Involvement of brain structures in childhood epilepsy with centrotemporal spikes.

BACKGROUND: We aimed to investigate electroencephalography (EEG)-functional magnetic resonance imaging (fMRI) findings to elucidate the interictal epileptiform discharge (IED)-related functional alterations in deep brain structures and the neocortex in childhood epilepsy with centrotemporal spikes (CECTS). METHODS: Ten children with CECTS (median age 8.2 years), referred to our hospital within a year of onset, were eligible for inclusion. They underwent EEG-fMRI recording during sleep. Llongitudinal evaluations, including medical examinations, intelligence tests, and questionnaires about developmental disabilities, were performed. The initial evaluation was performed at the same time as the EEG-fMRI, and the second evaluation was performed over 2 years after the initial evaluation. RESULTS: Three children were unable to maintain sleep during the EEG-fMRI recording, and the remaining seven children were eligible for further assessment. All patients showed unilateral-dominant centrotemporal spikes during scans. One patient had only positive hemodynamic responses, while the others had both positive and negative hemodynamic responses. All patients showed IED-related hemodynamic responses in the bilateral neocortex. For deep brain structures, IED-related hemodynamic responses were observed in the cingulate gyrus (n = 4), basal ganglia (n = 3), thalamus (n = 2), and default mode network (n = 1). Seizure frequencies at the second evaluation were infrequent or absent, and the longitudinal results of intelligence tests and questionnaires were within normal ranges. CONCLUSIONS: We demonstrated that IEDs affect broad brain areas, including deep brain structures such as the cingulate gyrus, basal ganglia, and thalamus. Deep brain structures may play an important role in the pathophysiology of CECTS.

Acute encephalopathy with biphasic seizures and late reduced diffusion: Predictive EEG findings.

BACKGROUND: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a common type of acute encephalopathy in Japan; the condition is clinically characterized by prolonged seizures as the initial neurological symptom, followed by late seizures 4-6 days later. It is difficult to differentiate AESD from prolonged febrile seizures (PFSs). Here, we explored the use of electroencephalography to differentiate AESD from PFSs. METHODS: We studied the electroencephalograms (EEGs) of children <6 years of age diagnosed with AESD or PFSs; all EEGs were recorded within 48 h of seizure onset (i.e., before the late seizures of AESD). Two pediatric neurologists evaluated all EEGs, focusing on the basic rhythm, slowing during wakefulness/arousal by stimuli, spindles, fast waves, and slowing during sleep. RESULTS: The EEGs of 14 children with AESD and 31 children with PFSs were evaluated. Spindles were more commonly reduced or absent in children with AESD than in those with PFSs (71% vs. 31%, p = 0.021). Fast waves were also more commonly reduced or absent in children with AESD (21% vs. 0%, p = 0.030). The rates of all types of slowing did not differ between children with AESD and those with PFSs, but continuous or frequent slowing during sleep was more common in the former (50% vs. 17%, p = 0.035). CONCLUSIONS: EEG findings may usefully differentiate AESD from PFSs. Reduced or absent spindles/fast waves and continuous or frequent slowing during sleep are suggestive of AESD in children with prolonged seizures associated with fever.

Repetitive sleep starts: An important differential diagnosis of infantile spasms.

OBJECTIVE: Repetitive sleep starts (RSS) are clusters of nonepileptic, spasm-like movements occurring during sleep onset. However, their characteristics have yet to be defined. We conducted a clinicoelectroencephalographic study of children with RSS to clarify their detailed characteristics. METHODS: To differentiate starts from epileptic spasms, we recruited children with brief "crescendo-decrescendo" muscle contractions that simultaneously involved the limbs and trunk without electroencephalogram changes, and that fulfilled the following criteria: (1) repeated occurrence (five or more) and (2) manifestation during sleep stage N1-N2. A total of nine children met these criteria. Their clinical information and video-electroencephalogram data were analyzed retrospectively. RESULTS: The background conditions observed at onset of RSS were perinatal hypoxic-ischemic encephalopathy (n = 4), West syndrome of unknown etiology (n = 1), and traumatic brain injury (n = 1). The age at onset of RSS, the number of starts in a given RSS cluster, the interval between starts, and the duration of surface electromyogram activity were between 3 and 46 months, 5 and 547, <1 and 60 s, and 0.3 and 5.4 s, respectively. None of the median value of these parameters differed between children with and without corticospinal tract injury. During the median follow-up period of 33 months, RSS disappeared spontaneously in five. CONCLUSION: This is the largest case series of RSS clarifying their clinicoelectroencephalographic characteristics reported to date. To avoid unnecessary antiepileptic therapies, clinicians should be aware of RSS and distinguish it from other disorders involving involuntary movements or seizures, especially epileptic spasms.

