Page Pennell - Academia.edu (original) (raw)
Papers by Page Pennell
Epilepsy currents / American Epilepsy Society
Children born to mothers taking antiepileptic drugs (AEDs) are at increased risk for findings of ... more Children born to mothers taking antiepileptic drugs (AEDs) are at increased risk for findings of fetal anticonvulsant syndrome. Accepted treatment paradigms to minimize fetal risks include use of AED monotherapy and folic acid supplementation. However, as data are acquired from several ongoing pregnancy registries, differential risks among the various AED monotherapy regimens are being defined, further improving fetal outcomes.
Steroids, 2015
Analytical techniques used to quantify neurosteroids in biological samples are often compromised ... more Analytical techniques used to quantify neurosteroids in biological samples are often compromised by non-specificity and limited dynamic range which can result in erroneous results. A relatively rapid and inexpensive gas chromatography-mass spectrometry (GC-MS) was developed to simultaneously measure nine neurosteroids, including allopregnanolone, estradiol, and progesterone, as well as 25-hydroxy-vitamin D3 in plasma samples collected from adult women subjects during and after pregnancy. Sample preparation involved solid-phase extraction and derivatization, followed by automated injection on a GC equipped with a mass selective detector (MSD) operated in single ion monitoring (SIM) mode to yield a run time of less than 11min. Method detection limits for all neurosteroids ranged from 30 to 200pg/mL (parts per trillion), with coefficients of variation that ranged from 3% to 5% based on intra-assay comparisons run in triplicate. Although concentrations of estradiol measured by chemilumi...
International review of neurobiology, 2008
The ideal management of women with epilepsy during pregnancy involves achieving an optimal balanc... more The ideal management of women with epilepsy during pregnancy involves achieving an optimal balance between minimizing fetal exposure to the deleterious influences of both antiepileptic drugs (AEDs) and of seizures. Women with increased seizures during pregnancy tend to have subtherapeutic AED concentrations. Multiple physiological changes during pregnancy influence drug disposition, including increased volume of distribution, increased renal elimination, altered hepatic enzyme activity, and a decline in plasma protein concentrations. Many of the AEDs are characterized by significant increases in clearance during pregnancy. Studies performed thus far provide convincing findings for significant increases in the clearance of lamotrigine and phenytoin during pregnancy; other studies support that phenobarbital, oxcarbazepine, and levetiracetam clearances also most likely increase during pregnancy. Therapeutic drug monitoring of lamotrigine with adjustment of dosages during pregnancy to m...
Epilepsy currents / American Epilepsy Society
Neurology, 2003
The ideal management of women with epilepsy during pregnancy and the postpartum period involves a... more The ideal management of women with epilepsy during pregnancy and the postpartum period involves achieving an optimal balance between minimizing fetal and neonatal exposure to the deleterious influences both of antiepileptic drugs (AEDs) and of seizures. Women with increased seizures during pregnancy tend to have subtherapeutic AED concentrations. Multiple physiologic changes during pregnancy influence drug disposition, including increased volume of distribution, increased renal elimination, altered hepatic enzyme activity, and a decline in plasma protein concentrations. Noncompliance can also be a major factor. The majority of AEDs are characterized by significant increases in clearance during pregnancy. Lamotrigine (LTG) clearance markedly increases throughout pregnancy, to an extent greater than with the older AEDs. Studies during and after birth in mothers taking the older AEDs indicate extensive transplacental transfer and low to moderate excretion into breast milk. Limited stud...
Neurology, Jan 10, 2003
The great majority of women with epilepsy who become pregnant have normal pregnancies and healthy... more The great majority of women with epilepsy who become pregnant have normal pregnancies and healthy infants. However, in utero exposure to antiepileptic drugs (AEDs) can put infants of women with epilepsy at increased risk for a variety of abnormalities, including intrauterine growth retardation, minor anomalies, major congenital malformations, microcephaly, and cognitive dysfunction. Various combinations of these findings can occur in an individual infant and are referred to as the fetal anticonvulsant syndrome (FAS). The most common major malformations are cleft lip/palate, heart defects, neural tube defects, and urogenital defects. Although AEDs have teratogenic risks, withdrawal of all AEDs before pregnancy is not a realistic option for many women with epilepsy. The results of several studies indicate that AED monotherapy reduces the risk for development of FAS compared with polytherapy exposure in utero. Current treatment guidelines advise use of AED monotherapy when possible and...
