Onset Of Spasms Research Articles

Early Neurodevelopmental Screening in Tuberous Sclerosis Complex: A Potential Window of Opportunity

BackgroundInfants born with tuberous sclerosis complex, a genetic condition resulting from a mutation in TSC1 or TSC2, are at increased risk for intellectual disability and/or autism. Features of epilepsy, neuropathology, genetics, as well as timing and type of mechanism-based medications have been proposed as risk factors. Neurodevelopmental outcomes have been reported among these studies; however, few include data about the individuals' early neurodevelopmental profile, a factor that may contribute significantly to these outcomes. Further, there is no clinical standard for the neurodevelopmental assessment of these infants. The paucity of data regarding the natural history of neurodevelopment in infants with tuberous sclerosis complex and the lack of a gold standard for neurodevelopmental evaluation present a significant challenge for clinicians and researchers. MethodDuring the first year of life, we tracked the onset of infantile spasms, the type and timing of antiepileptic treatments, and the associated response of two age-matched infants with tuberous sclerosis complex. We also employed Capute Scales as a part of a structured neurodevelopmental evaluation to characterize and compare their neurodevelopmental profiles. ResultsInfant 1 developed infantile spasms with confirmed hypsarrhythmia at 4 months of age. Treatment with vigabatrin was initiated within 24 hours with near immediate cessation of seizures and no further seizures to date. Expressive language delay was detected at 12 months and treated with speech and/or language therapy. Infant 2 developed complex partial seizures at 1 month. Treatment included levetiracetam, oxcarbazepine, and the ketogenic diet. Vigabatrin was initiated on detection of hypsarrhythmia after 4 months. Intractable epilepsy persists to date. Global developmental delay was evident by 8 months and treated with physical, occupational, and speech and/or language therapy. ConclusionMany risk factors have been associated with intellectual disability and/or autism in individuals with tuberous sclerosis complex; however, few data are available regarding practical clinical tools for early identification. In our case series, inclusion of the Capute Scales as a part of routine medical care led to the identification of developmental delays in the first 12 months of life and selection of targeted neurodevelopmental interventions. Development of a risk-based assessment using this approach will be the focus of future studies as it may provide a potential window of opportunity for both research and clinical purposes. In research, it may serve as an objective outcome measure. Clinically, this type of assessment has potential for informing clinical treatment decisions and serving as a prognostic indicator of long-term cognitive and psychiatric outcomes.

G339(P) Seizure and Developmental Outcome of Infantile (epileptic) Spasms Starting as FE in Early Infancy

ObjectiveThis study sought to compare the clinical course, seizure and developmental outcome of infantile spasms (IS) that start off as focal epilepsy (FE) with those who present with IS from...

Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome

The first described patients with pyridox(am)ine 5'-phosphate oxidase deficiency all had neonatal onset seizures that did not respond to treatment with pyridoxine but responded to treatment with pyridoxal 5'-phosphate. Our data suggest, however, that the clinical spectrum of pyridox(am)ine 5'-phosphate oxidase deficiency is much broader than has been reported in the literature. Sequencing of the PNPO gene was undertaken for a cohort of 82 individuals who had shown a reduction in frequency and severity of seizures in response to pyridoxine or pyridoxal 5'-phosphate. Novel sequence changes were studied using a new cell-free expression system and a mass spectrometry-based assay for pyridoxamine phosphate oxidase. Three groups of patients with PNPO mutations that had reduced enzyme activity were identified: (i) patients with neonatal onset seizures responding to pyridoxal 5'-phosphate (n = 6); (ii) a patient with infantile spasms (onset 5 months) responsive to pyridoxal 5'-phosphate (n = 1); and (iii) patients with seizures starting under 3 months of age responding to pyridoxine (n = 8). Data suggest that certain genotypes (R225H/C and D33V) are more likely to result in seizures that to respond to treatment with pyridoxine. Other mutations seem to be associated with infertility, miscarriage and prematurity. However, the situation is clearly complex with the same combination of mutations being seen in patients who responded and did not respond to pyridoxine. It is possible that pyridoxine responsiveness in PNPO deficiency is affected by prematurity and age at the time of the therapeutic trial. Other additional factors that are likely to influence treatment response and outcome include riboflavin status and how well the foetus has been supplied with vitamin B6 by the mother. For some patients there was a worsening of symptoms on changing from pyridoxine to pyridoxal 5'-phosphate. Many of the mutations in PNPO affected residues involved in binding flavin mononucleotide or pyridoxal 5'-phosphate and many of them showed residual enzyme activity. One sequence change (R116Q), predicted to affect flavin mononucleotide binding and binding of the two PNPO dimers, and with high residual activity was found in Groups (ii) and (iii). This sequence change has been reported in the 1000 Genomes project suggesting it could be a polymorphism but alternatively it could be a common mutation, perhaps responsible for the susceptibility locus for genetic generalized epilepsy on 17q21.32 (close to rs72823592). We believe the reduction in PNPO activity and B6-responsive epilepsy in the patients reported here indicates that it contributes to the pathogenesis of epilepsy.

