ScienceDaily (May 19, 2010) — A newly published study reported that children with new/recent onset epilepsy have significantly slowed expansion of white matter volume compared to healthy children over a two year interval. The reduced white matter volume may affect brain connectivity and influence cognition.
Results of this study conducted by researchers from the University of Wisconsin School of Medicine and Public Health are now available online and will appear in the July issue of Epilepsia, a journal published by Wiley-Blackwell on behalf of the International League Against Epilepsy.
Epilepsy, a common nervous system disorder, frequently develops in early childhood and causes recurrent seizures. Seizures can range from mild staring spells to major convulsions. According to the Epilepsy Foundation there are 326,000 children under the age of 15 with epilepsy in the U.S. More than 45,000 new cases of epilepsy are diagnosed in children each year.
A research team, led by Bruce Hermann, Ph.D., investigated the neurodevelopmental changes in brain structure in children with new or recent-onset epilepsy. Thirty-four healthy children (control group) and 38 with new/recent onset epilepsy were enrolled in the study. The epilepsy group contained 21 children with localization-related epilepsy and 17 with idiopathic generalized epilepsy. Children in both groups had a mean age of 12.9 years and underwent magnetic resonance imaging (MRI) at baseline and 2 years later.
At the 2 year follow-up, seizure frequency was evaluated. During the prior year, 53% of children with epilepsy were seizure free; 34% reported only one seizure. In the remaining children with epilepsy, 5% reported monthly, 5% weekly, and 3% daily seizures.
"Our study determined that children with new or recent-onset epilepsy exhibited an altered brain development pattern characterized by delayed age-appropriate increase in white matter volume," said Dr. Hermann. The research team found that total cerebral white matter volume increased significantly in the healthy control group over the 2-year period. However, the epilepsy group did not show significant change in white matter volume in the total cerebrum and across all lobes -- the difference from normal controls being most pronounced in the frontal lobes.
Researchers suspect that the delayed white matter volume increase in children with epilepsy may affect cognitive development by reducing brain connectivity. With altered brain development, children with epilepsy may also experience impaired executive function -- mental tasks such as organizing, planning, and paying attention which are commonly reported in people with epilepsy.
"Research into the symmetry between patterns of cognitive change and age-appropriate brain development remains to be addressed in childhood epilepsy," concluded Dr. Hermann. "Further exploration of how subtle neurodevelopmental alterations in brain development affect cognition is needed. Longer term follow-up is also needed to determine whether this finding represents a temporary delay in brain development versus a fixed difference."
Sunday, July 17, 2011
Monday, October 4, 2010
US Neurologists Agree on Protocols for Treatment of Infantile Spasms
ScienceDaily (Sep. 3, 2010)
Researchers from across the U.S., as part of the Infantile Spasms Working Group (ISWG), established guidelines for the diagnosis and treatment of infantile spasms (IS). The goal of the ISWG is to improve patient outcomes by creating protocols that educate pediatricians on early diagnosis and treatment options. Full details of this study appear online in Epilepsia, a journal published by Wiley-Blackwell on behalf of the International League Against Epilepsy.
Infantile spasms -- known also as West syndrome and named after Dr. William James West who provided the first account of the disease in his 1841 medical article -- is a rare epileptic disorder that typically presents in infants between 3 and 7 months of age.
Symptoms of IS include spasms of the limbs and trunk (extending or stiffening of the arms, legs, neck or trunk) that occur in clusters, an electroencephalography (EEG) pattern of hypsarrhythmia, and psychomotor delay or arrest.
The IS incidence ranges from 2 to 3.5 per 10,000 live births, occurring in more boys than girls (60:40). Approximately 90% of all IS cases occur during the first year of life, but can affect children up to the age of 4. While some cases have unknown cause (cryptogenic IS), many experts cite tuberous sclerosis (benign growth of brain tumors) and lack of oxygen to the baby at birth as common causes of symptomatic IS.
As part of their investigation, the ISWG (led by John Pellock, M.D.) examined scores of related studies and reviewed current clinical practice. The goal was to establish criteria that target early diagnosis, timely treatment options, and support IS patients and their families. Dr. Pellock, commenting on the agreed protocols, said "We strongly recommend broad clinical evaluation, including: detailed clinical neurophysiology; continued use of vigabatrin (VGB) or adrenocorticotropic hormone (ACTH) as first-line treatment to suppress clinical spasms and abolish hypsarrhythmic EEG; a timely assessment of treatment efficacy (regardless of chosen medication), with prompt therapy modification to avoid serious adverse events and with a particular goal of establishing an 'all-or-none' response where effective IS treatment should produce cessation of spasms and resolution of hypsarrhythmia on EEG."
To establish an IS diagnosis, a clinical evaluation is needed whereby doctors begin with a complete history and physical examination of the patient. Spasms observed by parents or physicians may vary from a cluster of as few as 2 to more than 100, lasting from less than 1 minute to more than 10 minutes. A full EEG evaluation is conducted to uncover any hypsarrhythmic pattern characterizing IS. Next, the etiologic diagnosis is made, aided by MRI, to understand the cause of the disorder. Such a diagnosis will aid in establishing the appropriate treatment strategy. "Following the completion of the history, physical, and neurological examinations, as well as EEG and MRI analysis, roughly 70% of patients will have an established diagnosis without the need for extensive metabolic testing" noted the ISWG team. "This saves valuable time to initiation of treatment and reduces evaluation costs."
