[Effective therapy in highly active pediatric multiple sclerosis]. / Magas aktivitású sclerosis multiplex hatásos kezelése gyermekkorban.

Multiple sclerosis (MS) is typically a disease of young adults. Childhood MS can be defined in patients under 18 years of age, although some authors set the limit un-der the age of 16 formerly known as "early-onset multiple sclerosis" or "juvenile multiple sclerosis", seen in 3-5% of all MS patients. Nowadays, owing to ever-evolving, better diagnostic tools and well-traced, strictly defined diagnostic criteria, childhood MS is showing an increasing incidence worldwide (0.05-2.85/100 000). MS is characterized by recurrent episodes of the central nervous system with demyelination separated in space and time. In childhood almost exclusively the relapsing-remitting (RR) type of MS occurs. Based on experience in adults, the goal in the pediatric population is also the early diagnosis, to initiate adequate DMT as soon as possible and to achieve symptom relief and good quality of life. Based on efficacy and safety studies in the adult population, inter-feron ß-1a and glatiramer acetate were first approved by the FDA and EMA for the treatment of childhood MS also. The increased relapse rate and rapid progression of childhood MS and unfavorable therapeutic response to nearly 45% of the first DMT necessitated the testing of more effective and second-line drugs in the population under 18 years of age (PARADIGMS, CONNECT). Although natalizumab was reported to be effective and well-tolerated in highly active RRMS in childhood, evidence based studies were not yet available when our patients' treatment started. In this article, we report on the successful treatment of three active RRMS patients with individually authorized off-label use of natalizumab.

Multicenter retrospective study of patients with PCDH19-related epilepsy: The first Hungarian cohort.

OBJECTIVE: PCDH19-related epilepsy occurs predominantly in girls and is caused by pathogenic variant of the protocadherin-19 gene. The initial seizures usually develop in association with fever, begin on average at 15 months of age, and often occur in clusters. Autistic symptoms, intellectual disability, and sleep disturbance are often associated. METHODS: In our retrospective, multicenter study, we reviewed clinical data of nine children with epilepsy genetically confirmed to be associated with PCDH19. RESULTS: In the Hungarian patient population aged 0-18 years, the prevalence of PCDH19-related epilepsy was found to be lower (1/100000 live births in females) than the reported international data (4-5/100000 live births in females). Four of our nine patients had positive family history of epilepsy (cousins, sister, and mother). We assessed brain anomalies in three patients (in one patient focal cortical dysplasia and left anterior cingulate dysgenesis, and in two children right or left hippocampal sclerosis) and in another three cases incidentally identified benign alterations on brain MRI were found. The first seizure presented as a cluster in seven out of nine children. In seven out of nine cases occurred status epilepticus. Six out of nine children had autistic symptoms and only one child had normal intellectual development. Seven of our patients were seizure free with combined antiseizure medication (ASM). The most effective ASMs were levetiracetam, valproate, and clobazam. SIGNIFICANCE: The prevalence of PCDH19-related epilepsy is presumably underestimated because of the lack of widely performed molecular genetic evaluations. Molecular genetic testing including PCDH19 pathogenic variants is recommended for female patients with an onset of seizures before the age of 3 years.

Four New Cases of Hypomyelinating Leukodystrophy Associated with the UFM1 c.-155_-153delTCA Founder Mutation in Pediatric Patients of Roma Descent in Hungary.

Ufmylation is a relatively newly discovered type of post-translational modification when the ubiquitin-fold modifier 1 (UFM1) protein is covalently attached to its target proteins in a three-step enzymatic reaction involving an E1 activating enzyme (UBA5), E2 conjugating enzyme (UFC1), and E3 ligase enzyme (UFL1). The process of ufmylation is essential for normal brain development and function in humans. Mutations in the UFM1 gene are associated with Hypomyelinating leukodystrophy type 14, presenting with global developmental delay, failure to thrive, progressive microcephaly, refractive epilepsy, and hypomyelination, with atrophy of the basal ganglia and cerebellum phenotypes. The c.-155_-153delTCA deletion in the promoter region of UFM1 is considered to be a founding mutation in the Roma population. Here we present four index patients with homozygous UFM1:c.-155_-153delTCA mutation detected by next-generation sequencing (whole genome/exome sequencing) or Sanger sequencing. This mutation may be more common in the Roma population than previously estimated, and the targeted testing of the UFM1:c.-155_-153delTCA mutation may have an indication in cases of hypomyelination and neurodegenerative clinical course in pediatric patients of Roma descent.