Infantile spasm: a review article.

Infantile spasm (IS) is a convulsive disease characterized by brief, symmetric axial muscle contraction (neck, trunk, and/or extremities). IS is a type of seizure that was first described by West in 1841, who witnessed the seizure in his own son. West's syndrome refers to the classic triad of spasms, characteristic EEG, and neurodevelopmental regression. Most cases involve flexors and extensors, but either of the types may be involved independently. IS, as its name implies, most often occurs during the first year of life with an incidence of approximately 1 per 2000-4000 live births. Most, but not all, patients with this disorder have severe EEG abnormalities; this pattern was originally referred to as hypsarrhythmia by Gibbs and Gibbs. Cases with known etiology or signs of brain damage are considered as symptomatic. The Overall prognosis of the disease is poor. Peak onset age of the epileptic syndrome is 3 to 7 months, which mainly occurs before 2 years of age in 93% of patients. Hypsarrhythmia is the EEG hallmark of IS, which comprised a chaotic, bilaterally asynchronous high-voltage polyspike, and slow wave discharges interspersed with multifocal spikes and slow waves. ETIOLOGICAL CLASSIFICATION IS AS FOLLOWS: 1) Symptomatic: with identifiable prenatal, perinatal, and postnatal causes with developmental delay at the presentation time; 2) Cryptogenic: unknown underlying cause, normal development at the onset of spasms, normal neurological exam and neuroimaging, and no abnormality in the metabolic evaluation; 3) Idiopathic: pure functional cerebral dysfunction with complete recovery, no residual dysfunction, normal neuroimaging and normal etiologic evaluation, and normal neurodevelopment.

Intellectual development before and after the onset of infantile spasms: A controlled prospective longitudinal study in tuberous sclerosis

Infantile spasms (IS) have long been suspected to be a risk factor for impairment in intellectual development, but there are no controlled, prospective longitudinal data in well-characterized conditions to confirm this suspicion. We tested the hypothesis in a longitudinal study of children with tuberous sclerosis (TS), who have a high risk of developing IS. Eleven infants with TS were recruited and studied longitudinally using the Mullen Scales of Early Learning. Seizure histories were assessed using a structured parent interview and by review of medical notes. Intellectual development was examined in relation to the onset and length of exposure to IS and other types of seizures. Six children developed IS and five children developed other types of seizure disorders. Among those that developed IS, estimated mean IQ dropped significantly (nonparametric test for trend p = 0.002) from 92 (prior to onset of spasms) to 73 (after exposure to IS for a month or less) and 62 (after exposure to IS for more than a month). By contrast, there was no significant drop in estimated IQ among the five infants exposed to other types of seizure disorders (nonparametric test for trend p = 0.9). All six children exposed to infantile spasms developed clinically significant intellectual impairment. These data provide the first clear evidence of clinically significant, dose dependent, impairment in intellectual development following exposure to infantile spasms. The mechanisms underlying this developmental impairment and methods for preventing it require in depth study.

