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Purpose: The aim of the present study was to investigate the possible frontal cognitive dysfunction in patients with juvenile myoclonic epilepsy (JME) and to compare the results with those of patients with frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE), as well as with controls.
Methods: A total of 50 patients with JME, 40 patients with FLE, 40 patients with TLE, and 40 normal controls, all matched for age, education, and IQ, were administered tests to assess frontal functions (the Word Fluency Test and the Wisconsin Card Sorting Test [WCST]). All participants had a normal intelligence level based on the Wechsler Adult Intelligence Scale, and did not take medications other than antiepileptics (AEDs) or have a psychiatric history.
Results: Patients with JME had severe impairment in all administered tasks, similar to that of patients with FLE; TLE patients and controls followed in order. Multiple regression analysis did not disclose any significant effect of clinical variables on the cognitive deficits.
Discussion: These results clearly suggest that JME patients can show some frontal dysfunction, which may affect both epileptogenic features and cognitive processes. Further studies are needed to confirm these findings.
Juvenile myoclonic epilepsy (JME) was first recognized as a syndrome by Janz and Christian in 1957 (Janz & Christian, 1957). According to the Revised Classification of Epilepsies and Epileptic Syndromes, JME is characterized by seizures with bilateral, single or repetitive, arrhythmic, irregular, myoclonic jerks, predominantly in the arms (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). There are often generalized tonic–clonic seizures and, sometimes, absences. The seizures usually occur shortly after awakening and are often caused by sleep deprivation. Interictal and ictal EEG have rapid, generalized, often irregular, spike and polyspike waves. The disorder may be inherited and the gender distribution is equal. The response to appropriate drug treatment is generally good (Janz, 1997). It has been noted that JME may be related to some specific personality characteristics, such as impressionability, unreliability, emotional instability, characteristics which are similar to those observed in patients with frontal lobe lesions (Janz & Durner, 1997; Hommet et al., 2006). Some cognitive functions are impaired in patients with frontal lobe epilepsy (FLE); concept formation, abstract reasoning, mental flexibility, and planning have been reported to be dysfunctional in JME patients as well (Bech et al., 1977; Karachristianou et al., 2004).
The neuropsychiatric profiles of patients with JME have been evaluated in several studies (Perini et al., 1996; Trimble, 2000; Gelisse et al., 2001; de Araujo et al., 2006; Trinka et al., 2006; de Araujo et al., 2007; Plattner et al., 2007), while very few investigations have been dedicated to describing the cognitive deficits of this syndrome. Devinsky et al. administered a battery of neuropsychological tests sensitive to frontal dysfunction to 15 patients with JME and 15 patients with temporal lobe epilepsy (TLE) (Devinsky et al., 1997). The patients with JME performed worse than the TLE group on some frontal tasks, even though the results of the patients with JME were not homogeneous (Devinsky et al., 1997). Another study highlighted that patients with JME had impaired visual working memory; this deficit was intermediate between controls and FLE (Swartz et al., 1994). Sonmez et al. (2004) and Pascalicchio et al. (2007) reported similar results, confirmed by others published in abstract form, which pointed out the existence of specific disturbances in executive function processes in JME patients (Gershengorn et al., 1992; De Toffol et al., 1997; Lavandier et al., 2002). Savic et al., besides, found prefrontal cerebral changes in JME (Savic et al., 2000). More particularly, these authors noticed significantly reduced prefrontal concentrations of N-acetyl aspartate (NAA) in patients with JME compared to controls, which could indeed support the hypothesis of prefrontal neuronal lesion and, consecutively, the presence of a specific cognitive impairment related to this dysfunction.
Considering that all the previous investigations did not include large samples of patients and did not simultaneously analyze the neuropsychological data in different types of epilepsy, we initiated a new project on the possible neuropsychological dysfunction associated with JME in order to provide more detailed information. In fact, no study has been carried out thus far that has compared the cognitive profile of patients with JME with those of patients with FLE, TLE, and normal controls.
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Patients with JME had a significant impairment in all the administered tasks assessing frontal functions compared to TLE patients and controls (p < 0.05). These deficits were similar to those of FLE patients (p > 0.05) (Table 2). A pairwise comparison between the controls and the epilepsy groups is reported in Table 3.
Table 2. Cognitive performances of FLE, JME, TLE, and controls
| ||FLE (n = 40)||JME (n = 50)||TLE (n = 40)||Controls (n = 40)||F||p|
| Categories (mean)||3.4||3.9||4.8||5.6||9.330||<0.05|
| SD||1.6||1.5||1.4||0.8|| |
| Perseverative resp. (mean)||29.3||28.2||11.8||6.8||41.831||<0.05|
| SD||12.1||12.8||10.3||1.1|| |
| Errors (mean)||46.8||46.2||16.6||7.5||73.602||<0.05|
| SD||12.3||14.4||11.5||1.9|| |
|• Word fluency (mean)||15.5||16.7||25.6||26.7||19.675||<0.05|
| SD||8.6||9.7||7.8||5.4|| |
Table 3. Pairwise comparison between the controls and the epilepsy groups
| ||WCST categories||WCST perseverative resp.||WCST errors||Word fluency|
|JME vs. FLE||p = 0.089||p = 0.447||p = 0.653||p = 0.563|
|JME vs. TLE||p = 0.000||p = 0.000||p = 0.000||p = 0.000|
|JME vs. controls||p = 0.000||p = 0.000||p = 0.000||p = 0.000|
|FLE vs. TLE||p = 0.000||p = 0.000||p = 0.000||p = 0.000|
|FLE vs. controls||p = 0.000||p = 0.000||p = 0.000||p = 0.000|
|TLE vs. controls||p = 0.090||p = 0.000||p = 0.003||p = 0.513|
The linear regression analysis performed in the JME group showed that no clinical variables, such as the duration of epilepsy, the frequency of seizures, the treatment, the type of seizures were associated with the neuropsychological impairment identified (Table 4).
