Comparative analysis of background EEG activity in juvenile myoclonic epilepsy during valproic acid treatment: a standardized, low-resolution, brain electromagnetic tomography (sLORETA) study.

BACKGROUND: By definition, the background EEG is normal in juvenile myoclonic epilepsy (JME) patients and not accompanied by other developmental and cognitive problems. However, some recent studies using quantitative EEG (qEEG) reported abnormal changes in the background activity. QEEG investigation in patients undergoing anticonvulsant treatment might be a useful approach to explore the electrophysiology and anticonvulsant effects in JME. METHODS: We investigated background EEG activity changes in patients undergoing valproic acid (VPA) treatment using qEEG analysis in a distributed source model. In 17 children with JME, non-parametric statistical analysis using standardized low-resolution brain electromagnetic tomography was performed to compare the current density distribution of four frequency bands (delta, theta, alpha, and beta) between untreated and treated conditions. RESULTS: VPA reduced background EEG activity in the low-frequency (delta-theta) bands across the frontal, parieto-occipital, and limbic lobes (threshold log-F-ratio = ±1.414, p < 0.05; threshold log-F-ratio= ±1.465, p < 0.01). In the delta band, comparative analysis revealed significant current density differences in the occipital, parietal, and limbic lobes. In the theta band, the analysis revealed significant differences in the frontal, occipital, and limbic lobes. The maximal difference was found in the delta band in the cuneus of the left occipital lobe (log-F-ratio = -1.840) and the theta band in the medial frontal gyrus of the left frontal lobe (log-F-ratio = -1.610). CONCLUSIONS: This study demonstrated the anticonvulsant effects on the neural networks involved in JME. In addition, these findings suggested the focal features and the possibility of functional deficits in patients with JME.

Frontal lobe cognitive functions and electroencephalographic features in juvenile myoclonic epilepsy.

PURPOSE: The study aimed to examine the relationship between frontal lobe functions and interictal electroencephalography (EEG) discharge characteristics of patients with juvenile myoclonic epilepsy (JME). METHOD: Thirty patients with JME who had EEG with asymmetrical generalized discharge (aEEG), 15 patients with JME who had EEG with symmetrical generalized discharge (sEEG), and 15 healthy controls were included in the study. To evaluate attention, the digit span and Corsi block tests were used; to evaluate memory, we applied verbal and visual memory tests; to evaluate frontal lobe functions, we used clock drawing, verbal fluency, the Stroop test, trail making, mental control, and antisaccadic eye movement tests as well as the continuous performance (CPT) tests. ETHICAL CONSIDERATIONS: The research was approved by the Research Ethics Committee of the Bakirkoy Research and Training Hospital for Psychiatry, Neurology, Neurosurgery, with protocol number: 41340010/4891-262, date: 05.02.2013. RESULTS: The mean age of the 45 patients with JME was 22.89 ±â€¯6.77 years, and 34 (75.6%) were female. The age at onset of seizures and disease duration of the patients with JME was 15.56 ±â€¯4.06 years (range, 9-26 years) and 7.20 ±â€¯5.59 years (range, 1-25 years), respectively. All patients were under valproate (VPA) treatment, and the mean VPA dosage was 783.33 ±â€¯379.14 mg/day. Patients with JME scored worse than the control group in attention, memory, and frontal lobe functions. In patients with aEEG, scores of attention, memory, and frontal lobe function tests were lower than in patients with sEEG; however, with the exception of CPT, they were not statistically significant. CONCLUSION: Cognitive functions in JME have been shown to be impaired. Furthermore, we concluded that the frontal lobe cognitive functions may be worse in patients with aEEG than in patients with sEEG. Further studies in patients with JME with aEEG abnormalities may lead to a better understanding of the pathophysiology of JME.

High-dose versus low-dose valproate for the treatment of juvenile myoclonic epilepsy: Going from low to high.

Juvenile myoclonic epilepsy (JME) is a genetic generalized epilepsy accounting for 3-12% of adult cases of epilepsy. Valproate has proven to be the first-choice drug in JME for controlling the most common seizure types: myoclonic, absence, and generalized tonic-clonic (GTC). In this retrospective study, we analyzed seizure outcome in patients with JME using valproate monotherapy for a minimum period of one year. Low valproate dose was considered to be 1000mg/day or lower, while serum levels were considered to be low if they were at or below 50mcg/dl. One hundred three patients met the inclusion criteria. Fifty-six patients (54.4%) were female. The current average age was 28.4±7.4years, while the age of epilepsy onset was 13.6±2.9years. Most patients corresponded to the subsyndrome of classic JME. Forty-six (44.7%) patients were free from all seizure types, and 76 (73.7%) patients were free from GTC seizures. No significant difference was found in seizure freedom among patients using a low dose of valproate versus a high dose (p=0.535) or among patients with low blood levels versus high blood levels (p=0.69). In patients with JME, it seems appropriate to use low doses of valproate (500mg to 1000mg) for initial treatment and then to determine if freedom from seizures was attained.

