Papers by Miguel A Cortez
Frontiers in Neurology, Dec 22, 2022
Seizure, 2018
Hypsarrhythmia is an electroencephalographic pattern associated with epileptic spasms and West sy... more Hypsarrhythmia is an electroencephalographic pattern associated with epileptic spasms and West syndrome. West syndrome is a devastating epileptic encephalopathy, originating in infancy. Hypsarrhythmia has been deemed to be the interictal brain activity, while the electrodecremental event associated with the spasms is denoted as the ictal event. Though characterized as chaotic, asynchronous and disorganized based on visual inspection of the EEG, little is known of the dynamics of hypsarrhythmia and how it impacts the developmental arrest of these infants. As an exploratory and feasibility study, we explored the dynamics of both hypsarrhythmia and electrodecremental events with EEG phase synchronization methods, and in a convenience sample of three outpatients with epileptic spasms. As ictal events are associated with prolonged phase synchronization, we hypothesized that if hypsarrhythmia was indeed the interictal brain activity that it would have lower phase synchronization than the ...
Jia et al. Orphanet Journal of Rare Diseases (Springer Nature), 2018
Background: Infantile spasms represent the catastrophic, age-specific seizure type associated wit... more Background: Infantile spasms represent the catastrophic, age-specific seizure type associated with acute and long-term neurological morbidity. However, due to rarity and heterogenous determination, there is persistent uncertainty of its pathophysiological and epidemiological characteristics. The purpose of the current study was to address a historically suspected latitudinal basis of infantile spasms incidence, and to interrogate a geographical basis of epidemiology, including the roles of latitude and other environmental factors, using meta-analytic and-regression methods. Methods: A systematic search was performed in Ovid MEDLINE and Embase for primary reports on infantile spasms incidence and prevalence epidemiology. Results: One thousand fifteen studies were screened to yield 54 eligible publications, from which 39 incidence figures and 18 prevalence figures were extracted. The pooled incidence was 0.249 cases/1000 live births. The pooled prevalence was 0.015 cases/1000 population. Univariate meta-regression determined a continental effect, with Europe demonstrating the highest onset compared from Asia (OR = 0.51, p = 0.004) and from North America (OR = 0.50, p = 0.004). Latitude was also positively correlated with incidence globally (OR = 1.02, p < 0.001). Sub-analyses determined a particularly elevated Scandinavian incidence compared to the rest of world (OR = 1.88, p < 0.001), and lack of latitudinal effect with Scandinavian exclusion (p = 0.10). Metrics of healthcare quality did not predict incidence. Multiple meta-regression determined that latitude was the key predictor of incidence (OR = 1.02, p = 0.001). Conclusions: This is the first systematic epidemiological study of infantile spasms. Limitations included lack of Southern hemispheric representation, insufficient study selection and size to support some sub-continental analyses, and lack of accessible ethnic and healthcare quality data. Meta-analyses determined a novel, true geographical difference in incidence which is consistent with a latitudinal and/or ethnic contribution to epileptogenesis. These findings justify the establishment of a global registry of infantile spasms epidemiology to promote future systematic studies, clarify risk factors, and expand understanding of the pathophysiology.
The clinical and electroencephalographic features of a canine generalized myoclonic epilepsy with... more The clinical and electroencephalographic features of a canine generalized myoclonic epilepsy with photosensitivity and onset in young Rhodesian Ridgeback dogs (6 wk to 18 mo) are described. A fully penetrant recessive 4-bp deletion was identified in the DIRAS family GTPase 1 (DIRAS1) gene with an altered expression pattern of DIRAS1 protein in the affected brain. This neuronal DIRAS1 gene with a proposed role in cholinergic transmission provides not only a candidate for human myoclonic epilepsy but also insights into the disease etiology, while establishing a spontaneous model for future intervention studies and functional characterization.
