Identification of novel BCL11A variants in patients with epileptic encephalopathy: Expanding the phenotypic spectrum.

BCL11A encodes a zinc finger protein that is highly expressed in hematopoietic tissues and the brain, and that is known to function as a transcriptional repressor of fetal hemoglobin (HbF). Recently, de novo variants in BCL11A have been reported in individuals with intellectual disability syndrome without epilepsy. In this study, we performed whole-exome sequencing of 302 patients with epileptic encephalopathies (EEs), and identified 2 novel BCL11A variants, c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr). Both the patients shared major physical features characteristic of BCL11A-related intellectual disability syndrome, suggesting that characteristic physical features and the persistence of HbF should lead clinicians to suspect EEs caused by BCL11A pathogenic variants. Patient 1, with a frameshift variant, presented with Lennox-Gastaut syndrome, which expands the phenotypic spectrum of BCL11A haploinsufficiency. Patient 2, with a p.Lys784Thr variant, presented with West syndrome followed by drug-resistant focal seizures and more severe developmental disability. These 2 newly described patients contribute to delineating the associated, yet uncertain phenotypic characteristics of BCL11A disease-causing variants.

The somatosensory evoked magnetic fields.

Averaged magnetoencephalography (MEG) following somatosensory stimulation, somatosensory evoked magnetic field(s) (SEF), in humans are reviewed. The equivalent current dipole(s) (ECD) of the primary and the following middle-latency components of SEF following electrical stimulation within 80-100 ms are estimated in area 3b of the primary somatosensory cortex (SI), the posterior bank of the central sulcus, in the hemisphere contralateral to the stimulated site. Their sites are generally compatible with the homunculus which was reported by Penfield using direct cortical stimulation during surgery. SEF to passive finger movement is generated in area 3a or 2 of SI, unlike with electrical stimulation. Long-latency components with peaks of approximately 80-120 ms are recorded in the bilateral hemispheres and their ECD are estimated in the secondary somatosensory cortex (SII) in the bilateral hemispheres. We also summarized (1) the gating effects on SEF by interference tactile stimulation or movement applied to the stimulus site, (2) clinical applications of SEF in the fields of neurosurgery and neurology and (3) cortical plasticity (reorganization) of the SI. SEF specific to painful stimulation is also recorded following painful stimulation by CO(2) laser beam. Pain-specific components are recorded over 150 ms after the stimulus and their ECD are estimated in the bilateral SII and the limbic system. We introduced a newly-developed multi (12)-channel gradiometer system with the smallest and highest quality superconducting quantum interference device (micro-SQUID) available to non-invasively detect the magnetic fields of a human peripheral nerve. Clear nerve action fields (NAFs) were consistently recorded from all subjects.

Dermatome versus homunculus; detailed topography of the primary somatosensory cortex following trunk stimulation.

OBJECTIVE: Identification of a detailed topography of the receptive area for each of the thoracic dermatomes in humans using somatosensory evoked magnetic fields (SEF). METHODS: We analyzed the location of the equivalent current dipole (ECD) of SEF following electrical stimulation of the skin at Th4, Th6, Th8, Th10 and Th12 dermatomes in 14 normal subjects. RESULTS: Three deflections, M18, M25 and M40, were obtained within 60 ms of stimulation of Th6, Th8 and Th10 dermatomes. No consistent deflection could be identified following Th4 and Th12 dermatomal stimulation, probably due to a poor signal-to-noise ratio and difficulty in fixing the stimulation electrodes. M18 was absent or small in amplitude. The latency of M25 ranged from short to long in the order Th6, Th8 and Th10 (P<0.05). ECDs of all components for each site stimulation were located in the truncal area of the primary somatosensory cortex. Although the locations of the ECDs tend to be arranged from lateral to medial in the sequence Th6, Th8 and Th10, the difference was not significant. CONCLUSION: The representation area of the trunk is small, and the receptive areas for the stimulation of Th6, Th8 and Th10 dermatomes are considered to be very close or to overlap.

Relation between the date of cyst formation observable on ultrasonography and the timing of injury determined by serial electroencephalography in preterm infants with periventricular leukomalacia.

