FARS2 deficiency; new cases, review of clinical, biochemical, and molecular spectra, and variants interpretation based on structural, functional, and evolutionary significance.

An increasing number of mitochondrial diseases are found to be caused by pathogenic variants in nuclear encoded mitochondrial aminoacyl-tRNA synthetases. FARS2 encodes mitochondrial phenylalanyl-tRNA synthetase (mtPheRS) which transfers phenylalanine to its cognate tRNA in mitochondria. Since the first case was reported in 2012, a total of 21 subjects with FARS2 deficiency have been reported to date with a spectrum of disease severity that falls between two phenotypes; early onset epileptic encephalopathy and a less severe phenotype characterized by spastic paraplegia. In this report, we present an additional 15 individuals from 12 families who are mostly Arabs homozygous for the pathogenic variant Y144C, which is associated with the more severe early onset phenotype. The total number of unique pathogenic FARS2 variants known to date is 21 including three different partial gene deletions reported in four individuals. Except for the large deletions, all variants but two (one in-frame deletion of one amino acid and one splice-site variant) are missense. All large deletions and the single splice-site variant are in trans with a missense variant. This suggests that complete loss of function may be incompatible with life. In this report, we also review structural, functional, and evolutionary significance of select FARS2 pathogenic variants reported here.

Hypersynchronous ictal onset in the perirhinal cortex results from dynamic weakening in inhibition.

We obtained field, K(+) selective and "sharp" intracellular recordings from the rat entorhinal (EC) and perirhinal (PC) cortices in an in vitro brain slice preparation to identify the events occurring at interictal-to-ictal transition during 4-aminopyridine application. Field recordings revealed interictal- (duration: 1.1 to 2.2s) and ictal-like (duration: 31 to 103s) activity occurring synchronously in EC and PC; in addition, interictal spiking in PC increased in frequency shortly before the onset of ictal oscillatory activity thus resembling the hypersynchronous seizure onset seen in epileptic patients and in in vivo animal models. Intracellular recordings with K-acetate+QX314-filled pipettes in PC principal cells showed that spikes at ictal onset had post-burst hyperpolarizations (presumably mediated by postsynaptic GABAA receptors), which gradually decreased in amplitude. This trend was associated with a progressive positive shift of the post-burst hyperpolarization reversal potential. Finally, the transient elevations in [K(+)]o (up to 4.4mM from a base line of 3.2mM) - which occurred with the interictal events in PC - progressively increased (up to 7.3mM) with the spike immediately preceding ictal onset. Our findings indicate that hypersynchronous seizure onset in rat PC is caused by dynamic weakening of GABAA receptor signaling presumably resulting from [K(+)]o accumulation.

Loss-of-function mutation in RUSC2 causes intellectual disability and secondary microcephaly.

Inherited aberrancies in intracellular vesicular transport are associated with a variety of neurological and non-neurological diseases. RUSC2 is a gene found on chromosome 9p13.3 that codes for iporin, a ubiquitous protein with high expression in the brain that interacts with Rab proteins (GTPases implicated in intracellular protein trafficking). Although mutations in Rab proteins have been described as causing brain abnormalities and intellectual disability, until now no disease-causing mutations in RUSC2 have ever been reported in humans. We describe, to our knowledge for the first time, three patients with inherited homozygous nonsense mutations identified in RUSC2 on whole-exome sequencing. All three patients had central hypotonia, microcephaly, and moderate to severe intellectual disability. Two patients had additional features of early-onset epilepsy and absence of the splenium. This report adds to the ever-expanding landscape of genetic causes of intellectual disability and increases our understanding of the cellular processes underlying this important neurological entity.

Dynamics of interictal spikes and high-frequency oscillations during epileptogenesis in temporal lobe epilepsy.

