loring said.

Consider AED Adverse Effects on Cognition

When selecting and dosing AED treatments, one might consider choosing a treatment not only for efficacy but also to minimize AEs, which can include cognitive impairment. Kees Braun, MD, PhD, of the Department of Child Neurology at University Medical Center Utrecht in The Netherlands, found that vigilance, attention, psychomotor speed, memory, and learning are most affected.9

“High-dose regimens and polypharmacy increase the chance of [adverse] effects, and children appear to be most susceptible,” Braun warned. “The cumulative cognitive consequences of chronic AED use during a critical stage of development can permanently affect educational progress and eventual functioning.”9

In addition to selecting an AED with a favorable AE profile when possible, Braun recommended minimizing the dosage to that required for symptom control, trying to prevent polypharmacy, switching drugs when cognitive AEs are suspected, and discontinuing the medication whenever it is safe to do so. “Many parents will report an increased alertness and improved learning capacity once an AED is discontinued in their seizure-free child, even if they had not recognized the [AE] during its use,” Braun observed.9

A recent study discerned differences in cognitive and behavioral function based on particular AED effects in children with partial epilepsy who were seizure controlled on AED monotherapy for 1 year.10 Thomas Burns, PsyD, ABPP, CN, of Children’s Healthcare of Atlanta in Georgia, and colleagues identified a cohort of 98 seizure-controlled children on AED monotherapy with either topiramate, divalproex sodium, lamotrigine, levetiracetam, or oxcarbazepine. The groups did not differ on age, region of focal epilepsy, or full-scale IQ.

Measures included the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV), with verbal attention and working memory examined using standard scores from the scale’s Digit Span Forward and Backward tasks. The investigators measured a broad range of executive skills with the Delis-Kaplan Executive Function System, with verbal fluency and motor processing speed assessed with the Verbal Fluency and Trail Making motor speed subtests, respectively.

Measures of maladaptive behaviors such as irritability and hyperactivity included the parent-reported Behavior Assessment System for Children, Second Edition, and the parent-reported Behavior Rating Inventory of Executive Function. Burns and colleagues explained that maladaptive behaviors have been associated with some AED treatments and that executive function deficits in everyday living may contribute to these behaviors and emotional changes.

The investigators reported that children treated with divalproex sodium or topiramate demonstrated weaker working memory and verbal uency compared with those on other AEDs. In addition, parents of children receiving topiramate reported greater deficits in executive function and adaptive skills.

“The pattern of findings suggests that children prescribed divalproex sodium or topiramate generally demonstrated a higher risk of cognitive and behavioral impairments compared [with] the other AEDs,” Burns and colleagues reported.10

In a systematic review11 of investigations of the AEs of AEDs in cognition and behavior in children with epilepsy, Adriana Ulate- Campos, MD, of the Department of Neurology at National Children’s Hospital, in San José, Costa Rica, and Iván Sánchez Fernández, MD, MPH, of the Department of Neurology at Boston Children’s Hospital, Harvard Medical School, in Massachusetts, found that lamotrigine and levetiracetam demonstrated favorable cognitive profiles but that levetiracetam was also associated with prominent behavioral AEs. Oxcarbazepine was not associated with cognitive impairment, and they found some suggestion of improvement. Ethosuximide also appeared to have minimal behavioral and cognitive AEs.

Among older AEDs, Ulate-Campos and Fernández found that carbamazepine reportedly had a better cognitive and behavioral profile than phenobarbital and phenytoin but with deficits in the memory domain. The reviewers found that divalproex sodium was associated with mild behavioral changes, including irritability, hyperactivity, and aggression, and with mild impaired attention and cognition.

Clobazam was linked to behavioral AEs including irritability and aggression, but the reviewers noted that these AEs tended to improve over time or with dose reduction, and they deemed clobazam to generally have a more acceptable AE profile than other benzodiazepines.

The reviewers also found extensive literature associating topiramate with cognitive and behavioral deterioration but indicated that the association appeared stronger in children with preexisting intellectual disability and that the adverse drug effect could be reduced by dose adjustment. Rufinamide was associated with mood changes and behavioral problems, and they described gabapentin as frequently causing prominent behavioral AEs.