The aim of this study was to clarify the relation between the date of cyst formation and the timing of injury in preterm infants with periventricular leukomalacia in order to address the issue of whether or not we can determine the timing of injury on the basis of ultrasonographic findings. We studied 33 preterm infants with cystic periventricular leukomalacia, the gestational ages being 32 weeks or less. As 27 of them exhibited either acute or chronic stage abnormalities in the initial electroencephalogram, the timing of injury was presumed to be before or around birth. For the remaining six infants, the timing of injury was considered to be postnatal in two infants, and was not determined in another four. The median date of cyst formation was 18 days of age (range, 10-39 days) in the 27 infants with abnormal initial electroencephalograms. For these 27 infants, the gestational age did not influence the date of cyst formation. In contrast, the date of cyst formation was significantly earlier in infants with widespread cysts than in those with localized cysts. In conclusion, it is difficult to determine the timing of injury from ultrasonographic findings, because the range of the date of cyst formation on ultrasonography was very wide among infants whose timing of injury was not greatly different.

Physical condition of preterm infants with periventricular leukomalacia.

The aim of this study is to determine the general condition of preterm infants with severe brain lesions and to compare it with that of normal preterm infants. The Score for Neonatal Acute Physiology (SNAP) was calculated in nine preterm infants with periventricular leukomalacia (PVL) whose initial electroencephalograms showed grade IV depression (PVL group), 18 preterm infants who did not require mechanical ventilation during the neonatal period, Spontaneous respiration (SR group), and 18 preterm infants who required mechanical ventilation (MV group). The sum of the following four items in SNAP was separately calculated and called the 'lung score': PaO(2), PaO(2)/FiO(2) ratio, PaCO(2), and oxygenation index. In addition to SNAP, we evaluated some neonatal variables. SNAP is lower in the SR group than in the PVL (P<0.05) or MV (P<0.01) groups. The lung score was also lower in the SR group than in the PVL (P<0.05) or MV (P<0.01) groups. On the other hand, the residual score (SNAP minus lung score) was not significantly different among the three groups. The physical condition of infants with PVL was not poor, although respiratory distress was often observed.

A pilot study on benign partial epilepsy in children with complex partial seizures.

In a review of 145 children with partial onset epilepsy, the authors were able to determine a focus of children whose complex partial seizures (CPS) ran a benign course, who had no identifiable lesion on scanning and whose EEG focus was not fixed, but tended to shift. The authors suggest that a benign form of CPS in children can be recognised.

[Clinical studies on SY5555 in the field of pediatrics].

Clinical studies on SY5555 dry syrup, a new oral penem antibiotic, were carried out in the field of pediatrics. The following results were obtained. 1. SY5555 was administered to 10 children with various bacterial infections (2 patients with acute tonsillitis, 2 with acute bronchitis, 1 with pharyngitis, 2 with scarlet fever, 1 with pertussis and 2 with urinary tract infections). The overall clinical efficacy rate was 90%. 2. Side effects or abnormal laboratory test values were not observed except for loose stool in 1 and eosinophilia in 1.

[Laboratory and clinical studies on tazobactam/piperacillin in the field of pediatrics].

Laboratory and clinical studies on tazobactam/piperacillin (TAZ/PIPC), a combination drug of piperacillin (PIPC) with the new beta-lactamase inhibitor tazobactam (TAZ), were carried out in the field of pediatrics. 1. After intravenous administration of TAZ/PIPC at a dose of 25 mg/kg to one child, the peak plasma levels of TAZ and PIPC were 24.4 micrograms/ml and 119 micrograms/ml respectively after 5 min. The half-lives of TAZ and PIPC were 0.48 and 0.60 hours respectively. Same as 50 mg/kg to two children, the peak plasma levels of TAZ and PIPC were 17.5, 32.2 micrograms/ml and 92.8, 163 micrograms/ml after 5 min. The half-lives of TAZ and PIPC were 0.37, 0.50 hours and 0.51, 0.59 hours. A ratio of TAZ to PIPC was about 1 to 4 in plasma levels. The cumulative urinary recovery rates of TAZ and PIPC in the first 6 hours after intravenous administration were 15.8, 64.9% and 39.8, 53.4%. 2. The antibacterial activity of TAZ/PIPC against clinically isolated organisms was determined. The MICs of TAZ/PIPC were < or = 0.05 microgram/ml against Haemophilus influenzae and Streptococcus pneumoniae and > or = 1.56 micrograms/ml against Escherichia coli, Staphylococcus aureus and Haemophilus parainfluenzae. 3. The clinical efficacy of TAZ/PIPC could be evaluated in 14 patients with various bacterial infections, and was evaluated as "excellent" in 9 patients and as "good" in 5. The overall clinical efficacy rate in 14 cases was 100% and excellent was 64.3%. Bacteriological efficacy rate was 91.7% (10/11). 4. As a side effect, loose stool was observed in one case, no abnormal laboratory test values were observed. It has been concluded that TAZ/PIPC was a useful drug in the field of pediatrics.