Mesial temporal lobe epilepsy (MTLE) is characterized in humans and in animal models by a seizure-free latent phase that follows an initial brain insult; this period is presumably associated to plastic changes in temporal lobe excitability and connectivity. Here, we analyzed the occurrence of interictal spikes and high frequency oscillations (HFOs; ripples: 80-200Hz and fast ripples: 250-500Hz) from 48h before to 96h after the first seizure in the rat pilocarpine model of MTLE. Interictal spikes recorded with depth EEG electrodes from the hippocampus CA3 area and entorhinal cortex (EC) were classified as type 1 (characterized by a spike followed by a wave) or type 2 (characterized by a spike with no wave). We found that: (i) there was a switch in the distribution of both types of interictal spikes before and after the occurrence of the first seizure; during the latent phase both types of interictal spikes predominated in the EC whereas during the chronic phase both types of spikes predominated in CA3; (ii) type 2 spike duration decreased in both regions from the latent to the chronic phase; (iii) type 2 spikes associated to fast ripples occurred at higher rates in EC compared to CA3 during the latent phase while they occurred at similar rates in both regions in the chronic phase; and (iv) rates of fast ripples outside of spikes were higher in EC compared to CA3 during the latent phase. Our findings demonstrate that the transition from the latent to the chronic phase is paralleled by dynamic changes in interictal spike and HFO expression in EC and CA3. We propose that these changes may represent biomarkers of epileptogenicity in MTLE.

Juvenile idiopathic epilepsy in Egyptian Arabian foals, a potential animal model of self-limited epilepsy in children.

BACKGROUND: Juvenile idiopathic epilepsy (JIE) is categorized as a generalized epilepsy. Epilepsy classification entails electrocortical characterization and localization of epileptic discharges (ED) using electroencephalography (EEG). HYPOTHESIS/OBJECTIVES: Characterize epilepsy in Egyptian Arabian foals with JIE using EEG. ANIMALS: Sixty-nine foals (JIE, 48; controls, 21). METHODS: Retrospective study. Inclusion criteria consisted of Egyptian Arabian foals: (1) JIE group diagnosed based on witnessed or recorded seizures, and neurological and EEG findings, and (2) control group of healthy nonepileptic age-matched foals. Clinical data were obtained in 48 foals. Electroencephalography with photic stimulation was performed under standing sedation in 37 JIE foals and 21 controls. RESULTS: Abnormalities on EEG were found in 95% of epileptic foals (35 of 37) and in 3 of 21 control asymptomatic foals with affected siblings. Focal ED were detected predominantly in the central vertex with diffusion into the centroparietal or frontocentral regions (n = 35). Generalization of ED occurred in 14 JIE foals. Epileptic discharges commonly were seen during wakefulness (n = 27/37 JIE foals) and sedated sleep (n = 35/37 JIE foals; 3/21 controls). Photic stimulation triggered focal central ED in 15 of 21 JIE foals. CONCLUSIONS AND CLINICAL IMPORTANCE: Juvenile idiopathic epilepsy has a focal onset of ED at the central vertex with spread resulting in clinical generalized tonic-clonic seizures with facial motor activity and loss of consciousness. Electroencephalography with photic stimulation contributes to accurate phenotyping of epilepsy. Foals with this benign self-limiting disorder might serve as a naturally occurring animal model for self-limited epilepsy in children.

Normal imaging in patients with cerebral palsy: what does it tell us?

OBJECTIVE: To identify distinctive clinical features characterizing children with cerebral palsy (CP) and normal-appearing magnetic resonance imaging (MRI) findings. STUDY DESIGN: Using a population-based CP registry, the Registre de la Paralysie Cérébrale au Québec (Quebec Cerebral Palsy Registry), various antenatal, perinatal, and postnatal predictor variables, as well as current phenotype, were compared in patients with normal-appearing MRI findings and those with abnormal MRI findings. RESULTS: Of the 213 patients evaluated, 126 (60%) had MRI imaging results available and were included in our analysis. Of these 126 patients, 90 (71%; 51 males, 39 females) had abnormal findings and 36 (29%; 17 males and 19 females) had normal-appearing findings. Compared with other CP variants, normal-appearing MRI was more prevalent (P = .001) in dyskinetic CP (72.7%; 8 of 11) and less prevalent (P = .002) in spastic hemiplegic CP (10%; 4 of 40). There were no significant differences between the 2 groups (P > .05) in terms of the prevalence of perinatal or postnatal clinical features or clinical outcomes. Furthermore, 42% (15 of 36) of the children with normal-appearing MRI exhibited a high degree of functional disability (Gross Motor Functional Classification System IV-V), compared with 33% (30 of 90) with abnormal MRI. CONCLUSION: No clinical features, except a higher prevalence of dyskinetic CP, was identified in the children with normal-appearing MRI. More refined imaging techniques may be needed to evaluate patients with normal-appearing MRI findings. Furthermore, genetic or functional, rather than gross structural lesions, may underlie the pathophysiology of CP in this cohort. Finally, the high proportion of substantial functional disability underscores the importance of continuous follow-up even in the absence of early structural abnormalities on imaging.