Neurodevelopmental and epilepsy outcome in children aged one to five years with infantile spasms—A North Indian cohort

The present study was planned as there is paucity of outcome data of children with infantile spasms, from India where profile of patients is different from the western world. Moreover, most previous studies have either not used strict inclusion criteria or standardized psychometric tests for developmental outcome. Ninety-five children, aged one-to-five years under follow up for more than six months in Pediatric Neurology Clinic of a tertiary care hospital with the diagnosis of infantile spasm were enrolled in this cross-sectional study if they had completed one or more years after the onset of spasms. The study period was January-December 2011. Neurodevelopment of each child was assessed using Development Profile 3 and Gross Motor Function Classification System. History regarding epilepsy frequency and control in the last one year was taken. Perinatal asphyxia was the commonest etiology in 43/95 children (45.2%). Favorable neurodevelopmental outcome was observed in 8/95 patients. Favorable epilepsy outcome in 58/95 (61.1%) patients was associated with treatment lag≤3 months between apparent onset of spasms and institution of therapy {OR 2 (1.1-3.8)} and response to first line antiepileptic drug {5 (2.6-10)}. The commonest etiology was potentially preventable perinatal cause. Early appropriate treatment may have a favorable epilepsy outcome.

Efficacy and tolerability of the galanin analog NAX 5055 in the multiple-hit rat model of symptomatic infantile spasms

Infantile spasms are seizures manifesting in infantile epileptic encephalopathies that are associated with poor epilepsy and cognitive outcomes. The current therapies are not always effective or are associated with serious side effects. Early cessation of spasms has been proposed to improve long-term outcomes. To identify new therapies for infantile spasms with rapid suppression of spasms, we are using the multiple-hit rat model of infantile spasms, which is a model of refractory infantile spasms. Here, we are testing the efficacy and tolerability of a single dose of the galanin receptor 1 preferring analog, NAX 5055, in the multiple-hit model of spasms. To induce the model, postnatal day 3 (PN3) male Sprague-Dawley rats underwent right intracerebral infusions of doxorubicin and lipopolysaccharide; p-chlorophenylalanine was then injected intraperitoneally (i.p.) at PN5. After the onset of spasms at PN4, 11-14 rats/group were injected i.p. with either NAX 5055 (0.5, 1, 2, or 4mg/kg) or vehicle. Video monitoring for spasms included a 1h pre-injection period, followed by 5h of recording post-injection, and two 2h sessions on PN5. The study was conducted in a randomized, blinded manner. Neurodevelopmental reflexes were assessed daily as well as at 2h after injection. Respiratory function, heart rate, pulse distension, oximetry and blood glucose were measured 4h after injection. The relative expression of GalR1 and GalR2 mRNA over β-actin in the cerebral cortex and hippocampus was determined with real time reverse transcription polymerase chain reaction. There was no acute effect of NAX 5055 on spasm frequency after the single dose of NAX 5055 (n=11-13 rats/group, following exclusions). Neurodevelopmental reflexes, vital signs, blood glucose measured 4h post-injection, and survival were not affected. A reduction in pulse and breath distention of unclear clinical significance was observed with the 7mg/kg NAX 5055 dose. GalR1 mRNA was present in the cerebral cortex and hippocampus of PN4 and adult rats. The hippocampal - but not the cortical - GalR1 mRNA expression was significantly lower in PN4 pups than in adults. GalR1 mRNA was also at least 20 times less abundant in the PN4 cortex than GalR2 mRNA. In conclusion, a single dose of NAX 5055 has no acute efficacy on spasms or toxicity in the multiple hit rat model of medically refractory infantile spasms. Our findings cannot exclude the possibility that repetitive NAX 5055 administration may show efficacy on spasms. The higher expression of GalR2 in the PN4 cortex suggests that GalR2-preferring analogs may be of interest to test for efficacy on spasms.