[Pharmacokinetic and clinical studies with cefluprenam in the pediatric field. Pediatric Study Group of Gefluprenam].

Evaluation of efficacy and safety of cefluprenam (code number: E1077, abbreviation: CFLP), a newly developed injectable cephem antibiotics was conducted on adult patients with various infections, and followed by the study group organized from 39 institutions in pediatric field, as the drug showed no toxicity problems in suckling animals. Informed consents from legal representatives were obtained prior to the study. 1. Clinical efficacy. Two-hundred eighty one cases were included for analysis of clinical efficacy after 40 cases of exclusion or drop-out were subtracted from a total of 321 cases. However, the cumulative number of cases evaluable for analysis was considered to be 289, because 8 cases that had 2 different diseases at the same time were counted in each category of disease. In the cases in which causative organisms were identified (group A), 148 of 154 cases were rated as good or excellent, with an efficacy rate of 96.1%. As for clinical efficacies by disease, efficacy rates were 6/6 for purulent meningitis, 4/5 for sepsis, 95.7% (62/65) for pneumonia, 100.0% (29/29) for urinary tract infections, and 94.1% (16/17) for skin and soft tissue infections. The rate of excellent responses among excellent and good responses was 73.6% (109/148), showing a higher value than any of recent injectable beta-lactams. On 32 cases with S. pneumoniae infection, the efficacy rate of CFLP was 100.0%. In the cases where causative organisms were not identified (group B), 128 of 135 cases were rated as good or excellent, with an efficacy rate of 94.8%. In the all cases including both the group A and the group B, the efficacy rate was 95.2% (276/289) and the rate of excellent responses among excellent and good response was 70.7% (195/276). Against severe infections, CFLP exhibited excellent clinical efficacy, showing an efficacy rate of 8/8 for meningitis, 3/5 for sepsis and 100.0% (22/22) for severe pneumonia. As for bacteriological responses, eradication rates were 95.2% (177/186) in total. Against Gram-positive cocci, the eradication rate was 92.7% (76/82), with eradication rates of 94.3% (33/35) for Staphylococcus aureus, and 93.3% (28/30) for Streptococcus pneumoniae. Against Gram-negative rods, the eradication rate was 97.1% (101/104), and eradication rates were 100.0% (22/22) for Escherichia coli, 97.5% (39/40) for Haemophilus influenzae and 100.0% (19/19) for Molaxella catarrhalis. In cases in which more than 3 days of treatment with previous chemotherapy resulted in no response, the efficacy rate of CFLP was 94.2% (98/104), rated excellent in 68 cases and good in 30 cases. In these cases, the eradication rate was 98.1% (52/53). 2. Pharmacokinetics. CFLP was intravenously administerrd to 12 subjects at doses of 20 to 40 mg (potency)/kg. In 9 subjects aged more than 12 months, maximum serum levels (Cmax), T 1/2 beta and AUC of CFLP were 155.3 +/- 9.8 micrograms/ml, 1.43 +/- 0.18 hours and 111.7 +/- 15.0 micrograms.hr/ml, respectively, when a dose of 20 mg (potency)/kg was used. In 2 subjects aged not more than 12 months, the mean Cmax, T 1/2 beta and AUC were 153 micrograms/ml, 1.6 hour and 81 micrograms.hr/ml, respectively, at a dose of 20 mg(potency)/kg. The mean Cmax, T 1/2 beta and AUC were 332 micrograms/ml, 0.93 hours and 157.3 micrograms.hr/ml, respectively, in 1 subject at a dose of 40 mg (potency)/kg. In 10 subjects dosed 20 mg (potency)/kg, urinary levels were 2413 +/- 512, 1471 +/- 524, and 470 +/- 115 micrograms/ml in 0-2, 2-4, and 4-6 hours after dosing, respectively, showing a cumulative urinary excretion rate of 61.4 +/- 6.3%. In 1 subject dosed 40 mg (potency)/kg, urinary levels were 5700 and 4770 micrograms/ml in 0-2 p3d 2-4 hours after dosing, respectively, showing a cumulative urinary excretion rate of 42.1%. Cerebrospinal fluid concentrations of CFLP, on 10 subjects with purulent meningitis dosed 40-103 mg (potency)/kg were 3.2-32.9 micrograms/ml at 0.5-2 hours after administration within 4 days after the onset of

PET in infancy predicts long-term outcome during adolescence in cryptogenic West syndrome.

