Estimate of the incidence of PANDAS and PANS in 3 primary care populations.

Objective: Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection (PANDAS) and Pediatric Acute-Onset Neuropsychiatric syndrome (PANS) are presumed autoimmune complications of infection or other instigating events. To determine the incidence of these disorders, we performed a retrospective review for the years 2017-2019 at three academic medical centers. Methods: We identified the population of children receiving well-child care at each institution. Potential cases of PANS and PANDAS were identified by including children age 3-12 years at the time they received one of five new diagnoses: avoidant/restrictive food intake disorder, other specified eating disorder, separation anxiety disorder of childhood, obsessive-compulsive disorder, or other specified disorders involving an immune mechanism, not elsewhere classified. Tic disorders was not used as a diagnostic code to identify cases. Data were abstracted; cases were classified as PANDAS or PANS if standard definitions were met. Results: The combined study population consisted of 95,498 individuals. The majority were non-Hispanic Caucasian (85%), 48% were female and the mean age was 7.1 (SD 3.1) years. Of 357 potential cases, there were 13 actual cases [mean age was 6.0 (SD 1.8) years, 46% female and 100% non-Hispanic Caucasian]. The estimated annual incidence of PANDAS/PANS was 1/11,765 for children between 3 and 12 years with some variation between different geographic areas. Conclusion: Our results indicate that PANDAS/PANS is a rare disorder with substantial heterogeneity across geography and time. A prospective investigation of the same question is warranted.

Functional brain connectivity in electrical status epilepticus in sleep.

Electrical status epilepticus in sleep (ESES) is an age-related, self-limited epileptic encephalopathy. The syndrome is characterized by cognitive and behavioral abnormalities and a specific EEG pattern of continuous spikes and waves during slow-wave sleep. While spikes and sharp waves are known to result in transient cognitive impairment during learning and memory tasks performed during the waking state, the effect of epileptiform discharges during sleep on cognition and behavior is unclear. There is increasing evidence that abnormalities of coherence, a measure of the consistency of the phase difference between two EEG signals when compared over time, is an important feature of brain oscillations and plays a role in cognition and behavior. The objective of this study was to determine whether coherence of EEG activity is altered during slow-wave sleep in children with ESES when compared to typically developing children. We examined coherence during epochs of ESES versus epochs when ESES was not present. In addition, we compared coherence during slow-wave sleep between typically developing children and children with ESES. ESES was associated with remarkably high coherences at all bandwidths and most electrode pairs. While the high coherence was largely attributed to the spikes and spike-and-wave discharge, activity between spikes and spike-and-wave discharge also demonstrated high coherence. This study indicates that EEG coherence during ESES is relatively high. Whether these increases in coherence correlate with the cognitive and behavioral abnormalities seen in children with this EEG pattern remains to be determined.

A comparison of continuous video-EEG monitoring and 30-minute EEG in an ICU.

AIM: To determine whether there is added benefit in detecting electrographic abnormalities from 16-24 hours of continuous video-EEG in adult medical/surgical ICU patients, compared to a 30-minute EEG. METHODS: This was a prospectively enroled non-randomized study of 130 consecutive ICU patients for whom EEG was requested. For 117 patients, a 30-minute EEG was requested for altered mental state and/or suspected seizures; 83 patients continued with continuous video-EEG for 16-24 hours and 34 patients had only the 30-minute EEG. For 13 patients with prior seizures, continuous video-EEG was requested and was carried out for 16-24 hours. We gathered EEG data prospectively, and reviewed the medical records retrospectively to assess the impact of continuous video-EEG. RESULTS: A total of 83 continuous video-EEG recordings were performed for 16-24 hours beyond 30 minutes of routine EEG. All were slow, and 34% showed epileptiform findings in the first 30 minutes, including 2% with seizures. Over 16-24 hours, 14% developed new or additional epileptiform abnormalities, including 6% with seizures. In 8%, treatment was changed based on continuous video-EEG. Among the 34 EEGs limited to 30 minutes, almost all were slow and 18% showed epileptiform activity, including 3% with seizures. Among the 13 patients with known seizures, continuous video-EEG was slow in all and 69% had epileptiform abnormalities in the first 30 minutes, including 31% with seizures. An additional 8% developed epileptiform abnormalities over 16-24 hours. In 46%, treatment was changed based on continuous video-EEG. CONCLUSION: This study indicates that if continuous video-EEG is not available, a 30-minute EEG in the ICU has a substantial diagnostic yield and will lead to the detection of the majority of epileptiform abnormalities. In a small percentage of patients, continuous video-EEG will lead to the detection of additional epileptiform abnormalities. In a sub-population, with a history of seizures prior to the initiation of EEG recording, the benefits of continuous video-EEG in monitoring seizure activity and influencing treatment may be greater.