There was consensus in the ISWG that use of ACTH is effective as first-line therapy for IS. However, the team believed there was insufficient evidence to define precisely the optimum ACTH dose and duration of treatment for IS; in general, short duration was preferred (i.e., approximately 2 weeks followed by taper). The ISWG also agreed on the efficacy of VGB as a first-line treatment option, with a dose of 50 mg/kg/day up to 100-150 mg/kg/ day in patients requiring escalation. Since prior studies have established a risk of visual field loss with VGB treatment, the ISWG suggested that infants who respond to this therapy may continue for 6-9 months, with continued ophthalmic evaluation.
Raili Riikonen, M.D., from Children's Hospital at the University of Kuopio in Finland, said in her commentary, "The goals of the ISWG are certainly worthwhile, but it should be appreciated that treatment approaches differ in Europe from the protocols described in this U.S. perspective." In Europe there are differing opinions on first-line treatment options for IS. After two weeks of VGB therapy, seizure freedom was seen in 26% of patients (Granström et al., 1999), 23% of patients (Elterman et al., 2000), and 54% of patients (Lux et al., 2004). In the first two of these studies, the number of IS patients who were seizure-free increased to roughly 65% after 3 months. "These data suggested the response with VGB comes later than with ACTH," Dr. Riikonen stated.
In Japan, treatment strategies for IS also differ from the recommended U.S. protocols. "The dosage of ACTH administered in Japan is strikingly different than prescribed amounts in the U.S.," commented Yukio Fukuyama, M.D., Ph.D., from the Child Neurology Institute in Tokyo, Japan in his commentary on the study by Pellock et al. A 6-month old infant with 8 kg body weight and 0.4 m2 body surface, would be administered a daily dose of ACTH of 60 IU/day (0.6 mg/day) in the U.S. versus 5 IU/day (0.05 mg/day) in Japan. The dosage difference between the U.S. and Japan is likely due to the different preparation forms (simple natural vs. prolonged synthetic). "Despite this large difference in dosage, the rate of seizure disappearance and EEG amelioration appears to be similar. Since the introduction of this low dosage scheme in Japan, it has been rare to observe serious side effects of ACTH (e.g., obesity, hypertension, hypertrichosis, electrolyte imbalance, manifest immunodepression, cardiac dilation, brain shrinkage on CT/MRI) in our daily practice," noted Dr. Fukuyama. VGB is currently not commercially available in Japan.
Oliver Dulac, M.D. and colleagues stated in their commentary, "Pellock et al. provide an excellent overview of IS in the form of a consensus report by a reliable panel of experts." This European team emphasized that IS is not a disease per se, but a common denominator of several conditions, mainly determined by etiology. Patients with different IS etiologies experience different disease courses, requiring different and specific treatment strategies and durations. Both Pellock et al. and Dulac et al. agree that length of IS therapy is one of the most challenging current questions in effectively and safely treating IS patients. VGB treatment, in particular, needs a balanced approach to curb retinal toxicity. "Patients with no cortical lesion (e.g. Down syndrome, leukodystrophy, or cryptogenic cases) usually require no chronic treatment following the control of spasms -- ACTH treatment may be stopped after only one month, and VGB after 6 months," said Dr. Dulac.
While IS is a rare condition, the outcomes for patients with the disorder include higher mortality, ongoing development of additional seizure disorders as the patient matures, and often severe cognitive and developmental delay. A 2003 study by Hrachovy and Frost reviewed 67 published studies, with an average follow-up period of 31 months, and found only 16% of patients with IS had normal development. Additional studies indicated that severe learning difficulties may be present in 70% to 90% of IS patients. An IS study in an Atlanta birth cohort (1975-1977) found that 15% of patients died by age 11 and 35% died by age 25 (Trevathan et al., 1999).
"The establishment of an IS patient registry, and the development of a continuum of care for patients with this disorder are critical for improving outcomes," added Dr. Pellock. The ISWG suggested the need for a comprehensive approach for optimal management of children with IS, including access to and evaluation by a variety of professionals, including child neurologists, pediatricians, psychiatrists, rehabilitation services (physical, occupational and speech therapy), nurses, vocational rehabilitation counselors, neuropsychologists, social workers, and pharmacists. "Further studies are needed to determine ideal treatment strategies for IS; carefully controlled comparative studies or patient registries will allow a standard format for gathering important clinical data (e.g. IS recurrence rates, administered therapy details, developmental outcomes) from a large patient sample," concluded Dr. Pellock.
Researchers from across the U.S., as part of the Infantile Spasms Working Group (ISWG), established guidelines for the diagnosis and treatment of infantile spasms (IS). The goal of the ISWG is to improve patient outcomes by creating protocols that educate pediatricians on early diagnosis and treatment options. Full details of this study appear online in Epilepsia, a journal published by Wiley-Blackwell on behalf of the International League Against Epilepsy.
Infantile spasms -- known also as West syndrome and named after Dr. William James West who provided the first account of the disease in his 1841 medical article -- is a rare epileptic disorder that typically presents in infants between 3 and 7 months of age.
Symptoms of IS include spasms of the limbs and trunk (extending or stiffening of the arms, legs, neck or trunk) that occur in clusters, an electroencephalography (EEG) pattern of hypsarrhythmia, and psychomotor delay or arrest.
The IS incidence ranges from 2 to 3.5 per 10,000 live births, occurring in more boys than girls (60:40). Approximately 90% of all IS cases occur during the first year of life, but can affect children up to the age of 4. While some cases have unknown cause (cryptogenic IS), many experts cite tuberous sclerosis (benign growth of brain tumors) and lack of oxygen to the baby at birth as common causes of symptomatic IS.
