Address correspondence to Matthias J. Koepp, UCL Institute of Neurology, 33 Queen Square, London WC1N 3BG, U.K. E-mail: firstname.lastname@example.org
Juvenile myoclonic epilepsy is the most common idiopathic epilepsy syndrome and is considered a benign seizure disorder that responds well to antiepileptic drug treatment, in particular sodium valproate. By definition, routine brain imaging shows no abnormalities, but advanced imaging studies have identified functional and structural abnormalities in the frontal cortex and thalamus. Neuropsychological studies revealed subtle cognitive deficits in patients with JME, mainly implicating the frontal lobes. These findings are in keeping with anecdotal reports of behavioral problems in JME. Cognitive dysfunction in otherwise healthy siblings of patients with JME and a high heritability support the concept of a genetically determined thalamo-frontocortical network dysfunction, accounting for the cognitive impairment and cognitively triggered “motor seizures.”
Juvenile myoclonic epilepsy (JME) is a common idiopathic epilepsy syndrome affecting up to 10% of all epilepsies (MacAllister & Schaffer, 2007) with a high genetic predisposition (Zifkin et al., 2005). Patients present with symmetric, myoclonic jerks, mostly affecting upper limbs, generalized tonic–clonic seizures, and more rarely absence seizures. Disease onset peaks between the ages of 14 and 16 years, with a range of 8–26 years. Seizures commonly follow a circadian rhythm with preponderance upon awakening (Janz, 1985).
In early reports, Janz (1985) anecdotally described a JME-specific personality profile, which is similar to behavioral changes observed in patients with frontal lobe injuries, characterized by social immaturity, disinhibition, and lack of endurance. The electroencephalography (EEG) typically shows bilateral spike or polyspike and wave discharges, often with a frontocentral emphasis (Montalenti et al., 2001). By syndrome definition, routine brain imaging shows no pathology (ILAE, 1989).
Early histopathologic studies in patients with idiopathic generalized epilepsy report subtle gray and white matter abnormalities, suggestive of microdysgenesis (Meencke & Janz, 1985). However, these findings could not be replicated in a controlled and blinded study (Opeskin et al., 2000). Quantitative analysis of high resolution magnetic resonance imaging (MRI) identified changes of the medial prefrontal cortex (Woermann et al., 1999; O’Muircheartaigh et al., 2011), as well as the thalamus (Pulsipher et al., 2009), with molecular imaging studies reporting abnormalities of the dorsolateral prefrontal cortex (Koepp et al., 1997), indicative of an underlying thalamo-frontocortical network dysfunction. In keeping with this hypothesis, neuropsychological studies have reported subtle cognitive deficits affecting mainly frontal lobe functions.
This review aims to critically reflect upon the available evidence on cognitive impairment and its potential pathophysiology in JME, focusing on frontal lobe functions, that is, working memory, executive functions, and prospective memory. A PubMed search was carried out using combinations of the keywords “juvenile myoclonic epilepsy,”“cognition,”“cognitive dysfunction,”“executive functions,” and “working memory.” Original and review articles, as well as relevant citations were included. Fifteen original articles were identified (see Table S1). In addition, the phenomenon of cognitive seizure precipitants is briefly discussed.
Frontal Lobe Functions
The frontal lobes play an important role in cognitive functions, such as working memory, executive functions, and prospective memory.
Working memory is a limited capacity system that enables the short-term storage and immediate manipulation of recently acquired information. It is an indispensable component of complex cognitive functions, such as reasoning. A generally acknowledged working memory model by Baddeley (1986) identifies two separate subsystems for initial processing and short-term storage: the visual-spatial sketchpad for nonverbal information and the phonologic loop for verbal information. Both systems are supervised and coordinated by an attentional control system, the central executive. The episodic buffer, a recently added component, stores information in a multidimensional code and is crucial for long-term episodic learning (Baddeley, 2000).