Brain connectivity in West syndrome.

PURPOSE: Hypsarrhythmia, the pathognomonic EEG pattern of West syndrome, is typically characterized by a high amplitude, arrhythmic, and asynchronous pattern. While this severely aberrant pattern would suggest severe abnormalities in connectivity, coherence has not yet been systematically assessed in hypsarrhythmia. METHODS: We evaluated the EEGs of 28 infants, 12 with infantile spasms with hypsarrhythmia and 16 similarly age control infants for coherence and spectral power. RESULTS: Children with infantile spasms and hypsarrhythmia EEGs had marked abnormalities in coherence and spectral power compared to normal children of similar ages. During sleep increases in delta, theta, alpha and beta coherences were seen, particularly at long inter-electrode distances while at short inter-electrode distances coherences were decreased in the theta and beta range, particularly in the frontal region. The enhanced coherences at long inter-electrode distances suggest that during sleep in children with infantile spasms widely spread cortical region do not have functional differentiation whereas in the frontal lobe there is reduced functional connectivity and integration of local cortical regions. Children with continued seizures and developmental delay showed persistent abnormalities in coherence. CONCLUSION: This study demonstrates that hypsarrhythmic EEGs have marked abnormalities in coherence spectral power and such abnormalities may be related to cognitive impairment.

Transitory effect of spike and spike-and-wave discharges on EEG power in children.

BACKGROUND: Spikes and spike-and-wave discharges on the EEG of children are a strong biomarker of epilepsy. There is increasing evidence that these EEG abnormalities also impair brain function and result in transitory cognitive impairment. Studies in animal models have shown that EEG spikes alters single cell firing and that such impairment in firing may extend beyond the duration of the spike-and-wave discharge. Whether interictal epileptiform discharges have lasting effects on EEG activity in humans is not known. METHODS AND RESULTS: The EEGs of 60 consecutive children with focal or interictal spike-and-wave discharges were evaluated using power spectral analysis to determine if there were any changes in power spectra from before to after the interictal abnormalities. Neither focal spike-and-wave nor generalized spike-and-wave discharges had any effect on the EEG frequency or spectral power following the discharge. CONCLUSION: While interictal EEG discharges temporarily alter neural activity during the duration of the spike-and-wave discharge, there is no evidence that alterations of spectral power continue beyond the duration of the interictal discharge. The effects of interictal activity on EEG rhythms therefore appear to be quite transient and confined to the duration of the interictal discharge.

Stiripentol in Dravet syndrome: results of a retrospective U.S. study.

PURPOSE: To review the efficacy and tolerability of stiripentol in the treatment of U.S. children with Dravet syndrome. METHODS: U.S. clinicians who had prescribed stiripentol for two or more children with Dravet syndrome between March 2005 and 2012 were contacted to request participation in this retrospective study. Data collected included overall seizure frequency, frequency of prolonged seizures, and use of rescue medications and emergency room (ER)/hospital visits in the year preceding stiripentol initiation, and with stiripentol therapy. We separately assessed efficacy in the following treatment groups: group A, stiripentol without clobazam or valproate; group B, stiripentol with clobazam but without valproate; group C, stiripentol with valproate but without clobazam; and group D, stiripentol with clobazam and valproate. In addition, adverse effects were recorded. KEY FINDINGS: Thirteen of 16 clinicians contacted for study participated and provided data on 82 children. Stiripentol was initiated a median of 6.0 years after seizure onset and 1.2 years after diagnosis of Dravet syndrome. Compared to baseline, overall seizure frequency was reduced in 2/6 in group A, 28/35 in group B, 8/14 in group C, and 30/48 in group D. All children with prolonged seizure frequency greater than quarterly during the baseline period experienced a reduction in this frequency on the various treatment arms with stiripentol. Similarly, 2/4 patients in group A, 25/25 in group B, 5/10 in group C, and 26/33 in group D experienced reduction in frequency of rescue medication use and 1/1 in group A, 12/12 in group B, 3/5 in group C, and 18/19 in group D had reduction in frequency of ER/hospital visits. Adverse effects were reported in 38, most commonly sedation and reduced appetite. Four patients (5%) discontinued stiripentol for adverse effects and two (2%) for lack of efficacy. SIGNIFICANCE: Stiripentol is an effective and well-tolerated therapy that markedly reduced frequency of prolonged seizures in Dravet syndrome.

