Researchers have discovered that epileptic brains are more ordered than non-epileptic ones and also that certain flicking colours seem more likely to cause fits.
In 1997, more than seven hundred children in Japan suffered an epileptic attack while watching an episode of Pokemon cartoon. This was later diagnosed as a case of photosensitive epilepsy (a kind of epilepsy caused by visual stimulus) triggered by a specific segment of the cartoon containing a colourful flickering stimulus. Recently in 2007, the animated video footage promoting the 2012 London Olympics faced similar complaint from the viewers.
Because of the widespread usages of television and video games, it is important to detect the crucial visual parameters in triggering an epileptic attack. Common guidelines are available on specific visual parameters of the stimuli like spatial/temporal frequency, stimulus contrast, patterns etc. However, despite the ubiquitous presence of colourful displays and materials, very little is known about the relationship between colour-combinations (chromaticity) and photosensitivity. Further it is also not precisely known how the patients' brain responses differ from healthy brains against such colourful stimuli.
In a study published in the PLoS ONE on September 25, researchers led by Joydeep Bhattacharya at Goldsmiths, University of London, investigated brain rhythms of photosensitivity against combinational chromatic flickering in nine adult controls, an unmedicated patient suffering from photosensitive epilepsy, two age-matched controls, and another medicated patient.
Their results show that when perturbed by potentially epileptic-triggering stimulus, healthy human brain manages to maintain a non-deterministic, possibly a chaotic state with a high degree of disorder, but an epileptic brain represents a highly ordered state which making it prone to hyper-excitation. Further their study has found how complexities underlying brain dynamics could be modulated by certain colour combinations more than the other, for example, red-blue flickering stimulus causes larger cortical excitation than red-green or blue-green stimulus.
Dr. Bhattacharya said, "These findings support the 'decomplexification hypothesis': a healthy brain is more 'complex' than a pathological brain."
However, he added, "It is important to extend the research with larger number of patients to find at what extent these statistical and complexity measures applied in the present paper would have diagnostic potential."
Wednesday, October 14, 2009
Sunday, October 11, 2009
Some Mysteries of Neonatal Seizures Solved in a Study at MassGeneral Hospital for Children
New insights into the mechanism of neonatal seizures, which have features very different from seizures in older children
and adults has been provided in a study
led by MassGeneral Hospital for Children (MGHfC) investigators.
In their report in the Sept. 10 issue of Neuron, the researchers describe finding how neurons in different parts of the brains of newborn mammals respond differently to the neurotransmitter GABA, an observation that may explain why seizure activity in the neonatal brain often does not produce visible convulsions and why the common antiseizure drug phenobarbital can exacerbate the invisible nature of neonatal seizures.
"The incidence of seizures is higher in the newborn period than at any other stage of life," says Kevin Staley, MD, MGHfC chief of Neurology, senior author of the Neuron paper. "This is a time of transition when brain cells begin to switch the way they respond to the neurotransmitter GABA, which increases the activity of immature brain cells but decreases the activity of mature cells. Many of our most powerful seizure medicines work by enhancing the action of GABA, but this treatment may backfire for brain cells that have not yet made that transition."
GABA acts by mediating the flow of chloride ions into and out of neurons, and previous research has shown that neurons in structures deep within the developing mammalian brain change the expression of proteins that pump ions in or out of cells at an earlier stage than do neurons in the neocortex, the outer part of the brain that matures last and where seizures originate. The current study was designed to investigate whether the different expression of chloride pumps in specific regions of the brain might explain why newborns often have seizures not accompanied by convulsions.
The researchers first confirmed in newborn mice that chloride levels in deep-brain structures like the thalamus are much lower than cortical levels, a difference that decreases as the animals mature and cortical chloride levels drop. They then showed that GABA inhibits the activity of thalamic neurons but stimulates cortical neurons in neonatal rats, a difference that was enhanced by the induction of seizures.