Shuffling babies and autism spectrum disorder.

BACKGROUND AND PURPOSE: Bottom shuffling is a locomotion strategy that precedes independent walking in some infants. Shuffling babies are generally considered to have favorable outcomes. The aim of the present study was to reveal clinical features and neurodevelopmental outcomes of shuffling babies who visited a child developmental center. METHODS: We studied 48 shuffling babies who visited Toyota Municipal Child Development Center from April 2007 to March 2015. We excluded patients with cerebral palsy, Down syndrome, or congenital disorders. In 2018, we retrospectively reviewed the clinical charts of the enrolled children. We investigated family history, neurological findings, and the developmental outcome during the follow-up period. RESULTS: During the follow-up period, 20 children (42%) were diagnosed with ASD. Gross motor development in infancy was not different between infants with and without ASD. The rate of poor eye contact at the first visit and a delay in the first word speech were significantly higher in infants with ASD than in infants without ASD. A family history of bottom shuffling was significantly less frequent in infants with ASD (10%) than in those without (39%). CONCLUSION: Some of bottom shufflers may represent ASD during follow-up. Paying attention to social and cognitive functions in shuffling babies is important.

Lenticular nuclei to thalamic ratio on PET is useful for diagnosis of GLUT1 deficiency syndrome.

PURPOSE: To establish an objective method of [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) that can assist in the diagnosis of glucose transporter 1 deficiency syndrome (GLUT1-DS). METHODS: FDG-PET was performed in 8 patients with a mean age of 12.5 years (range, 2-22 years) with GLUT1-DS. Their PET findings were compared with those of 45 controls with a mean age of 11.2 years (range, 2-21 years) by statistical parametric mapping (SPM12, Welcome Neurological Institute). The controls had epilepsy of unknown etiology and normal MRI findings. The age-adjusted ratios of mean radioactivities in regions of interest (ROIs) of bilateral lenticular nuclei, thalami, and the whole cerebral cortex were also measured. The sensitivities and specificities of the ratios for the differential diagnosis of GLUT1-DS were also determined. RESULTS: SPM showed significantly decreased uptake in bilateral thalami and increased uptake in bilateral lenticular nuclei in patients with GLUT1-DS. There were no areas in the cerebral cortex with significant differences between patients and controls. On ROI analysis, by setting the cut-off value of the age-adjusted lenticular nuclei/thalami radioactivity ratio to 1.54, patients with GLUT1-DS were differentiated from controls with sensitivity of 1.00 and specificity of 0.98. CONCLUSION: The age-adjusted lenticular nuclei/thalami radioactivity ratio on PET can distinguish patients with GLUT1-DS from patients with epilepsy of unknown etiology with high sensitivity and specificity. It is important to pay attention to the metabolism of the lenticular nuclei and thalami on PET for the diagnosis of GLUT1-DS.

Change of White Matter Integrity in Children With Hematopoietic Stem Cell Transplantation.

BACKGROUND: Advances in hematopoietic stem cell transplantation have improved the survival rate of malignant diseases and congenital immunodeficiencies. It has become important to assess long-term complications in survivors. To assess neurological abnormalities in children treated by transplantation, diffusion tensor imaging was performed. METHODS: Forty children who underwent head diffusion tensor imaging before and after their first transplantation were enrolled. Patients with brain lesions on conventional MRI were excluded. Fractional anisotropy and mean diffusivity were compared between patients and 28 control subjects using tract-based spatial statistics. The Strengths and Difficulties Questionnaire was administered as a behavioral evaluation after transplantation, and diffusion tensor images of patients with and without behavioral abnormalities were compared. RESULTS: The age of patients and controls was 0 to 19 years and 0 to 16 years, respectively. The date of diffusion tensor imaging was 10 to 57 days before and 40 to 153 days after transplantation. Tract-based spatial statistics showed fractional anisotropy reduction in widespread white matter in patients before and after transplantation. Mean diffusivity was high before transplantation and normalized after transplantation. Analysis comparing before and after hematopoietic stem cell transplantation shows no difference in fractional anisotropy and a higher mean diffusivity before hematopoietic stem cell transplantation. In patients with behavioral abnormalities, low fractional anisotropy and high mean diffusivity remained after transplantation. CONCLUSIONS: Longitudinal diffusion tensor imaging showed white matter abnormalities in children without conventional MRI abnormalities, which were related to behavioral problems after transplantation. Diffusion tensor imaging is useful for behavioral assessment in children undergoing transplantation.

