Infantile spasms in children with Down syndrome

Down syndrome (DS) is the most common genetic cause of mental retardation. It is estimated that 5-13% of persons affected by DS have seizures. Infantile spasms are the most common type of seizures and usually are well controlled with steroids and antiepileptic drugs. We present 11 children at the age of 3 years and 4 months to 10 years and 7 months with DS and infantile spasms, treated at Children's Hospital Zagreb from January 2000 until July 2009. Infantile spasms began at the age of 5 to 10.5 months in 10 children, in one child at the age of 16 months. Only one child had perinatal risk factors for the development of IS. Changes in EEG correlated to hypsarrhythmia. Infantile spasms were treated initially with antiepileptic drugs, most often with valproic acid. Treatment was inefficient in 10/11 patients. After application of ACTH, infantile spasms stopped between 7 and 15 days in 6 patients, until 28th day in 4 patients. Hypsarrhythmia vanished in all children. During follow-up period (2 years and 7 months to 9 years and 5 months) none of the children developed another type of seizures. No major epileptogenic changes were registered in EEG. Antiepileptic therapy was discontinued in 4 children (aged 4 years and 2 months to 5 years). In this group is the boy who died of heart failure. Infantile spasms associated with DS are categorized into symptomatic group. The existence of cerebral pathology and delayed psycho-motor development precedes occurrence of seizures. It is possible to achieve good control of seizures and disappearance of hypsarrhythmia with application of ACTH and antiepileptic drugs.     

Multiscale Entropy of Electroencephalogram as a Potential Predictor for the Prognosis of Neonatal Seizures

Objective

Increasing animal studies supported the harmful effects of prolonged or frequent neonatal seizures in developing brain, including increased risk of later epilepsy. Various nonlinear analytic measures had been applied to investigate the change of brain complexity with age. This study focuses on clarifying the relationship between later epilepsy and the changes of electroencephalogram (EEG) complexity in neonatal seizures.

Methods

EEG signals from 19 channels of the whole brain from 32 neonates below 2 months old were acquired. The neonates were classified into 3 groups: 9 were normal controls, 9 were neonatal seizures without later epilepsy, and 14 were neonatal seizures with later epilepsy. Sample entropy (SamEn), multiscale entropy (MSE) and complexity index (CI) were analyzed.

Results

Although there was no significant change in SamEn, the CI values showed significantly decreased over Channels C3, C4, and Cz in patients with neonatal seizures and later epilepsy compared with control group. More multifocal epileptiform discharges in EEG, more abnormal neuroimaging findings, and higher incidence of future developmental delay were noted in the group with later epilepsy.

Conclusions

Decreased MSE and CI values in patients with neonatal seizures and later epilepsy may reflect the mixed effects of acute insults, underlying brain immaturity, and prolonged seizures-related injuries. The analysis of MSE and CI can therefore provide a quantifiable and accurate way to decrypt the mystery of neonatal seizures, and could be a promising predictor.     

An aphasic syndrome in children

The paper presents case reports of nine children, all of whom had severe disturbances of language function of abrupt or gradual onset. Seizures occurred in seven of the children and all nine had EEG abnormalities.There was no apparent correlation between the seizures, the EEG changes and the aphasia. One patient had a brain biopsy performed at another hospital and the tissue was said to be normal. The cause of the abnormal language function is unknown. Five of the children failed to acquire normal speech subsequently. Three of the four children who made a complete recovery were treated with steroids.     

Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study

ObjectiveTo compare the safety and efficacy of midazolam given intranasally with diazepam given intravenously in the treatment of children with prolonged febrile seizures.DesignProspective randomised study.SettingPaediatric emergency department in a general hospital.Subjects47 children aged six months to five years with prolonged febrile seizure (at least 10 minutes) during a 12 month period.InterventionsIntranasal midazolam (0.2 mg/kg) and intravenous diazepam (0.3 mg/kg).ResultsIntranasal midazolam and intravenous diazepam were equally effective. Overall, 23 of 26 seizures were controlled with midazolam and 24 out of 26 with diazepam. The mean time from arrival at hospital to starting treatment was significantly shorter in the midazolam group (3.5 (SD 1.8) minutes, 95% confidence interval 3.3 to 3.7) than the diazepam group (5.5 (2.0), 5.3 to 5.7). The mean time to control of seizures was significantly sooner (6.1 (3.6), 6.3 to 6.7) in the midazolam group than the diazepam group (8.0 (0.5), 7.9 to 8.3). No significant side effects were observed in either group.ConclusionSeizures were controlled more quickly with intravenous diazepam than with intranasal midazolam, although midazolam was as safe and effective as diazepam. The overall time to cessation of seizures after arrival at hospital was faster with intranasal midazolam than with intravenous diazepam. The intranasal route can possibly be used not only in medical centres but in general practice and, with appropriate instructions, by families of children with recurrent febrile seizures at home.     

Epileptic seizures cause extended postictal cerebral vascular dysfunction that is prevented by HO-1 overexpression

The extended postictal state is characterized by neurological problems in patients. Inadequate blood supply to the brain and impaired cerebral autoregulation may contribute to seizure-induced neuronal damage. Recent evidence in newborn pigs indicates that activation of the antioxidative enzyme heme oxygenase (HO) at the onset of seizures is necessary for increased cerebral blood flow during the ictal episode and for normal cerebral vascular functioning during the immediate postictal period. We hypothesized that seizures cause prolonged postictal cerebral vascular dysfunction that can be accentuated by HO inhibition and rescued by HO overexpression. Cerebral vascular responses to endothelium-dependent (hypercapnia, bradykinin) and -independent (isoproterenol, sodium nitroprusside) stimuli were assessed 48 h after bicuculline-induced seizures in: 1) saline-control newborn piglets, 2) HO-inhibited animals (HO was inhibited by tin protoporphyrin, SnPP, 3 mg/kg iv), and 3) HO-overexpressing piglets (HO-1 was upregulated by cobalt protoporphyrin, CoPP, 50 mg/kg ip). Extended alterations of HO expression in cerebral microvessels were confirmed by measuring CO production and inducible HO (HO-1) and constitutive HO (HO-2) proteins. Our data provide evidence that seizures cause a severe, sustained, postictal cerebral vascular dysfunction as reflected by impaired vascular reactivity to physiologically relevant dilators. During the delayed postictal state, vascular reactivity to all dilator stimuli was reduced in saline control and, to a greater extent, in HO-inhibited animals. In CoPP-treated piglets, no reduction in postictal cerebral vascular reactivity was observed. These findings may indicate that CoPP prevents postictal cerebral vascular dysfunction by upregulating HO-1, a finding that might have implications for preventing postictal neurological complications.     

Long Term Streptomycin Toxicity in the Treatment of Buruli Ulcer: Follow-up of Participants in the BURULICO Drug Trial

Background

Buruli Ulcer (BU) is a tropical infectious skin disease that is currently treated with 8 weeks of intramuscular streptomycin and oral rifampicin. As prolonged streptomycin administration can cause both oto- and nephrotoxicity, we evaluated its long term toxicity by following-up former BU patients that had received either 4 or 8 weeks of streptomycin in addition to other drugs between 2006 and 2008, in the context of a randomized controlled trial.

Methods

Former patients were retrieved in 2012, and oto- and nephrotoxicity were determined by audiometry and serum creatinine levels. Data were compared with baseline and week 8 measurements during the drug trial.

Results

Of the total of 151 former patients, 127 (84%) were retrieved. Ototoxicity was present in 29% of adults and 25% of children. Adults in the 8 week streptomycin group had significantly higher hearing thresholds in all frequencies at long term follow-up, and these differences were most prominent in the high frequencies. In children, no differences between the two treatment arms were found. Nephrotoxicity that had been detected in 14% of adults and in 13% of children during treatment, was present in only 2.4% of patients at long term follow-up.

Conclusions

Prolonged streptomycin administration in the adult study subjects caused significant persistent hearing loss, especially in the high frequency range. Nephrotoxicity was also present in both adults and children but appeared to be transient. Streptomycin should be given with caution especially in patients aged 16 or older, and in individuals with concurrent risks for renal dysfunction or hearing loss.     