Treatment with phenobarbital suppressed seizure activity in subcortical structures but not in the neocortex. That finding could explain the suppression of convulsions, which require the passage of seizure signals from the cortex through subcortical structures and out to the muscles, while a cortical seizure persists. Adding the diuretic bumetanide, which blocks the chloride pump responsible for immature neurons' excitatory response to GABA, to phenobarbital treatment successfully suppressed seizure activity in both cortical and subcortical regions.
"Our study provides a logical mechanism for the clinical invisibility of many neonatal seizures, information that may help determine the best way to monitor newborns with brain injuries for seizures and select the best strategies for anticonvulsant treatment," Staley explains. "For example, by blocking the protein responsible for immature brain cells' excitatory response to GABA, bumetanide essentially converts that immature response to a mature response and allows antiseizure medicines to work properly. We are excited to be participating in a trial of bumetanide as an adjunctive treatment of neonatal seizures currently being carried out in collaboration with colleagues at Childrens Hospital Boston and Brigham and Women's Hospital."
and adults has been provided in a study
led by MassGeneral Hospital for Children (MGHfC) investigators.
In their report in the Sept. 10 issue of Neuron, the researchers describe finding how neurons in different parts of the brains of newborn mammals respond differently to the neurotransmitter GABA, an observation that may explain why seizure activity in the neonatal brain often does not produce visible convulsions and why the common antiseizure drug phenobarbital can exacerbate the invisible nature of neonatal seizures.
"The incidence of seizures is higher in the newborn period than at any other stage of life," says Kevin Staley, MD, MGHfC chief of Neurology, senior author of the Neuron paper. "This is a time of transition when brain cells begin to switch the way they respond to the neurotransmitter GABA, which increases the activity of immature brain cells but decreases the activity of mature cells. Many of our most powerful seizure medicines work by enhancing the action of GABA, but this treatment may backfire for brain cells that have not yet made that transition."
GABA acts by mediating the flow of chloride ions into and out of neurons, and previous research has shown that neurons in structures deep within the developing mammalian brain change the expression of proteins that pump ions in or out of cells at an earlier stage than do neurons in the neocortex, the outer part of the brain that matures last and where seizures originate. The current study was designed to investigate whether the different expression of chloride pumps in specific regions of the brain might explain why newborns often have seizures not accompanied by convulsions.
The researchers first confirmed in newborn mice that chloride levels in deep-brain structures like the thalamus are much lower than cortical levels, a difference that decreases as the animals mature and cortical chloride levels drop. They then showed that GABA inhibits the activity of thalamic neurons but stimulates cortical neurons in neonatal rats, a difference that was enhanced by the induction of seizures.
Treatment with phenobarbital suppressed seizure activity in subcortical structures but not in the neocortex. That finding could explain the suppression of convulsions, which require the passage of seizure signals from the cortex through subcortical structures and out to the muscles, while a cortical seizure persists. Adding the diuretic bumetanide, which blocks the chloride pump responsible for immature neurons' excitatory response to GABA, to phenobarbital treatment successfully suppressed seizure activity in both cortical and subcortical regions.
"Our study provides a logical mechanism for the clinical invisibility of many neonatal seizures, information that may help determine the best way to monitor newborns with brain injuries for seizures and select the best strategies for anticonvulsant treatment," Staley explains. "For example, by blocking the protein responsible for immature brain cells' excitatory response to GABA, bumetanide essentially converts that immature response to a mature response and allows antiseizure medicines to work properly. We are excited to be participating in a trial of bumetanide as an adjunctive treatment of neonatal seizures currently being carried out in collaboration with colleagues at Childrens Hospital Boston and Brigham and Women's Hospital."
Wednesday, October 7, 2009
Diet May Eliminate Spasms For Infants With Epilepsy
Infantile spasms are a severe and potentially devastating epilepsy condition affecting children aged typically 4-8 months. In a new study appearing in Epilepsia, researchers have found that the ketogenic diet, a high fat, low carbohydrate diet more traditionally used for intractable childhood epilepsy, is an effective treatment for this condition before using drugs.
The study is the first description of the ketogenic diet as a first-line therapy for infantile spasms.
