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A: Among children with Dravet Spectrum Disorder there exists a wide range of ultimate developmental outcomes depending on where on the spectrum they fall. Individuals with GEFS+ may have normal development and can lead independent lives as adults. Patients on the severe end of the spectrum, who have been diagnosed with Dravet Syndrome tend to have more severe impairment, although there are sporadic case reports of adults with low-normal IQ who had a classic progression of seizures during infancy and have tested positive for an SCN1A mutation.
According to the recent literature, children with Dravet syndrome tend to have fairly normal development in the first two years of life. Onset of cognitive decline begins in the second year of life, but may not be evident until after the fourth birthday. Some children will exhibit actual regression, with loss of previously acquired milestones. However, for most children, there is developmental plateauing or stagnation so that the gap between the developmental quotient (DQ) and the chronologic age of the patient steadily increases. Recent data published by Ragona et al does not differ greatly from that published previously by Drs. Wolff and Dravet.
In the context of this question, for a 5 year old with mild delays, the most common scenario is very slow acquisition of new developmental milestones relative to the age of the patient, so that by age 10, the child will still be functioning at a kindergarten or 1st grade level. However, there is ongoing debate about the role that seizure control and medication side-effects play versus the impact of the underlying condition. Experts universally recommend early implementation of aggressive developmental and educational interventions, while attempting to gain optimum seizure control with a minimum of drug side-effects. It is imperative to remember that this is a spectrum disorder with a wide range of outcomes.
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A: Medical Advisory Board Member #1: "I think the genetic testing complements the clinical picture, but I would not call this a Dravet Spectrum Disorder unless the patient met clinical criteria as well: i.e., onset of prolonged hemiconvulsive seizures in the first 18 months of life. In the absence of other clear clinical data that would say this is a Dravet Spectrum Disorder, I would call it an SCN1A Related Seizure Disorder for now."
Medical Advisory Board Member #2: "If the mutation is de novo with a clinical history that is ever moderately convincing, then you have made anetiological diagnosis for this patient. In other words, the SCN1A mutation is the cause of the epilepsy, full stop.
The only question is whether de novo mutation was germ-line in the parent (=> recurrence risk is 50%) or in the child (recurrence risk is background risk, meaning ~0%)
Having said that, whether you put the descriptive diagnosis of "Dravet Spectrum Disorder" on it doesn't matter. In some ways, it's a step backwards (for example, "Robertsonian translocation of chromosome 21" means a whole lot more than "Down Syndrome," even though both are accurate). In my opinion, the term "Dravet Syndrome" is an archaic entry in our lexicon, and is not distinct from the previously-described "Doose Syndrome" or other forms of severe epilepsy that begin in infancy or early childhood. What patients really want to know is what the future holds, and how we can help them. And the answer is "probably static" (not further progressive), and "avoid phenytoin, carbamazepine, oxcarbazepine, and lamotrigine." We obviously need better SCN1A-specific treatments, but right now they don't exist."
Medical Advisory Board Member #3: "Are all DNA variants on SCN1A considered in a Dravet Spectrum Disorder? Probably, but this is being sorted out now, as we learn more and more with the new genetic tests. Because the variant does not have a named phenotype, should it be referred to as a SCN1A Related Seizure Disorder? This depends on the clinical phenotype. Is further chromosomal array or LP, or other testing to identify causes warranted? No. The family has already participated in studies, but with this identified variant, will the son and/or the family qualify to participate in Dravet Spectrum Disorder related studies or registries? Probably; it depends on the inclusion/exclusion criteria of the individual studies."
Medical Advisory Board Member #4: "I am not a geneticist, but the diagnosis of Dravet Syndrome rests more on clinical features such as onset age, history, seizure types, response to drugs, cognitive and behavioural course, etc. than on genetic alterations."
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[There were no Ask the Expert questions submitted in September, 2012.]