Electroencephalographic evaluation under standing sedation using sublingual detomidine hydrochloride in Egyptian Arabian foals for investigation of epilepsy.

BACKGROUND: A standardized protocol for electroencephalography (EEG) under standing sedation for the investigation of epilepsy in foals is needed. HYPOTHESIS/OBJECTIVES: To evaluate a modified standardized EEG protocol under standing sedation using sublingual detomidine hydrochloride in Egyptian Arabian foals. ANIMALS: Nineteen foals (controls, 9; juvenile idiopathic epilepsy [JIE], 10). METHODS: Descriptive clinical study. Foals were classified as controls or epileptic based on history or witnessed seizures and neurological examination. Foals were sedated using sublingual detomidine hydrochloride at a dosage of 0.08 mg/kg to avoid stress associated with injectable sedation. Once foals appeared sedated with their heads low to the ground and with wide base stance (30 minutes), topical lidocaine hydrochloride was applied at the determined locations of EEG electrodes. Fifteen minutes were allowed for absorption and electrodes were placed, protected, and EEG recording performed. RESULTS: Level of sedation was considered excellent with no need of redosing. The EEG recording lasted from 27 to 51 minutes and provided interpretable data. Epileptic discharges (ED) were noted predominantly in the central-parietal region in 9 of 10 epileptic foals. Photic stimulation triggered ED in 7 of 10 epileptic foals and in none of the controls. Foals were not oversedated and recovered uneventfully. CONCLUSIONS AND CLINICAL IMPORTANCE: Sublingual detomidine hydrochloride is a safe, painless, simple, and effective method of sedation for EEG recording in foals. Sublingual sedation allowed the investigation of cerebral electrical activity during states of sleep and arousal, and during photic stimulation for the investigation of epilepsy in foals.

Clinical clues to differentiating inherited and noninherited etiologies of childhood ataxias.

OBJECTIVE: To identify clinical features at presentation that differentiate inherited and noninherited etiologies of childhood ataxias. STUDY DESIGN: A retrospective chart review analysis was conducted on 167 patients evaluated in neurology outpatient clinics for ataxia or ataxia-related symptoms. The frequency of clinical features, determined a priori, in the 2 groups was compared. RESULTS: A larger proportion of patients were diagnosed with a nongenetic cause than with a genetic cause (89% [148 patients] vs 11% [19 patients]). The majority of patients in the nongenetic group (56% [83/148]) presented early for medical evaluation, compared with 31% (6/19) in the genetic group. Consanguinity (16% vs 4%) and positive family history (16% vs 2%) were more frequent in the genetic group. Presenting symptoms of abnormal gait (95% vs 57%) and muscle weakness (47% vs 8%), including physical findings of abnormal muscle tone (63% vs 32%), abnormal reflexes (63% vs 16%), clonus (26% vs 9%), dysmetria (32% vs 5%), pes cavus (21% vs 1%), sensory deficits (16% vs 0%), and nonneurologic musculoskeletal abnormalities (58% vs 19%), were more prevalent in the genetic group. CONCLUSION: Certain clinical features can help delineate between inherited and noninherited causes of childhood ataxia and thus guide physicians in the targeted evaluation of patients.

Landscape of childhood epilepsies - A multi-ethnic population-based study.

OBJECTIVE: To describe the clinical features of childhood epilepsy in Qatar. METHODS: A retrospective cross-sectional chart review analysis was conducted at the only tertiary pediatric hospital in Qatar in 1422 patients with epilepsy followed between November 2016 and October 2019. RESULTS: 55% (781) were males and 70% were non-Qatari. Age of epilepsy onset was in the neonatal period in 9% (114/1207 patients). In the non-neonatal cohort, mean age of onset was 4 yrs 9mos ( ± 1.4mos). Focal epilepsy was the predominant epilepsy type in 45% (594/1314 patients) versus generalized epilepsy in 37% and combined focal/generalized epilepsy in 12%. Etiology was unknown in most children (782/1363, 57%) whereas structural and genetic causes represented 23% and 11% of cases respectively. No differences in epilepsy type and etiology were found between different ethnic groups. Children with genetic or structural epilepsies had an earlier epilepsy onset compared to those with unknown etiologies. At the last follow up, only 36% of patients were seizure-free and 12% (170/1422) had a history of status epilepticus. Medically refractory epilepsy was found in 37% (527/1407) of patients, with the most common etiologies being unknown (36%) and structural (37%). Neurodevelopmental co-morbidities were present in most patients (62%), with global developmental delay (47%) and learning/school difficulties (22%) being the most prevalent. 94% of patients with somatic co-morbidities had concomitant neurodevelopmental co-morbidities. Risk factors associated with an increased risk of co-morbidities and intractable epilepsy included early age of epilepsy onset (< 2 years of age); etiology; antenatal risk factors; history of previous central nervous system infection; history of status epilepticus and a family history of consanguinity and epilepsy. SIGNIFICANCE: This large multi-ethnic population-based study confirms that the prevalence, incidence and clinical features of epilepsy in Qatar is in accordance with other epidemiologic studies and highlights risk factors for the development of co-morbidities and medically-intractable epilepsy.