ACTH and vigabatrin, medications that are the commonly-used first treatments worldwide, can have potentially-serious side effects such as hypertension, gastric ulceration, cortical atrophy, and visual field constriction. ACTH, though it is effective in 60-70 percent of cases, also costs more than $80,000 for a one-month supply and vigabatrin is not currently available in the U.S. Both drugs have about a 30-40 percent recurrence rate of spasms as well. Other therapies are not yet proven.
"We decided to review our experience at Johns Hopkins using the ketogenic diet to treat infantile spasms before medications were tried and compare this to our use of ACTH over the same time period," says Eric Kossoff, M.D, a pediatric neurologist at Johns Hopkins Hospital and lead author of the study. "We knew that the ketogenic diet worked well for difficult-to-control infantile spasms, so we thought it would also be effective earlier."
If the diet stopped the spasms, infants were kept on it for usually 6 months. The diet worked in 8-of-13 infants within approximately one week. Only 1-of-8 had recurring spasms, and that infant was controlled again with the addition of topiramate to the diet. Side effects were fewer than ACTH in this series and the recurrence rate was also lower with the diet. In the 5 patients in which the diet did not work, ACTH was started immediately; it worked quickly in 4 of the 5 infants. ACTH did lead to a normal EEG quicker, but long-term developmental outcomes were identical.
As a result of the findings, the ketogenic diet is now one of the typically-offered first-line therapies for new-onset infantile spasms at Johns Hopkins. Other hospitals are beginning to use the ketogenic diet similarly. The researchers hope this novel use of the ketogenic diet may be the first step in finding another treatment to control new-onset infantile spasms.
The study is the first description of the ketogenic diet as a first-line therapy for infantile spasms.
ACTH and vigabatrin, medications that are the commonly-used first treatments worldwide, can have potentially-serious side effects such as hypertension, gastric ulceration, cortical atrophy, and visual field constriction. ACTH, though it is effective in 60-70 percent of cases, also costs more than $80,000 for a one-month supply and vigabatrin is not currently available in the U.S. Both drugs have about a 30-40 percent recurrence rate of spasms as well. Other therapies are not yet proven.
"We decided to review our experience at Johns Hopkins using the ketogenic diet to treat infantile spasms before medications were tried and compare this to our use of ACTH over the same time period," says Eric Kossoff, M.D, a pediatric neurologist at Johns Hopkins Hospital and lead author of the study. "We knew that the ketogenic diet worked well for difficult-to-control infantile spasms, so we thought it would also be effective earlier."
If the diet stopped the spasms, infants were kept on it for usually 6 months. The diet worked in 8-of-13 infants within approximately one week. Only 1-of-8 had recurring spasms, and that infant was controlled again with the addition of topiramate to the diet. Side effects were fewer than ACTH in this series and the recurrence rate was also lower with the diet. In the 5 patients in which the diet did not work, ACTH was started immediately; it worked quickly in 4 of the 5 infants. ACTH did lead to a normal EEG quicker, but long-term developmental outcomes were identical.
As a result of the findings, the ketogenic diet is now one of the typically-offered first-line therapies for new-onset infantile spasms at Johns Hopkins. Other hospitals are beginning to use the ketogenic diet similarly. The researchers hope this novel use of the ketogenic diet may be the first step in finding another treatment to control new-onset infantile spasms.
Controversial Medication May Decrease Spasms For Infants With Epilepsy
ScienceDaily (Feb. 3, 2009) — The antiepileptic drug vigabatrin (VGB) has been shown to be one of the best treatments against a special form of epilepsy in infants, called infantile spasm. However, its use has been limited in many countries because it has been shown to cause a permanent narrowing of visual fields in approximately 40percent of adults who have been exposed at school age or later.
A new study published in Epilepsia examined school-aged children who had been treated with VGB in infancy. The findings showed normal visual fields in 15 of the 16 children studied children.