Outcome of frontal lobe epilepsy surgery.

PURPOSE: There is still controversy in deciding which patients with frontal lobe epilepsy (FLE) should undergo resective surgery, even though it is a well-established therapy. The aim of this study is to define multiple outcome measures and determine whether there are certain subpopulations of preferred surgical candidates that have a more favorable seizure prognosis. METHODS: Fifty-eight patients underwent resective FLE surgery with a mean follow-up period of 79.3 months (range 12-208 months). Patient demographics, clinical seizure characteristics, seizure-onset zone within the frontal lobes, and diagnostic tests were tabulated. Engel class, International League Against Epilepsy (ILAE) class, postoperative seizure patterns, time to first recurrent seizure, and seizures and employment during the last year of follow-up were used as outcome measures. Neuropsychological performance and Beck Depression Inventory (BDI) scores were used to define neuropsychological outcome and examined as predictors of seizure outcome. KEY FINDINGS: Thirty-three (57%) patients with resective surgery had an Engel class I outcome and 29 (50%) had an ILAE class I outcome. Mean time to first seizure after surgery was 33.3 months (range 0-208). Only 14 patients (24%) were completely seizure-free without auras (Engel IA) throughout the entire follow-up period. The most common pattern of seizure recurrence was mixed, with prolonged periods of seizure freedom intermixed with recurrences. In addition, 32% of patients made gains in employment and 52% were able to reduce use of antiepileptic drugs (AEDs), although only 9% discontinued AEDs. No significant association was found between class I or class IA outcome and the presence of a focal magnetic resonance imaging (MRI) abnormality, any specific localization of seizure focus within the frontal lobe, or neuropsychological change. SIGNIFICANCE: Findings indicate that that long-term outcome is generally favorable in FLE resective surgery, and support the need for considering multiple outcome measures to more fully characterize clinically relevant postsurgical changes. Outcome can be favorable even in MRI-negative patients.

SCN1A mutations in Dravet syndrome: impact of interneuron dysfunction on neural networks and cognitive outcome.

Dravet syndrome (DS) is a childhood disorder associated with loss-of-function mutations in SCN1A and is characterized by frequent seizures and severe cognitive impairment. Animal studies have revealed new insights into the mechanisms by which mutations in this gene, encoding the type I voltage-gated sodium channel (Na(v)1.1), may lead to seizure activity and cognitive dysfunction. In this review, we further consider the function of fast-spiking GABAergic neurons, one cell type particularly affected by these mutations, in the context of the temporal coordination of neural activity subserving cognitive functions. We hypothesize that disruptions in GABAergic firing may directly contribute to the poor cognitive outcomes in children with DS, and discuss the therapeutic implications of this possibility.

The neurologic findings in Taybi-Linder syndrome (MOPD I/III): case report and review of the literature.

Taybi-Linder syndrome, also known as microcephalic osteodysplastic primordial dwarfism types I and III, is a rare disorder with presumed autosomal recessive inheritance. It is characterized by intrauterine growth retardation, distinctive bone dysplasia, and central nervous system malformations. We present two siblings with Taybi-Linder syndrome, with an emphasis on the neurological profile in this disease, which includes brain malformations, intractable epilepsy, sensory deficits, profound cognitive deficits, and neuroendocrine dysfunction. We also present distinctive correlative neuroimaging (MRI) and electroencephalographic (EEG) findings. Increased knowledge of the neurological profile of Taybi-Linder syndrome may be helpful for clinicians and genetic counselors managing these patients.

Maturation of EEG oscillations in children with sodium channel mutations.