As part of their investigation, the ISWG (led by John Pellock, M.D.) examined scores of related studies and reviewed current clinical practice. The goal was to establish criteria that target early diagnosis, timely treatment options, and support IS patients and their families. Dr. Pellock, commenting on the agreed protocols, said "We strongly recommend broad clinical evaluation, including: detailed clinical neurophysiology; continued use of vigabatrin (VGB) or adrenocorticotropic hormone (ACTH) as first-line treatment to suppress clinical spasms and abolish hypsarrhythmic EEG; a timely assessment of treatment efficacy (regardless of chosen medication), with prompt therapy modification to avoid serious adverse events and with a particular goal of establishing an 'all-or-none' response where effective IS treatment should produce cessation of spasms and resolution of hypsarrhythmia on EEG."
To establish an IS diagnosis, a clinical evaluation is needed whereby doctors begin with a complete history and physical examination of the patient. Spasms observed by parents or physicians may vary from a cluster of as few as 2 to more than 100, lasting from less than 1 minute to more than 10 minutes. A full EEG evaluation is conducted to uncover any hypsarrhythmic pattern characterizing IS. Next, the etiologic diagnosis is made, aided by MRI, to understand the cause of the disorder. Such a diagnosis will aid in establishing the appropriate treatment strategy. "Following the completion of the history, physical, and neurological examinations, as well as EEG and MRI analysis, roughly 70% of patients will have an established diagnosis without the need for extensive metabolic testing" noted the ISWG team. "This saves valuable time to initiation of treatment and reduces evaluation costs."
There was consensus in the ISWG that use of ACTH is effective as first-line therapy for IS. However, the team believed there was insufficient evidence to define precisely the optimum ACTH dose and duration of treatment for IS; in general, short duration was preferred (i.e., approximately 2 weeks followed by taper). The ISWG also agreed on the efficacy of VGB as a first-line treatment option, with a dose of 50 mg/kg/day up to 100-150 mg/kg/ day in patients requiring escalation. Since prior studies have established a risk of visual field loss with VGB treatment, the ISWG suggested that infants who respond to this therapy may continue for 6-9 months, with continued ophthalmic evaluation.
Raili Riikonen, M.D., from Children's Hospital at the University of Kuopio in Finland, said in her commentary, "The goals of the ISWG are certainly worthwhile, but it should be appreciated that treatment approaches differ in Europe from the protocols described in this U.S. perspective." In Europe there are differing opinions on first-line treatment options for IS. After two weeks of VGB therapy, seizure freedom was seen in 26% of patients (Granström et al., 1999), 23% of patients (Elterman et al., 2000), and 54% of patients (Lux et al., 2004). In the first two of these studies, the number of IS patients who were seizure-free increased to roughly 65% after 3 months. "These data suggested the response with VGB comes later than with ACTH," Dr. Riikonen stated.
In Japan, treatment strategies for IS also differ from the recommended U.S. protocols. "The dosage of ACTH administered in Japan is strikingly different than prescribed amounts in the U.S.," commented Yukio Fukuyama, M.D., Ph.D., from the Child Neurology Institute in Tokyo, Japan in his commentary on the study by Pellock et al. A 6-month old infant with 8 kg body weight and 0.4 m2 body surface, would be administered a daily dose of ACTH of 60 IU/day (0.6 mg/day) in the U.S. versus 5 IU/day (0.05 mg/day) in Japan. The dosage difference between the U.S. and Japan is likely due to the different preparation forms (simple natural vs. prolonged synthetic). "Despite this large difference in dosage, the rate of seizure disappearance and EEG amelioration appears to be similar. Since the introduction of this low dosage scheme in Japan, it has been rare to observe serious side effects of ACTH (e.g., obesity, hypertension, hypertrichosis, electrolyte imbalance, manifest immunodepression, cardiac dilation, brain shrinkage on CT/MRI) in our daily practice," noted Dr. Fukuyama. VGB is currently not commercially available in Japan.
Oliver Dulac, M.D. and colleagues stated in their commentary, "Pellock et al. provide an excellent overview of IS in the form of a consensus report by a reliable panel of experts." This European team emphasized that IS is not a disease per se, but a common denominator of several conditions, mainly determined by etiology. Patients with different IS etiologies experience different disease courses, requiring different and specific treatment strategies and durations. Both Pellock et al. and Dulac et al. agree that length of IS therapy is one of the most challenging current questions in effectively and safely treating IS patients. VGB treatment, in particular, needs a balanced approach to curb retinal toxicity. "Patients with no cortical lesion (e.g. Down syndrome, leukodystrophy, or cryptogenic cases) usually require no chronic treatment following the control of spasms -- ACTH treatment may be stopped after only one month, and VGB after 6 months," said Dr. Dulac.
While IS is a rare condition, the outcomes for patients with the disorder include higher mortality, ongoing development of additional seizure disorders as the patient matures, and often severe cognitive and developmental delay. A 2003 study by Hrachovy and Frost reviewed 67 published studies, with an average follow-up period of 31 months, and found only 16% of patients with IS had normal development. Additional studies indicated that severe learning difficulties may be present in 70% to 90% of IS patients. An IS study in an Atlanta birth cohort (1975-1977) found that 15% of patients died by age 11 and 35% died by age 25 (Trevathan et al., 1999).
"The establishment of an IS patient registry, and the development of a continuum of care for patients with this disorder are critical for improving outcomes," added Dr. Pellock. The ISWG suggested the need for a comprehensive approach for optimal management of children with IS, including access to and evaluation by a variety of professionals, including child neurologists, pediatricians, psychiatrists, rehabilitation services (physical, occupational and speech therapy), nurses, vocational rehabilitation counselors, neuropsychologists, social workers, and pharmacists. "Further studies are needed to determine ideal treatment strategies for IS; carefully controlled comparative studies or patient registries will allow a standard format for gathering important clinical data (e.g. IS recurrence rates, administered therapy details, developmental outcomes) from a large patient sample," concluded Dr. Pellock.