While VGB is an effective drug for infantile spasms, there have been no previous reports on later visual field testing after treatment in infancy. This study used a form of peripheral vision testing, called kinetic perimetry, which is effective in detecting peripheral field defects typical of VGB toxicity, and produces more reliable results in children.
Vigabatrin treatment began at a mean age of 7.6 months, and the mean duration of therapy was 21 months, with a mean cumulative dose of 655 grams. Three of the children had been previously treated with another anti-epileptic drug (AED), five had received only hormonal treatment, and eight children had never been treated with any form of AED.
The findings show that the risk of permanent visual field defects caused by VGB may be lower for treatments in infants than in adults. Results showed that 15 children had normal visual fields and mild visual field loss was observed in one child who had been treated with VGB for 19 months and received a cumulative dose of 572 grams. This frequency is lower than previous observations using kinetic perimetry in older children or adults.
The cumulative VGB doses and treatment durations in the study were, on average, lower than in previous studies, which correspond to the much younger age and weight of the tested patients.
“Our results may encourage doctors to use vigabatrin to treat infantile spasms as the risk for visual field damage may be relatively low in many children compared to
the risks caused by continuous seizures,” says Dr. Eija Gaily, co-author of the study.
Visual field testing can be carried out in normally developed children from the age of six years. It is important to note that not all children with normal fields manifest normal results at the first visual field testing because good cooperation and attention are required in order to get reliable results. All abnormal findings in children should always be confirmed by repeating the test.
A new study published in Epilepsia examined school-aged children who had been treated with VGB in infancy. The findings showed normal visual fields in 15 of the 16 children studied children.
While VGB is an effective drug for infantile spasms, there have been no previous reports on later visual field testing after treatment in infancy. This study used a form of peripheral vision testing, called kinetic perimetry, which is effective in detecting peripheral field defects typical of VGB toxicity, and produces more reliable results in children.
Vigabatrin treatment began at a mean age of 7.6 months, and the mean duration of therapy was 21 months, with a mean cumulative dose of 655 grams. Three of the children had been previously treated with another anti-epileptic drug (AED), five had received only hormonal treatment, and eight children had never been treated with any form of AED.
The findings show that the risk of permanent visual field defects caused by VGB may be lower for treatments in infants than in adults. Results showed that 15 children had normal visual fields and mild visual field loss was observed in one child who had been treated with VGB for 19 months and received a cumulative dose of 572 grams. This frequency is lower than previous observations using kinetic perimetry in older children or adults.
The cumulative VGB doses and treatment durations in the study were, on average, lower than in previous studies, which correspond to the much younger age and weight of the tested patients.
“Our results may encourage doctors to use vigabatrin to treat infantile spasms as the risk for visual field damage may be relatively low in many children compared to
the risks caused by continuous seizures,” says Dr. Eija Gaily, co-author of the study.
Visual field testing can be carried out in normally developed children from the age of six years. It is important to note that not all children with normal fields manifest normal results at the first visual field testing because good cooperation and attention are required in order to get reliable results. All abnormal findings in children should always be confirmed by repeating the test.
Monday, October 5, 2009
Diagnosing Infantile Spasm
Although the epileptogenic mechanisms of infantile spasms is not well understood, an etiologic diagnosis can be identified in more than 70% of cases (4, 5), which may lead to a specific therapy that can have a dramatic influence on the outcome of the patient. It is, therefore, essential that an appropriate diagnostic evaluation be performed in every patient. Because infantile spasms has such characteristic clinical and electrographic features, it is easy to make the diagnosis if the epileptic nature of the spells is recognized. However, sometimes the spasms are subtle enough that the syndrome is not even considered.
Three key factors lead to the diagnosis. The first factor is age. Infantile spasms is a disorder of the developing nervous system and the spasms typically begin in the first year of life, most commonly between 4 and 8 months of age (6). Occasionally, they may begin in the neonatal period (7) or, rarely, much later in childhood (8). An atypical age of onset may help with etiologic diagnosis. For example, neonatal onset is associated with cortical dysplasia (9), whereas late onset (after 1 year of age) often is associated with genetic anomalies, hypoxic ischemic encephalopathy, and cortical dysplasia.
