Ongoing fluctuations of neuronal activity have long been considered intrinsic noise that introduc... more Ongoing fluctuations of neuronal activity have long been considered intrinsic noise that introduces unavoidable and unwanted variability into neuronal processing, which the brain eliminates by averaging across population activity (Georgopoulos et al., 1986; Lee et al., 1988; Shadlen and Newsome, 1994; Maynard et al., 1999). It is now understood, that the seemingly random fluctuations of cortical activity form highly structured patterns, including oscillations at various frequencies, that modulate evoked neuronal responses (Arieli et al., 1996; Poulet and Petersen, 2008; He, 2013) and affect sensory perception (Linkenkaer-Hansen et al., 2004; Boly et al., 2007; Sadaghiani et al., 2009; Vinnik et al., 2012; Palva et al., 2013). Ongoing cortical activity is driven by proprioceptive and interoceptive inputs. In addition, it is partially intrinsically generated in which case it may be related to mental processes (Fox and Raichle, 2007; Deco et al., 2011). Here we argue that respiration, ...
Sudden unexplained death in epilepsy (SUDEP) is associated with generalized tonic-clonic seizures... more Sudden unexplained death in epilepsy (SUDEP) is associated with generalized tonic-clonic seizures and occurs most often when patients are in bed. There are several seizure detection monitors on the market, but little data are available on the sensitivity and specificity of these devices. We recently tested 2 models of seizure detection alarms with disappointing results. Here we tested the Emfit movement monitor on children with various seizure types who also had standard video electroencephalography (EEG), cardiopulmonary, and nursing monitoring. Video EEG records were reviewed to detect any seizures. In 45 patients, 78 seizures were recorded by video EEG. The Emfit movement monitor captured 23 seizure events (30%) in total, and 15 of the 28 (54%) that occurred during sleep. Most importantly, the alarm was activated with 11 of the 13 (85%) generalized tonic-clonic seizures that occurred in sleeping children. The Emfit movement monitor performed very well in comparison to previously ...
The Journal of Pediatric Pharmacology and Therapeutics, 2020
We describe an 11-year-old female who presented with severe hypersomnolence after receiving 1 wee... more We describe an 11-year-old female who presented with severe hypersomnolence after receiving 1 week of modest doses of clobazam (CLB). In reviewing the above case, we considered that the hypersomnolence could be related to a pharmacodynamic, pharmacokinetic, or pharmacogenomic issue associated with CLB or to a combination of these factors. Although serum concentrations of CLB and its active metabolite are sensitive to factors that affect cytochrome-dependent metabolism, drug-drug interactions were omitted as a cause of the hypersomnolence. Subsequent DNA analysis of the cytochrome P450 2C19 gene revealed the patient as *2/*2 genotype with poor metabolizer enzyme activity. Because genetic testing of all patients treated with CLB is currently not practical, CLB dose/concentration ratios and pharmacokinetic drug-drug interaction impact models may be indicated. Genetic testing should be considered when an adverse effect suggests the possibility of a polymorphism important to drug metabol...
Developmental epilepsies are age-dependent seizure disorders for which genetic causes have been i... more Developmental epilepsies are age-dependent seizure disorders for which genetic causes have been increasingly identified. Here we report six unrelated individuals with mutations in salt-inducible kinase 1 (SIK1) in a series of 101 persons with early myoclonic encephalopathy, Ohtahara syndrome, and infantile spasms. Individuals with SIK1 mutations had short survival in cases with neonatal epilepsy onset, and an autism plus developmental syndrome after infantile spasms in others. All six mutations occurred outside the kinase domain of SIK1 and each of the mutants displayed autophosphorylation and kinase activity toward HDAC5. Three mutations generated truncated forms of SIK1 that were resistant to degradation and also showed changes in sub-cellular localization compared to wild-type SIK1. We also report the human neuropathologic examination of SIK1-related developmental epilepsy, with normal neuronal morphology and lamination but abnormal SIK1 protein cellular localization. Therefore, ...
The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG
We describe the use of topiramate in a healthy 12-year-old (88-kg) male who developed refractory ... more We describe the use of topiramate in a healthy 12-year-old (88-kg) male who developed refractory generalized convulsive status epilepticus. Seizures persisted despite aggressive use of benzodiazepines (intravenous lorazepam; oral clorazepate), barbiturates (i.e., phenobarbital, pentobarbital), and hydantoins. The child's seizures were controlled with nasogastrically administered topiramate in doses up to 500 mg twice daily (11.4 mg/kg/day). The patient did not display any clinical or laboratory signs of metabolic acidosis while receiving topiramate. Topiramate should be considered as a treatment option in refractory status epilepticus.
Epileptic disorders : international epilepsy journal with videotape, 2007
Childhood epilepsies are a heterogeneous group of conditions that differ in diagnostic criteria a... more Childhood epilepsies are a heterogeneous group of conditions that differ in diagnostic criteria and management and have dramatically different outcomes. Despite increasing data on treatment of epilepsy, research findings on childhood epilepsy are more limited and many clinical questions remain unanswered, so that clinicians must often rely on clinical judgment. In such clinical situations, expert opinion can be especially helpful. A survey on pediatric epilepsy and seizures (33 questions and approximately 650 treatment options) was sent to 57 European physicians specializing in pediatric epilepsy, 42 (74%) of whom completed it. In some questions, the experts were asked to recommend overall treatment approaches for specific syndromes (the order in which they would use certain strategies). Most of the questions asked the experts to rate options using a modified version of the RAND 9-point scale for medical appropriateness. Consensus was defined as a non-random distribution of scores b...