BACKGROUND AND PURPOSE: Developmental and seizure outcomes in patients with cryptogenic West syndrome are variable. Our aim was to clarify the relationship between FDG-PET findings in infancy and long-term seizure and developmental outcome in cryptogenic West syndrome. MATERIALS AND METHODS: From 1991 to 1999, we prospectively performed FDG-PET from the onset of cryptogenic West syndrome in 27 patients. PET was performed at onset and at 10 months of age. In 2012, we evaluated the educational status, psychomotor development, and seizure outcome in 23 of the 27 patients (13-22 years of age). The correlation between PET findings and outcome was evaluated. RESULTS: At onset, PET showed hypometabolism in 13 patients (57%). The second PET after the initial treatment revealed cortical hypometabolism in 7 patients (30%). While hypometabolism at onset disappeared on the second PET in 9 patients, it was newly revealed in 3 patients on the second PET. In 2012, seven patients had persistent or recurrent seizures. Eight patients had intellectual impairment. The first PET did not correlate with seizure or developmental outcome. Five of 7 patients (71%) with hypometabolism seen on the second PET had persistent or recurrent seizures, while 14 of 16 (88%) patients with normal findings on the second PET were free of seizures. Five of 7 patients (71%) showing hypometabolism on the second PET had intellectual impairment. Thirteen of 16 (81%) patients with normal findings on the second PET showed normal intelligence. A significant correlation was found between the second PET and long-term seizure (P = .01) or developmental outcome (P = .03). CONCLUSIONS: Cortical hypometabolism is not permanent; it changes with clinical symptoms. Hypometabolism after initial treatment predicts long-term seizures and poor developmental outcome.

A unique area of the homonculus: the topography of the primary somatosensory cortex in humans following posterior scalp and shoulder stimulation.

We recorded somatosensory evoked magnetic field (SEF) to investigate the differentiation in the receptive area for the face, lower part of the posterior scalp (mastoid) and shoulder, which occupy an unique area in the homunculus. We analyzed the location of the equivalent current dipole (ECD) of SEF following electrical stimulation of the skin at the face, mastoid and shoulder in 20 normal subjects. Three deflections (1M, 2M and 3M) were obtained within 50 ms of the stimulation in 16 of 20 subjects. The peak latency of the 1M and 2M was not significantly different at any stimulus sites. The amplitude of the 1M was significantly larger following the face than mastoid stimulation (p<0.05). The 16 subjects were classified according to the locations of the ECD on stimulation of the mastoid: close to that for shoulder stimulation, but significantly (p<0.05) more superior and medial to that following the face stimulation (Type 1, eleven subjects); close to that for face stimulation, but significantly (P<0.05) more inferior and lateral to that following the shoulder stimulation (Type 2, five subjects). The site of the receptive area for the posterior scalp shows interindividual variation, possibly due to anatomical differences.

Benign myoclonic epilepsy in infants: video-EEG features and long-term follow-up.

We report video-EEG findings and a long-term follow-up study in 10 patients with benign myoclonic epilepsy in infants (BMEI). A high incidence of a past and family history of febrile convulsions was noted. Six of the 10 patients manifested characteristic vocalization associated with myoclonic seizures. It consisted of a sudden, brief expiratory noise and is considered to be characteristic of BMEI. Afebrile convulsions occurred before the onset of myoclonic seizures or during the clinical course in six patients, but the accurate type of these seizures remains to be clarified. Monotherapy with valproatic acid (VPA) was very effective, but plasma VPA levels over 100 micrograms/ml were initially necessary in most of the cases, although they did not need to be maintained for further seizure control. All patients showed a favorable long-term seizure outcome, although one showed moderate mental retardation.

Epileptic spasms preceded by partial seizures with a close temporal association.

