Pediatric Klüver-Bucy Syndrome: Report of Two Cases and Review of the Literature.

Klüver-Bucy syndrome (KBS) is a rare behavioral phenotype described in monkeys and humans that appears most often after bilateral temporal damage. The main features of KBS are compulsion to examine objects orally, increased sexual activity, placidity, hypermetamorphosis, visual agnosia, and amnesia. Cases in children are scarce, and the most frequently reported etiology is herpes encephalitis. Hyperorality (90%), hypersexuality (82%), and epilepsy (70%) were the most common features of the 51 cases reported in the literature to date. Carbamazepine, selective serotonin reuptake inhibitors (SSRIs), and neuroleptics have been used for symptomatic treatment with variable control. Corticosteroids or immunosupressive agents, such as rituximab, can be an option to use in some cases, according to etiology suspicion. Cognitive and behavioral disturbances after KBS are often severe, but improvement can occur over a long time and residual disabilities vary from major to fairly mild.We report two new encephalitis-associated pediatric patients and review all of the pediatric KBS cases in the literature to better describe the clinical features of this rare neurobehavioral condition.

Proxy-reported quality of life in adolescents and adults with dyskinetic cerebral palsy is associated with executive functions and cortical thickness.

PURPOSE: Quality of life (QOL) is a key outcome for people with cerebral palsy (CP), and executive functioning is an important predictor of QOL in other health-related conditions. Little is known about this association in CP or about its neural substrate. We aim to analyze the influence of executive functioning (including cognitive flexibility) as well as that of other psychological, motor, communication and socioeconomic variables on QOL and to identify neuroanatomical areas related to QOL in adolescents and adults with CP. METHODS: Fifty subjects diagnosed with dyskinetic CP (mean age 25.96 years) were recruited. Their caregivers completed the primary caregiver proxy report version of the CP QOL-Teen questionnaire. Motor status, communication, IQ, four executive function domains, anxiety/depression and socioeconomic status were evaluated. Correlations and multiple linear regression models were used to relate CP QOL domains and total score to these variables. Thirty-six participants underwent an MRI assessment. Correlations were examined between cortical thickness and CP QOL total score and between cortical thickness and variables that might predict the CP QOL total score. RESULTS: Executive functions predict scores in four domains of CP QOL (General well-being and participation, Communication and physical health, Family health and Feelings about functioning) in the regression model. Among the cognitive domains that comprise executive function, only cognitive flexibility measured in terms of performance on the Wisconsin card sorting test (WCST) predicts the CP QOL total score. Monthly income, fine motor functioning and communication ability predict scores on the domains Access to services and Family Health, Feelings about functioning and School well-being, respectively. The clusters resulting from the correlation between cortical thickness and both CP QOL total score and WCST performance overlapped in the posterior cingulate and precuneus cortices. CONCLUSIONS: Cognitive flexibility predicts proxy report CP QOL-Teen total score in dyskinetic CP. This relationship has its anatomical correlate in the posterior cingulate and precuneus cortices.

Candidate-gene association study searching for genetic factors involved in migraine chronification.

INTRODUCTION: Chronic migraine (CM) is at the severe end of the clinical migraine spectrum, but its genetic background is unknown. Our study searched for evidence that genetic factors are involved in the chronification process. METHODS: We initially selected 144 single-nucleotide polymorphisms (SNPs) from 48 candidate genes, which we tested for association in two stages: The first stage encompassed 262 CM patients, the second investigated 226 patients with high-frequency migraine (HFM). Subsequently, SNPs with p values < 0.05 were forwarded to the replication stage containing 531 patients with CM or HFM. RESULTS: Eight SNPs were significantly associated with CM and HFM in the two-stage phase. None survived replication in the third stage. DISCUSSION: We present the first comprehensive genetic association study for migraine chronification. There were no significant findings. Future studies may benefit from larger, genome-wide data sets or should use other genetic approaches to identify genetic factors involved in migraine chronification.

EPITRANS. Quality assessment of the epilepsy transition process.