Executive functions are higher cognitive processes that facilitate a flexible adaption to novel situations while overcoming learned and stereotyped behavioral patterns (Gilbert & Burgess, 2008). Executive functions comprise a set of distinct processes that are closely interlinked; examples are the ability to suppress a learned behavioral response that is currently not purposeful (response inhibition), planning, switching between different tasks (flexibility; task organization and switching), and initiating an action despite absent external prompting (self-initiation).
Prospective memory (PM) describes the ability to fulfill previously planned intentions (Ellis, 1996). Successful PM performance is indispensable for managing activities of daily living, for example, remembering to post a letter or to take food out of the oven on time. In patients with acquired brain injuries, PM dysfunction restricts their ability to cope with activities of daily living (Kinsella et al., 1996) and represents an important predictor for leading an independent life (Thoene-Otto & Walther, 2001). According to Ellis’ model (Ellis, 1996), PM comprises four different phases: Intention formation, during this phase a specific intention is developed and its successful implementation planned; during intention retention, the intention has to be actively remembered despite ongoing activities and distracting stimuli; intention initiation describes the recognition of the intention-related cue in order to initiate the intention; intention execution is the fulfillment of the intention in accordance with the initial plan. Successful PM performance requires intact executive functions. Kliegel et al. (2000) correlated executive functions with PM performance in 80 healthy adults and showed that intention formation depends on planning abilities, intention initiation and execution on response inhibition and working memory, respectively.
Neuropsychological and Imaging Studies in JME
Basic cognitive functions: general cognitive abilities, attention, and episodic memory
Sonmez et al. (2004) found no differences between JME patients and healthy controls using digit span to estimate global attention. Roebling et al. (2009) did not find any impairment of attention in JME using the Trail Making Test and the Stroop Test. In contrast, patients were affected on both tests in a different study population (Pascalicchio et al., 2007). Another study reported significantly slower reaction times in patients with JME compared with healthy controls on a measure of alertness (Wandschneider et al., 2010).
Functions of the temporal lobes, such as verbal and nonverbal episodic memory, are generally reported as spared (Roebling et al., 2009; Wandschneider et al., 2010). Two studies, however, have reported more widespread cognitive dysfunction. Sonmez et al. (2004) observed verbal and nonverbal learning deficits in addition to impairments on a range of frontal lobe tasks. In a study of 50 patients with JME and 50 controls, Pascalicchio et al. (2007) reported weak short- and long-term verbal and long-term nonverbal memory. The JME group was globally impaired in almost all other cognitive domains, including IQ, attention, processing speed, working memory, and executive functions. The findings of both these studies do not provide specific evidence for compromised temporal lobe functions.
Working memory in neuropsychological and imaging studies
Swartz et al. (1994) performed a visual working memory study, using patients with JME initially as a “patient control” group for comparisons of 15 patients with frontal lobe epilepsy (FLE), nine patients with JME, and 15 healthy controls. Pairs of abstract visual images were presented and subjects had to indicate by pressing a button whether the images matched. Defined by the delay between the two images, two conditions were created: The immediate match to sample task (IMS), with an image delay of 100 msec, controlled for attention, motivation, motor function, and habituation, and the delayed match to sample task (DMS), with an image delay of 8,000 msec, evaluated visual working memory. Two categories of errors (match-on-mismatch and mismatch-on-match) were recorded as well as reaction times. The FLE group presented with the weakest performance showing impairment on both tasks, particularly during the DMS condition. The JME patients’ performance was comparable to controls on the IMS task, but it was impaired during the DMS, the working memory condition, holding an intermediate position between the FLE group and the controls. Age and educational level were not found to be related to test performance.