The potential role of mitochondrial dysfunction in seizure-associated cell death in the hippocampus and epileptogenesis

Epilepsy is considered one of the most common neurological disorders worldwide. The burst firing neurons associated with prolonged epileptic discharges could lead to a large number of changes with events of cascades at the cellular level. From its role as the cellular powerhouse, mitochondria also play a crucial role in the mechanisms of cell death. Emerging evidence has shown that prolonged seizures may result in mitochondrial dysfunction and increase of oxidative and nitrosative stress in the hippocampus that precede neuronal cell death and cause subsequent epileptogenesis. The selective dysfunction of mitochondrial respiratory chain Complex I has been suggested to be a biochemical hallmark of seizure-induced neuronal cell death and epileptogenesis. Therefore, protection of mitochondria from bioenergetic failure and oxidative stress in the hippocampus may open a new vista to the development of effective neuroprotective strategies against seizure-induced brain damage and to the design of novel treatment perspectives against therapy-resistant forms of epilepsy.     

Neuroprotection in epilepsy

Brain damage and neuronal loss caused by traumatic brain injury, ischemic stroke, and symptomatic status epilepticus can lead to severe long-term consequences, such as impairment in learning and memory and cognitive functions, and development of chronic epilepsy. This can be the result of morphologic and functional changes underlying temporal lobe epilepsy. Epilepsy patients have increased risk of status epilepticus. It is a life-threatening condition when seizures last for more than 30 min and trigger processes leading to neuronal apoptosis and necrosis in various parts of brain. Administration of neuroprotective drugs preventing these pathologic processes could improve the prognosis for such patients. However despite of active research of neuroprotective drugs, the effective ways to prevent brain damage resulting from prolonged seizures are yet to be found. Studies of neuroprotective properties of classic and novel anticonvulsant drugs showed that most of them do not have the sufficient neuroprotective effect and are not able to prevent epileptogenesis. Thus the studies of other potential neuroprotective drugs seem to be promising.     

Hypoxia in patients with acute hemiplegia.

Sixteen patients with an early dense hemiplegia due to cerebrovascular accidents were shown to have a greater degree of hypoxia than 16 matched control patients. The patients with hemiplegia had a reflex compensatory fall in arterial carbon dioxide tensions (PaCO2) with possible reduction in cerebral blood flow. Oxygen treatment led to an increase in PaCO2 in the patients with hemiplegia, but the increase in oxygen tensions in these patients was significantly less than that in the control group, suggesting increased pulmonary shunting as the cause for the hypoxia. Oxygen treatment may improve cerebral blood flow and oxygenation and have a useful role in the early management of patients with a dense hemiplegia.     

Cerebral energy metabolism during experimental status epilepticus.

—The concentration of ATP, ADP, AMP, phosphocreatine and of 5 intermediates of carbohydrate metabolism were determined in rodent brain after single and repeated seizures induced by either electroshock (ES), flurothyl or pentylenetetrazol (PTZ). In paralysed-ventilated rats, one ES produced a 4–5 fold increase in cortical glycolytic flux (estimated from changes in glucose and lactate), and associated increases in pyruvate and in the lactate/pyruvate ratio. Total high energy phosphates declined during the seizure; a decrease was also calculated in cortical tissue pH and in the cytoplasmic [NAD⁺]/[NADH] ratio. Similar changes in brain were observed in ventilated mice after ES, but in paralysed animals, no decrease in high energy phosphates occurred during the first seizure. More vigorous and prolonged chemically-induced seizures in both rats and mice elicited a decrease in the cerebral energy reserves with a rise in lactate and in the lactate/pyruvate ratio. At all times during the seizures the cerebral venous blood had a higher oxygen tension than that of control animals (rats) or was visibly reddened (mice), implying that oxygen availability to brain exceeded metabolic demands. It is proposed that the development of‘non-hypoxic’cerebral lactacidosis during seizures is part of the overall metabolic response of the brain to an abrupt increase in energy consumption. The response constitutes a homeostatic influence which promotes cerebral vasodilatation, thereby increasing blood flow and the delivery of substrates. With repeated seizures, delivered 2 min apart, glycogen declined progressively, but concentrations of the adenine nucleotides appeared to plateau, suggesting that a new energy balance had been established. However, after 20–25 seizures, the attacks became self-generating and there was a further reduction in the tissue high energy phosphate stores, a fall in brain glucose and in the brain/blood glucose ratio. It is concluded that the brain possesses a limited capacity to adjust its metabolism to meet the increased energy requirements of single or repeated seizures, but that this mechanism ultimately fails during status epilepticus unless the abnormal electrical discharges, themselves, are brought under control.     