Seizure, 2014
Intravenous (IV) formulations are useful when treating patients where oral administration is not ... more Intravenous (IV) formulations are useful when treating patients where oral administration is not possible and to study certain pharmacokinetic parameters such as bioavailability. We developed a stable-labeled IV formulation of lamotrigine (LTG) for studying pharmacokinetics in epilepsy patients. Stable-labeled IV LTG was given to 20 persons with epilepsy (6 men; 14 women) with a mean age of 34.8 years (SD 11.7). A 50mg dose of LTG (stable labeled) was given intravenously and replaced 50mg of the regular morning oral dose of LTG (unlabeled, commercially available formulation). No significant changes in blood pressure, heart rate, or adverse events including rash were attributed to administration of a 50-mg dose of the intravenous LTG formulation. Our results show that LTG base that is complexed with 2-hydroxypropyl-β-cyclodextrin and stable-labeled can be given safely as a tracer replacement dose.
Annals of Clinical and Translational Neurology, 2014
Objective: To reassess the evidence for management issues related to the care of women with epile... more Objective: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy. Methods: Systematic review of relevant articles published between January 1985 and June 2007. Results: It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine and possi- ble compared to phenytoin or lamotrigine. Compared to untreated WWE, it is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the develop- ment of MCMs. It is probable that antiepileptic drug (AED) polytherapy as compared to mono- therapy regimens contributes to the development of MCMs and to reduced cognitive outcomes. For monotherapy, intrauterine exposure to VPA probably reduces cognitive out- comes. Further, monotherapy exposure to phenytoin or phenobarbital possibly reduces cogni- tive outcomes. Neonates of WWE taking AEDs probably have an in...
Seminars in Neurology, 2002
Seizure, 2013
Patients with intracerebral hemorrhage (ICH) are often initiated on antiepileptic drugs without a... more Patients with intracerebral hemorrhage (ICH) are often initiated on antiepileptic drugs without a clear indication. We compared the percentage of patients with spontaneous ICH who had seizures at onset or during hospitalization, and examined empiric use of antiepileptic drugs (AEDs) in these patients in 2 cohorts 10 years apart. Using a clinical data registry at a tertiary care adult hospital, we retrospectively selected admissions for spontaneous ICH between 1/1/99-12/31/00 (Cohort A, n=30) and 1/1/09-12/31/10 (Cohort B, n=108). Clinical, neurophysiological and radiological data were collected in both cohorts. In Cohorts A and B respectively, AEDs were started in 53.3% and 50.0%, and continued on discharge in 50.0% and 20.4% of patients; 86.6% and 59.1% of patients discharged on AEDs did not have a clinical/electrographic seizure or epileptiform EEG findings. Seizures occurred in 6.6% and 13.0% in Cohorts A and B respectively. The presence of a seizure at presentation (p=0.01) and during hospitalization (p=0.02) were predictors for continuing AED on discharge. In both cohorts, a significant number of patients were discharged on AEDs without a clear indication, though there is a change in practice between the two cohorts.
New England Journal of Medicine, 2009
Neuron, 2001
Mechanisms underlying seizure generation are traditionally thought to act over seconds to minutes... more Mechanisms underlying seizure generation are traditionally thought to act over seconds to minutes before clinical seizure onset. We analyzed continuous 3- to 14-day intracranial EEG recordings from five patients with mesial temporal lobe epilepsy obtained during evaluation for epilepsy surgery. We found localized quantitative EEG changes identifying prolonged bursts of complex epileptiform discharges that became more prevalent 7 hr before seizures and highly localized subclinical seizure-like activity that became more frequent 2 hr prior to seizure onset. Accumulated energy increased in the 50 min before seizure onset, compared to baseline. These observations, from a small number of patients, suggest that epileptic seizures may begin as a cascade of electrophysiological events that evolve over hours and that quantitative measures of preseizure electrical activity could possibly be used to predict seizures far in advance of clinical onset.