In a subsequent 18-fluorodeoxyglucose–positron emission tomography (18FDG-PET) study, the same visual working memory paradigm was evaluated in nine patients with JME and 14 controls (Swartz et al., 1996). The JME group performed less well than the controls on the working memory task, whereas performance during the IMS task was again comparable in both groups. At resting state, 18FDG uptake in patients was decreased in the ventral premotor cortex, caudate, the dorsolateral prefrontal cortex (DLPFC) bilaterally, and the left premotor area, representing widespread frontal impairment. Controls activated areas that are thought to support working memory function, whereas patients presented with a “hypofrontality state” (Swartz et al., 1996) in keeping with their poorer performance on the DMS task. Increased metabolism of the lateral orbital and medial temporal regions in the JME group was interpreted as a compensatory mechanism for prefrontal dysfunction. The authors concluded that dysfunctional thalamo-frontocortical networks might account for both ictogenesis and poor working memory performance in JME.
A more recent functional imaging study examined 19 patients with JME using a verbal and nonverbal functional MRI (fMRI) working memory paradigm (Roebling et al., 2009). During the visual-spatial paradigm, subjects were assessed with a modified version of the Sternberg Item Recognition Test. A visual grid was presented, holding either a triangle or a square, and subjects were asked to memorize the positions of the items within the grid. After an interval, the grid was presented again, containing either a triangle or a square. Participants had to decide whether one of the symbols had been in the same position in the previous grid, irrespective of shape. During the verbal memory task, phonologically similar letters were shown, either in upper or lower case. During the response condition, a single letter was presented, and subjects had to decide whether it had been shown in the previous condition, irrespective of case. Both groups performed equally well on these tasks and no significant group differences were detected on fMRI-activation patterns. The authors suggested that these inconsistent findings may indicate a heterogeneous epilepsy syndrome, in which frontal lobe dysfunction is present only in a JME subgroup. However, this failure to detect differences between groups might be caused by an insufficiently challenging working memory task.
Vollmar et al. (2011) investigated a larger JME population (n = 30) with a different, and more challenging, working memory fMRI paradigm, the dot back task (Kumari et al., 2009). During the task, dots were randomly presented on a spatial grid. There were three different response conditions: During the “0-back” task, participants were instructed to move a joystick toward the current position of the dot; in the “1-back” condition to the position of the dot in the previous grid and in the “2-back” to its position two stimuli back. Patients and controls performed equally well on all three tasks and showed significant fMRI activation of working memory networks, after subtracting “0-back” from “1-back” and “2-back” in order to control for the motor component. FMRI cortical activation patterns, however, differed significantly with increasing task demand. During the “2-back” condition, the motor cortex and supplementary motor area (SMA) increasingly coactivated with working memory networks in patients (Fig. 1). The authors also described increased functional connectivity between the motor system and areas of higher cognitive functions within the frontal and parietal lobes. This increased functional connectivity in the JME group was interpreted as a possible mechanism for seizures triggered by cognitive effort, in line with clinical observations that myoclonic jerks are often precipitated by cognitive tasks (Inoue & Kubota, 2000). These studies underscore the importance of imaging studies to detect differences in cognitive networks, whereas group differences are too subtle to be detected during conventional neuropsychological testing.
Executive functions in neuropsychological and imaging studies
Executive functions in JME are controversially discussed (see Table S2).
Devinsky et al. (1997) assessed 15 patients with JME and 15 with TLE, with tests sensitive to executive functions: inhibition and psychomotor speed (Trailmaking Test, Stroop Test); abstract reasoning, concept formation and, mental flexibility (Wisconsin Card Sorting Test [WCST], Booklet Categories Test); planning (Mazes from the WISC-R); and verbal fluency (Controlled Oral Word Association Test). In the JME group, performance was variable. Some patients were impaired on only 3 of 11 tests, whereas others were impaired on at least 4 tests. The poorest results were reported for concept formation and mental flexibility (60–64% of patients impaired), followed by cognitive speed (47–53% of patients) and planning (33%). In comparison with the TLE group, patients with JME performed less well on tests requiring mental flexibility and concept formation. No specific pattern of cognitive dysfunction was elicited in JME, although the authors concluded that their findings were supportive of frontal lobe dysfunction, which may lead to maladaptive behavior with social consequences.
To date, few imaging studies evaluated structural and functional brain correlates of executive dysfunction in JME.