OBJECTIVE: To analyze the differences in clinical management during the epilepsy transition process from pediatric to adult care and to determine the quality of life and degree of satisfaction of patients and caregivers during the transition. METHODS: This is a longitudinal study including patients with epilepsy transferred from pediatric to adult epilepsy care between 2013 and 2017. Patients had a minimum follow-up of 3 years before the transition visit and at least 3 years consulting in the adults section. Clinical characteristics were retrieved from the medical chart. Quality of life and satisfaction questionnaires were administered by online access to patients and caregivers at the end of the adult follow-up period. RESULTS: 99 patients (50.5 % women, mean transition age 16.5 ± 1 years old) were included. Before the transition visit, 90 % of patients received a transition discussion and 88 % had a formal clinical report. In the pediatric period, patients were visited more frequently, had more EEGs and genetic studies, and were seen by the same neuropediatrician (P<0.05). In the adult period, patients underwent a larger number of prolonged video EEGs and were prescribed polytherapy more often (P<0.05). Quality of life remained steady during the entire transition, but satisfaction with the care received was significantly higher during the pediatric period. CONCLUSIONS: Significant differences were seen in epilepsy care during transition from pediatric to adult management, and this had an impact on the degree of satisfaction reported by patients and caregivers. Our results provide evidence of the potential value of development and early implementation of a protocolled transition program.

Association study of the serotoninergic system in migraine in the Spanish population.

In order to evaluate the contribution of 19 serotonin-related genes to the susceptibility to migraine in a Spanish population we performed a case-control association study of 122 single nucleotide polymorphisms (SNPs), selected according to genetic coverage parameters, in 528 migraine patients -308 with migraine without aura (MO) and 220 with migraine with aura (MA)- and 528 sex-matched migraine-free controls. The single-marker analysis identified nominal associations with the migraine phenotype or with the MO or MA subtypes. The multiple-marker analysis revealed risk haplotypes in three genes that remained significantly associated with migraine after correction by permutations. Two-marker risk haplotypes were identified in the HTR2B (rs16827801T-rs10194776G) and MAOA (rs3027400G-rs2072743C) genes conferring susceptibility to MO, and a four-marker haplotype in DDC was specific of MA (rs2329340A-rs11974297C-rs2044859T-rs11761683G). The present study supports the involvement of HTR2B and MAOA genes in the genetic predisposition to MO, while DDC might confer susceptibility to MA. These results suggest a differential involvement of serotonin-related genes in the genetic background of MO and MA.

Lack of association of hormone receptor polymorphisms with migraine.

BACKGROUND AND PURPOSE: Previous studies concerning the role of hormone receptor genetic variants in migraine have provided conflicting results. The aim of this study was to investigate the role of common polymorphisms in the estrogen receptor gene (ESR1) and the progesterone receptor gene (PGR) in the risk for migraine in a Spanish population. METHODS: In a case-control study, including 210 Caucasoid migraine patients and 210 controls, we examined association between three single nucleotide polymorphisms in the coding region of ESR1, rs2077642, rs1801132, and rs2228480, and an Alu insertion in PGR, and migraine, migraine without aura or migraine with aura. Genotypic, allelic and reconstructed haplotype distributions were compared. RESULTS: We found no significant differences between cases and controls in the distribution of genotypes or alleles for either polymorphism. No haplotype was over-represented in patients. CONCLUSIONS: Our study does not support a major contribution of ESR1 and PGR to the pathogenesis of migraine.

A clinical diagnostic algorithm for early onset cerebellar ataxia.

Early onset cerebellar Ataxia (EOAc) comprises a large group of rare heterogeneous disorders. Determination of the underlying etiology can be difficult given the broad differential diagnosis and the complexity of the genotype-phenotype relationships. This may change the diagnostic work-up into a time-consuming, costly and not always rewarding task. In this overview, the Childhood Ataxia and Cerebellar Group of the European Pediatric Neurology Society (CACG-EPNS) presents a diagnostic algorithm for EOAc patients. In seven consecutive steps, the algorithm leads the clinician through the diagnostic process, including EOA identification, application of the Inventory of Non-Ataxic Signs (INAS), consideration of the family history, neuro-imaging, laboratory investigations, genetic testing by array CGH and Next Generation Sequencing (NGS). In children with EOAc, this algorithm is intended to contribute to the diagnostic process and to allow uniform data entry in EOAc databases.

Genetic analysis of 27 Spanish patients with hemiplegic migraine, basilar-type migraine and childhood periodic syndromes.