CPP‐115, a vigabatrin analogue, decreases spasms in the multiple‐hit rat model of infantile spasms

Infantile spasms (IS) have poor outcomes and limited treatment options, including vigabatrin, a γ-aminobutyric acid (GABA) aminotransferase inactivator. Vigabatrin has been associated with retinal toxicity. A high affinity vigabatrin analogue (CPP-115; Catalyst Pharmaceutical Partners, Inc., Coral Gables, FL, U.S.A.) has shown lower risk of retinal toxicity. Here, we test the efficacy of CPP-115 in reducing spasms and its tolerability in the multiple-hit rat model of IS, in which daily vigabatrin reduced spasms for only one day, but was not well tolerated. Male rats were treated with the protocol of the multiple-hit model of IS on postnatal day 3 (PN3). Using a randomized, blinded, vehicle-controlled, dose-response study design, CPP-115 (0.1, 1, or 5 mg/kg intraperitoneally [i.p.]) or vehicle was given daily (PN4-12) or as a single injection (PN7) after spasm onset. Intermittent video- or video-electroencephalography (EEG) monitoring was done. Secondary end points included the following: daily weights, survival, performance on open field activity, surface righting time, and negative geotaxis (PN3-20), horizontal bar (PN13-20), and Barnes maze (PN16-19). Statistics used a linear mixed model of raw or normalized log-transformed data, taking into account the repeated observations on each animal. The lower CPP-115 doses (0.1-1 mg/kg/day, PN4-12) reduced spasms between PN6 and 7 without increasing mortality. CPP-115 at 5 mg/kg/day (PN4-12) reduced spasms earlier (PN5), but was eventually lethal. A single CPP-115 injection (1 mg/kg, i.p.) decreased electroclinical spasms acutely but transiently. CPP-115 transiently improved the probability to >50% reduction of spasms, but did not accelerate spasm cessation. CPP-115 did not alter neurodevelopmental outcomes or visuospatial learning. We provide proof-of-concept evidence that CPP-115, a vigabatrin analogue, decreases spasms in the multiple-hit rat model of IS at considerably lower and better tolerated doses than vigabatrin did in our previous studies. Further optimization of the treatment protocol is needed. CPP-115 may be a promising new candidate treatment for IS with better tolerability than vigabatrin.

Anticonvulsant effects of kaurenoic acid isolated from the root bark of Annona senegalensis

The herbal preparations of Annona senegalensis Pers. (Annonaceae) root bark are used in Nigerian ethnomedicine for the treatment of epilepsy and febrile seizures. The scientific evidence to this effect has been reported [1]. This study aims to identify and characterize the active constituent(s) responsible for the anticonvulsant effect. Bioactive-guided fractionation of the methanol-methylene chloride root bark extract (MME) of A. senegalensis using pentylenetetrazole (PTZ)-induced seizures in mice, afforded a potent anticonvulsant ethyl-acetate fraction (EF). Further fractionation of the EF yielded eight sub-fractions (F1-F8) which were tested for anticonvulsant activity. The sub fraction F2 yielded whitish crystals that were purified to obtain A. senegalensis crystals, AS2. The AS2, which exhibited potent anticonvulsant effects, was characterized by 1D and 2D NMR spectroscopy, mass spectroscopy and X-ray crystallography. The AS2 was characterized as kaur-16-en-19-oic acid (KA), a diterpenoid phytoconstituent and exhibited the most potent anticonvulsant effect. The AS2 indicated an estimated LD50 of 3800 mg/kg. The results showed that the MME, EF and AS2 significantly (P < 0.05) and dose dependently delayed the onset of myoclonic spasms and tonic-clonic phases of seizures induced by PTZ and maximal electroshock seizure (MES). The anticonvulsant effects of the MME, EF and AS2 indicated the possible mediation of the anticonvulsant activity through central inhibitory mechanisms. Kaurenoic acid was identified as the anticonvulsant principle in the root bark extract of A. senegalensis.