In a quantitative MR spectroscopy (MRS) study, Savic et al. (2004) compared patients with either JME or idiopathic generalized epilepsy (IGE) with generalized tonic–clonic seizures (GTCS) to a group of healthy controls. N-Acetyl aspartate (NAA) is a neuron-specific metabolite. Reduced levels can be associated with neuronal dysfunction or damage (Savic et al., 2000). The authors reported reduced frontal lobe NAA concentrations in the JME group (n = 25) in relation to both healthy controls (n = 10) and GTCS patients (n = 20). In addition, JME patients with low frontal NAA concentrations showed frontal lobe dysfunction on a brief neuropsychological assessment. In contrast, frontal lobe functions were spared in JME patients with normal NAA concentrations, GTCS patients, and controls. Hence, although a prefrontal neuronal lesion may be present in some JME patients, JME seems to be a heterogeneous condition. Low NAA levels did not correlate with any other clinical parameter, such as current seizure frequency or seizure number over lifetime.
Pulsipher et al. (2009) aimed to investigate the integrity of thalamo-frontocortical networks in relation to executive function in recent-onset JME. Twenty JME patients within 12 months of diagnosis were compared to an epilepsy control group of 12 patients with recent-onset benign childhood epilepsy with centrotemporal spikes (BECTS) and 51 healthy controls (first-degree cousins). Groups were matched for gender, duration of epilepsy, and IQ. JME patients were significantly older than both the BECTS and healthy control groups, yet age was not found to be related to test performance. Participants were assessed with three subtests of the Delis-Kaplan Executive Function System (D-KEFS) and a questionnaire for parents, the Behavior Rating Inventory of Executive Function (BRIEF). JME patients performed less well than controls on D-KEFS Inhibition. Behavioral Regulation and Metacognition scores of the BRIEF were also significantly lower in the JME group. Quantitative MRI measurements revealed smaller thalamic volumes and greater frontal cerebrospinal fluid (CSF) in JME patients than in healthy controls and BECTS patients. Thalamic and frontal volumes predicted D-KEFS performance only for the JME group. Of interest, JME patients were showing volumetric abnormalities already within 12 months of seizure onset, suggesting a clinically significant disruption of the thalamo-frontocortical circuitry, leading to both seizures and neurocognitive deficits. It remains uncertain how early structural abnormalities present in disease evolution, although the distinct volumetric abnormalities seem unlikely to be the result of chronic seizures.
In a resting FDG-PET study (McDonald et al., 2006), regional cerebral rates of glucose uptake values (rCMRGlc) were regressed on various executive function test scores in patients with frontal lobe epilepsy (FLE; n = 18), JME (n = 10) and healthy controls (n = 14). The executive function battery included measures of cognitive flexibility, fluency, response inhibition, working memory, and sustained attention. In the JME group, frontal hypometabolic values predicted impairment on measures of figural fluency and cognitive flexibility.
O’Muircheartaigh et al. (2011) reported subtle dysfunctions in verbal fluency, comprehension and expression, mental flexibility, and response inhibition in a cohort of 28 JME patients. In a structural and diffusion tensor MRI (DTI) study, voxel-based morphometry revealed reductions in gray matter volume in the SMA and posterior cingulate cortex. Fractional anisotropy (FA) in the SMA predicted performance in tasks of word naming and expression. Gray matter volumes of the posterior cingulate cortex and FA correlated with scores on the mental flexibility task. The authors describe their JME cohort as relatively high functioning but with neuropsychological evaluation revealing subtle cognitive impairments.
The finding of reduced frontal FA was recently replicated in another JME cohort (Kim et al., 2012) and correlated with disease severity but not with the reduced neuropsychological performance observed in JME.
A diffusion tensor tractography study in JME revealed increased structural connectivity between the prefrontal cortex and the motor cortex and SMA, which correlated with the functional connectivity of adjacent areas depicted by fMRI, supporting the hypothesis of network alterations facilitating the cognitive triggering of seizures. The authors discussed that an increased proportion of fibers crossing the SMA could be an explanation for reduced FA findings in the mesial frontal region, rather than neuronal loss (Vollmar et al., 2012).