Imaging the cortical effect of lamotrigine in patients with idiopathic generalized epilepsy: a low-resolution electromagnetic tomography (LORETA) study.

PURPOSE: Anatomical localization of the cortical effect of lamotrigine (LTG) in patients with idiopathic generalized epilepsy (IGE). METHODS: 19 patients with untreated IGE were investigated. EEG was recorded in the untreated condition and 3 months later when LTG treatment abolished the seizures. 19-channel EEG was recorded, and a total of 2min artifact-free, waking EEG was processed to low-resolution electromagnetic tomography (LORETA) analysis. Activity (that is, current source density, A/m(2)) was computed in four frequency bands (delta, theta, alpha, and beta), for 2394 voxels that represented the cortical gray matter and the hippocampi. Group differences between the untreated and treated conditions were computed for the four bands and all voxels by multiple t-tests for interdependent datasets. The results were presented in terms of anatomical distribution and statistical significance. RESULTS: p<0.01 (uncorrected) changes (decrease of activity) emerged in the theta and the alpha bands. Theta activity decreased in a large cluster of voxels including parts of the temporal, parietal, occipital cortex bilaterally, and in the transverse temporal gyri, insula, hippocampus, and uncus on the right side. Alpha activity decreased in a relatively smaller cortical area involving the right temporo-parietal junction and surrounding parts of the cortex, and part of the insula on the right side. CONCLUSIONS: LTG decreased theta activity in several cortical areas where abnormally increased theta activity had been found in a prior study in another cohort of untreated IGE patients [Clemens, B., Bessenyei, M., Piros, P., Tóth, M., Seress, L., Kondákor, I., 2007b. Characteristic distribution of interictal brain electrical activity in idiopathic generalized epilepsy. Epilepsia 48, 941-949]. These LTG-related changes might be related to the decrease of seizure propensity in IGE.

Three-dimensional localization of abnormal EEG activity in migraine: a low resolution electromagnetic tomography (LORETA) study of migraine patients in the pain-free interval.

Investigating the brain of migraine patients in the pain-free interval may shed light on the basic cerebral abnormality of migraine, in other words, the liability of the brain to generate migraine attacks from time to time. Twenty unmedicated "migraine without aura" patients and a matched group of healthy controls were investigated in this explorative study. 19-channel EEG was recorded against the linked ears reference and was on-line digitized. 60 x 2-s epochs of eyes-closed, waking-relaxed activity were subjected to spectral analysis and a source localization method, low resolution electromagnetic tomography (LORETA). Absolute power was computed for 19 electrodes and four frequency bands (delta: 1.5-3.5 Hz, theta: 4.0-7.5 Hz, alpha: 8.0-12.5 Hz, beta: 13.0-25.0 Hz). LORETA "activity" (=current source density, ampers/meters squared) was computed for 2394 voxels and the above specified frequency bands. Group comparison was carried out for the specified quantitative EEG variables. Activity in the two groups was compared on a voxel-by-voxel basis for each frequency band. Statistically significant (uncorrected P < 0.01) group differences were projected to cortical anatomy. Spectral findings: there was a tendency for more alpha power in the migraine that in the control group in all but two (F4, C3) derivations. However, statistically significant (P < 0.01, Bonferroni-corrected) spectral difference was only found in the right occipital region. The main LORETA-finding was that voxels with P < 0.01 differences were crowded in anatomically contiguous cortical areas. Increased alpha activity was found in a cortical area including part of the precuneus, and the posterior part of the middle temporal gyrus in the right hemisphere. Decreased alpha activity was found bilaterally in medial parts of the frontal cortex including the anterior cingulate and the superior and medial frontal gyri. Neither spectral analysis, nor LORETA revealed statistically significant differences in the delta, theta, and beta bands. LORETA revealed the anatomical distribution of the cortical sources (generators) of the EEG abnormalities in migraine. The findings characterize the state of the cerebral cortex in the pain-free interval and might be suitable for planning forthcoming investigations.