High-amplitude fast activity in EEG: An early diagnostic marker in children with beta-propeller protein-associated neurodegeneration (BPAN).

OBJECTIVE: The early diagnosis of beta-propeller protein-associated neurodegeneration (BPAN) before distinct brain magnetic resonance imaging (MRI) findings of iron deposition occur remains challenging. This study examined whether children with BPAN have characteristic high-amplitude (>50 µV) fast activity (HAFA) on electroencephalography (EEG). METHODS: We conducted a retrospective analysis of EEG performed during childhood in five patients with BPAN. We also examined 143 EEGs from 59 patients with different etiologies, including epilepsy (n = 33), acute encephalopathy (n = 6), neurodevelopmental disorders (n = 5), non-epileptic events (n = 4), and others (n = 11). Trained electroencephalographers reviewed all of the EEGs. When excessive fast activity was observed, the amplitude, frequency, and locality were assessed. RESULTS: All five patients with BPAN underwent initial EEGs at 12-21 months old, and diffuse continuous HAFA (range 20-50 Hz) was observed on both awake and sleep EEGs. In the awake records, there was no clear posterior dominant rhythm in 4 of the 5 patients. Although 28% of the 143 EEGs had continuous excessive fast activity, mainly in the sleep records, only two (1.4%) exhibited HAFA when asleep, and their awake EEGs had clear posterior dominant rhythm. CONCLUSIONS: The EEGs of children with BPAN showed diffuse HAFA continuously when both awake and asleep, which is uncommon in children with other etiologies. SIGNIFICANCE: This study provides an important clue for the early diagnosis of BPAN.

Subsecond EEG-fMRI analysis for presurgical evaluation in focal epilepsy.

OBJECTIVE: The authors recently reported a novel subsecond analysis method of analyzing EEG-functional MRI (fMRI) to improve the detection rate of epileptic focus. This study aims to validate the utility of this method for presurgical evaluation in pharmacoresistant focal epilepsy. METHODS: Among 13 patients with focal epilepsy undergoing presurgical examinations including simultaneous EEG-fMRI at 3T, 11 patients had interictal epileptiform discharges (IEDs) during fMRI. The authors used the sequence of topographic maps during the IEDs as a reference to obtain subsecond fMRI activation maps with the same temporal resolution as the EEG data, and constructed "spike-and-slow-wave-activation-summary" (SSWAS) maps that showed the activation frequency of voxels during IEDs. Clusters were defined by thresholding the SSWAS maps (voxel value > 10), and those containing voxels with the top 3 highest activation frequencies were considered significant. Significant hemodynamic responses using conventional event-related (ER) analysis and SSWAS maps were compared with the resection areas and surgical outcomes at 1 year after surgery. RESULTS: Using ER analysis, 4 (36%) of 11 patients had significant hemodynamic responses. One of 4 patients had significant hemodynamic responses in the resection area and good surgical outcome. Using SSWAS maps, 10 (91%) of 11 patients had significant hemodynamic responses. Six of 10 patients had significant hemodynamic responses in the resection area, and 5 of the 6 patients achieved good surgical outcomes. The remaining 4 patients had significant hemodynamic responses distant from the resection area, and only 1 of the 4 patients achieved good surgical outcomes. The sensitivity, specificity, positive predictive value, and negative predictive value of SSWAS maps were 83.3%, 75.0%, 83.3%, and 75.0%, respectively. CONCLUSIONS: This study demonstrated the clinical utility of SSWAS maps for presurgical evaluation of pharmacoresistant focal epilepsy. The findings indicated that subsecond EEG-fMRI analysis may help surgeons choose the resection areas that could lead to good surgical outcomes.

Pseudo-sawtooth pattern on amplitude-integrated electroencephalography in neonatal hypoxic-ischemic encephalopathy.