Epilepsy currents / American Epilepsy Society
Children born to mothers taking antiepileptic drugs (AEDs) are at increased risk for findings of ... more Children born to mothers taking antiepileptic drugs (AEDs) are at increased risk for findings of fetal anticonvulsant syndrome. Accepted treatment paradigms to minimize fetal risks include use of AED monotherapy and folic acid supplementation. However, as data are acquired from several ongoing pregnancy registries, differential risks among the various AED monotherapy regimens are being defined, further improving fetal outcomes.
Steroids, 2015
Analytical techniques used to quantify neurosteroids in biological samples are often compromised ... more Analytical techniques used to quantify neurosteroids in biological samples are often compromised by non-specificity and limited dynamic range which can result in erroneous results. A relatively rapid and inexpensive gas chromatography-mass spectrometry (GC-MS) was developed to simultaneously measure nine neurosteroids, including allopregnanolone, estradiol, and progesterone, as well as 25-hydroxy-vitamin D3 in plasma samples collected from adult women subjects during and after pregnancy. Sample preparation involved solid-phase extraction and derivatization, followed by automated injection on a GC equipped with a mass selective detector (MSD) operated in single ion monitoring (SIM) mode to yield a run time of less than 11min. Method detection limits for all neurosteroids ranged from 30 to 200pg/mL (parts per trillion), with coefficients of variation that ranged from 3% to 5% based on intra-assay comparisons run in triplicate. Although concentrations of estradiol measured by chemilumi...
International review of neurobiology, 2008
The ideal management of women with epilepsy during pregnancy involves achieving an optimal balanc... more The ideal management of women with epilepsy during pregnancy involves achieving an optimal balance between minimizing fetal exposure to the deleterious influences of both antiepileptic drugs (AEDs) and of seizures. Women with increased seizures during pregnancy tend to have subtherapeutic AED concentrations. Multiple physiological changes during pregnancy influence drug disposition, including increased volume of distribution, increased renal elimination, altered hepatic enzyme activity, and a decline in plasma protein concentrations. Many of the AEDs are characterized by significant increases in clearance during pregnancy. Studies performed thus far provide convincing findings for significant increases in the clearance of lamotrigine and phenytoin during pregnancy; other studies support that phenobarbital, oxcarbazepine, and levetiracetam clearances also most likely increase during pregnancy. Therapeutic drug monitoring of lamotrigine with adjustment of dosages during pregnancy to m...
Epilepsy currents / American Epilepsy Society
Neurology, 2003
The ideal management of women with epilepsy during pregnancy and the postpartum period involves a... more The ideal management of women with epilepsy during pregnancy and the postpartum period involves achieving an optimal balance between minimizing fetal and neonatal exposure to the deleterious influences both of antiepileptic drugs (AEDs) and of seizures. Women with increased seizures during pregnancy tend to have subtherapeutic AED concentrations. Multiple physiologic changes during pregnancy influence drug disposition, including increased volume of distribution, increased renal elimination, altered hepatic enzyme activity, and a decline in plasma protein concentrations. Noncompliance can also be a major factor. The majority of AEDs are characterized by significant increases in clearance during pregnancy. Lamotrigine (LTG) clearance markedly increases throughout pregnancy, to an extent greater than with the older AEDs. Studies during and after birth in mothers taking the older AEDs indicate extensive transplacental transfer and low to moderate excretion into breast milk. Limited stud...
Neurology, Jan 10, 2003
The great majority of women with epilepsy who become pregnant have normal pregnancies and healthy... more The great majority of women with epilepsy who become pregnant have normal pregnancies and healthy infants. However, in utero exposure to antiepileptic drugs (AEDs) can put infants of women with epilepsy at increased risk for a variety of abnormalities, including intrauterine growth retardation, minor anomalies, major congenital malformations, microcephaly, and cognitive dysfunction. Various combinations of these findings can occur in an individual infant and are referred to as the fetal anticonvulsant syndrome (FAS). The most common major malformations are cleft lip/palate, heart defects, neural tube defects, and urogenital defects. Although AEDs have teratogenic risks, withdrawal of all AEDs before pregnancy is not a realistic option for many women with epilepsy. The results of several studies indicate that AED monotherapy reduces the risk for development of FAS compared with polytherapy exposure in utero. Current treatment guidelines advise use of AED monotherapy when possible and...