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A: Every patient’s experience is unique as they become an adolescent. Some will experience a reappearance of atypical absence seizures with or without eyelid flutter, though this is not frequent. Usually adolescent children experience more generalized tonic-clonic seizures during sleep. No scientific studies of this age group of patients with Dravet Syndrome appear to have been undertaken, though a research institute in Italy is in the early stages of a study that involves children of this age.
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A: Medical Advisory Board Member #1: "I look after quite a few adults with Dravet Syndrome. In general they are on multiple drugs, often four. The same principles apply as in children with some drugs being useful and others making them worse. Research has shown that using the right drugs can improve the patient's functioning. Of the drugs you have identified, I would be concerned that Trileptal and Lyrica could make the patient worse. I am unfamiliar with Onfi.
"In general my patients are on a combination of topiramate, valproate, clobazam, and stiripentol if it works. Levetiracetam can be good as well, as can Lamotrigine, even though there have been negative reports. I stay away from carbamazepine and oxcarbazepine."
Medical Advisory Board Member #2: "I am a pediatric neurologist but looking after many carry-over adult patients with Dravet syndrome. I recommend to try topiramate, clonazepam, high-dose phenobarbitol (if tolerable) or potassium bromide depending on the patient's treatment history. It is ideal to use within three anti-epileptic drugs, although it is sometimes difficult to reduce from four to three anti-epileptic drugs."
Medical Advisory Board Member #3: "Answering this type of question is extremely difficult. Adult patients with Dravet Syndrome usually have already received all the recommended anti-epileptic drugs for this syndrome and there is no 'optimal treatment.' We should know much more on the history and different therapeutics of one patient to give good advice.
"I do not understand if the five anti-epileptic drugs mentioned were given together or separately. I do not think it is good to give five drugs together and at least one of them should be taken off.
"I read that Trileptal, i.e. oxcarbazepine, was among the different combinations that were tried for the patient. Oxcarbazepine has the same effects as Tegretol and is contra-indicated for Dravet Syndrome in children. In our experience some adult patients were improved by this drug but that is rather exceptional and it would be preferable not to use it if seizures remain frequent. I do not have any experience of Lyrica in Dravet Syndrome. If Onfi did not have a good effect, clonazepam can be substituted to it.
"On the other hand it is not noted whether the generalized tonic-clonic seizures are diurnal or nocturnal. In the latter case, and if they are not prolonged, maybe it is better to accept them than to increase the treatment."
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A: Seizures are common when the brain is undergoing transitions - either falling asleep or shortly before waking. This is common for seizures from any cause. Children with Dravet Syndrome do tend to transition to mostly nocturnal generalized tonic-clonic convulsions as they get older (age varies). Daytime seizures may still occur, but are frequently triggered by illness or fever.
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A: Medical Advisory Board Member #1: "I have certainly seen tonic-clonic clustering in children with Dravet Syndrome; it is even more characteristic of PCDH19-related epilepsies. We have seen a reduction in frequency and even the abolition of clusters with the use of bromides. Phenytoin can sometimes make seizure clusters worse. Ensure that the child is not on lamotrigine. Seizure clusters tend to reduce with age. My last patient with cluster seizures recently stopped having them on keppra. However, she had neither an SCN1A or a PCDH19 mutation identified."
Medical Advisory Board Member #2: "I have one patient with a similar history of very bad tonic-clonic clusters. The patient is doing remarkably better on acetazolamide. I would focus on the overall blockade of seizures, not on abortive medical care as that seemed strikingly unsuccessful."
Medical Advisory Board Member #3: "We have had one patient with a very similar story, although it turns out that she is usually in non-convulsive status epilepticus between tonic-clonic seizures. Conventional treatments were very unsatisfactory. We used low-dose intravenous pentathal or propathal in the emergency room; usually she is able to go home a few hours later. She has continued this pattern for many years."
Medical Advisory Board Member #4: "We have two patients presenting this type of seizure, both with SCN1A mutations. Usually, we see this more often in patients with PCDH19 mutations. One of our patients had a good response to the ketogenic diet and the other to bromide (not administered during the cluster, but as a chronic treatment). We usually use clonazepam; however, that was not efficient in these two patients. We use less phenytoin, but it was also not efficient in these particular cases."