Ongoing fluctuations of neuronal activity have long been considered intrinsic noise that introduc... more Ongoing fluctuations of neuronal activity have long been considered intrinsic noise that introduces unavoidable and unwanted variability into neuronal processing, which the brain eliminates by averaging across population activity (Georgopoulos et al., 1986; Lee et al., 1988; Shadlen and Newsome, 1994; Maynard et al., 1999). It is now understood, that the seemingly random fluctuations of cortical activity form highly structured patterns, including oscillations at various frequencies, that modulate evoked neuronal responses (Arieli et al., 1996; Poulet and Petersen, 2008; He, 2013) and affect sensory perception (Linkenkaer-Hansen et al., 2004; Boly et al., 2007; Sadaghiani et al., 2009; Vinnik et al., 2012; Palva et al., 2013). Ongoing cortical activity is driven by proprioceptive and interoceptive inputs. In addition, it is partially intrinsically generated in which case it may be related to mental processes (Fox and Raichle, 2007; Deco et al., 2011). Here we argue that respiration, ...
Sudden unexplained death in epilepsy (SUDEP) is associated with generalized tonic-clonic seizures... more Sudden unexplained death in epilepsy (SUDEP) is associated with generalized tonic-clonic seizures and occurs most often when patients are in bed. There are several seizure detection monitors on the market, but little data are available on the sensitivity and specificity of these devices. We recently tested 2 models of seizure detection alarms with disappointing results. Here we tested the Emfit movement monitor on children with various seizure types who also had standard video electroencephalography (EEG), cardiopulmonary, and nursing monitoring. Video EEG records were reviewed to detect any seizures. In 45 patients, 78 seizures were recorded by video EEG. The Emfit movement monitor captured 23 seizure events (30%) in total, and 15 of the 28 (54%) that occurred during sleep. Most importantly, the alarm was activated with 11 of the 13 (85%) generalized tonic-clonic seizures that occurred in sleeping children. The Emfit movement monitor performed very well in comparison to previously ...
The Journal of Pediatric Pharmacology and Therapeutics, 2020
We describe an 11-year-old female who presented with severe hypersomnolence after receiving 1 wee... more We describe an 11-year-old female who presented with severe hypersomnolence after receiving 1 week of modest doses of clobazam (CLB). In reviewing the above case, we considered that the hypersomnolence could be related to a pharmacodynamic, pharmacokinetic, or pharmacogenomic issue associated with CLB or to a combination of these factors. Although serum concentrations of CLB and its active metabolite are sensitive to factors that affect cytochrome-dependent metabolism, drug-drug interactions were omitted as a cause of the hypersomnolence. Subsequent DNA analysis of the cytochrome P450 2C19 gene revealed the patient as *2/*2 genotype with poor metabolizer enzyme activity. Because genetic testing of all patients treated with CLB is currently not practical, CLB dose/concentration ratios and pharmacokinetic drug-drug interaction impact models may be indicated. Genetic testing should be considered when an adverse effect suggests the possibility of a polymorphism important to drug metabol...
Developmental epilepsies are age-dependent seizure disorders for which genetic causes have been i... more Developmental epilepsies are age-dependent seizure disorders for which genetic causes have been increasingly identified. Here we report six unrelated individuals with mutations in salt-inducible kinase 1 (SIK1) in a series of 101 persons with early myoclonic encephalopathy, Ohtahara syndrome, and infantile spasms. Individuals with SIK1 mutations had short survival in cases with neonatal epilepsy onset, and an autism plus developmental syndrome after infantile spasms in others. All six mutations occurred outside the kinase domain of SIK1 and each of the mutants displayed autophosphorylation and kinase activity toward HDAC5. Three mutations generated truncated forms of SIK1 that were resistant to degradation and also showed changes in sub-cellular localization compared to wild-type SIK1. We also report the human neuropathologic examination of SIK1-related developmental epilepsy, with normal neuronal morphology and lamination but abnormal SIK1 protein cellular localization. Therefore, ...
The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG
We describe the use of topiramate in a healthy 12-year-old (88-kg) male who developed refractory ... more We describe the use of topiramate in a healthy 12-year-old (88-kg) male who developed refractory generalized convulsive status epilepticus. Seizures persisted despite aggressive use of benzodiazepines (intravenous lorazepam; oral clorazepate), barbiturates (i.e., phenobarbital, pentobarbital), and hydantoins. The child's seizures were controlled with nasogastrically administered topiramate in doses up to 500 mg twice daily (11.4 mg/kg/day). The patient did not display any clinical or laboratory signs of metabolic acidosis while receiving topiramate. Topiramate should be considered as a treatment option in refractory status epilepticus.
Epileptic disorders : international epilepsy journal with videotape, 2007
Childhood epilepsies are a heterogeneous group of conditions that differ in diagnostic criteria a... more Childhood epilepsies are a heterogeneous group of conditions that differ in diagnostic criteria and management and have dramatically different outcomes. Despite increasing data on treatment of epilepsy, research findings on childhood epilepsy are more limited and many clinical questions remain unanswered, so that clinicians must often rely on clinical judgment. In such clinical situations, expert opinion can be especially helpful. A survey on pediatric epilepsy and seizures (33 questions and approximately 650 treatment options) was sent to 57 European physicians specializing in pediatric epilepsy, 42 (74%) of whom completed it. In some questions, the experts were asked to recommend overall treatment approaches for specific syndromes (the order in which they would use certain strategies). Most of the questions asked the experts to rate options using a modified version of the RAND 9-point scale for medical appropriateness. Consensus was defined as a non-random distribution of scores b...
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Papers by James Wheless