Epilepsy in the first 10 years of life: findings of the child health and education study.

OBJECTIVES--To identify children with afebrile seizures in a national cohort, classify the seizures, and document progress in the first 10 years of life. DESIGN--Population based birth cohort study. SETTING--The child health and education study, which includes 16,004 neonatal survivors (98.5% of infants born in the United Kingdom during one week of April 1970). SUBJECTS--14,676 children for whom relevant information was available. MAIN OUTCOME MEASURES--Responses to parental and general practitioner questionnaires and hospital records at 5 and 10 years after birth. RESULTS--84 children (42 boys, 42 girls) had had one or more afebrile seizure (incidence 5.7/1000). 63 children (31 boys, 32 girls) had epilepsy (incidence 4.3/1000). 49 of 55 children had a second seizure within a year of the first. The commonest seizure types were tonic-clonic (42) and complex partial (25). A greater proportion of children with complex partial seizures had recurrences. Children who had infantile spasms or a mixed seizure disorder had a poor outcome. All six children who died had symptomatic seizures in the first year, but seizures were not the direct cause of death. CONCLUSIONS--The results of this study are probably representative of seizure patterns in the general population. Outcome after seizures is determined more by the underlying disease than by the seizures themselves.     

Ubiquitin Carboxy-Terminal Hydrolase L1 (UCH-L1) is increased in cerebrospinal fluid and plasma of patients after epileptic seizure

ABSTRACT: BACKGROUND: Clinical and experimental studies have demonstrated that seizures can cause molecular and cellular responses resulting in neuronal damage. At present, there are no valid tests for assessing organic damage to the brain associated with seizure. The aim of this study was to investigate cerebrospinal fluid (CSF) and plasma concentrations of Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a sensitive indicator of acute injury to brain neurons, in patients with tonic--clonic or partial secondarily generalized seizures due to various etiologies. METHODS: CSF and plasma concentrations of UCH-L1 were assessed in 52 patients within 48 hours after epileptic seizure and in 19 controls using ELISA assays. RESULTS: CSF obtained within 48 hours after seizure or status epilepticus (SE) presented significantly higher levels of UCH-L1 compared to controls (p = 0.008). Plasma UCH-L1 concentrations were negatively correlated with time to sample withdrawal. An analysis conducted using only the first 12 hours post-seizure revealed significant differences between concentrations of UCH-L1 in plasma and controls (p = 0.025). CSF and plasma concentrations were strongly correlated with age in patients with seizure, but not in control patients. Plasma UCH-L1 levels were also significantly higher in patients after recurrent seizures (n = 4) than in those after one or two seizures (p = 0.013 and p = 0.024, respectively). CONCLUSION: Our results suggest that determining levels of neuronal proteins may provide valuable information on the assessment of brain damage following seizure. These data might allow clinicians to make more accurate therapeutic decisions, to identify patients at risk of progression and, ultimately, to provide new opportunities for monitoring therapy and targeted therapeutic interventions.     

Chronic theophylline administration has no apparent effect on theophylline concentrations required to produce seizures in rats

Theophylline, the widely used antiasthmatic drug, can cause life-threatening, generalized seizures when administered in excessive doses. The plasma concentrations of theophylline associated with these seizures vary widely among patients, thereby complicating efforts to prevent seizures by timely initiation of appropriate treatment. Some investigators suspect that chronic administration increases the neurotoxicity of theophylline but others have suggested the opposite. We have studied this problem in an animal model of theophylline-induced seizures. Osmotic pumps containing theophylline solution or drug-free solvent (for the surgical control group) were implanted in adult female Lewis rats, yielding almost constant serum theophylline concentrations of about 14 mg/liter for 7 days in the treated group. On the seventh day, theophylline was administered by much more rapid iv infusion to the two groups of animals and to one nonimplanted (nonsurgical) control group until onset of maximal seizures. There were no statistically significant differences between the three groups with respect to the concentrations of theophylline in serum, serum water, brain, and cerebrospinal fluid at onset of seizures. The concentrations of theophylline metabolites were either very low or undetectable. Under the experimental conditions, preexposure of rats for 7 days to theophylline in the human therapeutic concentration range had no apparent effect on the acute neurotoxicity of the drug.     