In summary, imaging studies support dysfunction within thalamo-frontocortical networks as possible neuronal correlate of executive function impairment in JME.
Cognitive abilities of patients with epilepsy can be influenced by several factors. Evidence relating to disease activity, subclinical epileptiform discharges, genetic factors, and medication are briefly discussed.
Parameters of disease activity include seizure frequency and disease duration. Pascalicchio et al. (2007) reported a positive correlation of disease duration and the risk of cognitive impairment in JME. Vollmar et al. (2011) observed abnormal motor-cortex coactivation in an fMRI working memory task, which was more prominent in patients with a more active disease and shorter seizure-free interval. However, another study reported no association of disease duration and cognitive impairment (Sonmez et al., 2004).
Subclinical epileptiform discharges
The phenomenon of transitory cognitive impairment (TCI) during subclinical epileptiform discharges has been reported in up to 50% of epilepsy patients (Binnie, 2003). Associated deficits were reported to be site and material specific, that is, impairment occurs in the cognitive domain related to the area where subclinical discharges occur. However, the distinction between subclinical and clinically evident discharges is challenging, as illustrated by Porter and Penry (1973). They applied a paroxysm-triggered method to measure reaction time as an indicator of responsiveness at specific time points during spike-wave discharges of absence seizures. Fifty-four percent of reaction times were reported abnormal at the onset of spike-wave discharges. The relationship of generalized spike-wave discharges and cognitive functions has been studied mostly in patients with absence seizures (Blumenfeld, 2005). The level and nature of cognitive impairment is highly variable. It has been suggested that specific subcortical-cortical networks are preferentially involved even in “generalized” seizures, which may account for some of the variability (Blumenfeld, 2005). This is supported by a recent EEG-related fMRI study (Aghakhani et al., 2004), showing that the cortical areas that are activated during generalized discharges differ among patients and may extend the spatial distribution of spike-wave in the EEG. Surprisingly, the blood oxygen level dependent–response was highly variable in terms of activation or deactivation in the thalamus and cortex.
Findings of cognitive impairment depend on tests applied and are more likely to be detected with higher cognitive load (Binnie, 2003). Impairments have been especially observed in tasks requiring a response to verbal questions, decision making, complex motor performance, and short-term memory. Deficits were more subtle when discharges occurred without any obvious clinical manifestation (Binnie, 2003; Blumenfeld, 2005). Greater discharge generalization and amplitude, as well as longer duration and frontocentral distribution, have been associated with worse performance in some studies (Blumenfeld, 2005).
In JME, Lavandier et al. (2002; cited by Hommet et al., 2006) investigated performance on cognitive tasks in relation to subclinical EEG discharges in a JME cohort. Executive function tasks were administered during continuous EEG and video monitoring. In view of the circadian seizure distribution in JME, the assessment was always performed in the morning. Patients who presented epileptiform discharges during rest were significantly more impaired on tests of abstract reasoning, concept formation, and mental flexibility than patients without paroxysmal EEG changes. There was no increase in EEG abnormalities during the cognitive tasks. Whether executive dysfunction is at least partially attributable to interictal paroxysmal discharges still remains to be ascertained.
In the above-discussed studies, only Swartz et al. (1994) correlated performance to interictal EEG changes and reported no interaction.