An osteoporotic fracture mimicking cervical dystonia in idiopathic Parkinson's disease

We report on a case of a 65-year-old (CD) woman who sustained an atraumatic neck fracture. A combination of Parkinson's disease with motor fluctuations, chronic cervical dystonia and osteoporosis provided the basis for this interesting diagnosis. Mrs CD had progressed to complex phase idiopathic Parkinson's disease within 13 years of diagnosis. During this time she remained independent, only using a wheelchair when her motor fluctuations were bad. In 2011, she developed a sudden onset of neck spasm and occipital neuralgia, initially attributed to severe spasmodic cervical dystonia. Despite a titration regime of analgesics and weaning off of her Parkinson's disease medications, the pain persisted. An X-ray of her cervical spine showed degenerative discopathies from C4 to C7. Mrs CD underwent a trial of Botox injections to no avail and she was admitted acutely under the spinal team after an MRI of her spine showed abnormal oedema of the odontoid peg. Subsequent CT diagnosed a type II fracture of the odontoid peg on the background of severe osteoporotic bone (spinal T score -3.4 on subsequent DEXA scan) and she underwent a successful occipital cervical fusion of C1-C6. What makes this case interesting is the fact that this lady's profound powerful neck movements on a background of osteoporosis led to fracture of her neck. Post-operatively, she admitted to non-adherence to her bisphosphonates, prioritising levodopa in the morning with food rather than taking her alendronate on an empty stomach. She is now pain free and receives annual zolendronate infusions.

Periodic Eye Movements and Epileptic Spasms in West Syndrome

In addition to the typical infantile spasm symptoms, several other symptoms, such as eye movements, have been reported to be associated with infantile spasms, although the relationship between the typical spasms and these other events is not fully understood. Here we present a case with West syndrome. We observed the appearance of periodic eye movements followed by the onset of typical spasms and the appearance/disappearance of periodic eye movements during withdrawal/increases of vigabatrin. We believe that the case strongly supports the notion that periodic eye movements and typical spasms represent a spectrum of symptoms related to the same phenomenon of West syndrome.

Anticonvulsant effect of kaurenoic acid isolated from the root bark of Annona senegalensis

ContextThe herbal preparations of Annona senegalensis Pers. (Annonaceae) root bark are used in Nigerian ethnomedicine for the treatment of epilepsy and febrile seizures. The scientific evidence for this effect has been reported. ObjectiveThe aim of this study was to identify and characterize the active constituent responsible for the anticonvulsant effect. Materials and methodsBioactive-guided fractionation of the methanol-methylene chloride root bark extract (MME) of A. senegalensis using pentylenetetrazole (PTZ)-induced seizures in mice, afforded a potent anticonvulsant ethyl-acetate fraction (EF). Further fractionation of the EF yielded eight sub-fractions (F1–F8) which were tested for anticonvulsant activity. The sub-fraction F2 yielded white crystals that were purified to obtain A. senegalensis crystals, AS2. The AS2, which exhibited potent anticonvulsant effects, was characterized by 1D and 2D NMR spectroscopy, mass spectroscopy and X-ray crystallography. ResultsThe AS2 was characterized as kaur-16-en-19-oic acid (KA), a diterpenoid. The AS2 indicated an oral LD50 of 3800mg/kg. The results showed that the MME, EF and AS2 significantly (P<0.05) and dose-dependently delayed the onset of myoclonic spasms and tonic–clonic phases of seizures induced by PTZ and maximal electroshock seizures (MES). Discussion and conclusionKaurenoic acid was identified as the anticonvulsant principle in the root bark extract of A. senegalensis. The anticonvulsant effect of the MME, EF and AS2 is most likely being mediated through central inhibitory mechanisms.

α3Na+/K+-ATPase Deficiency Causes Brain Ventricle Dilation and Abrupt Embryonic Motility in Zebrafish

Na(+)/K(+)-ATPases are transmembrane ion pumps that maintain ion gradients across the basolateral plasma membrane in all animal cells to facilitate essential biological functions. Mutations in the Na(+)/K(+)-ATPase α3 subunit gene (ATP1A3) cause rapid-onset dystonia-parkinsonism, a rare movement disorder characterized by sudden onset of dystonic spasms and slow movements. In the brain, ATP1A3 is principally expressed in neurons. In zebrafish, the transcripts of the two ATP1A3 orthologs, Atp1a3a and Atp1a3b, show distinct expression in the brain. Surprisingly, targeted knockdown of either Atp1a3a or Atp1a3b leads to brain ventricle dilation, a likely consequence of ion imbalances across the plasma membrane that cause accumulation of cerebrospinal fluid in the ventricle. The brain ventricle dilation is accompanied by a depolarization of spinal Rohon-Beard neurons in Atp1a3a knockdown embryos, suggesting impaired neuronal excitability. This is further supported by Atp1a3a or Atp1a3b knockdown results where altered responses to tactile stimuli as well as abnormal motility were observed. Finally, proteomic analysis identified several protein candidates highlighting proteome changes associated with the knockdown of Atp1a3a or Atp1a3b. Our data thus strongly support the role of α3Na(+)/K(+)-ATPase in zebrafish motility and brain development, associating for the first time the α3Na(+)/K(+)-ATPase deficiency with brain ventricle dilation.