Dravet syndrome (DS) is a severe epileptic encephalopathy beginning in infancy in which children have difficult to control seizures and cognitive impairment. The majority of children with DS carry mutations of the gene Scn1a, which codes for the alpha subunit of the type 1 voltage-gated sodium channel and is important for the function of interneurons. Interneurons have a critical role in the generation of brain rhythms involved in cognitive processing. We hypothesized that children with DS with Scn1a mutations would have abnormal oscillatory activity. To address this hypothesis, we used EEG power spectral analysis during the wakening to determine if frequency and power are altered in 23 EEGs from 12 children with DS compared to 18 age-matched controls. While there were few differences between the EEG power spectra in DS and controls in children under 2years, in older children group differences were apparent. In DS children between 3 and 5years there were significant decreases in percentage of alpha power compared to controls and in DS children over age 6years there was a marked increase of theta and decrease of alpha compared to controls. Developmental status paralleled the power spectral analysis with an increasing likelihood of having severe cognitive problems with increasing age. These results demonstrate that Scn1a mutations result in an age-dependent alteration in oscillatory process. Such abnormalities in developmental progression of oscillations may play an important role in poor cognitive development in children with DS.

Education of a child neurologist: epilepsy and electroencephalography.

Epilepsy is one of the most common disorders encountered in pediatric neurology. A well-trained child neurologist should have an understanding of the neurobiological causes of seizures, classification of seizures and epilepsy, etiologic evaluation, and treatment of both seizures and associated comorbid conditions. Electroencephalography (EEG) is an important diagnostic test in epilepsy, and child neurologists should be knowledgeable in the physiological basis of EEG and how to identify normal and abnormal patterns in neonates and children.

Intractable occipital lobe epilepsy: clinical characteristics and surgical treatment.

Intractable occipital lobe epilepsy remains a surgical challenge. Clinical characteristics of 14 patients were analyzed. Twelve patients had surgery, seven patients had visual auras (50%) and only eight patients (57%) had posterior scalp EEG changes. Ictal single-proton emission computed tomography (SPECT) incorrectly localized in 7 of 10 patients. Six patients (50%) had Engel's class I outcome. Patients with inferior occipital seizure onset appeared to fare better (three of four class I) than patients with lateral or medial occipital seizure onset (three of eight class I). Patients who had all three occipital surfaces covered with electrodes had a better outcome (four of five class I) than patients who had limited electroencephalography (EEG) coverage (two of seven class I). Magnetic resonance imaging (MRI) lesions did not guarantee a seizure free outcome. In conclusion, visual auras, scalp EEG, and imaging findings are not reliable for correct identification of occipital onset. Occipital seizure onset can be easily missed in nonlesional epilepsy. Comprehensive intracranial EEG coverage of all three occipital surfaces leads to better outcomes.

Choreoathetosis after herpes simplex encephalitis with basal ganglia involvement on MRI.

Children with herpes simplex virus encephalitis have a relapse in approximately 25% of cases, which rarely may present as a movement disorder, most often choreoathetosis. The anatomic basis for herpes simplex virus encephalitis-associated movement disorders has been poorly understood, because neuroimaging, to date, has not been able to show the direct involvement of the areas of the brain that typically govern such movements. We present a patient with abnormal involuntary movements after herpes simplex virus encephalitis, with new lesions on MRI between the time of initial presentation and the development of choreoathetosis. To our knowledge, this is the first patient with a post-herpes simplex virus encephalitis movement disorder with neuroradiographic evidence of thalamic involvement correlating with the onset of abnormal involuntary movements. We describe this patient and review the literature on movement disorders and herpes simplex virus encephalitis. Current understanding of the pathophysiology of post-herpes simplex virus encephalitis movement disorders proposes 2 possible mechanisms that may be responsible: reinfection with the resumption of viral replication, or a postinfectious, immune-mediated process.

Deletion of chromosome 21 disturbs human brain morphogenesis.