Several studies attribute adverse effects of antiepileptic medication on cognition (for overview see, e.g., Hermann et al. (2010)). Processing speed and sustained attention are among the domains most vulnerable. In the studies reviewed herein, antiepileptic medication was varied and the study samples were relatively small, rendering the statistical analysis of the impact of specific antiepileptic drugs difficult. Swartz et al. (1994) divided patients into groups with sedative (phenobarbital, primidone, and/or phenytoin) and nonsedative (carbamazepine and/or valproic acid [VPA]) medications. They found no association between the type of medication and the performance variables correct responses and reaction time. Roebling et al. (2009) compared patients taking VPA to untreated patients or patients on lamotrigine (LTG) monotherapy, respectively. The VPA group was significantly more impaired on the verbal memory test, and the authors concluded that cognitive dysfunction in this cohort is at least partially caused by medication side effects. On the contrary, Vollmar et al. (2011) reported a beneficial VPA effect in JME. In their fMRI working memory study, abnormal left motor cortex coactivation correlated negatively with an increasing daily VPA dose, implying a “normalization” of function through VPA, which may also reflect its beneficial effect in suppressing motor seizures.
Therefore, the evidence on possible confounders of cognitive performance in JME remains inconclusive. One study even reported no correlation with any clinical variable, that is, disease duration, seizure frequency, seizure type, and seizure treatment (Piazzini et al., 2008).
JME is characterized by a high genetic predisposition and syndrome concordance (Marini et al., 2004; Zifkin et al., 2005). Hence, neuropsychological family studies enable the investigation of whether a distinct cognitive impairment pattern is genetically determined and part of the epilepsy syndrome.
Sonmez et al. (2004) correlated family history of seizures with cognitive outcome in their cohort. In patients with a positive family history, more general cognitive impairment, as well as dysfunction of the right hemisphere and frontal lobes was reported.
Studies in healthy siblings may also allow evaluation of JME specific cognitive traits without seizure-related confounders, such as medication or seizure frequency.
Three neuropsychological family studies were identified. Levav et al. (2002) investigated 10 JME families, 25 families with childhood absence epilepsy (CAE), 30 TLE, and 16 healthy control families. Epilepsy families were defined by one affected family member. In the JME group, 11 patients and 19 first-degree relatives were investigated. The test battery was age-group adapted and assessed sustained attention, encoding and verbal memory, executive and focused attention, and attentional flexibility/regulation of impulsivity. When all scores were compared, relatives’ performance tended to fall between those of the patients’ group and controls’. Among the relatives, JME relatives acquired the lowest scores for sustained attention and mental flexibility. However, 3 of 19 JME relatives had a neuropsychiatric disorder, which might also account for cognitive impairment.
Iqbal et al. (2009) assessed eight pairs of JME patients and unaffected siblings during and without video-EEG monitoring. Performance was compared to a control group. The neuropsychological test battery included tests of intelligence, visual-spatial skills, language, memory, attention and reaction time, as well as executive functions. Patients and siblings were tested at the same time of the day, accounting for circadian variability of disease activity in JME. Patients were more impaired than controls on tests of semantic and phonemic fluency. Siblings held an intermediate position between patients and controls on these two tests, presenting no significant differences in comparison to either group, indicating subtle cognitive under-functioning. In addition, patients more frequently reported behavioral traits associated with executive dysfunction (i.e., impulsivity) on a behavior rating scale. Impaired cognitive performance appeared to be independent of subclinical EEG discharges, as no discharges were recorded during testing.
Wandschneider et al. (2010) investigated performance on a complex prospective memory (PM) paradigm in addition to measures of executive functions, working memory, attention, verbal and nonverbal memory, and general intellectual abilities. Patients (n = 19), unaffected siblings (n = 21), and controls (n = 21) were matched for age, gender, and educational exposure. The PM paradigm allowed the evaluation of different phases, namely, intention formation, intention retention, intention initiation, and execution. Patients and siblings developed less complex plans than controls during intention formation. During intention execution, both groups presented significantly more rule breaks than controls. In addition, patients completed fewer tasks. JME patients were impaired on verbal fluency and response inhibition. It is assumed that PM performance is highly dependent on executive function (Kliegel et al., 2000). Hence, performance during each PM phase was correlated post hoc with scores on executive function measures. As expected, planning abilities predicted overall performance during intention formation, and response inhibition and planning performance during intention execution. In a post hoc subgroup analysis, there was only a significant correlation between intention formation and planning in the healthy control group. Surprisingly, patients and siblings were unimpaired on a specific measure for planning performance (Tower of London task). This may indicate that patients and siblings fail to use their planning abilities efficiently when they are needed in more cognitively demanding tasks, such as the PM paradigm.