Perirhinal cortex hyperexcitability in pilocarpine-treated epileptic rats.

The perirhinal cortex (PC), which is heavily connected with several epileptogenic regions of the limbic system such as the entorhinal cortex and amygdala, is involved in the generation and spread of seizures. However, the functional alterations occurring within an epileptic PC network are unknown. Here, we analyzed this issue by using in vitro electrophysiology and immunohistochemistry in brain tissue obtained from pilocarpine-treated epileptic rats and age-matched, nonepileptic controls (NECs). Neurons recorded intracellularly from the PC deep layers in the two experimental groups had similar intrinsic and firing properties and generated spontaneous depolarizing and hyperpolarizing postsynaptic potentials with comparable duration and amplitude. However, spontaneous and stimulus-induced epileptiform discharges were seen with field potential recordings in over one-fifth of pilocarpine-treated slices but never in NEC tissue. These network events were reduced in duration by antagonizing NMDA receptors and abolished by NMDA + non-NMDA glutamatergic receptor antagonists. Pharmacologically isolated isolated inhibitory postsynaptic potentials had reversal potentials for the early GABA(A) receptor-mediated component that were significantly more depolarized in pilocarpine-treated cells. Experiments with a potassium-chloride cotransporter 2 antibody identified, in pilocarpine-treated PC, a significant immunostaining decrease that could not be explained by neuronal loss. However, interneurons expressing parvalbumin and neuropeptide Y were found to be decreased throughout the PC, whereas cholecystokinin-positive cells were diminished in superficial layers. These findings demonstrate synaptic hyperexcitability that is contributed by attenuated inhibition in the PC of pilocarpine-treated epileptic rats and underscore the role of PC networks in temporal lobe epilepsy.

Amelioration of Levetiracetam-Induced Behavioral Side Effects by Pyridoxine. A Randomized Double Blind Controlled Study.

BACKGROUND: Levetiracetam is a relatively new-generation antiseizure drug approved for the treatment of focal and generalized seizures. Despite its favorable side effect profile and minimal drug-drug interactions, neuropsychiatric side effects are reported in up to 13% of children. A few case series have suggested that supplementation of pyridoxine may mitigate these side effects, but controlled trials are lacking. To address this issue, a randomized interventional study was carried out in a pediatric tertiary hospital to qualify and quantify the potential beneficial effect of pyridoxine in attenuating the neuropsychiatric side effects of levetiracetam in children. METHODS: A total of 105 children with epilepsy who were taking levetiracetam (as a monotherapy or an adjunct) who showed behavioral symptoms coinciding with the start of levetiracetam, were included. Patients randomly and blindly received either a therapeutic (pyridoxine group, 46 of 105, 44%) or a homeopathic dose of pyridoxine (placebo, 59 of 105, 56%). A 30-item behavioral checklist was used to qualify and quantify the behavioral side effects at baseline and at different time points following initiation of treatment. RESULTS: Both placebo and pyridoxine groups experienced a statistical reduction in behavioral scores when compared with baseline. Our study indicated that although there was a placebo effect, the improvement in neuropsychiatric symptoms was more prominent in children who received therapeutic doses of pyridoxine. CONCLUSIONS: These data provide clinicians with pertinent evidence-based information that suggests that a trial of pyridoxine in patients who experience behavioral side effects due to the use of levetiracetam may avoid unnecessary change of antiseizure medications.

Identifying Clinical Clues in Children With Global Developmental Delay / Intellectual Disability With Abnormal Brain Magnetic Resonance Imaging (MRI).