OBJECTIVE: The objective of this study was to describe a novel amplitude-integrated electroencephalography (aEEG) pattern in infants with hypoxic-ischemic encephalopathy (HIE) and to assess the clinical significance. METHODS: The aEEG traces of infants with HIE who were treated with therapeutic hypothermia (TH) from 2012 to 2017 were analyzed. A pseudo-sawtooth (PST) pattern was defined as a periodic increase of the upper and/or lower margin of the trace on aEEG without showing seizure activities on conventional EEG (CEEG). RESULTS: Of the 46 infants, 6 (13%) had the PST pattern. The PST pattern appeared following a flat trace or a continuous low-voltage pattern and was followed by a burst-suppression pattern. On CEEG, the PST pattern consists of alternating cycles of low-voltage irregular activities and almost flat tracing. The PST pattern was associated with neuroimaging abnormalities and with various degrees of neurodevelopmental outcomes. Positive predictive values of the PST or worse pattern for adverse outcomes were high at 12 h after birth. CONCLUSION: A novel aEEG background pattern in infants with HIE was reported. The PST pattern likely indicates a suppressed background pattern and may be linked to unfavorable outcomes. Further multicenter validation study is needed to clarify its clinical significance.

Risk factors for absence of catch-up growth in small for gestational age very low-birthweight infants.

BACKGROUND: Many small for gestational age (SGA) infants have catch-up growth during the first 2 years of life, but approximately 10% have no catch-up growth, and short stature continues into adulthood. Identification of risk factors for absence of catch-up growth at an early age may be useful for earlier diagnosis and earlier treatment. METHODS: This was a retrospective multicenter study. The subjects were SGA infants with very low-birthweight (VLBW), who were followed up until the age of 3 years. The risk factors for absence of catch-up growth were identified on statistical analysis. RESULTS: Of the 217 SGA infants in this study, 181 were in the catch-up group and 36 were in the no catch-up group. The catch-up rate was 83%. On multivariate analysis adjusted for gestational age, birthweight, birth height, and birth head circumference, multipara, Z and ΔZ scores of length at 12 months of corrected age, and the Z score of height at 24 months of corrected age were risk factors for lack of catch-up at 3 years. CONCLUSIONS: The length Z and ΔZ scores at 12 months of corrected age may be useful for an earlier diagnosis and earlier initiation of growth hormone treatment in VLBW infants.

Cytotoxic edema at onset in West syndrome of unknown etiology: A longitudinal diffusion tensor imaging study.

OBJECTIVE: To clarify longitudinal changes in white matter microstructures from the onset of disease in patients with West syndrome (WS) of unknown etiology. METHODS: Diffusion tensor imaging (DTI) was prospectively performed at onset and at 12 and 24 months old in 17 children with WS of unknown etiology. DTI was analyzed using tract-based spatial statistics (TBSS) and tract-specific analysis (TSA) of 13 fiber tracts, and fractional anisotropy (FA) and mean diffusivity (MD) were compared with those of 42 age-matched controls. Correlations of FA and MD with developmental quotient (DQ) at age 24 months were analyzed. Multiple comparisons were adjusted for using the false discovery rate (q-value). RESULTS: TBSS analysis at onset showed higher FA and lower MD in the corpus callosum and brainstem in patients. TSA showed lower MD in bilateral uncinate fasciculi (UF) (right: q < 0.001; left: q = 0.03) at onset in patients. TBSS showed a negative correlation between FA at onset and DQ in the right frontal lobe, whereas FA at 24 months old exhibited a positive correlation with DQ in the diffuse white matter. MD for bilateral UF at 24 months old on TSA correlated positively with DQ (q = 0.04, both). SIGNIFICANCE: These findings may indicate the existence of cytotoxic edema in the immature white matter and dorsal brainstem at onset, and subsequent alterations in the diffuse white matter in WS of unknown etiology. Microstructural development in the UF might play important roles in cognitive development in WS.

Paroxysmal nonepileptic events in children with epilepsy.