The second factor is the semiology. Clusters of flexion jerks of the neck, trunk, and extremities lasting 1–2 seconds are typical. Variations occur, such as extension of upper and lower extremities or both. Or, the spells may be very subtle, such as just a brief head drop (so-called Blitz-Nick-Krämpfe or “lightening neck spasms"), and often are misdiagnosed as a Moro reflex or simple startle reflex. In such cases, the epileptic nature of the spells may remain unappreciated for weeks or months. Although the spasms may happen as single jerk event, clusters are more common and often occur on awakening in the morning or after a nap (6). Other seizure types may arise concurrently or sequentially with infantile spasms.
The third factor is a very distinct EEG pattern. It is interesting to note that infantile spasm syndrome was not recognized as an epileptic disorder until the 1950s when Gibbs et al. described the characteristic and pathognomonic EEG abnormality called hypsarrhythmia (13). Hypsarrhythmia is a very high-voltage, disorganized pattern of EEG abnormality. A less chaotic pattern, called modified hypsarrhythmia, actually may be more common than hypsarrhythmia (14). Hypsarrhythmia or modified hypsarrhythmia is seen in about two thirds of cases. Other patterns, such as multifocal independent spike discharges (MISD), are present in the remainder. Although infantile spasms may be associated with other EEG abnormalities, hypsarrhythmia virtually never occurs in other epilepsy syndromes.Because infantile spasm seizures are frequent, it is common to capture the spells on a routine EEG, revealing the characteristic feature of electrodecrement immediately after the individual clinical spasm. If the EEG is normal, the diagnosis of infantile spasms should be reconsidered, as there are benign disorders that may appear clinically similar to infantile spasms (e.g., benign infantile myoclonus (15) or benign familial infantile convulsions.
These three factors are so distinctive that the clinical diagnosis of infantile spasms can be made with certainty in the vast majority of cases. Whereas the diagnosis of infantile spasms syndrome is usually easy, determining an etiologic diagnosis may be difficult. However, the etiologic diagnosis has such a profound impact on treatment and prognosis that an appropriate evaluation is essential in all cases.
Three key factors lead to the diagnosis. The first factor is age. Infantile spasms is a disorder of the developing nervous system and the spasms typically begin in the first year of life, most commonly between 4 and 8 months of age (6). Occasionally, they may begin in the neonatal period (7) or, rarely, much later in childhood (8). An atypical age of onset may help with etiologic diagnosis. For example, neonatal onset is associated with cortical dysplasia (9), whereas late onset (after 1 year of age) often is associated with genetic anomalies, hypoxic ischemic encephalopathy, and cortical dysplasia.
The second factor is the semiology. Clusters of flexion jerks of the neck, trunk, and extremities lasting 1–2 seconds are typical. Variations occur, such as extension of upper and lower extremities or both. Or, the spells may be very subtle, such as just a brief head drop (so-called Blitz-Nick-Krämpfe or “lightening neck spasms"), and often are misdiagnosed as a Moro reflex or simple startle reflex. In such cases, the epileptic nature of the spells may remain unappreciated for weeks or months. Although the spasms may happen as single jerk event, clusters are more common and often occur on awakening in the morning or after a nap (6). Other seizure types may arise concurrently or sequentially with infantile spasms.
The third factor is a very distinct EEG pattern. It is interesting to note that infantile spasm syndrome was not recognized as an epileptic disorder until the 1950s when Gibbs et al. described the characteristic and pathognomonic EEG abnormality called hypsarrhythmia (13). Hypsarrhythmia is a very high-voltage, disorganized pattern of EEG abnormality. A less chaotic pattern, called modified hypsarrhythmia, actually may be more common than hypsarrhythmia (14). Hypsarrhythmia or modified hypsarrhythmia is seen in about two thirds of cases. Other patterns, such as multifocal independent spike discharges (MISD), are present in the remainder. Although infantile spasms may be associated with other EEG abnormalities, hypsarrhythmia virtually never occurs in other epilepsy syndromes.Because infantile spasm seizures are frequent, it is common to capture the spells on a routine EEG, revealing the characteristic feature of electrodecrement immediately after the individual clinical spasm. If the EEG is normal, the diagnosis of infantile spasms should be reconsidered, as there are benign disorders that may appear clinically similar to infantile spasms (e.g., benign infantile myoclonus (15) or benign familial infantile convulsions.