Global developmental delay / intellectual disability are common pediatric conditions. Brain magnetic resonance imaging (MRI), although an important diagnostic tool in the evaluation of these patients, often requires general anesthesia. Recent literature suggests that unnecessary general anesthesia exposure should be avoided in early years because of possible long-term negative neurodevelopmental sequelae. This study sought to identify clinical clues associated with brain MRI abnormalities in children with global developmental delay / intellectual disability in an attempt to provide guidance to physicians on selecting patients who would benefit from an MRI. Retrospective chart review analysis was conducted for patients presenting to a pediatric neurology tertiary care center between 2014 and 2017 for a first clinic evaluation for global developmental delay / intellectual disability. Detailed clinical history and physical examination findings were analyzed and correlated with brain MRI findings. The majority (218/327, 67%) of children referred for evaluation of global developmental delay / intellectual disability underwent complete clinical and radiologic evaluations. Mean age was 37.9 months (±32.5 standard deviation) and 116 were males (53%). Motor deficits were predominant in most subjects (122/218, 56%). Abnormal MRI findings were observed in 153 children (70%), with the most prevalent abnormalities noted within the white matter (104/153, 68%), corpus callosum (77/153, 50%), and the hippocampus (50/153, 33%). Abnormal MRI findings were prevalent in children with predominant motor delay (84, 69%) and cognitive disability (3, 100%) as well as those with visual and hearing impairment (P < .05). The presence of facial dysmorphisms (57/71, P = .02); cranial nerve abnormalities (79/100; P = .007) and abnormal reflexes (16, P = .01) on examination also correlated significantly with increased MRI abnormalities.

Does angiogenesis play a role in the establishment of mesial temporal lobe epilepsy?

Mesial temporal lobe epilepsy (MTLE) is a focal epileptic disorder that is frequently associated with hippocampal sclerosis. This study investigated whether blocking angiogenesis prevents the development of seizures and hippocampal atrophy in the pilocarpine rat model of MTLE. To block angiogenesis, a subset of animals were given sunitinib orally. Continuous video recordings were performed to identify seizures. Brains were then extracted and sectioned, and hippocampal surfaces and angiogenesis were assessed. After a latent period of 6.6 ± 2.6 days, the sham-treated pilocarpine rats presented convulsive seizures, while the pilocarpine rats treated with sunitinib did not develop seizures. Sham-treated pilocarpine rats but not sunitinib-treated pilocarpine rats had significantly smaller hippocampi. Endothelial cell counts in sham-treated pilocarpine rats were significantly greater than in controls and sunitinib-treated pilocarpine rats. Blocking angiogenesis immediately following the initial insult in this animal model prevented thus angiogenesis and hippocampal atrophy and averted the development of clinical seizures.

GABA(B) receptor activation and limbic network ictogenesis.

Rat brain slices containing interconnected hippocampus and entorhinal cortex (EC) responded to 4-aminopyridine (50 microM) application by generating: (i) CA3-driven interictal discharges that propagated to the EC; and (ii) N-methyl-D-aspartic (NMDA) acid receptor-dependent ictal events originating in EC (cf. J. Neurosci. 17 (1997) 9308 for experiments made in brain slices). Ictal discharges disappeared within 1-2 h, but were re-established by cutting the Schaffer collaterals, which abolished CA3-driven interictal discharge propagation to EC. In intact slices, GABA(B) receptor activation by baclofen (5-40 microM): (i) depressed CA3-driven interictal activity; and (ii) disclosed non-NMDA glutamatergic receptor-dependent ictal discharges originating in CA3 and propagating to EC. These effects were reversed by the GABA(B) receptor antagonist CGP 35348 (0.5 mM). Application of increasing baclofen doses to slices in which hippocampus and EC networks were surgically isolated decreased epileptiform events with an IC50 that was lower in EC (0.6 microM; n = 12) than in CA3 (2.5 microM; n = 12). Hence, under control conditions, EC ictogenesis depends on NMDA receptor function and is controlled by CA3-driven output activity; in contrast, following GABA(B) receptor activation EC excitability is depressed to a greater extent than CA3, which leads to non-NMDA glutamatergic receptor-mediated ictogenesis in CA3. We propose that GABA(B) receptor modulation may represent an important mechanism for setting the site of initiation, the modalities of propagation and the glutamatergic receptor properties of ictogenesis in the limbic system and, perhaps, in mesial temporal lobe epilepsy patients.