Tuesday, June 22, 2010
Epilepsy: Exposure To Valproate During Pregnancy Can Impair A Child's Cognitive Development
Three-year-olds whose mothers took the antiepileptic drug valproate during pregnancy had average IQs six to nine points lower than children exposed to three other antiepileptic drugs, a landmark multi-center study has found.
The study's authors say that women of childbearing age should avoid valproate as a first choice drug for the treatment of epilepsy.
The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study is following more than 300 children born to women with epilepsy between 1999 and 2004. Investigators at 25 epilepsy centers in the United States and the United Kingdom are participating. At enrollment, the women were taking a single antiepileptic agent: carbamazepine, lamotrigine, phenytoin or valproate.
The NEAD study previously found that valproate exposure also increases the risk of anatomical birth defects, even though it was not designed to look for them.
"There are clear risks associated with valproate, and physicians have an obligation to inform women about them," says lead study author Kimford Meador, MD, professor of neurology at the Emory University School of Medicine. "Valproate still has an important role in treating epilepsy, because some patients' seizures can only be controlled with valproate. However, we are recommending that women with epilepsy try another drug first."
Around 15 percent of patients with primary generalized epilepsy respond only to valproate, but this selectivity does not apply to other forms of epilepsy, Meador says.
Meador stresses that women who are pregnant and take valproate should not stop without consulting a physician, to avoid seizures with potentially serious consequences.
Valproate's effects on child IQ appear to be dose-dependent, so it may be possible to reduce risk by taking it in lower doses more frequently or in a sustained release formulation, Meador says.
A child's IQ is usually strongly influenced by the mother's IQ. Out of the four antiepileptic drugs studied, only valproate disrupted this relationship.
Preliminary results describing the children's IQs at 2 years of age were reported at the end of 2006. The studies' findings were strengthened by researchers' ability to include more children and measure their progress after three years. The researchers plan to follow the children until age 6.
Valproate is also prescribed for bipolar disorder and migraine headaches. It is sold under the brand name Depakote. Last year the FDA approved a generic version.
The NEAD study was funded by the National Institute of Neurological Disorders and Stroke and the United Kingdom Epilepsy Research Foundation.
The study's authors say that women of childbearing age should avoid valproate as a first choice drug for the treatment of epilepsy.
The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study is following more than 300 children born to women with epilepsy between 1999 and 2004. Investigators at 25 epilepsy centers in the United States and the United Kingdom are participating. At enrollment, the women were taking a single antiepileptic agent: carbamazepine, lamotrigine, phenytoin or valproate.
The NEAD study previously found that valproate exposure also increases the risk of anatomical birth defects, even though it was not designed to look for them.
"There are clear risks associated with valproate, and physicians have an obligation to inform women about them," says lead study author Kimford Meador, MD, professor of neurology at the Emory University School of Medicine. "Valproate still has an important role in treating epilepsy, because some patients' seizures can only be controlled with valproate. However, we are recommending that women with epilepsy try another drug first."
Around 15 percent of patients with primary generalized epilepsy respond only to valproate, but this selectivity does not apply to other forms of epilepsy, Meador says.
Meador stresses that women who are pregnant and take valproate should not stop without consulting a physician, to avoid seizures with potentially serious consequences.
Valproate's effects on child IQ appear to be dose-dependent, so it may be possible to reduce risk by taking it in lower doses more frequently or in a sustained release formulation, Meador says.
A child's IQ is usually strongly influenced by the mother's IQ. Out of the four antiepileptic drugs studied, only valproate disrupted this relationship.
Preliminary results describing the children's IQs at 2 years of age were reported at the end of 2006. The studies' findings were strengthened by researchers' ability to include more children and measure their progress after three years. The researchers plan to follow the children until age 6.
Valproate is also prescribed for bipolar disorder and migraine headaches. It is sold under the brand name Depakote. Last year the FDA approved a generic version.
The NEAD study was funded by the National Institute of Neurological Disorders and Stroke and the United Kingdom Epilepsy Research Foundation.
Saturday, January 23, 2010
UV LED Therapy Shows Promising Results In Preventing Focal Seizures
Researchers from the University of Minnesota Medical School discovered that light from an ultraviolet diode (UV LED) reduced "seizure-like" activity in a rat epilepsy model. During the study, UV light released gamma aminobutyric acid (GABA) from the "caged" compound carbonyl amino butanoic acid (BC204). GABA then decreased the abnormal electrical activity in the CA1 area of the brain. Results of this study have considerable potential in treating focal epilepsy in humans. Details of this study are available in the January 2010 issue of Epilepsia, a journal published by Wiley-Blackwell on behalf of the International League Against Epilepsy.
Focal (or partial) epilepsy is very common in both adults and can occur in children. It is caused by an abnormality in a localized area of the brain resulting from such conditions as stroke, trauma, or infections. Up to one-third of epileptic patients fail to respond to conventional medical therapies and are subject to toxic effects from antiepileptic drugs (AEDs). While surgery has benefited some patients with focal epilepsy, a substantial number of patients do not experience a complete remission after operation, prompting researchers to investigate alternative treatments.
Steven Rothman, M.D., and colleagues conducted experiments with UV LEDs to control seizure-like activity in rodent brain slices. Population spikes in CA1 (which reflect the discharge of a population of neurons) were elicited by delivering constant current pulses through a microelectrode placed in the CA3 brain area. Researchers induced seizure-like activity by adding the convulsant, 4-aminopyridine (4-AP; 100 µM) and removing magnesium from the fluid solution outside the cells. Caged GABA, BC204, was perfused into the preparation for at least 30 minutes prior to the first illumination.