Familial hemiplegic migraine (FHM) is a rare type of migraine with aura. Mutations in three genes have been described in FHM patients: CACNA1A (FHM1), ATP1A2 (FHM2) and SCN1A (FHM3). We screened 27 Spanish patients with hemiplegic migraine (HM), basilar-type migraine or childhood periodic syndromes (CPS) for mutations in these three genes. Two novel CACNA1A variants, p.Val581Met and p.Tyr1245Cys, and a previously annotated change, p.Cys1534Ser, were identified in individuals with HM, although they have not yet been proven to be pathogenic. Interestingly, p.Tyr1245Cys was detected in a patient displaying a changing, age-specific phenotype that began as benign paroxysmal torticollis of infancy, evolving into benign paroxysmal vertigo of childhood and later becoming HM. This is the first instance of a specific non-synonymous base change being described in a subject affected with CPS. The fact that the molecular screen identified non-synonymous changes in < 15% of our HM patients further stresses the genetic heterogeneity underlying the presumably monogenic forms of migraine.

Hypermanganesemia due to mutations in SLC39A14: further insights into Mn deposition in the central nervous system.

BACKGROUND: The SLC39A14, SLC30A10 and SLC39A8 are considered to be key genes involved in manganese (Mn) homeostasis in humans. Mn levels in plasma and urine are useful tools for early recognition of these disorders. We aimed to explore further biomarkers of Mn deposition in the central nervous system in two siblings presenting with acute dystonia and hypermanganesemia due to mutations in SLC39A14. These biomarkers may help clinicians to establish faster and accurate diagnosis and to monitor disease progression after chelation therapy is administered. RESULTS: A customized gene panel for movement disorders revealed a novel missense variant (c.311G > T; p.Ser104Ile) in SLC39A14 gene in two siblings presenting at the age of 10 months with acute dystonia and motor regression. Mn concentrations were analyzed using inductively coupled mass spectrometry in plasma and cerebrospinal fluid, disclosing elevated Mn levels in the index case compared to control patients. Surprisingly, Mn values were 3-fold higher in CSF than in plasma. We quantified the pallidal index, defined as the ratio between the signal intensity in the globus pallidus and the subcortical frontal white matter in axial T1-weighted MRI, and found significantly higher values in the SLC39A14 patient than in controls. These values increased over a period of 10 years, suggesting the relentless pallidal accumulation of Mn. Following genetic confirmation, a trial with the Mn chelator Na2CaEDTA led to a reduction in plasma Mn, zinc and selenium levels. However, parents reported worsening of cervical dystonia, irritability and sleep difficulties and chelation therapy was discontinued. CONCLUSIONS: Our study expands the very few descriptions of patients with SLC39A14 mutations. We report for the first time the elevation of Mn in CSF of SLC39A14 mutated patients, supporting the hypothesis that brain is an important organ of Mn deposition in SLC39A14-related disease. The pallidal index is an indirect and non-invasive method that can be used to rate disease progression on follow-up MRIs. Finally, we propose that patients with inherited defects of manganese transport should be initially treated with low doses of Na2CaEDTA followed by gradual dose escalation, together with a close monitoring of blood trace elements in order to avoid side effects.

Genetic testing among Spanish pediatric neurologists: Knowledge, attitudes and practices.

Advances in genetic testing applied to child neurology have enabled the development of genetic tests with greater sensitivity in elucidating an etiologic diagnosis for common neurological conditions. The objective of the current study was to examine child neurologists' perspectives and insights into genetic testing. We surveyed 118 Spanish child neurologists, exploring their knowledge, attitudes, and practices concerning genetic tests. All of them had requested at least one genetic test in the past six months. Global developmental delay or intellectual disability in absence of a strong specific etiologic suspicion and autism spectrum disorders were the disorders for which genetic testing was most frequently requested. The most commonly requested genetic test was CGH-array. Overall, child neurologist perception of readiness for making genetic-related decisions was not bad, although many would like to have a greater support from geneticists and were interested in increasing the time dedicated to genetics within their continuing education program. These data have important implications for future practice, research, and education.

Evidence of nuclear DNA fragmentation following hypoxia-ischemia in the infant rat brain, and transient forebrain ischemia in the adult gerbil.

Wistar rats, eight days old, were subjected to permanent bilateral forebrain ischemia, followed by hypoxia for 15 minutes. A cerebral infarct, mainly involving the cerebral neocortex, hippocampus, amygdala, striatum and subcortical white matter was produced. Neurons and glia showing punctate chromatin condensation and karyorrhectic cells were observed 12 hours after hypoxia-ischemia. Their number increased during the first two days and recruitment of cells with degenerating nuclei occurred until day five. In situ labeling of nuclear DNA fragmentation stained many normal-appearing nuclei, as well as punctate chromatin condensations and nuclear fragments in karyorrhectic cells. Delayed neuronal death in the CA1 area of the hippocampus was observed after 20 minutes of transient forebrain ischemia in the adult gerbil. In situ labeling of nuclear DNA fragmentation demonstrated stained punctate chromatin condensation in a few degenerating cells at 48 hours post-ischemia. Substantial labeling of CA1 neurons occurred in the fourth day. Agarose gel electrophoresis of extracted brain DNA from ischemic infant rats and adult gerbils showed a ladder-type pattern which is typical of nuclear DNA fragmentation into oligonucleosomal fragments (internucleosomal cleavage). These findings suggest that endonuclease(s) activation may play a role in cell death induced by different forms of hypoxia-ischemia.