Medical Advisory Board Member #5: "In Japan, we prescribe bromide to all patinets with Dravet Syndrome unless the patients experience frequent prolonged seizures all the time. The patients usually experience prolonged seizures or status epilepticus much less often. However, they later experience clusters of brief general tonic-clonic seizures whenever they have fever that is refractory to a diazepam suppository. In this case, we often use an intravenous midazolam drip infusion for one to two days under medical supervision. We provide sufficient treatment such as bromide, stripentol, or ketogenic diet for patients with Dravet Syndrome unless the emergency treatment drugs appear less effective."
A: Febrile seizures are common occurring in up to 5% of children (published statistics vary). They are most common in 18 to 22 month olds, but can occur from about 6 months to 6 years of age. Most children will experience only 1 febrile seizure in their lifetime, but 30 to 40% of children will go one to have more than 1 febrile seizure. Only 3% of children will go on to be diagnosed with epilepsy. Epilepsy is generally defined as 2 or more unprovoked seizures, meaning not immediately due to fever, infection, or other identifiable insults to the brain. Children who have recurrent febrile seizures are generally not considered to have epilepsy and are not treated with anti-epileptic medications in most cases.
Febrile seizures can run in families in an autosomal dominant pattern (the genetic mutation is inherited from only one parent). In these cases, children experience one or more simple febrile seizures before outgrowing them at around age 6, just as in non-inherited febrile seizures. Mutations in several genes have been identified as causing inherited febrile seizures.
There also exist several epilepsy syndromes that begin with febrile seizures in infancy. Generalized Epilepsy with Febrile Seizures Plus (GEFS+) is one syndrome in which patients have febrile seizures starting in infancy or early childhood, but then develop afebrile seizures as well. Afebrile seizures may be tonic-clonic, myoclonic, or focal. Most affected patients outgrow the febrile seizures by age 6. Other seizure types may also resolve or may persist throughout life. The decision to initiate anti-epielptic medications is made on a case-by-case basis. Developmental delays in affected patients are uncommon, but can occur.
Several commercial labs in the US offer genetic testing for the most common mutations known to be associated with febrile seizures. dravet.org's website offers a list of labs in the US and Europe that offer epilepsy-related panels.
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A: At this time, the specific mutation can't be accurately correlated with phenotype, nor with early intevention or therapy strategies. Researchers are working hard to make connections between mutation type and what that means in terms of clinical presentation, but are currently unable. Her stop codon terminates the protein roughly 1/3 to 1/2 of the way through production, which likely renders the protein unusable if it is produced and transported to the membrane in the first place, which we can't be 100% certain of.
Regardless, early intervention is highly recommended by all of the doctors for anyone diagnosed early enough to receive therapies. Though we can't correlate the results with mutation type, it does appear that early intervention in general reduces developmental delays overall.
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A: Depakote is a type of valproic acid (VPA). The way VPA works varies depending on the form that the patient is taking, since some are short-acting and others are extended release. Ask your pharmacist about the specific type of VPA prescribed and ask them to provide you with the package insert, which will give specific information for that product.