Ulate-Campos and Fernández offered a summary recommendation: “In children in whom deterioration of cognitive function may be a concern when initiating a new AED, PB [phenobarbital] and TPM [topiramate] are generally to be avoided, and choices like ETX [ethosuximide], OXC [oxcarbazepine], or especially LTG [lamotrigine] and LEV [levetiracetam] might be better. In children in whom behavioral deterioration may be a concern when initiating a new AED, CLB [clobazam], LEV [levetiracetam], RFM [rufinamide], GBP [gabapentin], [and] TPM [topiramate] are generally to be avoided, and LTG [lamotrigine] might be better.”11

Enhance Cognitive Outcomes in Epilepsy

A long-term follow-up study of patients following temporal lobe epilepsy surgery, conducted by Helmstaedter and colleagues, revealed that cognitive course is usually stable and may even improve if epilepsy symptoms remain controlled and AED regimens can be reduced.12 Although recovery occurred more frequently than continuing decline when surgery successfully controlled seizures, Helmstaedter and colleagues cautioned that “recovery takes time and that age is a limiting factor.”12

In a review of studies with the ketogenic diet, which has been applied to control seizures in some patients with drug-refractory epilepsy, Annemiek van Berkel, a PhD candidate in the Department of Functional Genomics at the Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, in The Netherlands, and colleagues found that the intervention can lead to cognitive benefits. Although the putative cognitive benefit could have been linked to seizure reduction, it appeared independent of reduced AED.13

Van Berkel and colleagues found that studies using subjective measures had identified improvements in the domains of alertness, attention, and global cognition. When objective measures were applied, benefits on alertness were confimed but without improvement in global cognition.

“There are indications that these improvements are caused by both seizure reduction and directs effects of ketogenic diet on cognition,” van Berkel and colleagues related.13

Interventions that have been investigated for possible direct enhancement of cognitive outcomes in epilepsy include pharmacologic agents as well as neuromodulatory interventions. In a recent review, Claire Jacobs, MD, PhD, of the Division of Epilepsy, Department of Neurology, at Massachusetts General Hospital and Harvard Medical School, in Boston, and colleagues considered the potential cognition benefit of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) and of agents in 3 pharmacologic classes: the acetylcholinesterase inhibitors donepezil and galantamine, the N-methyl-D-aspartate noncompetitive antagonist memantine, and the psychostimulant methylphenidate.14

They reported that no efficacy on cognitive performance in epilepsy had been found with the acetylcholinesterase inhibitors, which they attributed to the memory dysfunction in epilepsy being mediated by mechanisms other than loss of cholinergic neurons. Although a trial with memantine suggested some benefit, the investigators noted that it might have reflected the effect of study participation and that it would need to be replicated before any conclusions could be drawn.

Methylphenidate appeared to improve mood and processing speed without increasing seizure activity, but Jacobs and colleagues cautioned that the risks of increased seizure frequency with long-term use remain to be determined. They also found that TMS appeared to have some beneficial effect on the Stroop test for selective attention capacity but not on any other cognitive measures. The tDCS was associated with some improvement in declarative memory in a group who took a nap after the procedure but not in those without the nap.

“Research into noninvasive neuromodulation is ongoing,” Jacobs and colleagues indicated, “and it may still have a role in cognitive enhancement through reduction in frequency of epileptiform discharges, sleep-dependent memory consolidation, or other mechanisms.” 14

Helmstaedter and Witt agreed with the need for further research into assessing and enhancing cognition in epilepsy that focuses on targets other than the processes underlying seizures. Research directed primarily on the seizures, they indicated, assumes that the patient’s other problems would be resolved if the seizures were controlled.

“However, this is not the case, and just focusing on the seizures may prevent the search for any underlying, active, or past disease process [that], when treated, may improve the patient’s overall condition, including cognitive and behavioral problems,” Helmstaedter and Witt advised.1

Loring opined that “there [may be] some sort of common, underlying brain substrate that predisposes a person to express...either some behavioral problems, cognitive problems, or actually the seizures themselves.”
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3. Holmes GL. Cognitive impairment in epilepsy: the role of network abnormalities. Epileptic Disord. 2015;17(2):101-116. doi: 10.1684/epd.2015.0739.
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11, Ulate-Campos A, Fernández IS. Cognitive and behavioral comorbidities: an unwanted effect of antiepileptic drugs in children. Semin Pediatr Neurol. 2017;24(4):320-330. doi: 10.1016/j.spen.2017.10.011.
12. Helmstaedter C, Elger CE, Vogt VL. Cognitive outcomes more than 5 years after temporal lobe epilepsy surgery: remarkable functional recovery when seizures are controlled. Seizure. 2018;62:116-123. doi: 10.1016/j.seizure.2018.09.023.
13. van Berkel AA, Ijff DM, Verkuyl JM. Cognitive benefits of the ketogenic diet in patients with epilepsy: a systematic review. Epilepsy Behav. 2018;87:69-77. doi: 10.1016/j.yebeh.2018.06.004.
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