Clinical, aetiological and evolutive aspects of West syndrome in Yaound&#233; (Cameroon)

Background: West syndrome (WS) is an epileptic syndrome of the infant occurring between the 3rd and 12th months of life and characterized by the triad: infantile spasms in flexion, extension or mixed; global developmental delay; and hypsarrythmia on the electroencephalogram (EEG). Its incidence varies between 2.9 and 4.5 per 10,000 live births. West syndrome is caused by a brain dysfunction whose origins can be prenatal, neonatal and postnatal. Sometimes the aetiology is genetic or unknown. Purpose: To determine the main clinical, aetiological and major evolutive aspects of West syndrome in child neurology unit in a university-affiliated hospital in Yaoundé. Materials and Methods: It was a retrospective descriptive study conducted from September 2011 to January 2012 inthe child neurology unit of the Yaoundé gynaeco-obstetric and paediatric hospital. The medical records of 68 children followed for West syndrome (WS) in the service during the period from February 2008 to January 2012 (48 months) were used. All infants of 1- to 16-month-old with the diagnosis of WS were included. The diagnosis of WS was based on clinical evidence of spasm in flexion and/or in extension with global development delay, and EEG evidence of hypsarythmia or focal/multifocal epileptic abnormalities when hypsarythmia is absent. For each included infant, relevant medical history and complete physical examination were performed. The following data were collected and reported on a standardized questionnaire: prenatal, perinatal and postnatal past histories, age at onset of spasms, age at diagnosis, semiology of spasms, psychomotor development, the EEG and CT aspects and the evolutive modes of WS under treatment. Psychomotor development was assessed using theDenverdevelopmental screening test (DDST) which assesses the mental age compared to chronological age. Results: The age of onset of spasms varied between 1 and 16 months with a mean of 4.69 (±1.98) months. Males were highly represented with a sex ratio of 1.72. Flexion spasms were the most common clinical presentation (79.41%). 82.83% of the patients had a global developmental delay on the onset of spasms. Structural causes or symptomatic West syndrome was the most frequent presentation (77.94%). Perinatal aetiologies were highly represented (73.58%) with the main cause being neonatal asphyxia (55.88%). A hypsarrythmic tracing was found on the electroencephalogram (EEG) in 73.53% of cases. The most frequent CT abnormality was cortico-subcortical atrophy (38.24%). At the end of our study, global developmental delay persisted in 89.72%. Conclusion: The main aetiologies of West syndrome in our context are the sequelae of neonatal asphyxia and viral embryofoetopathies. There is a high incidence of associated global developmental delay. More prevention methods on risk factors for foetal distress and proper monitoring of deliveries to minimize severe neonatal asphyxia are indispensable.