Modern management of juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is a common genetic epilepsy syndrome usually presenting in adolescence and characterized by myoclonic jerks, predominately in the arms, associated with tonic-clonic seizures and less often generalized absences. Although the evidence base for treating JME is weak, most experts regard sodium valproate as drug of first choice. The recent diktat from the European regulatory agency - recommending that sodium valproate should not be prescribed to female children, adolescents or women of childbearing potential unless other treatments were ineffective or not tolerated - has substantially changed the way JME is being managed in this population. This paper reviews the literature underpinning the pharmacological treatment of JME. Data reporting associated symptoms of frontal lobe dysfunction in some patients with JME are discussed, as is the importance of counselling on lifestyle issues as an essential component of management. Long-term studies examining pharmacological and quality-of-life outcomes are reviewed, indicating a range of different phenotypes and likely genotypes underpinning this fascinating disorder. Lastly, a practical approach to managing JME in young men and women is summarized.

[Juvenile myoclonic epilepsy]. / Juvenil myoklonusepilepsi.

BACKGROUND: Juvenile myoclonic epilepsy (JME) is a generalised epilepsy with seizure onset in youth. The aim of this review is to present updated knowledge about the etiology, diagnosis and treatment of JME. MATERIAL AND METHOD: The review is based on a judicious selection of original English language articles, meta-analyses, and reviews found in PubMed, and the authors' own experience with the patient group. RESULTS: Seizure onset occurs in adolescence. All have myoclonias, about 90 % have generalized tonic-clonic seizures, and one third have absences. Myoclonic jerks are frequently the debut symptom, while tonic-clonic seizures appear later on. Patients are particularly susceptible to seizures shortly after waking. It is important to ask specifically about myoclonias as most patients do not report jerks spontaneously. The electroencephalograms of 44-81 % of the patients show discharges of 4-6 Hz polyspike waves. Focal EEG abnormalities may be seen in about 30 %. When patients are treated with valproate and seizure-precipitating factors are avoided, especially sleep deprivation, about 80 % become seizure-free. Lamotrigine and levetiracetam are alternative therapies for women of childbearing age. Attempts to taper off the medication after several years of seizure freedom entail a high risk of seizure relapse. INTERPRETATION: As there may be features of focal epilepsy in the seizure semiology and/or the EEGs, it may be difficult to diagnose JME. Thus, many patients are misdiagnosed as having a focal epilepsy and are given antiepileptic drugs that may aggravate the tendency to seizures.

Can changes in cortical excitability distinguish progressive from juvenile myoclonic epilepsy?

PURPOSE: We used transcranial magnetic stimulation (TMS) to investigate whether there were any characteristic cortical excitability changes in progressive myoclonic epilepsy (PME) compared to juvenile myoclonic epilepsy (JME). METHODS: Six patients with PME were studied. Motor threshold (MT) at rest and recovery curve analysis using paired-pulse stimulation at a number of interstimulus intervals (ISIs) was determined. Results were compared to those of 9 patients with chronic refractory JME and 10 with chronic well-controlled JME. RESULTS: PME showed a marked increase in cortical excitability at all the long ISIs (p < 0.01), compared to refractory JME (effect sizes ranging from 1.4 to 1.9) and well-controlled JME (effect sizes ranging from 2.0 to 2.4). Significant differences at the short ISIs 2-5 ms were seen only on comparison with the well-controlled group (p < 0.05, effect size 0.6, 0.7). There were no significant differences in MTs of PME compared to either JME groups. CONCLUSION: Our findings demonstrate specific differences in cortical excitability using TMS between PME and those with JME, particularly at long latencies in the paired-pulse paradigm, implicating a role for γ-aminobutyric acid (GABA)(B) -mediated networks.

Provocative and inhibitory effects of a video-EEG neuropsychologic protocol in juvenile myoclonic epilepsy.

PURPOSE: Studies suggest that higher cognitive functions could precipitate seizures in juvenile myoclonic epilepsy (JME). The present study aimed to analyze the effects of higher mental activity on epileptiform discharges and seizures in patients with JME and compare them to those of habitual methods of activation. METHODS: Seventy-six patients with JME (41 female) underwent a video-EEG (electroencephalography) neuropsychologic protocol (VNPP) and habitual methods of activation for 4-6 h. RESULTS: Twenty-nine of the 76 (38.2%) presented provocative effect, and inhibition was seen in 28 of 31 (90.3%). A mixed effect was observed in 11 (35.5%), and 30 patients (39.5%) suffered no effect of VNPP. Action-programming tasks were more effective than thinking in provoking epileptiform discharges (23.7% and 11.0% of patients, respectively, p = 0.03). Inhibitory effect was observed equally in the various categories of tasks, except in mental calculation, which had a higher inhibitory rate. Habitual methods of activation were more effective than VNPP in provoking discharges. Anxiety disorders were diagnosed in 24 of 58 patients (41.4%); anxious patients had greater discharge indexes and no significant inhibitory effect on VNPP. DISCUSSION: Praxis exerted the most remarkable provocative effect, in accordance with the motor circuitry hyperexcitability hypothesis in JME. Inhibitory effect, which had no such task specificity, might be mediated by a widespread cortical-thalamic pathway, possibly involving the parietal cortex. The frequent inhibitory effect found under cortical activation conditions, influenced by the presence of anxiety, supports nonpharmacologic therapeutic interventions in JME.