Chorioamnionitis and cerebral palsy: lessons from a patient registry.

AIM: The fetal neuroinflammatory response has been linked to the development of brain injury in newborns and subsequent neurologic impairment. We aimed to explore the maternal and child factors associated with histologic chorioamnionitis in cerebral palsy. METHODS: We conducted an observational study on a cohort of children with cerebral palsy who were identified from the Quebec Cerebral Palsy Registry. Placental pathology was reported prospectively. Maternal and child factors associated with histological chorioamnionitis were explored. RESULTS: Placental reports were available in 455 of 534 (85%) children with cerebral palsy, and of these 12% had histological signs of chorioamnionitis on reports. These children were more likely to have large placentas over 90th percentile for gestational age (53.7% versus 30.7%, p = 0.001) and were born significantly more prematurely (<32 weeks in 51.9% vs 24.1%, p = 0.007) than children without chorioamnionitis. A clinical sign of perinatal infection was reported in 61.1% of children with chorioamnionitis, however each clinical sign was seen in a minority of these children. Children with chorioamnionitis were more likely to have spastic diplegic cerebral palsy subtype (37% vs 19.2%, p = 0.003) and periventricular white matter injury on neuroimaging (52.9% vs 35.8%, p = 0.004). However no differences in neuroimaging or subtypes were seen when stratified by prematurity. DISCUSSION: Histological chorioamnionitis was a frequent pathological finding in children with cerebral palsy born prematurely, with larger placentas relative to gestation and birth weight. Future case control studies are needed to shed light on the role of inflammatory placental findings in pregnancy outcomes.

Perirhinal cortex and temporal lobe epilepsy.

The perirhinal cortex-which is interconnected with several limbic structures and is intimately involved in learning and memory-plays major roles in pathological processes such as the kindling phenomenon of epileptogenesis and the spread of limbic seizures. Both features may be relevant to the pathophysiology of mesial temporal lobe epilepsy that represents the most refractory adult form of epilepsy with up to 30% of patients not achieving adequate seizure control. Compared to other limbic structures such as the hippocampus or the entorhinal cortex, the perirhinal area remains understudied and, in particular, detailed information on its dysfunctional characteristics remains scarce; this lack of information may be due to the fact that the perirhinal cortex is not grossly damaged in mesial temporal lobe epilepsy and in models mimicking this epileptic disorder. However, we have recently identified in pilocarpine-treated epileptic rats the presence of selective losses of interneuron subtypes along with increased synaptic excitability. In this review we: (i) highlight the fundamental electrophysiological properties of perirhinal cortex neurons; (ii) briefly stress the mechanisms underlying epileptiform synchronization in perirhinal cortex networks following epileptogenic pharmacological manipulations; and (iii) focus on the changes in neuronal excitability and cytoarchitecture of the perirhinal cortex occurring in the pilocarpine model of mesial temporal lobe epilepsy. Overall, these data indicate that perirhinal cortex networks are hyperexcitable in an animal model of temporal lobe epilepsy, and that this condition is associated with a selective cellular damage that is characterized by an age-dependent sensitivity of interneurons to precipitating injuries, such as status epilepticus.

Updates in the treatment of spasticity associated with cerebral palsy.

OPINION STATEMENT: Spasticity affects up to 80 % of patients with cerebral palsy (CP) and often plays a significant role in limiting the child's ability to function and participate in daily activities. The treatment of spasticity involves a multifaceted approach that includes pharmacological treatment with antispasmodics, physical therapy to maintain range of motion and prevent contractures, as well as a variety of orthopedic and neurosurgical interventions. Pharmacological agents currently used in clinical practice to treat spasticity in children have existed for almost two decades and continue to be used despite lack of solid evidence for their efficacy. Studies detailing safety profiles and optimal dosing in the pediatric population are greatly warranted. Intramuscular injection of botulinum neurotoxin is becoming increasingly popular for the treatment of segmental spasticity and current literature suggests it is safe and effective (Level A). Constraint-induced movement therapy (CIMT) and repetitive transcranial magnetic stimulation (rTMS) are emerging as effective interventions in improving motor function in hemiplegic CP. However, the role of these as of yet >interventions in reducing spasticity remains to be clarified.

Abnormal myelination in ring chromosome 18 syndrome.