Anticonvulsant activity of alcoholic extract of bark of Pinus roxburghii Sarg

To study the anticonvulsant activity of alcoholic extract of bark of Pinus roxburghii Sarg. (AEPR) used in Indian traditional medicine system in treating convulsion. Anticonvulsant activity was evaluated by maximal electroshock (MES) and pentylenetetrazole (PTZ)-induced seizures in Wistar albino rats. In the MES model, 150 mA current for 0.2 s was given through ear electrodes to induce convulsions in rats. The duration of tonic extension of hind limb was used as the end point, namely, prevention or decrease in the duration of hind limb extension was considered as a protective action. In the PTZ model, the anticonvulsant property of AEPR was assessed by its ability to delay the onset of myoclonic spasm and clonic convulsions produced by intraperitoneal administration of PTZ. In the MES-induced seizure model, AEPR in doses of 300 and 500 mg/kg body weight reduced all the phases of convulsion significantly (P<0.01). Standard drug phenytoin at a dose of 25 mg/kg significantly reduced flexion phase (P<0.01) and abolished all phases of convulsion. In the PTZ-induced seizure model, the administration of the extract at doses of 300 and 500 mg/kg 30 min prior to injection of PTZ significantly delayed the onset of clonic seizure (P<0.01). AEPR at the dose of 100 mg/kg body weight could not exert any significant protective effect on PTZ-induced convulsions. Standard drug diazepam at a dose of 4 mg/kg showed much delayed onset of clonic seizure. The study suggests that AEPR would be effective against generalized tonic-clonic and partial seizures. Thus AEPR possesses anticonvulsant property against MES- and PTZ-induced seizures in Wistar rats. However, further research is in progress to isolate the compound responsible for its activity.

Coexisting seizures in patients with infantile spasms confirmed by long-term video-electroencephalography monitoring

We performed this study to evaluate the frequency, types, and ictal electroencephalography (EEG) findings of coexisting seizures in patients with infantile spasms at the onset of spasms. We also evaluated the effect of coexisting seizures on short-term seizure control. We retrospectively reviewed the long-term video-EEG and electronic medical records of 109 patients (58 boys and 51 girls) diagnosed with infantile spasms at the Seoul National University Children's Hospital. Coexisting seizure types were classified according to the International League Against Epilepsy seizure and epilepsy classification. Ictal EEG findings were also reviewed. Short-term seizure control rates were compared between groups with or without coexisting seizures. We identified 27 coexisting seizures in 24 of the 109 patients (22%). The most common type of seizure was generalized tonic seizure followed by myoclonic, focal tonic, tonic-clonic, hypokinetic, and versive seizures. Rates of preterm birth and birth asphyxia were significantly higher in patients with coexisting seizures. Initial anticonvulsant was vigabatrin (103 patients), valproic acid (five patients), and topiramate (one patient). There was no significant difference in short-term seizure freedom (overall seizure-free rates in patients without coexisting seizures vs. those with: 29.2% vs. 11.1% at 2 months, 36.1% vs. 22.2% at 4 months, and 41.7% vs. 27.8% at 6 months). Seizure freedom was significantly lower in the symptomatic groups compared with non-symptomatic groups. Long-term video-EEG monitoring is required as an initial evaluation in patients with infantile spasms, especially when there are reports of coexisting seizures, or a history of preterm birth or birth asphyxia. Presence of coexisting seizures was not related to poor seizure control in the short-term treatment period.

Heat tolerance, behavioural temperature selection and temperature-dependent respiration in larval Octopus huttoni

This study reports temperature effects on paralarvae from a benthic octopus species, Octopus huttoni, found throughout New Zealand and temperate Australia. We quantified the thermal tolerance, thermal preference and temperature-dependent respiration rates in 1–5 days old paralarvae. Thermal stress (1 °C increase h −1) and thermal selection (∼10–24 °C vertical gradient) experiments were conducted with paralarvae reared for 4 days at 16 °C. In addition, measurement of oxygen consumption at 10, 15, 20 and 25 °C was made for paralarvae aged 1, 4 and 5 days using microrespirometry. Onset of spasms, rigour (CT max) and mortality (upper lethal limit) occurred for 50% of experimental animals at, respectively, 26.0±0.2 °C, 27.8±0.2 °C and 31.4±0.1 °C. The upper, 23.1±0.2 °C, and lower, 15.0±1.7 °C, temperatures actively avoided by paralarvae correspond with the temperature range over which normal behaviours were observed in the thermal stress experiments. Over the temperature range of 10 °C–25 °C, respiration rates, standardized for an individual larva, increased with age, from 54.0 to 165.2 nmol larvae −1 h −1 in one-day old larvae to 40.1–99.4 nmol h −1 at five days. Older larvae showed a lesser response to increased temperature: the effect of increasing temperature from 20 to 25 °C ( Q 10) on 5 days old larvae ( Q 10=1.35) was lower when compared with the 1 day old larvae ( Q 10=1.68). The lower Q 10 in older larvae may reflect age-related changes in metabolic processes or a greater scope of older larvae to respond to thermal stress such as by reducing activity. Collectively, our data indicate that temperatures >25 °C may be a critical temperature. Further studies on the population-level variation in thermal tolerance in this species are warranted to predict how continued increases in ocean temperature will limit O. huttoni at early larval stages across the range of this species.