Quantitative EEG effects of carbamazepine, oxcarbazepine, valproate, lamotrigine, and possible clinical relevance of the findings.

UNLABELLED: Quantitative EEG (QEEG) effects of therapeutic doses of carbamazepine (CBZ), oxcarbazepine (OXC), valproate (VA) and lamotrigine (LA) monotherapy were investigated in patients with beginning epilepsy. Baseline waking EEG (EEG1) was recorded in the untreated state, the second EEG (EEG2) was done after 8 weeks of reaching the therapeutic dose. Left occipital data were used for analysis. QEEG target parameters were absolute band-power (delta: AD, theta: AT, alpha: AA, beta: AB), and alpha mean frequency (AMF). Group effects (untreated versus treated condition in the CBZ, VA, OXC, LA groups) were computed for each target parameter. One group with benign rolandic epilepsy remained untreated for clinical reasons and served to estimate the QEEG test-retest differences. In addition, the individual QEEG response to each drug was calculated as (EEG2-EEG1). RESULTS: statistically significant (p<0.05) group differences indicated the QEEG domain systematically affected by the drugs. CBZ caused AT increase and AMF decrease. OXC caused AMF decrease. VA and LA did not decrease AMF (LA even increased it), but reduced broad-band power. Individual power and AMF changes showed considerable variability in each group. >0.5 Hz AMF decrease (that was reported to predict cognitive impairment in prior studies) occurred in 10/41 patients in the CBZ group but never in the OXC, VA, LA groups. The results may be utilized in planning further studies addressing the relationship between antiepileptic drugs and their CNS effects. In addition, the relationship of AED-related cognitive impairment and AMF changes was discussed.

[Occipital spectral EEG parameters in newly diagnosed, untreated patients with epilepsy]. / Occipitalis spektrális EEG-paraméterek új, nem kezelt epilepsziás betegek esetében.

INTRODUCTION: Minor spectral EEG alterations hidden to the naked eye may be of interest in the field of epileptology, cognitive performances, and drug effects. In order to introduce new scientific results of brain wave research into the clinical field of epilepsy- and drug-related cognitive problems, a normative quantitative EEG database for epilepsy was constructed. PATIENTS AND METHODS: 171 newly referred, five to 50 years old patients with untreated "new" epilepsy (that is, clinical, EEG, MRI investigations had been done in 24 months after the first unprovoked seizure) were collected. EEG was recorded with closed eyes, in the waking-relaxed state. Effects that are known to influence EEG spectra (nearby seizures, drugs, etc.) were excluded as far as possible. A total of two minutes of waking-resting EEG activity was chosen for spectral analysis. Fast Fourier transformation of the selected samples were calculated resulting in absolute power, percent power and mean alpha frequency (AA, RA, and AMF respectively) for the right and left occipital derivations. For each patient (and also for 37 healthy controls), the deviation of the individual values from the age-adjusted normative mean was expressed in Z-score. Main diagnostic epilepsy categories were compared to the control group as well as to each other. In addition, effects of MRI-defined cerebral lesions and interictal spiking on spectral EEG parameters were investigated. RESULTS: All group averages were within the 95 per cent confidence interval. Overwhelming majority of the individual data fell within a 3Z range. Statistically significant differences were found for AA and RA, but seldom for AMF. Right and left alpha-parameters were surprisingly symmetrical in all groups. The main difference between epilepsy groups and controls was less AA and RA power in the epilepsy groups. MRI-defined lesions and interictal epileptiform activity did not significantly influence EEG spectral variables. CONCLUSION: These results might serve as reference data and might help planning of further quantitative EEG studies in the triangle of epilepsy, cognitive problems, and drug effects.

The electrophysiological "delayed effect" of focal interictal epileptiform discharges. A low resolution electromagnetic tomography (LORETA) study.