Table 4. Multiple regression analysis of four independent variables on frontal tests in patients with JME
| ||WCST categories||WCST errors||WCST perseverative responses||Word Fluency Test|
|Duration of epilepsy||0.406||0.687||−0.756||0.452||−0.965||0.340||0.657||0.514|
|Frequency of seizures||−0.308||0.759||0.166||0.869||0.617||0.540||−0.279||0.781|
|Type of seizures||−1.476||0.147||0.210||0.834||0.039||0.969||−1.207||0.234|
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The linear regression analysis performed indicated that the frontal cognitive deficits in patients with JME were not associated with other clinical factors, such as the duration of the pathology, the frequency of seizures, the treatment or the type of seizures. Some authors have hypothesized that these deficits may be mainly due to some neuroanatomic changes or to the effect of interictal spike-wave discharge on metabolism (Engel et al., 1982; Theodore et al., 1985; Rodin & Ancheta, 1987; Savic & Pauli, 1994).
Our results testify that JME patients have a serious impairment in frontal functions, meaning deficits in the cognitive processes involved in planning, concepts formation, elaborating strategies for the attainment of immediate or future goals, and verbal fluidity (Hommet et al., 2006). Swartz et al. confirmed the existence of similar neuropsychological deficits in JME, probably due to a cortical disorganization, which deeply affects frontal lobe functioning (Swartz et al., 1996). In an 18FDG-PET study, these authors documented an inability to activate the dorsolateral prefrontal, premotor and basal frontal cortex during a visual working memory paradigm. During this task, patients with JME, unlike control subjects, activated medial temporal structures.
Neuropathological studies of the brain in JME patients have noted the presence of microdysgenetic lesions in the neocortex and subcortical white matter of the frontal lobes and the hippocampus, which suggests a disorder in neuron migration and cortical disorganization (Mencke & Janz, 1984; Meeke, 1995; Hommet et al., 2006). Similar results were reported also by Simister et al. (2003), who analyzed patients with idiopathic generalized epilepsy by a point-resolved spectroscopy (PRESS)-localized short echo time MR spectroscopy (MRS). Woermann et al. (1999), using an interactive anatomical segmentation technique and volume of interest measurements by MRI, noted an increase in cortical grey matter in the mesial frontal lobe of patients with JME, pointing out a structural cerebral abnormality with the involvement of mesiofrontal cortical structures as well.
The cognitive deficits which exist in patients with JME can also be ascribed to epileptiform activity, which in JME is typically generalized 4–6 Hz spike-wave activity, maximum in the frontocentral regions (de Araujo wt al., 2006; Devinsky et al., 1997). For this reason, it is possible to speculate that patients with JME may show some specific impairment that anatomically corresponds with the seizure area, considering that the interactions between epileptiform EEG discharges and cognitive performances are complex and reciprocal (Tassinari & Rubboli, 2006). Lavandier et al. (2002) further investigated the link between epileptiform EEG discharges and frontal cognitive dysfunctions in JME; they remarked, using continuous EEG and video monitoring, that some frontal tasks were more impaired in patients with epileptiform EEG activity during rest than in those without discharges. It is not clear whether the deficits are due to a static or irreversible disorder or they are related to the impact of interictal epileptiform EEG activity on mental processes (Hommet et al., 2006). Clemens et al. (2000) investigated the EEG frequency profiles in patients with juvenile absence epilepsy, JME and epilepsy with grand mal seizures in the awakening area. Statistically significant bilateral absolute power differences were found in the frontal delta in patients with JME, whereas relative power differences were frontal delta and beta. The authors hypothesized that this profile reflects a cortical dysfunction more localized in the frontal lobes.
We decided to exclude patients with a psychiatric condition, in order to reach cleaner cognitive profiles, unaffected by the psychiatric state. We are aware that this selection has not taken into account the incidence of such disorders within the whole JME population; however, our primary goal was to capture the cognitive dimension of JME per se.
In our study sample, patients with FLE were those with the most significant impairment, as expected, followed by patients with JME, TLE and controls, in that order. The fact that patients with TLE performed worse than controls may be accounted for by the “neural noise” hypothesis, i.e., a propagation of neural noise via pathways which links the anterior temporal lobe and hippocampus with the frontal area (Hermann et al., 1988). Hermann et al. (1988) found that patients with TLE showed marked deficits on the WCST compared to a control group of patients with generalized epilepsy; they suggested that this dysfunction could be a result of the propagation of epileptiform spike activity to distant brain areas from the site of the primary area via ipsilateral and controlateral pathways.
Our study has some strengths and limitations. It is one of the largest surveys on frontal cognitive dysfunction in patients with JME and the only study that simultaneously evaluated the cognitive performances in three different types of epilepsy, as well as in normal controls. A limitation of the study is the reduced number of neuropsychological tests used, but the WCST and the Word Fluency Test are considered the most reliable validated Italian instruments for the age group considered (Giovagnoli & Piazzini, 1995).
This investigation confirms the importance of considering neuropsychological profiles of patients with JME. A detailed description of these patients can provide relevant information on their pathophysiologic status and on the relationship between paroxysmal and neuroanatomic abnormalities and cognitive tasks. We believe that more attention should be paid to this subject, so as to deeply understand the cognitive mechanisms, their deficiencies and strengths, and to provide patients with JME a better clinical and psychological care.