These three factors are so distinctive that the clinical diagnosis of infantile spasms can be made with certainty in the vast majority of cases. Whereas the diagnosis of infantile spasms syndrome is usually easy, determining an etiologic diagnosis may be difficult. However, the etiologic diagnosis has such a profound impact on treatment and prognosis that an appropriate evaluation is essential in all cases.
What is Infantile Spasm?
What are Infantile Spasms?
An infantile spasm (IS) is a specific type of seizure seen in an epilepsy syndrome of infancy and childhood known as West Syndrome. West Syndrome is characterized by infantile spasms, developmental regression, and a specific pattern on electroencephalography (EEG) testing called hypsarrhythmia (chaotic brain waves). The onset of infantile spasms is usually in the first year of life, typically between 4-8 months. The seizures primarily consist of a sudden bending forward of the body with stiffening of the arms and legs; some children arch their backs as they extend their arms and legs. Spasms tend to occur upon awakening or after feeding, and often occur in clusters of up to 100 spasms at a time. Infants may have dozens of clusters and several hundred spasms per day. Infantile spasms usually stop by age five, but may be replaced by other seizure types. Many underlying disorders, such as birth injury, metabolic disorders, and genetic disorders can give rise to spasms, making it important to identify the underlying cause. In some children, no cause can be found.
Is there any treatment?
Treatment with corticosteroids such as prednisone is standard, although serious side effects can occur. Several newer antiepileptic medications, such as topiramate may ease some symptoms. Some children have spasms as the result of brain lesions, and surgical removal of these lesions may result in improvement.
What is the prognosis?
The prognosis for children with IS is dependent on the underlying causes of the seizures. The intellectual prognosis for children with IS is generally poor because many babies with IS have neurological impairment prior to the onset of spasms. Spasms usually resolve by mid-childhood, but more than half of the children with IS will develop other types of seizures. There appears to be a close relationship between IS and Lennox-Gastaut Syndrome, an epileptic disorder of later childhood.
An infantile spasm (IS) is a specific type of seizure seen in an epilepsy syndrome of infancy and childhood known as West Syndrome. West Syndrome is characterized by infantile spasms, developmental regression, and a specific pattern on electroencephalography (EEG) testing called hypsarrhythmia (chaotic brain waves). The onset of infantile spasms is usually in the first year of life, typically between 4-8 months. The seizures primarily consist of a sudden bending forward of the body with stiffening of the arms and legs; some children arch their backs as they extend their arms and legs. Spasms tend to occur upon awakening or after feeding, and often occur in clusters of up to 100 spasms at a time. Infants may have dozens of clusters and several hundred spasms per day. Infantile spasms usually stop by age five, but may be replaced by other seizure types. Many underlying disorders, such as birth injury, metabolic disorders, and genetic disorders can give rise to spasms, making it important to identify the underlying cause. In some children, no cause can be found.
Is there any treatment?
Treatment with corticosteroids such as prednisone is standard, although serious side effects can occur. Several newer antiepileptic medications, such as topiramate may ease some symptoms. Some children have spasms as the result of brain lesions, and surgical removal of these lesions may result in improvement.
What is the prognosis?
The prognosis for children with IS is dependent on the underlying causes of the seizures. The intellectual prognosis for children with IS is generally poor because many babies with IS have neurological impairment prior to the onset of spasms. Spasms usually resolve by mid-childhood, but more than half of the children with IS will develop other types of seizures. There appears to be a close relationship between IS and Lennox-Gastaut Syndrome, an epileptic disorder of later childhood.
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