This website offers good information that is not too technical: "Considering that the role of colour in photosensitive epilepsy (PSE) remains unclear, we designed a study to determine the potential of different colours, colour combinations and white light to trigger photoparoxysmal responses (PPRs) under stringent controlled conditions. After assessing their photosensitivity to stroboscopic white light and black and white patterns, we studied 43 consecutive PSE patients (mean age 19 years, 34 women), using a specially designed colour stimulator. Stimuli included: pulse trains between 10 and 30 Hz of white light and of all primary colours, and also isoluminant alternating time-sequences of colours. Illuminance was kept constant at 100 lux. A progressive stepwise increase of the modulation-depth (MD) of the stimuli was used to determine PPRs threshold. Whereas all the 43 patients were found to be sensitive during the stroboscopic and pattern protocol, only 25 showed PPRs (Waltz's score >2) at least in one session when studied with the colour stimulator. Coloured stimuli elicited PPRs in all these patients, whereas white light did so only in 17 patients. Of the primary colours, red elicited more PPRs (54 in 22 patients) and at a lower MD (max Z-score 0.93 at 10 Hz). Of the alternating sequences, the red-blue was the most provocative stimulus, especially below 30 Hz (100% of patients, max Z-score: 1.65 at 15 Hz). Blue-green was the least provocative stimulus, since it elicited only seven PPRs in seven (28%) patients (max Z-score 0.44 at 10 Hz). Sensitivity to alternating colours was not correlated to sensitivity to individual colours. We conclude that colour sensitivity follows two different mechanisms: one, dependent on colour modulation, plays a role at lower frequencies (<30 Hz). Another, dependent on single-colour light intensity modulation correlates to white light sensitivity and is activated at higher frequencies. Our results suggest that the prescription of spectacles with coloured lenses, tailored to the patient, can be an effective preventative measure against visually induced seizures"
A: A frequency of developmental testing of about every 2 to 3 years starting from the age of school entry is generally recommended. This would vary depending on the child and whether there were significant changes in the child's status in the interim.
All research on children with epilepsy utilizes the Wechsler IQ tests:
While there are other IQ tests available, very little research has been done on them in the context of children with epilepsy.
Given that many Dravet patients have intellectual disabilities, testing should usually be paired with a measure of adaptive functioning, such as the Vineland Scales or the Adaptive Behavior Assessment System. For patients with language impairments, the Wecshler Non-Verbal IQ test can be used, as can the Leiter-R and the TONI-3 (Test of Non-Verbal Intelligence) tests.
With regard to frequency of testing, most physicians generally try not to test more than yearly to avoid potential practice effects (a skewing of the results caused by the patient's familiarity with the test after repeated testings). If significant changes appear to have occurred, earlier testing may be advisable. If things appear to be fairly stable, yearly testiing may not be necessary. Most school systems require triennial evaluations to maintain the child's IEP.
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A: There is not really a difference between febrile and non-febrile seizures. Fever or temperature elevation from other causes such as a hot bath or warm environment are known triggers for seizures in patients with SCN1A mutations. Medications that treat ""non-febrile"" seizures will also help control seizures triggered by fever. Unfortunately, patients with Dravet Spectrum Disorder will often have break-through seizures with fever regardless of what medications or other treatment they are on.
Developmental progress is difficult to predict at this time. A patient on the mild end of the spectrum (i.e. GEFS+) may have no developmental delays, whereas patients with classical Dravet syndrome will generally have severe delays. In a very young patient (under the age of 2 or 3) it is frequently difficult to ascertain where the child falls on the spectrum and developmental outcome is impossible to predict. An older patient who has not yet experienced delays is more likely to continue to do well.
Whether or not febrile seizures remit depends upon where on the Dravet Spectrum the patient falls. In the general population, febrile seizures generally do not persist beyond 6 years of age. Patients with a mutation of SNC1A and GEFS+ may never out-grow them, or may have only non-fever related seizures later in life. The literature suggests that, in patients with classical Dravet syndrome, non-convulsive seizures may improve after late childhood, but convulsive seizures persist throughout life and are often triggered by illness or fever.
A: Our medical experts are not aware of any published data regarding immunotherapy in Dravet patients. A patient's allergist should address the issue of whether allergy shots are appropriate in the setting of IgA deficiency.
A: To the best of our experts' knowledge, at this time reports on the effectiveness of language therapies in Dravet syndrome are largely anecdotal. The ability to do effective language therapy appears to have some dependence on the ability to manage seizures. PECS are widely used, as are voice-output electronic communication devices. Many reports indicate that photographs work better in this context than drawing/symbol pictures.
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A: Experts agree that seizures in general are more common during sleep, especially the transitional periods shortly after going to sleep or before waking. Any type of seizure will be more likely to occur during these times. This characteristic is not limited to Dravet syndrome, and has been observed in most types of epilepsy.