Seizures in the developing brain: cellular and molecular mechanisms of neuronal damage, neurogenesis and cellular reorganization

Epilepsy is a common neurological disorder that occurs more frequently in children than in adults. The extent that prolonged seizure activity, i.e. status epilepticus (SE), and repeated, brief seizures affect neuronal structure and function in both the immature and mature brain has been the subject of increasing clinical and experimental research. Earlier studies suggest that seizure-induced effects in the immature brain compared with the adult brain are different. This is manifested as differences in neuronal vulnerability, cellular and synaptic reorganization and regenerative processes. The focus of this review is first to give a short overview of currently used experimental models of epilepsy in immature rats, and then discuss more thoroughly seizure-induced acute and sub-acute cellular and molecular alterations, highlight the contribution of inflammatory-like reactions and intracellular cytoskeleton to the insult, and reveal changes in the structure and function of inhibitory GABA(A) and excitatory glutamate receptors. The role of seizure-activated reparative, plastic processes, synaptic remodelling, neurogenesis as well as the long-term consequences of seizures are briefly outlined. The main emphasis is put on studies carried out in experimental animals, and the focus of interest is the hippocampus, the brain area of great vulnerability in epilepsy. In vitro studies are discussed only to limited extent. Collectively, recent studies suggest that the deleterious effects of seizures may not solely be a consequence of neuronal damage and loss per se, but could be due to the fact that seizures interfere with the highly regulated developmental processes in the immature brain.     

新生小鼠缺氧缺血性脑损伤模型的制作研究

目的：通过对动物模型的制作模拟新生儿围产期缺氧缺血性脑损伤,研究其脑组织病理变化,为新生儿缺氧缺血性脑损伤的病理生理的研究以及进一步有效的治疗提供实验基础。方法：将40只7d新生昆明小鼠分四组,分别为正常组（A组）、单侧颈总动脉结扎组（B组）、单侧颈总动脉结扎＋缺氧组（C组）和双侧颈总动脉结扎组（D组）。单侧颈总动脉结扎组（B组）行右侧颈总动脉结扎;单侧颈总动脉结扎＋缺氧组（C组）行右侧颈总动脉结扎后将其置于20℃的恒温50mL密闭容器中,分不同的时间将其取出;双侧颈总动脉结扎组（D组）行双侧颈总动脉结扎,各组术后均送回母鼠身边继续母乳喂养,三天后再作病理检测。结果：行单侧颈总动脉结扎加缺氧60min时,小鼠结扎侧皮质及海马区出现病理改变,随着缺氧时间延长（90rain、100min、120min）病变范围逐渐扩大,病理改变越明显。结论：本实验显示单侧颈总动脉结扎同时缺氧一定时间可以导致小鼠脑组织损伤,脑细胞发生病理改变,且皮层及海马区域的神经细胞对缺氧缺血最为敏感,从而为进一步研究新生儿缺氧缺血性脑损伤提供了较为可靠的模型。     

Long-term Effects of Recurrent Neonatal Seizures on Neurobehavioral Function and Related Gene Expression and Its Intervention by Inhibitor of Cathepsin B

