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.
Monday, October 4, 2010
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.
Subscribe to:
Posts (Atom)