Pediatric …, Jan 1, 2009
Infantile spasms is a catastrophic childhood seizure disorder for which few animal models exist. ... more Infantile spasms is a catastrophic childhood seizure disorder for which few animal models exist. Children with Down syndrome are highly susceptible to infantile spasms. The Ts65Dn mouse is a valid model for Down syndrome; therefore, we tested the hypothesis that the Ts65Dn mouse represents a substrate for an animal model of infantile spasms. The baseline of naïve Ts65Dn mice showed spontaneous spike-and-wave discharges, a pattern that worsened with baclofen and ␥-butyrolactone, which induced acute epileptic extensor spasms (AEES) associated with epileptiform polyspike bursts and an electrodecremental response on the EEG. GABA B R-agonist-induced AEES were significantly reduced with vigabatrin, rodent ACTH fragment, valproic acid, ethosuximide, and CGP 35348. Porcine ACTH had no effect. GABA B R protein expression was significantly increased in the thalamus and medulla oblongata of Ts65D mice in comparison with wild-type controls. The GABA B R agonist-treated Ts65Dn mouse shows the unique clinical, electrographic, and pharmacologic signature of infantile spasms and represents a valid, acute model of this disorder. GABA B R-mediated mechanisms may contribute to the increased susceptibility of children with Down syndrome to infantile spasms.
Pediatric Neurology, 1997
Pediatric Research, 2009
Infantile spasms is a catastrophic childhood seizure disorder for which few animal models exist. ... more Infantile spasms is a catastrophic childhood seizure disorder for which few animal models exist. Children with Down syndrome are highly susceptible to infantile spasms. The Ts65Dn mouse is a valid model for Down syndrome; therefore, we tested the hypothesis that the Ts65Dn mouse represents a substrate for an animal model of infantile spasms. The baseline of naïve Ts65Dn mice showed spontaneous spike-and-wave discharges, a pattern that worsened with baclofen and ␥-butyrolactone, which induced acute epileptic extensor spasms (AEES) associated with epileptiform polyspike bursts and an electrodecremental response on the EEG. GABA B R-agonist-induced AEES were significantly reduced with vigabatrin, rodent ACTH fragment, valproic acid, ethosuximide, and CGP 35348. Porcine ACTH had no effect. GABA B R protein expression was significantly increased in the thalamus and medulla oblongata of Ts65D mice in comparison with wild-type controls. The GABA B R agonist-treated Ts65Dn mouse shows the unique clinical, electrographic, and pharmacologic signature of infantile spasms and represents a valid, acute model of this disorder. GABA B R-mediated mechanisms may contribute to the increased susceptibility of children with Down syndrome to infantile spasms.
Behavior Genetics, 2007
Disruption of the sleep-wake cycle has been reported among individuals with Down syndrome (DS).
Journal of Child Neurology, 2011
Infantile spasms is an epileptic encephalopathy of early infancy with specific clinical and elect... more Infantile spasms is an epileptic encephalopathy of early infancy with specific clinical and electroencephalographic (EEG) features, limited treatment options, and a poor prognosis. Efforts to develop improved treatment options have been hindered by the lack of experimental models in which to test prospective therapies. The neuropeptide adrenocorticotropic hormone (ACTH) is effective in many cases of infantile spasms, although its mechanism(s)
We studied daily rhythms of chronic seizure activity and behavior in adult rats and mice treated ... more We studied daily rhythms of chronic seizure activity and behavior in adult rats and mice treated with the cholesterol biosynthesis inhibitor AY-9944 (AY) during early postnatal development. Chronic atypical absence seizures were verified in the AYtreated animals by the presence of spontaneous 5-to 6-Hz slow spike-wave discharges (SSWDs) in the neocortex. General behavioral activity, as measured by total movements (TM), movement time (MT), ambulatory movement time (AMT), time spent in center of arena (CT), jumps (JFP), and rotational behavior (TURNS), were continuously recorded under a 12-hour light:12-hour dark photocycle. The average SSWD duration in AY-treated rats varied daily, with two peaks occurring at approximately dark phase and light phase onset. Mice treated with AY exhibited significant increases in all behavioral measures during the light and dark phases, with the exception of light-phase CT, which did not differ from that of controls. Consequently, the daily rhythm of total behavioral activity (TM) exhibited a significantly higher mean oscillation (mesor) and amplitude without evidence of phase shift compared with the TM rhythm of controls. The occurrence of SSWD activity in the AY model appears to be subject to regulation by biological timing mechanisms and, furthermore, associated with motor hyperactivity that does not alter the timing of behavioral rhythmicity.