When population spikes were measured (as a reflection of tissue excitability), the research team found that illumination of control slices with up to 200 mA LED current had no effect on peak amplitudes. Addition of BC204 (30 µM) and illumination using as little as 50 mA LED current produced a statistically significant reduction of the peak of the population spike. More important, BC204 (10 µM) significantly reduced the slice spikes and bursting induced by the 4-AP and low magnesium.
"Our strongly positive results, in an epilepsy model far more severe than the naturally occurring disease, suggest that this technique could translate to human epilepsy," said Dr. Rothman. Researchers believe that a programmable pump could deliver the caged GABA into the subarachnoid space over the epileptic area of the brain. UV LEDs could then be responsively activated to release GABA, using techniques similar to those used for cortical stimulation units that are currently in clinical trials.
The researchers are optimistic that an LED-based implantable device is feasible. "Optical stimulation would be a far more rapid delivery method than any mechanical device for direct administration of drug into the brain and would not subject patients to toxic doses of medication or irreversible brain damage from epilepsy resections," concluded Dr. Rothman.
Focal (or partial) epilepsy is very common in both adults and can occur in children. It is caused by an abnormality in a localized area of the brain resulting from such conditions as stroke, trauma, or infections. Up to one-third of epileptic patients fail to respond to conventional medical therapies and are subject to toxic effects from antiepileptic drugs (AEDs). While surgery has benefited some patients with focal epilepsy, a substantial number of patients do not experience a complete remission after operation, prompting researchers to investigate alternative treatments.
Steven Rothman, M.D., and colleagues conducted experiments with UV LEDs to control seizure-like activity in rodent brain slices. Population spikes in CA1 (which reflect the discharge of a population of neurons) were elicited by delivering constant current pulses through a microelectrode placed in the CA3 brain area. Researchers induced seizure-like activity by adding the convulsant, 4-aminopyridine (4-AP; 100 µM) and removing magnesium from the fluid solution outside the cells. Caged GABA, BC204, was perfused into the preparation for at least 30 minutes prior to the first illumination.
When population spikes were measured (as a reflection of tissue excitability), the research team found that illumination of control slices with up to 200 mA LED current had no effect on peak amplitudes. Addition of BC204 (30 µM) and illumination using as little as 50 mA LED current produced a statistically significant reduction of the peak of the population spike. More important, BC204 (10 µM) significantly reduced the slice spikes and bursting induced by the 4-AP and low magnesium.
"Our strongly positive results, in an epilepsy model far more severe than the naturally occurring disease, suggest that this technique could translate to human epilepsy," said Dr. Rothman. Researchers believe that a programmable pump could deliver the caged GABA into the subarachnoid space over the epileptic area of the brain. UV LEDs could then be responsively activated to release GABA, using techniques similar to those used for cortical stimulation units that are currently in clinical trials.
The researchers are optimistic that an LED-based implantable device is feasible. "Optical stimulation would be a far more rapid delivery method than any mechanical device for direct administration of drug into the brain and would not subject patients to toxic doses of medication or irreversible brain damage from epilepsy resections," concluded Dr. Rothman.
UV LED Therapy Shows Promising Results In Preventing Focal Seizures
Researchers from the University of Minnesota Medical School discovered that light from an ultraviolet diode (UV LED) reduced "seizure-like" activity in a rat epilepsy model. During the study, UV light released gamma aminobutyric acid (GABA) from the "caged" compound carbonyl amino butanoic acid (BC204). GABA then decreased the abnormal electrical activity in the CA1 area of the brain. Results of this study have considerable potential in treating focal epilepsy in humans. Details of this study are available in the January 2010 issue of Epilepsia, a journal published by Wiley-Blackwell on behalf of the International League Against Epilepsy.
Focal (or partial) epilepsy is very common in both adults and can occur in children. It is caused by an abnormality in a localized area of the brain resulting from such conditions as stroke, trauma, or infections. Up to one-third of epileptic patients fail to respond to conventional medical therapies and are subject to toxic effects from antiepileptic drugs (AEDs). While surgery has benefited some patients with focal epilepsy, a substantial number of patients do not experience a complete remission after operation, prompting researchers to investigate alternative treatments.
Steven Rothman, M.D., and colleagues conducted experiments with UV LEDs to control seizure-like activity in rodent brain slices. Population spikes in CA1 (which reflect the discharge of a population of neurons) were elicited by delivering constant current pulses through a microelectrode placed in the CA3 brain area. Researchers induced seizure-like activity by adding the convulsant, 4-aminopyridine (4-AP; 100 µM) and removing magnesium from the fluid solution outside the cells. Caged GABA, BC204, was perfused into the preparation for at least 30 minutes prior to the first illumination.
When population spikes were measured (as a reflection of tissue excitability), the research team found that illumination of control slices with up to 200 mA LED current had no effect on peak amplitudes. Addition of BC204 (30 µM) and illumination using as little as 50 mA LED current produced a statistically significant reduction of the peak of the population spike. More important, BC204 (10 µM) significantly reduced the slice spikes and bursting induced by the 4-AP and low magnesium.
"Our strongly positive results, in an epilepsy model far more severe than the naturally occurring disease, suggest that this technique could translate to human epilepsy," said Dr. Rothman. Researchers believe that a programmable pump could deliver the caged GABA into the subarachnoid space over the epileptic area of the brain. UV LEDs could then be responsively activated to release GABA, using techniques similar to those used for cortical stimulation units that are currently in clinical trials.
The researchers are optimistic that an LED-based implantable device is feasible. "Optical stimulation would be a far more rapid delivery method than any mechanical device for direct administration of drug into the brain and would not subject patients to toxic doses of medication or irreversible brain damage from epilepsy resections," concluded Dr. Rothman.