UK Infantile Spasms Study: Effect of Time to Treatment and Age at Onset on Developmental Outcome

The effects of lead time to treatment (time from onset of spasms to start of treatment), age at onset of spasms, etiology, and treatment on developmental outcome at 4 years were investigated using multiple linear regression in 77 infants with spasms treated in the UK Infantile Spasms Study (UKISS).

Carisbamate acutely suppresses spasms in a rat model of symptomatic infantile spasms

Infantile spasms are the signature seizures of West syndrome. The conventional treatments for infantile spasms, such as adrenocorticotropic hormone (ACTH) and vigabatrin, are not always effective, especially in symptomatic infantile spasms (SIS). We tested the efficacy of carisbamate, a novel neurotherapeutic drug, to suppress spasms in the multiple-hit rat model of SIS, and compared it with phenytoin to determine if its effect is via sodium-channel blockade. Sprague-Dawley rats received right intracerebral infusions of doxorubicin and lipopolysaccharide at postnatal day 3 (PN3) and intraperitoneal p-chlorophenylalanine at PN5. A single intraperitoneal injection of carisbamate was administered at PN4, after the onset of spasms, at the following doses: 10 mg/kg (CRS-10), 30 mg/kg (CRS-30), and 60 mg/kg (CRS-60), and was compared to vehicle-injected group (VEH). Video-monitoring of PN6-7 CRS-60 or VEH-injected pups was also done. Carisbamate acutely reduced both behavioral spasms (CRS-30 and CRS-60 groups only) and electroclinical spasms during the first 2-3 postinjection hours, without detectable toxicity or mortality. In contrast, phenytoin (20 or 50 mg/kg) failed to suppress spasms. Our findings provide preclinical evidence that carisbamate displays acute anticonvulsive effect on spasms through a sodium channel-independent mechanism. Because spasms in the multiple-hit rat model are refractory to ACTH and transiently sensitive to vigabatrin, carisbamate may constitute a candidate new therapy for SIS, including the ACTH-refractory spasms. Further confirmation with clinical studies is needed.

The effect of lead time to treatment and of age of onset on developmental outcome at 4 years in infantile spasms: Evidence from the United Kingdom Infantile Spasms Study

Infantile spasms is a severe infantile seizure disorder. Several factors affect developmental outcome, especially the underlying etiology of the spasms. Treatment also affects outcome. Both age at onset of spasms and lead time to treatment (the time from onset of spasms to start of treatment) may be important. We investigated these factors. Developmental assessment using Vineland Adaptive Behaviour Scales (VABS) at 4 years of age in infants enrolled in the United Kingdom Infantile Spasms Study. Date of or age at onset of spasms was obtained prospectively. Lead time to treatment was then categorized into five categories. The effects of lead time to treatment, age of onset of spasms, etiology, and treatment on developmental outcome were investigated using multiple linear regression. Age of onset ranged (77 infants) from <1 to 10 months (mean 5.2, standard deviation 2.1). Lead time to treatment was 7 days or less in 11, 8-14 days in 16, 15 days to 1 month in 8, 1-2 months in 15, >2 months in 21 and not known in 6. Each month of reduction in age at onset of spasms was associated with a 3.1 [95% confidence interval (CI) 0.64-5.5, p = 0.03] decrease, and each increase in category of lead time duration associated with a 3.9 (95% CI 7.3-0.4, p = 0.014) decrease in VABS, respectively. There was a significant interaction between treatment allocation and etiology with the benefit in VABS in those allocated steroid therapy being in children with no identified etiology (coefficient 29.9, p=0.004). Both prompt diagnosis and prompt treatment of infantile spasms may help prevent subsequent developmental delay. Younger infants may be more at risk from the epileptic encephalopathy than older infants.