Epilepsy & Behavior, 2008
Human succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder o... more Human succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of GABA metabolism associated with motor impairment and epileptic seizures. Similarly, mice with targeted deletion of the Aldh5a1 gene (Aldh5a1 −/− ) exhibit SSADH deficiency and seizures early in life. These seizures begin as absence seizures the second week of life, but evolve into generalized convulsive seizures that increase in severity and become lethal during the fourth postnatal week. The seizures are alleviated and survival is prolonged when the mutant animals are weaned onto a ketogenic diet (KD). The persistence of spontaneous, recurrent, generalized tonic-clonic seizures in KD-treated adult Aldh5a1 −/− mice allowed us to quantify their daily (circadian) distribution using a novel behavioral method based on the detection of changes in movement velocity. Adult KD-treated Aldh5a1 −/− mice exhibited a seizure phenotype characterized by fits of wild running clonus accompanied by jumping and bouncing. These hypermotor seizures were largely spontaneous and occurred daily in a nonrandom pattern. The seizure rhythm showed a peak shortly after dark phase onset (2008 hours) with near-24-hour periodicity. Age-matched wild-type littermates showed no evidence of abnormal motor behavior. These new data suggest that generalized tonicclonic seizures in Aldh5a1 −/− mice are more frequent during a specific time of day and will provide useful information to clinicians for the treatment of seizures associated with human SSADH deficiency.
Proceedings of the National Academy of Sciences, 2009
In a mouse mutagenesis screen, we isolated a mutant, Myshkin (Myk), with autosomal dominant compl... more In a mouse mutagenesis screen, we isolated a mutant, Myshkin (Myk), with autosomal dominant complex partial and secondarily generalized seizures, a greatly reduced threshold for hippocampal seizures in vitro, posttetanic hyperexcitability of the CA3-CA1 hippocampal pathway, and neuronal degeneration in the hippocampus. Positional cloning and functional analysis revealed that Myk/؉ mice carry a mutation (I810N) which renders the normally expressed Na ؉ ,K ؉ -ATPase ␣3 isoform inactive. Total Na ؉ ,K ؉ -ATPase activity was reduced by 42% in Myk/؉ brain. The epilepsy in Myk/؉ mice and in vitro hyperexcitability could be prevented by delivery of additional copies of wild-type Na ؉ ,K ؉ -ATPase ␣3 by transgenesis, which also rescued Na ؉ ,K ؉ -ATPase activity. Our findings reveal the functional significance of the Na ؉ ,K ؉ -ATPase ␣3 isoform in the control of epileptiform activity and seizure behavior.
Neuroscience Letters, 2007
We investigated the role of 5-HT 2A and 5-HT 2C receptors in atypical absence seizures (AAS) indu... more We investigated the role of 5-HT 2A and 5-HT 2C receptors in atypical absence seizures (AAS) induced by trans-1,4-bis[2-chlorobenzylaminomethyl] cyclohexane, dihydrocholoride (AY-9944). The total duration and number and mean duration of the spontaneous bursts of slow spike-and-wave discharges (SSWD) that characterize the AY model were measured using electrocorticographic (ECoG) recordings in freely moving animals. In a randomized counterbalanced dose response design, rats were treated with either the 5-HT 2A agonist 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI, 0.5, 1 or 2 mg/kg), the 5-HT 2C preferring agonist m-chlorophenylpiperazine (mCPP, 1, 2, or 4 mg/kg), the 5-HT 2A antagonist ketanserin (2.5 or 5 mg/kg), or vehicle. DOI significantly reduced the total duration and number of SSWD. In contrast, mCPP had no effect on total duration or number of SSWD. Ketanserin exacerbated the number of SSWD at 2.5 mg/kg but produced mixed results at 5.0 mg/kg. However, none of the treatments affected the mean SSWD duration. These data support the hypothesis that 5HT 2A receptors are involved in the pathology of experimental atypical absence seizures.
Epilepsia, 2006
Purpose: To test the hypothesis that serotonin (5-HT) plays a role in the modulation of experimen... more Purpose: To test the hypothesis that serotonin (5-HT) plays a role in the modulation of experimental atypical absence seizures.
Epilepsia, 2009
Purpose: We studied the variability of the slowspike-and-wave discharges (SSWDs) derived from AY-... more Purpose: We studied the variability of the slowspike-and-wave discharges (SSWDs) derived from AY-9944 (AY) treatment during brain development of Long-Evans hooded (LEh) rats. Methods: Although all LEh rats received the standard dose of AY (7.5 mg/kg), we have observed an intersubject variability of the total SSWD duration at postnatal day (P) 55. Therefore, we set out to investigate the underlying brain levels of norepinephrine (NE), dopamine (DA), and serotonin (5-HT) and its metabolite (5-HIAA), as determined by high-performance liquid chromatography (HPLC) analyses from four different brain regions: thalamus (Th), frontoparietal cortex (Cx), hippocampus (Hp), and brainstem (Bs).