Seizure, 2014
Intravenous (IV) formulations are useful when treating patients where oral administration is not ... more Intravenous (IV) formulations are useful when treating patients where oral administration is not possible and to study certain pharmacokinetic parameters such as bioavailability. We developed a stable-labeled IV formulation of lamotrigine (LTG) for studying pharmacokinetics in epilepsy patients. Stable-labeled IV LTG was given to 20 persons with epilepsy (6 men; 14 women) with a mean age of 34.8 years (SD 11.7). A 50mg dose of LTG (stable labeled) was given intravenously and replaced 50mg of the regular morning oral dose of LTG (unlabeled, commercially available formulation). No significant changes in blood pressure, heart rate, or adverse events including rash were attributed to administration of a 50-mg dose of the intravenous LTG formulation. Our results show that LTG base that is complexed with 2-hydroxypropyl-β-cyclodextrin and stable-labeled can be given safely as a tracer replacement dose.
Annals of Clinical and Translational Neurology, 2014
Objective: To reassess the evidence for management issues related to the care of women with epile... more Objective: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy. Methods: Systematic review of relevant articles published between January 1985 and June 2007. Results: It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine and possi- ble compared to phenytoin or lamotrigine. Compared to untreated WWE, it is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the develop- ment of MCMs. It is probable that antiepileptic drug (AED) polytherapy as compared to mono- therapy regimens contributes to the development of MCMs and to reduced cognitive outcomes. For monotherapy, intrauterine exposure to VPA probably reduces cognitive out- comes. Further, monotherapy exposure to phenytoin or phenobarbital possibly reduces cogni- tive outcomes. Neonates of WWE taking AEDs probably have an in...
Seminars in Neurology, 2002
Seizure, 2013
Patients with intracerebral hemorrhage (ICH) are often initiated on antiepileptic drugs without a... more Patients with intracerebral hemorrhage (ICH) are often initiated on antiepileptic drugs without a clear indication. We compared the percentage of patients with spontaneous ICH who had seizures at onset or during hospitalization, and examined empiric use of antiepileptic drugs (AEDs) in these patients in 2 cohorts 10 years apart. Using a clinical data registry at a tertiary care adult hospital, we retrospectively selected admissions for spontaneous ICH between 1/1/99-12/31/00 (Cohort A, n=30) and 1/1/09-12/31/10 (Cohort B, n=108). Clinical, neurophysiological and radiological data were collected in both cohorts. In Cohorts A and B respectively, AEDs were started in 53.3% and 50.0%, and continued on discharge in 50.0% and 20.4% of patients; 86.6% and 59.1% of patients discharged on AEDs did not have a clinical/electrographic seizure or epileptiform EEG findings. Seizures occurred in 6.6% and 13.0% in Cohorts A and B respectively. The presence of a seizure at presentation (p=0.01) and during hospitalization (p=0.02) were predictors for continuing AED on discharge. In both cohorts, a significant number of patients were discharged on AEDs without a clear indication, though there is a change in practice between the two cohorts.
New England Journal of Medicine, 2009
Neuron, 2001
Mechanisms underlying seizure generation are traditionally thought to act over seconds to minutes... more Mechanisms underlying seizure generation are traditionally thought to act over seconds to minutes before clinical seizure onset. We analyzed continuous 3- to 14-day intracranial EEG recordings from five patients with mesial temporal lobe epilepsy obtained during evaluation for epilepsy surgery. We found localized quantitative EEG changes identifying prolonged bursts of complex epileptiform discharges that became more prevalent 7 hr before seizures and highly localized subclinical seizure-like activity that became more frequent 2 hr prior to seizure onset. Accumulated energy increased in the 50 min before seizure onset, compared to baseline. These observations, from a small number of patients, suggest that epileptic seizures may begin as a cascade of electrophysiological events that evolve over hours and that quantitative measures of preseizure electrical activity could possibly be used to predict seizures far in advance of clinical onset.