Focal (or partial) epilepsy is very common in both adults and can occur in children. It is caused by an abnormality in a localized area of the brain resulting from such conditions as stroke, trauma, or infections. Up to one-third of epileptic patients fail to respond to conventional medical therapies and are subject to toxic effects from antiepileptic drugs (AEDs). While surgery has benefited some patients with focal epilepsy, a substantial number of patients do not experience a complete remission after operation, prompting researchers to investigate alternative treatments.
Steven Rothman, M.D., and colleagues conducted experiments with UV LEDs to control seizure-like activity in rodent brain slices. Population spikes in CA1 (which reflect the discharge of a population of neurons) were elicited by delivering constant current pulses through a microelectrode placed in the CA3 brain area. Researchers induced seizure-like activity by adding the convulsant, 4-aminopyridine (4-AP; 100 µM) and removing magnesium from the fluid solution outside the cells. Caged GABA, BC204, was perfused into the preparation for at least 30 minutes prior to the first illumination.
When population spikes were measured (as a reflection of tissue excitability), the research team found that illumination of control slices with up to 200 mA LED current had no effect on peak amplitudes. Addition of BC204 (30 µM) and illumination using as little as 50 mA LED current produced a statistically significant reduction of the peak of the population spike. More important, BC204 (10 µM) significantly reduced the slice spikes and bursting induced by the 4-AP and low magnesium.
"Our strongly positive results, in an epilepsy model far more severe than the naturally occurring disease, suggest that this technique could translate to human epilepsy," said Dr. Rothman. Researchers believe that a programmable pump could deliver the caged GABA into the subarachnoid space over the epileptic area of the brain. UV LEDs could then be responsively activated to release GABA, using techniques similar to those used for cortical stimulation units that are currently in clinical trials.
The researchers are optimistic that an LED-based implantable device is feasible. "Optical stimulation would be a far more rapid delivery method than any mechanical device for direct administration of drug into the brain and would not subject patients to toxic doses of medication or irreversible brain damage from epilepsy resections," concluded Dr. Rothman.
Friday, November 27, 2009
'Pacemaker for the brain' being studied
Brenda Talavera was pretty matter-of-fact when her doctor suggested that they implant a stimulator the size of a small cell phone inside her brain.
"If it was going to make me better, do it," the Seattle woman said while standing in her living room filled with hockey memorabilia. "If it didn't work, they could remove it."
Talavera, 39, had suffered from debilitating seizures since she was 13. They were so violent that she never remembered having them. Her only proof to herself was the same bite mark on the same part of her tongue after each one. She estimates that she suffered more than 10 a month. Medication alone didn't help.
As she reached adulthood, her only solace was knowing the grocery store where she worked was near a fire station. The firefighters who were called every time she had a seizure knew her well.
In 2006, she became the second patient enrolled in the pivotal trial (or final phase) at Swedish Medical Center that would implant a Responsive Neurostimulator System underneath her scalp. The trial, which is being conducted at 28 U.S. sites, will determine whether the Food and Drug Administration approves the treatment.
It works like a pacemaker for the brain, and is designed to detect abnormal electrical activity and deliver small amounts of electrical stimulation to prevent seizures, said Dr. Ryder Gwinn, director of epilepsy and functional neurosurgery at the Swedish Neuroscience Institute. Swedish enrolled 11 patients in Seattle and at Oregon Health Sciences University, where it is jointly conducting the trial.
The RNS is connected to one or two wires containing electrodes that are placed within the brain or rest on the brain surface where doctors determine the seizures start. It's different for each patient, and physicians use MRI scans to figure out where to place the electrodes. Gwinn said there is a period of adjustment as the device regulates to each patient's seizure activities.
The device stores about four seizures' worth of information, which is downloaded to a laptop computer using a hand-held wand Talavera hovers over her head every night. Then she hits a button and all of her seizure information for the day is sent directly to Gwinn.
"She can have a seizure and I can see it on my computer an hour later," he said.
The gold standard for treating epileptic seizures that can't be controlled by medication alone is to find the source of the seizure and remove that part of the brain, Gwinn said. But physicians want to be able to treat seizures without removing tissue and believe the implant is less dangerous.
From previous studies, "there were very few side effects and any effects (such as flashes of light or extra stimulations) can be adjusted to each patient. With permanent tissue removal, once it's done, it's done," Gwinn said.
Gwinn doesn't have specific numbers yet to prove how well the implants are working, but anecdotally, he sees that many of his patients' seizures have diminished.
Dr. John Miller, director of the University of Washington Regional Epilepsy Center at Harborview, calls the approach "very interesting research," but said the university declined to participate in the trial several years ago, partly because there was little experimental work done on animals before going directly to human trials. He also said there hasn't yet been enough evidence of significantly decreasing seizures to justify the risk of the surgical implant.
"It's not yet clear that the device makes people seizure-free and taking patients from 10 seizures to five doesn't really change their life that much," Miller said. "We're not at that point, but that may change -- the device is still under development and improving, but I'm reluctant to consider it for my patients at this time."
Gwinn expects the FDA to approve the epilepsy implant. A similar brain implant to help control tremors in Parkinson's disease patients was approved in 2002. While he doesn't know how much the device will eventually cost patients if approved, he said it would likely be cost-effective compared with how much patients pay now for weekly or monthly hospital visits and expensive medications.
"This is really just a first-generation device to treat epilepsy," Gwinn said. "It will take another five years to be perfected, but just the effectiveness I've see so far warrants its introduction."