Antiepileptic drugs: a case report in a pregnancy with a neural tube defect.

While receiving lamotrigine, a patient pregnant with triplets suffered a double fetal neural tube defect. Plasma homocysteine, folate, vitamins B12 and B6 (pyridoxal phosphate), and red cell folate levels were measured in samples while she was receiving folic acid therapy for 1 month during the second trimester of pregnancy. Some mutations were sought, involved in homocysteine metabolism and linked with the folate metabolism. Her results were compared with those of a pregnant woman with normal triplets and with those of 58 pregnant women, with a normal pregnancy. Results indicated a decrease in vitamin B12 and B6 values in plasma in the patient, and a genotype AG (polymorphism A66G) was observed, but was not found in the pregnant woman with normal triplets. Even if lamotrigine therapy is not known to be associated with significant changes in red cells or in serum folate, periconceptional folic acid supplementation is counseled for women, along with periconceptional B12 and B6 vitamin supplementation when their plasma values are decreased.

MRI volumetry shows increased anterior thalamic volumes in patients with absence seizures.

The interaction between thalamus and cortex appears to be critical to the pathophysiology of idiopathic generalized epilepsies (IGEs). The objective of this study was to investigate thalamic volumes of a group of patients with IGEs using high-resolution MRI. Thalamic segmentation was performed by the same rater, who was unaware of the diagnosis. Thalamic volumes were divided into anterior half and posterior half. One hundred forty-seven patients were scanned (71 with juvenile myoclonic epilepsy, 49 with generalized tonic-clonic seizures only, and 27 with absence epilepsy). Subgroup analyses with corrections for multiple comparisons showed that, when compared with those of controls, anterior thalamic volumes were increased in patients with absence epilepsy and juvenile myoclonic epilepsy with absence seizures, but not in patients with generalized tonic-clonic seizures only and juvenile myoclonic epilepsy without absence seizures. Our results demonstrated that the anterior thalamus is structurally different in patients with IGEs and absence seizures as compared with patients with IGEs without absence seizures.

Myoclonus and transcranial magnetic stimulation.

The neural dysfunction at the origin of myoclonus may locate at various anatomical levels within the central nervous system, including the motor cortices. Transcranial magnetic stimulation (TMS) can be used to assess the balance between inhibitory and excitatory processes involved in the regulation of motor cortex activity and thereby, may be of value to determine the pathophysiological mechanisms of myoclonus. Using paired-pulse paradigms with various interstimulus intervals, TMS studies showed that intracortical inhibition (ICI) was reduced in progressive myoclonic epilepsy (PME). In contrast, ICI was decreased only for short interstimulus intervals in patients with juvenile myoclonic epilepsy (JME). Transcallosal inhibition and sensorimotor integration were also both altered in PME but not in JME. Actually, the loss of inhibitory regulation within the central nervous system might represent an intrinsic mechanism of myoclonus, whether of epileptic origin or not. Finally, the other TMS parameters of excitability (motor threshold, silent period, intracortical facilitation) were found normal in most cases of myoclonus. According to these observations, it was quite conceivable that the application of repetitive trains of TMS (rTMS) at inhibitory low-frequency (around 1 Hz) might be able to relieve myoclonus by restoring ICI. A few reported cases illustrate the efficacy of low-frequency rTMS to alleviate myoclonic symptoms. Therapeutic-like perspectives are opened for rTMS in these forms of myoclonus that are related to motor cortical hyperexcitability secondary to the loss of ICI.

Low dose sodium valproate in the treatment of juvenile myoclonic epilepsy.

Fourteen patients with juvenile myoclonic epilepsy (JME) were treated with a single low dose of a sustained-release preparation of sodium valproate (VPA, 500 mg daily). The mean age of the onset of the low dose treatment was 19.2 years (range 14-26). Before this treatment, six patients had been treated with high dose VPA for a period of more than 2 years, three patients for 1 to 2 years, three patients less than 1 year and two patients initiated the treatment from the beginning with a low dose. The mean duration of low dose treatment is 35.6 months (range 25-59 months). (All patients are still under medication). Generalized tonic-clonic and absence seizures were controlled in all patients. Myoclonic jerks relapsed only in one patient, a young mother who was looking after her newly born baby and was deprived of sleep. No adverse reactions have been reported. We suggest that JME patients can effectively be treated with single low VPA dose (500 mg daily), while at the same time seizure precipitating factors, such as sleep deprivation and alcohol ingestion, should be avoided.