Neonatal hypoxic-ischemic or excitotoxic striatal injury results in a decreased adult number of substantia nigra neurons.

It has been shown that morphologic and biochemical presynaptic markers of dopaminergic terminals are preserved in a unilateral experimental model of neonatal hypoxic-ischemic injury to the striatum. As the substantia nigra is spared direct injury in this model, we anticipated that the number of tyrosine hydroxylase-positive dopaminergic neurons projecting to the striatum would also be normal. We have found, however, that following unilateral neonatal striatal injury the number of ipsilateral tyrosine hydroxylase-positive neurons is decreased, as is the mean area of the substantia nigra pars compacta. The decrease in neurons is correlated with the decrease in striatal size (r = 0.7, P = 0.01). Neuron loss is most pronounced in the substantia nigra pars reticulata, where it is 50%. Calbindin-positive neurons in the dorsal tier of the substantia nigra pars compacta appear to be preserved. We also examined effects on the nigra following a neonatal excitotoxic striatal lesion made with quinolinic acid. We observed a decrease in the number of substantia nigra tyrosine hydroxylase-positive neurons in the absence of direct nigral injury, and the decrease was closely correlated with reductions in striatal area (r = 0.91, p < 0.01). While there are a number of possible explanations for these observations, one major possibility is that there has been a reduction in tyrosine hydroxylase-positive neurons due to a diminution in developmental target-derived trophic support from the striatum. If striatum-derived trophic support plays a role in the developmental regulation of substantia nigra neuron number, then abnormalities in this supportive relationship may play a role in the loss of these neurons in some animal models of developmental nigral degeneration, and some forms of human parkinsonism.

Cell death and associated c-jun induction in perinatal hypoxia-ischemia. Effect of the neuroprotective drug dexamethasone.

Previous studies in a model of unilateral hypoxia-ischemia in the developing rat brain have shown induction of the mRNAs of c-fos and c-jun and presence of apoptotic DNA fragmentation. In this same model, dexamethasone confers neuroprotection if given before the insult. Since c-fos and c-jun have been involved in several models of cell death, we investigated whether the neuroprotective effect of dexamethasone could be associated with changes in expression of these genes. Rat pups, pre-treated with either 0.5 mg/kg dexamethasone or vehicle 48 h, 24 h and immediately before the injury, were subjected to ligation of the left common carotid artery followed by 3 h hypoxia. Analysis of c-fos and c-jun expression at 2 h, by means of in situ hybridization, revealed diminished induction in dexamethasone-treated animals. Jun immunoreactivity, but not Fos, and DNA fragmentation, assessed by in situ end-labeling of fragmented DNA, were present at 24 h only in vehicle-injected animals. Electrophoresis of brain extracted DNA revealed a ladder pattern in all the animals. Our results show a relationship between Jun overexpression and cell-death in the hypoxic-ischemic developing brain and suggest that dexamethasone exerts its protective effect anteceding immediate early gene induction, at some early point in post-ischemic signal transduction.

Evidence of internucleosomal DNA fragmentation and identification of dying cells in X-ray-induced cell death in the developing brain.

Newborn Sprague-Dawley rats received a single dose of 2 Gy X-rays and were killed 6 hr later. Dying cells were characterized by extreme chromatin condensation and nuclear fragmentation. Dying cells were distributed in the primary and secondary germinal zones and in other brain regions. Among these latter, dying cells occurred in the cortical layers of the olfactory bulb, layers II-III and VIb of the neocortex, piriform and entorhinal cortex, stratum oriens and pyramidale of the hippocampus, striatum, thalamus, amygdala, brainstem, internal granular layer of the cerebellum, and cerebral and cerebellar white matter. Dying cells were immature cells, neurons and glial cells (including radial glia). In-situ labeling of nuclear DNA fragmentation identified individual cells bearing fragmented DNA. Since the number of cells stained with this method was larger than the number of dying cells, as revealed with current histological techniques, it is suggested that nuclear DNA fragmentation precedes chromatin condensation and nuclear fragmentation in X-ray-induced apoptosis. Furthermore, agarose gel electrophoresis of extracted DNA from irradiated brains showed a "ladder" pattern which is typical of internucleosomal DNA fragmentation and endonuclease activation.