International Journal of Neuroscience, 2012
The GIRK2 subunit is involved in IS-like seizures induced by GABAB receptor agonists
Epilepsia, 2015
Infantile spasms (or IS) is a catastrophic childhood epilepsy that is particularly prevalent in c... more Infantile spasms (or IS) is a catastrophic childhood epilepsy that is particularly prevalent in children with Down syndrome. Previously, we have shown that the Ts65Dn (Ts) mouse model of Down syndrome is a useful substrate upon which to develop an animal model of infantile spasms. Specifically, the Ts mouse is exquisitely sensitive to the electroencephalography (EEG) and behavioral effects of γ-aminobutyric acid (GABA) B receptor (GABAB R) agonists with a resultant phenotype that bears behavioral, EEG, and pharmacologic semblance to infantile spasms in humans. The G protein-coupled inward rectifying potassium channel subunit 2 (GIRK2) gene, KCNJ6, is overexpressed in Ts mice, and the GABAB R-mediated GIRK2 current is significantly increased in these mutant animals as well. Therefore, we formulated the hypothesis that the GIRK2 channel plays a significant role in the behavioral (measured by acute extensor spasms quantification) and EEG (measured by the electrodecremental response dur...
Clinical and Neurophysiologic Spectrum Associated with Atypical Absence Seizures in Children with Intractable Epilepsy
Journal of Child Neurology, 2005
The aim of this study was to describe the clinical and neurophysiologic correlates of atypical ab... more The aim of this study was to describe the clinical and neurophysiologic correlates of atypical absence seizures in children with intractable epilepsy. In a retrospective review, 19 children with videoelectroencephalographic monitoring (female n=14; male n=5) fulfilled the electroclinical criteria for this seizure type. Atypical absence seizures occurred in a spectrum of clinical conditions associated with educational disability and intractable seizures. In comparison with children with only atypical absence seizures, children with atypical absence in association with multiple seizure types were more likely to have severe educational disability (n=11 of 13; P = .01), a slower ictal frequency (n=10 of 13; P = .01), and slow background rhythms for age (n = 13 of 13; P = .03). This study illustrates the broad clinical spectrum in which atypical absence seizures are encountered. Differentiation between children with only atypical absence seizures and children with multiple seizure types can be useful with respect to potential academic ability.
Epilepsia, 2002
The AY-9944 (AY)-treated rat is a reproducible and clinically relevant animal model of atypical a... more The AY-9944 (AY)-treated rat is a reproducible and clinically relevant animal model of atypical absence seizures. AY inhibits cholesterol synthesis, but the relation between brain sterol levels and the spontaneously recurrent absence seizures has not been determined. Methods: Long-Evans hooded rats were treated every 6 days from postnatal day (P)2 to P20 with AY (7.5 mg/kg, s.c.) or saline. Electrodes were permanently implanted under pentobarbital anesthesia at P50. Spike-and-wave discharge (SWD) duration and amplitude were quantified at P55. Changes in brain sterols after AY were examined in three different experiments, looking at brain regions (experiment 1), recovery after stopping AY (experiment 2), or gender differences (experiment 3). Results: Experiment 1: AY caused spontaneously recurrent slow SWD that lasted 59 times longer and had a 3.2-fold higher amplitude than that in controls. At P55, brain cholesterol was reduced and 7-dehydrocholesterol was increased in all brain regions (p < 0.0001). Experiment 2: Four hundred days after stopping AY-9944 treatment (P420), brain sterol levels had returned to normal levels, but the AY-induced SWD lasted twice as long as at P55. Experiment 3: At P55, AY-induced changes in plasma and liver (but not brain) sterols were significantly more severe in females compared with males. Conclusions: AY-induced seizures appear to be related to AY-induced changes in brain sterols but persisted long after the sterols had returned to normal after the last AY injection. Hence, there appears to be a critical developmental window during which the AY must be given but after which the AYinduced change in brain sterols is no longer essential to sustaining the seizures.
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Papers by Miguel A Cortez