Talavera keeps a diary of how many seizures she has and how severe they are. At 73 weeks into the trial, she said she is down to fewer than six a month, and they are much smaller and less severe.
When asked about how she feels about the good results so far with the implant, she's still matter-of-fact about the process, simply saying, "That's something good, less seizures."
EPILEPSY
What is a seizure? A seizure happens when a brief, strong surge of electrical activity affects part or all of the brain. It can last from a few seconds to a few minutes and have many symptoms, including convulsions and loss of consciousness.
How common are they? One in 10 adults will have a seizure. More than 3 million people in the U.S. have some form of epilepsy. About 200,000 new cases of seizure disorders and epilepsy are diagnosed each year.
What causes them? Seizures are symptoms of abnormal brain function, but the causes are usually unknown. Head trauma or genetic factors can be causes.
Source: Epilepsy Foundation
"If it was going to make me better, do it," the Seattle woman said while standing in her living room filled with hockey memorabilia. "If it didn't work, they could remove it."
Talavera, 39, had suffered from debilitating seizures since she was 13. They were so violent that she never remembered having them. Her only proof to herself was the same bite mark on the same part of her tongue after each one. She estimates that she suffered more than 10 a month. Medication alone didn't help.
As she reached adulthood, her only solace was knowing the grocery store where she worked was near a fire station. The firefighters who were called every time she had a seizure knew her well.
In 2006, she became the second patient enrolled in the pivotal trial (or final phase) at Swedish Medical Center that would implant a Responsive Neurostimulator System underneath her scalp. The trial, which is being conducted at 28 U.S. sites, will determine whether the Food and Drug Administration approves the treatment.
It works like a pacemaker for the brain, and is designed to detect abnormal electrical activity and deliver small amounts of electrical stimulation to prevent seizures, said Dr. Ryder Gwinn, director of epilepsy and functional neurosurgery at the Swedish Neuroscience Institute. Swedish enrolled 11 patients in Seattle and at Oregon Health Sciences University, where it is jointly conducting the trial.
The RNS is connected to one or two wires containing electrodes that are placed within the brain or rest on the brain surface where doctors determine the seizures start. It's different for each patient, and physicians use MRI scans to figure out where to place the electrodes. Gwinn said there is a period of adjustment as the device regulates to each patient's seizure activities.
The device stores about four seizures' worth of information, which is downloaded to a laptop computer using a hand-held wand Talavera hovers over her head every night. Then she hits a button and all of her seizure information for the day is sent directly to Gwinn.
"She can have a seizure and I can see it on my computer an hour later," he said.
The gold standard for treating epileptic seizures that can't be controlled by medication alone is to find the source of the seizure and remove that part of the brain, Gwinn said. But physicians want to be able to treat seizures without removing tissue and believe the implant is less dangerous.
From previous studies, "there were very few side effects and any effects (such as flashes of light or extra stimulations) can be adjusted to each patient. With permanent tissue removal, once it's done, it's done," Gwinn said.
Gwinn doesn't have specific numbers yet to prove how well the implants are working, but anecdotally, he sees that many of his patients' seizures have diminished.
Dr. John Miller, director of the University of Washington Regional Epilepsy Center at Harborview, calls the approach "very interesting research," but said the university declined to participate in the trial several years ago, partly because there was little experimental work done on animals before going directly to human trials. He also said there hasn't yet been enough evidence of significantly decreasing seizures to justify the risk of the surgical implant.
"It's not yet clear that the device makes people seizure-free and taking patients from 10 seizures to five doesn't really change their life that much," Miller said. "We're not at that point, but that may change -- the device is still under development and improving, but I'm reluctant to consider it for my patients at this time."
Gwinn expects the FDA to approve the epilepsy implant. A similar brain implant to help control tremors in Parkinson's disease patients was approved in 2002. While he doesn't know how much the device will eventually cost patients if approved, he said it would likely be cost-effective compared with how much patients pay now for weekly or monthly hospital visits and expensive medications.
"This is really just a first-generation device to treat epilepsy," Gwinn said. "It will take another five years to be perfected, but just the effectiveness I've see so far warrants its introduction."
Talavera keeps a diary of how many seizures she has and how severe they are. At 73 weeks into the trial, she said she is down to fewer than six a month, and they are much smaller and less severe.
When asked about how she feels about the good results so far with the implant, she's still matter-of-fact about the process, simply saying, "That's something good, less seizures."
EPILEPSY
What is a seizure? A seizure happens when a brief, strong surge of electrical activity affects part or all of the brain. It can last from a few seconds to a few minutes and have many symptoms, including convulsions and loss of consciousness.
How common are they? One in 10 adults will have a seizure. More than 3 million people in the U.S. have some form of epilepsy. About 200,000 new cases of seizure disorders and epilepsy are diagnosed each year.
What causes them? Seizures are symptoms of abnormal brain function, but the causes are usually unknown. Head trauma or genetic factors can be causes.
Source: Epilepsy Foundation
Thursday, November 12, 2009
Cause of severe pediatric epilepsy disorder discovered
Researchers at the University of California, San Diego School of Medicine have discovered that convulsive seizures in a form of severe epilepsy are generated, not on the brain's surface as expected, but from within the memory-forming hippocampus.
The scientists hope that their findings - based on a mouse model of severe epilepsy - may someday pave the way for improved treatments of childhood epilepsy, which affects more than two percent of children worldwide. Their study will be published online by the Proceedings of the National Academy of Science ( PNAS ) the week of March 16.
"A parent of an epileptic child will tell you that they think their child is going to die during their attacks," said senior author Joseph Gleeson, MD, director of the Neurogenetics Laboratory at the UC San Diego School of Medicine, professor in the department of neurosciences and Howard Hughes Medical Institute Investigator. "Parents of children with epilepsy, especially the most severe types of epilepsy, are desperate for a deeper understanding of the causes of the problems and for the development of new treatments."