Cathepsins are families of proteases that have been reported to play the key roles in neuroexcitotoxicity. The present study was sought to determine the effect of CBI, a cathepsin B inhibitor, in the prevention of neurobehavioral deficits after inhalant flurothyl-induced recurrent neonatal seizures in rats. We examined the expression pattern of autophagy-related genes at acute phase after the last seizures using western blot method, and evaluated behavioral deficits during postnatal day 28 (P28) to P35. The results showed improved neurological scores and learning ability in CBI-treated rats compared with the nontreated control. Flurothyl-induced increases in the ratio of LC3-II/LC3-I, Beclin-1 and Cathepsin-B were blocked by pre-treatment with CBI at 1.5, 3, 6 and 24 h after the last seizures in hippocampus and cerebral cortex by western blot analysis. Meanwhile, CBI also reversed flurothyl-induced down-regulation of Bcl-2 protein levels. Furthermore, in the long-term time point of 35 days (P35), PRG-1 mRNA and protein level in hippocampus and cerebral cortex of recurrent seizure group were up-regulated when compared to the control rats; meanwhile, the up-regulated expression of PRG-1 were robustly inhibited by CBI. These date demonstrated, for the first time, that lysosomal enzymes participate in neonatal seizure-induced brain damage and that modulation of cathepsin B may offer a new strategy for the development of therapeutic interventions for treatment of developmental seizure-induced brain damage.     

Neonatal `Brain Damage'—An Analysis of 250 Claims

Advances in perinatal care have resulted in decreased neonatal mortality. Increasingly, damage in survivors has been attributed to alleged negligence. We analyzed the 250 claims (1957 to 1982) from one major insurance company for factors to characterize high-risk pregnancies and then to distinguish preventable from nonpreventable causes within the group. Using predetermined criteria, 77 (31%) were classified preventable, 105 (42%) nonpreventable and 68 (27%) indeterminate. Preventable actions could be attributed to family members as well as health care providers.Twenty risk factors were significantly increased in the study group compared with those in a general population and included maternal, gestational, delivery and postdelivery risks. Furthermore, 13 of 25 factors differed significantly between preventable and nonpreventable cases. Those with significantly higher prevalence in preventable cases included prolonged gestation, the use of mid or high forceps, cesarean sections, meconium staining, low one- and five-minute Apgar scores, birth weight exceeding 4.5 kg (10 lb), poor tone, seizures and transfers to neonatal intensive care units. Increased in prevalence in the nonpreventable cases were congenital infections and malformations and the late onset of neurologic abnormalities.These findings suggest preventive measures to reduce unwarranted litigation and certain cases of neonatal brain damage.     

Postnatal Psychological Causes of Mental Retardation

The psychological factors present in 715 suspected retarded children were studied. Social, cultural and educational deprivation accounted for 57 cases. Personality and emotional conflicts were primary etiological factors in 15 children. Functional childhood psychosis was found in 18. A group of 89 children had no obvious definitive cause for retardation, although epilepsy, mixed eye and hand dominance, visual perceptive disorders, or poor muscle tone was present in some. In the remaining 523 children, primary brain damage was evident. A sample of 142 of these brain-damaged children revealed that 38 had neurotic symptoms, 23 were antisocial, 11 were psychotic, 28 had restless, disturbed activity, and 42 had intellectual lowering only. The authors suggest that both psychological and organic factors must be taken into consideration in order that complete diagnostic and therapeutic effectiveness be achieved.     

Anticipatory postural adjustments in children with hemiplegia and diplegia

Anticipatory postural adjustments (APAs) play an important role in the performance of many activities requiring the maintenance of standing posture. However, little is known about if and how children with cerebral palsy (CP) generate APAs. Two groups of children with CP (hemiplegia and diplegia) and a group of children with typical motor development performed arm flexion and extension movements while standing on a force platform. Electromyographic activity of six trunk and leg muscles and displacement of center of pressure (COP) were recorded. Children with CP were able to generate anticipatory postural adjustments and produce directionally specific APAs and COP displacements similar to those described in adults and typically developing children. However, children with diplegia were unable to generate APAs of the same magnitude as children with typical development and hemiplegia and had higher baseline muscle activity prior to movement. In children with diplegia, COP was posteriorly displaced and peak acceleration was smaller during bilateral extension compared to children with hemiplegia. The outcomes of the study highlight the role of APAs in the control of posture of children with CP and point out the similarities and differences in anticipatory control in children with diplegia and hemiplegia. These differences may foster ideas for treatment strategies to enhance APAs in children with CP.