Identification of necrotic cell death by the TUNEL assay in the hypoxic-ischemic neonatal rat brain.

The time course and localization of DNA fragmentation in a neonatal rat model of unilateral hypoxia-ischemia were assessed by means of the terminal transferase-mediated biotin dUTP nick end labeling (TUNEL) assay. TUNEL-positive cells were detected in the hemisphere ipsilateral to the ligation immediately after the injury and increased to reach a maximum 1-3 days later, then decreasing until day 10, in parallel with cell death identified by standard histological methods. Cells showing any of the different morphologies of chromatin condensation and fragmentation were labeled, particularly within the core of the ischemic lesion. These results, obtained in a paradigm of necrosis in the immature brain, add to previous evidence suggesting that some forms of non-apoptotic DNA fragmentation are labeled by the TUNEL assay.

Increased expression of bcl-2 immunoreactivity in the developing cerebral cortex of the rat.

Bcl-2 proto-oncogene encodes a protein which may cancel the cell death programme in normal development and experimentally induced conditions. Strong bcl-2 immunoreactivity occurs in the neocortex and hippocampus of the developing rat during the 1st postnatal week. Bcl-2 immunoreactivity rapidly decreases from this age onwards to steady very low levels in adulthood. Since increased expression of bcl-2 immunoreactivity during cortical neurogenesis is coincidental in time with a special vulnerability of cortical neurons to naturally occurring cell death, it is suggested that bcl-2 may have a role in regulating cell death and survival during cortical morphogenesis.

Naturally occurring cell death in the developing cerebral cortex of the rat. Evidence of apoptosis-associated internucleosomal DNA fragmentation.

Naturally occurring dead cells in the developing rat neocortex, subcortical white matter and hippocampus, which increase in number during the first postnatal week and decrease thereafter to disappear by the end of the first month, were examined by in situ labeling of nuclear DNA fragmentation. These cells showed peripheral chromatin condensation or extremely dark, often fragmented, nuclei. Southern hybridization following agarose gel electrophoresis of DNA extracted from the developing cortex, but not from adult brain, showed a 'ladder' pattern which is typical of internucleosomal DNA fragmentation. Taken together these results show that naturally occurring cell death (programmed cell death) in the developing cerebral cortex has the morphology of apoptosis and is associated with endonuclease activation.

Pseudotumor cerebri, spinal and radicular pain, and hyporeflexia: a clinical variant of the Guillain-Barré syndrome?

A 5-year-old patient developed pseudotumor cerebri, spinal and radicular pain, and hyporeflexia. Ataxia and multiple cranial nerve involvement also were evident. With the exception of residual hyporeflexia and the abnormalities present in the electrophysiologic studies, the patient's prompt recovery suggested the diagnosis of Guillain-Barré polyradiculoneuritis.

Painful ophthalmoplegia with reversible carotid stenosis in a child.

Painful ophthalmoplegia in childhood has different causes. One is Tolosa-Hunt syndrome, in which a first episode may be difficult to diagnose because of its clinical similarity to ophthalmoplegic migraine. A 10-year-old male with painful ophthalmoplegia and a cavernous sinus inflammation associated with an intracavernous carotid stenosis demonstrated by magnetic resonance imaging and angiography is reported. These findings resolved in follow-up imaging. This report suggests that in the presence of painful ophthalmoplegia, magnetic resonance imaging detection of cavernous sinus inflammation can facilitate the diagnosis of Tolosa-Hunt syndrome when other causes are excluded.

Bilateral striatal lesions in childhood.

From 1983 to 1991, 13 patients were identified with a clinical radiologic association characterized by acute or persistent neurologic dysfunction and bilateral lesions in the basal ganglia region demonstrated by ultrasound, computed tomography, or magnetic resonance imaging. Initial clinical manifestations of this group of patients were characterized by extrapyramidal signs (i.e., dystonia 9, hypotonia 2, athetosis 1, rigidity 1), altered state of consciousness in 5, and seizures in 3. The outcomes of most of these patients were poor: 10 had motor sequelae, 9 cognitive impairment, and 4 died. The outcomes of 2 patients, however, were much better than what was expected from the initial presentation. Based on current and previous reports, the diagnostic approach and classification of patients with neurologic dysfunction and bilateral striatal lesions are presented.