PURPOSE: To investigate the distinctive features of patients with West syndrome who had partial seizures followed by epileptic spasms (PS-ES). METHODS: We examined 45 patients with West syndrome whose epileptic spasms were recorded with simultaneous video-electroencephalography (EEG) monitoring between 1982 and 1996. We investigated the patients who had PS-ES and compared the PS-ES patients with the 37 patients without PS-ES. RESULTS: Of the 45 patients who had epileptic spasms in clusters (ES) and hypsarrhythmia on the interictal EEG, eight (17%) had ES preceded by partial seizures (PS) with a close temporal association. Seven of these eight were female patients. The underlying disorders were tuberous sclerosis (one patient), Aicardi syndrome (one), nonketotic hyperglycinemia (one), and focal cortical dysplasia (one). The etiology was unknown in the remaining four patients, but was suspected to be of prenatal origin in three. Three types of seizure sequence were identified: PS followed several seconds later by ES (two patients), alternating PS and ES starting with PS (three), and PS gradually replaced by ES with overlapping of the two (three). PS-ES disappeared or was replaced by other types of seizures in 1-34 months. Six patients could not walk, and all patients could not speak any sentences at age 3 years. CONCLUSIONS: Compared with patients without PS-ES, those with PS-ES more often had organic brain lesions of prenatal origin, other types of seizures before the onset of ES, asymmetric hypsarrhythmia on the EEG, and poor psychomotor outcome.

Representation of the ear in human primary somatosensory cortex.

We studied 13 healthy subjects with a multichannel magnetoencephalography (MEG) system to investigate the somatotopic representation of the ear in the primary somatosensory cortex (SI). We stimulated three parts of the left ear: the helix, the lobulus, and the tragus. The somatosensory-evoked magnetic fields (SEFs) were successfully measured in 7 of 13 subjects. Short-latency responses were analyzed using both single dipole and multidipole models (brain electric source analysis, BESA). From the single dipole model, the equivalent current dipole (ECD) following the helix stimulation was estimated to be near the neck area of SI in all the subjects. In the lobulus stimulation, the ECDs were estimated around the neck area of SI in four subjects, in the face area in one subject, and in the deep white matter in two subjects. In the tragus stimulation, the ECDs were estimated around the neck area of SI in three subjects, in the hand area of SI in two subjects, and in the deep white matter in two subjects. When the ECDs were estimated to be located in unlikely sites (hand area and deep white matter), a two-dipole model, (1) the neck area of SI and (2) face area of SI, was found to be the most appropriate. Although this might be a preliminary study due to a relatively small number of subjects, it revealed that receptive fields of some part of the ear, such as the lobulus and tragus, might be present in both the neck and face areas of SI. These findings suggested that the "ear area" of SI has variability between subjects, unlike the other areas of SI, possibly because the ear is located on the border between the neck and face.

Guillain-Barré syndrome associated with central nervous system lesions.

We report the clinical course, and neurophysiological and neuroimaging findings of a patient with Guillain-Barré syndrome associated with central nervous system lesions. During a course of intravenous immunoglobulin therapy, she had headache with meningism. Cerebral magnetic resonance imaging showed lesions in both frontal and right occipital lobes. Cerebrospinal fluid showed a raised protein concentration accompanied by mild pleocytosis. Her symptoms resolved within two months. Subsequent magnetic resonance imaging revealed cavity formation in the deep white matter and atrophic changes in the right occipital lobes.

Hypocarbia in preterm infants with periventricular leukomalacia: the relation between hypocarbia and mechanical ventilation.

OBJECTIVE: The aim of this study was to elucidate the relationship between mechanical ventilation and hypocarbia in infants with periventricular leukomalacia (PVL). STUDY DESIGN: Matched pair analysis was conducted for 26 infants with PVL and 26 with normal development, who were born between 27 and 32 weeks' gestational age and required mechanical ventilation. The time-averaged carbon dioxide (CO(2)) index, PaCO(2), and pH were calculated every 24 hours for samples obtained from indwelling arterial catheters within the first 72 hours of life. The time-averaged respiratory rate of the ventilator (RR), peak inspiratory pressure (PIP), mean airway pressure (MAP), and ventilator index (VI) were also determined. The time-averaged total respiratory rate (TRR) was determined by observing the movement of the chest wall. The patients' characteristics, antenatal and neonatal variables, and electroencephalographic findings were also compared. RESULTS: The time-averaged CO(2) index was larger, the time-averaged CO(2) lower and the time-averaged pH higher in infants with PVL than in those with normal development on the third day of life. There was no significant difference in the time-averaged RR, PIP, MAP, or VI on any day. TRR was larger in the PVL group than in the control group on each day, but there was no significant difference. No significant difference was observed in the clinical characteristics or neonatal variables. Electroencephalographic abnormalities within 48 hours of life were more frequent in infants with PVL than in those with normal development. CONCLUSION: Hypocarbia was associated with PVL because the time-averaged CO(2) index was larger and the time-averaged PaCO(2) lower in infants with PVL than in those with normal development. However, the ventilator settings were similar among the infants with and without PVL.