UNLABELLED: Collating the findings regarding the role of focal interictal epileptiform discharges (IEDs) on CNS functions raises the possibility that IEDs might have negative impact that outlasts the duration of the spike-and-wave complexes. The aim of this study was the electrophysiological demonstration of the "delayed effect" of the IEDs. 19-channel, linked-ears referenced, digital waking EEG records of 11 children (aged 6-14 years, eight with idiopathic, three with cryptogenic focal epilepsy, showing a single spike focus) were retrospectively selected from our database. A minimum of 20 (preferably, 30), 2-s epochs containing a single focal spike-and-wave complex were selected (Spike epochs). Thereafter, Postspike-1 (Ps1), Postspike-2 (Ps2) and Postspike-3 (Ps3) epochs were selected, representing the first and second seconds (Ps1), the third and fourth seconds (Ps2) and the fifth and sixth seconds (Ps3) after the Spike epoch, respectively. Interspike epochs (Is) were selected at a distance at least 10s after the Spike epoch. Individual analysis: the frequency of interest (FOI=the individual frequency of the wave component of the IEDs), and the region of interest (ROI=the site of the IEDs) were identified by reading the raw EEG waveform and the instant power spectrum. Very narrow band LORETA (low resolution electromagnetic tomography) analysis at the FOI and ROI was carried out. Age-adjusted, Z-transformed LORETA "activity" (=current source density, amperes/meters squared) was compared in the Spike, Ps1, Ps2, Ps3 and Is epochs. FINDINGS: the greatest (uppermost pathological) Z-scores and the greatest spatial extension of the LORETA-abnormality were always found in the Spike epochs, followed by the gradual decrease of activity in terms of severity and spatial extension in the Ps1, Ps2, Ps3 epochs. The lowest (baseline) level and extension of the abnormality was found in the Is epochs. Group analysis: average values of activity across the patients were computed for the temporal decrease of the abnormality. FINDINGS: a clear tendency for the decrease of abnormality was demonstrated. CONCLUSION: the "delayed effect" of the IEDs was demonstrated electrophysiologically and quantified. The method may be utilized in the individual assessment of the effect of IEDs on cortical activity, the degree and temporo-spatial extension of the abnormality.

Characteristic distribution of interictal brain electrical activity in idiopathic generalized epilepsy.

PURPOSE: To demonstrate the anatomic localization of the cortical sources of the interictal EEG activity in human idiopathic generalized epilepsy (IGE). METHODS: Multiple cortical and hippocampal sources of the interictal spontaneous EEG activity were investigated by low-resolution electromagnetic tomography in 15 untreated IGE patients and in 15 healthy controls. EEG activity (current density) in four frequency bands (delta: 1.5-3.5 Hz, theta: 3.5-7.5 Hz, alpha: 7.5-12.5 Hz, beta: 12.5-25.0 Hz) was computed for 2,397 voxels. Voxel-by-voxel group comparison was done between the patient and the control group. Voxels with p < 0.01 differences (between the two groups) were correlated with cortical anatomy. RESULTS: Areas of significantly increased or decreased activity were characterized by their anatomical extension and the frequency bands involved. Five areas of bilaterally increased activity were found: rostral part of the prefrontal cortex (delta, theta); posterior part of the insula (delta); hippocampus and mediobasal temporal cortex (all frequency bands); medial parietooccipital cortex (theta, alpha, beta); dorsal and polar parts of the occipital cortex (alpha). Bilaterally decreased delta, theta, alpha activity was found in the majority of the frontal and anterior parietal cortex on the lateral surface, and in parts of the medial surface of the hemispheres. The area of decreased beta activity was less extensive. The right lateral and laterobasal temporal cortex showed decreased delta, theta, alpha, and beta activity, while its left counterpart only showed decreased delta and alpha activity in a limited part of this area. CONCLUSIONS: (1) Pathological interictal EEG activity is not evenly distributed across the cortex in IGE. The prefrontal area of increased activity corresponds to the area that is essential in the buildup of the ictal spike-wave paroxysms (absence seizures). The existence of the posterior "center of gravity" of increased EEG activity in IGE was confirmed. The frontal area of decreased activity might be related to the cognitive deficit described in IGE patients. (2) Increased activity in a lot of ontogenetically older areas (including the hippocampi) and decreased activity in the majority of the isocortex is a peculiar pattern that argues for a developmental hypothesis for IGE.