Partial deletion of genetic material from the long arm of chromosome 18 results in a syndrome with multisystemic involvement, including dysmorphic features, intellectual disability, cardiac malformations, endocrine abnormalities, immunodeficiency, musculoskeletal deformities, and variable neurologic manifestations. Hypomyelination has been reported in patients with chromosome 18q- and postulated to be secondary to deletion of the gene coding for myelin basic protein found at 18q23. Little however is reported on cerebral anomalies seen in patients with ring chromosome 18, an analogous syndrome but with expectedly more severe phenotype secondary to the combined deletions of genetic material from both the short (p-) and long arm (q-) of chromosome 18. We are reporting a case of a girl with ring chromosome 18 and deletions involving 18p11.32-18p11.21 and 18q21.31-18q23. The abnormalities observed on magnetic resonance imaging are discussed with a specific focus on the evolution and significance of associated white matter changes.

Altered inhibition in lateral amygdala networks in a rat model of temporal lobe epilepsy.

Clinical and experimental evidence indicates that the amygdala is involved in limbic seizures observed in patients with temporal lobe epilepsy. Here, we used simultaneous field and intracellular recordings from horizontal brain slices obtained from pilocarpine-treated rats and age-matched nonepileptic controls (NECs) to shed light on the electrophysiological changes that occur within the lateral nucleus (LA) of the amygdala. No significant differences in LA neuronal intrinsic properties were observed between pilocarpine-treated and NEC tissue. However, spontaneous field activity could be recorded in the LA of 21% of pilocarpine-treated slices but never from NECs. At the intracellular level, this network activity was characterized by robust neuronal firing and was abolished by glutamatergic antagonists. In addition, we could identify in all pilocarpine-treated LA neurons: 1) large amplitude depolarizing postsynaptic potentials (PSPs) and 2) a lower incidence of spontaneous hyperpolarizing PSPs as compared with NECs. Single-shock stimulation of LA networks in the presence of glutamatergic antagonists revealed a biphasic inhibitory PSP (IPSP) in both NECs and pilocarpine-treated tissue. The reversal potential of the early GABA(A) receptor-mediated component, but not of the late GABA(B) receptor-mediated component, was significantly more depolarized in pilocarpine-treated slices. Furthermore, the peak conductance of both fast and late IPSP components had significantly lower values in pilocarpine-treated LA cells. Finally, paired-pulse stimulation protocols in the presence of glutamatergic antagonists revealed a less pronounced depression of the second IPSP in pilocarpine-treated slices compared with NECs. Altogether, these findings suggest that alterations in both pre- and postsynaptic inhibitory mechanisms contribute to synaptic hyperexcitability of LA networks in epileptic rats.

Rat subicular networks gate hippocampal output activity in an in vitro model of limbic seizures.

Evidence obtained from human epileptic tissue maintained in vitro indicates that the subiculum may play a crucial role in initiating epileptiform discharges in patients with mesial temporal lobe epilepsy. Hence, we used rat hippocampus-entorhinal cortex (EC) slices to identify the role of subiculum in epileptiform synchronization during bath application of 4-aminopyridine (4AP, 50 microM). In these slices, fast CA3-driven interictal-like events were restricted to the hippocampal CA3/CA1 areas and failed to propagate to the EC where slow interictal-like and ictal-like epileptiform discharges were recorded. However, antagonizing GABA(A) receptors with picrotoxin (50 microM) made CA3-driven interictal activity spread to EC. Sequential field potential analysis along the CA3-CA1-subiculum axis revealed that the amplitude of CA3-driven interictal discharges recorded in the presence of 4AP only diminished within the subiculum. Furthermore, CA1 electrical stimulation under control conditions elicited little or no subicular activation and never any response in EC; in contrast, robust subicular discharges that spread to EC could be evoked after picrotoxin. Intracellular recordings indicated that potentiation by picrotoxin was associated with blockade of hyperpolarizing IPSPs in subicular cells. Finally, when surgically isolated from adjacent structures, the subiculum generated low-amplitude synchronous discharges that corresponded to an intracellular hyperpolarization-depolarization sequence, were resistant to glutamatergic antagonists, and represented the activity of synchronized interneuronal networks. Bath application of picrotoxin abolished these 4AP-induced events and in their place robust network bursting occurred. In conclusion, our study demonstrates that the subiculum plays a powerful gating role on hippocampal output activity. This function depends on GABA(A) receptor-mediated inhibition and controls hippocampal-parahippocampal interactions that are known to modulate limbic seizures.