OBJECTIVE: The aim of this study was to clarify the characteristics of paroxysmal nonepileptic events (PNEs) suspected as being epileptic seizures by families of children with epilepsy. METHODS: The video-EEG (vEEG) recordings of habitual paroxysmal events in children with epilepsy at Nagoya University Hospital between October 2006 and January 2016 were reviewed. Based on the doctor's suspicion before the vEEG, the PNEs were divided into two groups that included PNEs suspected as epileptic seizures and PNEs suspected as PNEs. PNEs in the former group were classified based on the suspected seizure type. RESULTS: Of 886 habitual paroxysmal events, vEEG confirmed that 83 events (68 children) were PNEs. The median age of the 68 children was 3.2 years. Concurrent epilepsies included focal epilepsies (n=33), infantile spasms (n=16), and other types (n=19). The most common types of PNEs were sleep myoclonus (n=11), followed by stereotypies (n=9), awake myoclonus (n=8), paroxysmal ocular deviations (PODs, n=8), and tonic posturing (n=8). Even after direct observation or video viewing, the doctors suspected epileptic seizures in all three of the PODs and two of the tonic posturing children. Before the vEEG, however, the accurate visual information led to the speculation that the four psychogenic and two sleep myoclonus events were all PNEs. Myoclonus, stereotypies, and head drops were often misdiagnosed as epileptic spasms, while PODs and tonic posturing were often misdiagnosed as focal seizures with motor components. Additionally, staring and motion arrest during a drowsy state were often misdiagnosed as focal dyscognitive seizures. Seven of eight patients with PODs had epileptic spasms that were concurrent with epileptic seizures. A diffuse cerebral lesion or reduced visual acuity was seen in seven patients with PODs. CONCLUSION: We re-emphasize that vEEG is essential for accurate diagnosis and provides evidence for listing POD in the differential diagnosis of oculomotor paroxysmal events.

Clinical manifestations of children with microbiologically confirmed pertussis infection and antimicrobial susceptibility of isolated strains in a regional hospital in Japan, 2008-2012.

We conducted a retrospective study in 57 children (median age, 3.5 years; range, 1 month-14.5 years) with microbiologically confirmed pertussis infection over a recent 4-year period in a regional hospital in Japan. We obtained nasal swabs from all patients for Bordetella pertussis isolation as well as performed B. pertussis DNA detection using loop-mediated isothermal amplification (LAMP). Of the 57 cases, 34 (60%) were culture-positive and 57 (100%) were LAMP-positive. The frequency of each symptom was as follows: typical paroxysmal cough for over 14 days, 96% (55/57); paroxysms, 86% (49/57); posttussive vomiting, 33% (19/57); inspiratory whoop, 25% (14/57); and apnea, 12% (7/57). Hospitalization was required in 14 cases (25%), 93% (13/14) of which were aged <1 year. The proportion of patients previously immunized against diphtheria-tetanus-acellular pertussis vaccine (DTaP) was 19% (4/21) in children aged <1 year and 92% (11/12) in children aged ≥ 10 years. Minimum inhibitory concentrations for 6 antimicrobials (erythromycin, clarithromycin, azithromycin, minocycline, amoxicillin, and sulfamethoxazole/trimethoprim) were measured for 30 isolated strains, and all strains were susceptible to all aforementioned antimicrobials. Thus, an additional pertussis vaccination in older children is necessary, and the current macrolides-based treatment strategy is considered reasonable.

Assessment of the loop-mediated isothermal amplification assay for rapid diagnosis of Mycoplasma pneumoniae in pediatric community-acquired pneumonia.

Rapid diagnosis of Mycoplasma pneumoniae pneumonia is required for timely treatment with effective antibiotics; however, PCR-based methods are often too expensive and technologically intensive for general use in clinical practice. In this study, the efficacy of the loop-mediated isothermal amplification (LAMP) assay for diagnosis of M. pneumoniae pneumonia in clinical practice was prospectively evaluated. From July 2011 to March 2012, 531 children hospitalized for community-acquired pneumonia were enrolled. In all patients, throat swabs were obtained on admission for the detection of M. pneumoniae DNA, and paired serum samples were obtained to assay M. pneumoniae particle agglutination (PA) antibody titers. M. pneumoniae pneumonia was diagnosed by either a positive LAMP assay or an increase of 4-fold or greater in the PA titer. Overall, 271 children (51.0% of the patients with pneumonia) were diagnosed with M. pneumoniae pneumonia. Among these, 258 (95.2%) and 248 (91.5%) were identified by the LAMP assay and serological tests, respectively. When the results of serological tests were considered as standard, the sensitivity, specificity, and positive and negative predictive values of the LAMP assay were 94.8%, 91.9%, and 91.1% and 95.2%, respectively. The median duration of pharyngeal carriage, as measured by the LAMP assay, was 9.5 days. Thus, the LAMP assay is useful in the rapid diagnosis of M. pneumoniae pneumonia.