PURPOSE: Humans with small deletions of chromosome 21 provide important models for understanding the role of dosage-sensitive genes in brain morphogenesis. To identify chromosome 21 genes responsible for defects of the central nervous system, we determined the deleted regions and brain malformations in three unrelated individuals with overlapping partial deletions of chromosome 21. METHODS: Fluorescent in situ hybridization and magnetic resonance imaging were used to define the chromosomal structure and structural brain abnormalities present in these three individuals. RESULTS: The regions of chromosome 21 found to be deleted in these individuals were as follows: case 1: KCNJ6 to the telomere; case 2: ITSN1 to the telomere; and case 3: ITSN1 to PCNT2. The abnormalities of brain structure shared by all included microcephaly, pachygyria, polymicrogyria, colpocephaly, hypoplastic corpus callosum and white matter, hypoplastic cerebellum, and enlarged ventricular system. The clinical features in common included mental retardation, microcephaly, facial dysmorphism, and epilepsy (severe in one patient). CONCLUSION: From analyses of the molecular, cytogenetic, and neuroimaging data from these three individuals, combined with those from previously reported cases, we infer that deletion of an 8.4-Mb region in chromosome band 21q22.2-22.3 (KCNJ6-COL6A2) is associated with cortical dysplasia. We propose that one or more dosage-sensitive genes in this region contributes to cortical development and that deletion of 21q22.2-22.3 should be considered in the diagnosis of mentally retarded patients with facial dysmorphism and cerebral dysplasia.

Novel form of intermediate salla disease: clinical and neuroimaging features.

The objective of this article is to describe the clinical, radiographic, and molecular genetic features of a new intermediate form of free sialic storage disease. Free sialic storage disease is a rare autosomal recessive lysosomal disorder that results from mutations in SLC17A5, a gene that codes for sialin, a lysosomal membrane sialic acid transporting protein. Infantile sialic acid storage disease has a severe phenotype, and Salla disease (Finnish variant) is generally milder in phenotype; intermediate forms have also been described. There have been few reports of magnetic resonance imaging (MRI) in the sialic acid storage disorders; leukodystrophy has been the characteristic finding, along with hypoplasia of the corpus callosum. An 8-month-old non-Finnish child presented with hypotonia and global developmental delay. Serial MRIs with magnetic resonance spectroscopy at 9 and 16 months revealed severe hypomyelination and hypogenesis of the corpus callosum. There was mild elevation of urinary sialic acid (4.5 times above normal). Electron microscopy of a skin biopsy showed lysosomal enlargement with oligosaccharide storage, and confirmatory molecular genetic testing revealed compound heterozygosity for two new SLC17A5 mutations. Free sialic storage disease of the intermediate type is an important part of the differential diagnosis of a hypotonic, delayed child with abnormal white matter on MRI. Intermediate types of free sialic acid overlap in phenotype with infantile sialic acid storage disease and the milder Salla disease and thus might be more difficult to identify clinically; the lack of Finnish ethnicity should not preclude testing for this probably under-recognized disorder. White-matter abnormalities appear to be characteristic of the entire phenotypic spectrum.

Clinical, biochemical, and molecular diagnosis of a free sialic acid storage disease patient of moderate severity.

The allelic autosomal recessive lysosomal storage disorders Salla disease and infantile free sialic acid storage disease (ISSD) result from mutations in SLC17A5. This gene codes for sialin, a lysosomal membrane protein that transports the charged sugar, N-acetylneuraminic acid (sialic acid), out of lysosomes. ISSD has a severe phenotype with infantile onset, while the Finnish variant, Salla disease, has a milder phenotype with later onset. Both disorders cause developmental delay, and ISSD is generally fatal in early childhood. We describe a 30-month old non-Finnish, Caucasian child with global developmental delay of postnatal onset, language, and motor skills stagnant at a 3-4 month level, hypotonia, and mild but progressive coarsening of facial features. Urinary excretion of free sialic acid was elevated 4.5 times above control. EM of a skin biopsy revealed enlarged secondary lysosomes consistent with oligosaccharide storage. Free sialic acid in fibroblasts was 3.8+/-0.9 nmol/mg protein (concurrent normal controls, 0.5+/-0.1); differential centrifugation indicated a lysosomal location. Genomic analysis revealed compound heterozygosity for two new SLC17A5 mutations. This child's clinical manifestations of a lysosomal free sialic acid storage disease are consistent with her sialin mutations and biochemical findings. The differential diagnosis of postnatal developmental delay should include free sialic acid storage disorders such as ISSD and Salla disease.