One of the major causes of epilepsy in children is an alteration in the development of the cerebral cortex. The cerebral cortex is the main folded part of the brain, containing a large percentage of brain cells, and is integral to purposeful actions and thoughts. However, this complex structure is subject to all kinds of defects in development, many of them due to defective genes and many associated with epilepsy.
Cortical dysplasia, meaning disordered development of the cerebral cortex, is identified in 25 to 40 percent of children with the most severe and difficult-to-treat forms of epilepsy. These children often come to the attention of specialists due to stagnation in the acquisition of language and balance skills and accompanying epilepsy. The symptoms displayed by these children can range from very subtle - such as small muscle jerks or eyelid fluttering - to dramatic whole body, tonic-clonic spasms (a series of contractions and relaxations of the muscle) that can affect basic bodily function.
The Gleeson team, led by researchers Geraldine Kerjan, PhD and Hiroyuki Koizumi, PhD, has been studying a disorder called "lissencephaly." (In Greek, leios means smooth, and kephale means brain or head.) Children with lissencephaly have a smooth brain surface that lacks the normal hills and valleys that are characteristic of the human brain. The researchers were recently successful in developing a mouse model that showed some of the features of this disorder, usually the first step toward understanding the cause of a genetic disorder. But the severe epilepsy that is associated with lissencephaly was never displayed in any of the previous animals, so the team kept removing gene after gene until they hit upon a strain that showed epilepsy.
"We study the gene "doublecortin," which is defective in some forms of epilepsy and mental retardation in humans," said Kerjan, lead author of the study. "However, only after we removed a combination of two of the genes in the doublecortin family did we uncover epilepsy."
According to Gleeson, the findings were dramatic, as almost none of the mice in this strain survived to adulthood. Thinking that the deaths might be due to epilepsy, the scientists recorded electroencephalograms, which measure electrical activity produced by the firing of neurons in the brain, and found severe epilepsy in all of the mice tested. Even more surprising was the site of the epileptic focus - or site from which the seizures were generated - which was located beneath the surface of the brain, in the hippocampus.
"Researchers had thought that the cause of the seizures in this disease must be the brain surface, since this is the part that looks the most abnormal on brain MRI scans," said Gleeson. "However, we found that the epilepsy focus was actually deeper in the brain, within the hippocampus, the main memory-forming site."
The research team intends to continue studying in studying the mice, to explore potential mechanisms and utilize this model to test new treatments.
The scientists hope that their findings - based on a mouse model of severe epilepsy - may someday pave the way for improved treatments of childhood epilepsy, which affects more than two percent of children worldwide. Their study will be published online by the Proceedings of the National Academy of Science ( PNAS ) the week of March 16.
"A parent of an epileptic child will tell you that they think their child is going to die during their attacks," said senior author Joseph Gleeson, MD, director of the Neurogenetics Laboratory at the UC San Diego School of Medicine, professor in the department of neurosciences and Howard Hughes Medical Institute Investigator. "Parents of children with epilepsy, especially the most severe types of epilepsy, are desperate for a deeper understanding of the causes of the problems and for the development of new treatments."
One of the major causes of epilepsy in children is an alteration in the development of the cerebral cortex. The cerebral cortex is the main folded part of the brain, containing a large percentage of brain cells, and is integral to purposeful actions and thoughts. However, this complex structure is subject to all kinds of defects in development, many of them due to defective genes and many associated with epilepsy.
Cortical dysplasia, meaning disordered development of the cerebral cortex, is identified in 25 to 40 percent of children with the most severe and difficult-to-treat forms of epilepsy. These children often come to the attention of specialists due to stagnation in the acquisition of language and balance skills and accompanying epilepsy. The symptoms displayed by these children can range from very subtle - such as small muscle jerks or eyelid fluttering - to dramatic whole body, tonic-clonic spasms (a series of contractions and relaxations of the muscle) that can affect basic bodily function.
The Gleeson team, led by researchers Geraldine Kerjan, PhD and Hiroyuki Koizumi, PhD, has been studying a disorder called "lissencephaly." (In Greek, leios means smooth, and kephale means brain or head.) Children with lissencephaly have a smooth brain surface that lacks the normal hills and valleys that are characteristic of the human brain. The researchers were recently successful in developing a mouse model that showed some of the features of this disorder, usually the first step toward understanding the cause of a genetic disorder. But the severe epilepsy that is associated with lissencephaly was never displayed in any of the previous animals, so the team kept removing gene after gene until they hit upon a strain that showed epilepsy.
"We study the gene "doublecortin," which is defective in some forms of epilepsy and mental retardation in humans," said Kerjan, lead author of the study. "However, only after we removed a combination of two of the genes in the doublecortin family did we uncover epilepsy."
According to Gleeson, the findings were dramatic, as almost none of the mice in this strain survived to adulthood. Thinking that the deaths might be due to epilepsy, the scientists recorded electroencephalograms, which measure electrical activity produced by the firing of neurons in the brain, and found severe epilepsy in all of the mice tested. Even more surprising was the site of the epileptic focus - or site from which the seizures were generated - which was located beneath the surface of the brain, in the hippocampus.
"Researchers had thought that the cause of the seizures in this disease must be the brain surface, since this is the part that looks the most abnormal on brain MRI scans," said Gleeson. "However, we found that the epilepsy focus was actually deeper in the brain, within the hippocampus, the main memory-forming site."
The research team intends to continue studying in studying the mice, to explore potential mechanisms and utilize this model to test new treatments.
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