Overall, the findings of these three studies provide some support for the concept of a genetically determined distinct cognitive impairment pattern in JME. Patients are generally more impaired than their siblings, probably as a consequence of other disease-related factors such as medication side-effects.
Seizure Precipitation by Cognitive-Motor Function
Cognitive performance may be modulated by seizure frequency and subclinical epileptic discharges in JME. Conversely, cognitive-motor function has been identified as a seizure precipitant. The term praxis-induced epilepsy was introduced by Inoue et al. (1994) in order to emphasize the crucial role of the motor component during cognitive tasks in seizure precipitation. Seizures are provoked by dealing with a “complicated spatial task in a sequential fashion, making a decision and practically responding by using part of the body” (Inoue et al., 1994). Matsuoka et al. (2000) studied 480 epilepsy patients who underwent cognitive testing, which included measures of reading, speaking, writing, written calculation, mental calculation, and spatial construction during EEG recordings. A task-related excitatory EEG effect was found in 38 patients, mainly during tasks combining higher mental activity and hand movement (36/38 patients). Twenty-two of these 36 patients had JME. Similar findings were reported by Guaranha et al. (2009), who investigated 76 JME patients with a neuropsychological protocol during a video-EEG examination. Thirty-eight percent of patients demonstrated a provocative effect, particularly on action-programming tasks. Myoclonic jerks were the most common seizure type triggered.
Other reflex mechanisms, implicating parietal cortex functions, have been described in a patient cohort with features of idiopathic generalized epilepsy (Goossens et al., 1990). Myoclonic jerks were present in the majority of patients (76%), and the clinical pattern was suggestive of JME in most cases. Seizures were evoked by calculation, measuring, or cognitive spatial tasks, such as playing cards, chess, or drawing complex figures. In some cases, seizures can also be triggered and voluntarily induced by thinking, that is, noogenic seizures. Typically, the triggering mental activity is complex, and involves decision making and also emotional stress (Koutroumanidis et al., 1998).
Perioral reflex myoclonias (PORMs) are more frequent in JME than in focal epilepsies, despite their assumed localized reflex-like mechanism (Mayer et al., 2006). PORMs are induced by reading, speaking, or neuropsychological activation (Mayer et al., 2006).
Regions of cortical hyperexcitability may overlap with areas physiologically activated during cognitive or motor activities. Hence, a complex task involving several functional cortical systems may summon a critical mass of cortex activated, which leads to seizure precipitation (Ferlazzo et al., 2005). Recent fMRI findings (Vollmar et al., 2011) reporting an abnormal motor cortex coactivation during a working memory task, may represent the functional correlate of this mechanism.
The available evidence indicates a distinct cognitive impairment pattern in JME, although study numbers are limited and sample sizes are small. Generally, cognitive impairment patterns are mild but may have an impact on daily life functioning. Neuropsychological and functional imaging studies suggest frontal lobe cognitive functions are predominantly affected. However, structural imaging does not reveal underlying pathology on an individual level. Microstructural abnormalities have been described on a group level (Woermann et al., 1999; Vollmar et al., 2012), pointing to the SMA being a crucial hub in a thalamo-frontocortical network. Frontal lobe impairment appears to become more evident at a higher cognitive load, which may account for the variability among the findings with “normal” performance in JME patients on tests that are not sufficiently challenging. This also supports the idea of a dynamic network for both cognitive functioning and ictogenesis, in which “abnormalities” become more apparent as soon as a critical mass of the network is involved. The pathophysiologic concept of a genetically determined thalamo-frontocortical network dysfunction in JME is supported by family studies reporting subtle cognitive impairment in otherwise unaffected siblings of patients.
B.W. was supported by an ENS fellowship. This work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres’ funding scheme.
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.