"Genetic counseling. SCN1A-related seizure disorders are inherited in an autosomal dominant manner. A proband with an SCN1A-related seizure disorder may have a de novo mutation. The proportion of cases caused by de novo mutations varies by phenotype. The percentage of probands with an SCN1A-related seizure disorder and an affected parent decreases as the severity of the phenotype in the proband increases. Most SCN1A-related SMEI and ICE-GTC are the result of a de novo heterozygous mutation. Each child of an individual with an SCN1A-related seizure disorder has a 50% chance of inheriting the mutation; however, the risk of developing seizures is less than 100% because of reduced penetrance. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known."
To summarize, since SCN1A related seizure disorders are inherited in an autosomal dominant manner, each child of an individual with an SCN1A-related seizure disorder has a 50% chance of inheriting the mutation; however, the risk of developing seizures is less than 100% because of reduced penetrance. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known.
Thus the chance that the expectant father inherited the mutation is 50%. If he did, the chance that the new baby will have inherited the mutation is 50%, and due to the possibility of reduced penetrance, there is a possibility that even if the baby does inherit the mutation, it may never present with seizures. And given the nature of the sodium ion channel epilepsies, with their tendency to present a spectrum of clinical presentations (even for the same mutation - for example we have a family with identical twin girls, obviously with the same mutation, each girl with a different clinical presentation - one is far more severe than the other), if the baby does have epilepsy, it might be much milder than that of the aunt.
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A: While it would be nice to have a leading epileptologist for your child, not everyone has one nearby and they're often so highly sought after that they're not taking new patients. Epileptologists, or neurologists with a special interest in epilepsy who aren't as well known can take excellent care of your child as long as:
1) They are allied with an epilepsy center with current diagnostic equipment and procedures
2) They are or are willing to become educated about the diagnosis and treatment of Dravet syndrome, including its associated conditions
3) They are open to consulting neurologists with more expertise in Dravet syndrome when needed
4) They are open to partnering with parents/caregivers to collaboratively find the best treatments and resources
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A: Any child with a condition that affects the attainment of normal gross motor milestones can develop gait problems and orthopedic issues. These problems are NOT specific to Dravet syndrome. They are seen not only in other epilepsy syndromes, but ANY neurological, muscular, or ligamentous syndrome if severe enough to alter typical development or movement patterns. The development of the musculoskeletal system from infancy to adulthood depends on typical development and movement.
A: The mutation rate in any gene linked to disease is often specific to particular population i.e. racial and ethnic groups. There are currently no published data that would inform us on the mutational rate in healthy individuals. The presumed rate of any published genetic variant in the SCN1A gene presumed or confirmed to underlie Dravet syndrome is generally reported to be less than 1 percent. However, this is an extrapolation from studies that identified specific genetic variants in individuals with Dravet syndrome and then looked at the very change in healthy individuals. The problem is that while the particular healthy cohort did not harbor the mutation found in the patient the unaffected people can carry their own “private” genetic genes that are not seen because generally healthy individuals are not sequenced across the all the coding regions. Much of this complexity has been discussed in T Klassen, et al., "Exome Sequencing of Ion Channel Genes Reveals Complex Profiles Confounding Personal Risk Assessment in Epilepsy," Cell, Vol. 145, 1036–1048, June 24, 2011.
As noted in the Klassen paper, while the researchers identified a number of mutations in both cases and controls, the only known deleterious SCN1A mutation in the study cohort was in fact identified only in a neurologically healthy control. The researchers specifically went looking for previously reported mutations in the known human epilepsy genes in the control population. Interestingly, they not only found a mutation but the mutation actually causes channels not to shuttle to the membrane and results in “no current” in model cell based expression systems.
Dravet.org has been informed that further research is pending.
Here's a non-technical version of the answer to the above question:
There are no published studies addressing the rate of SCN1A mutation in healthy individuals. There is a wealth of information about SCN1A mutations (or lack thereof) in healthy individuals, but the information is more sporadic and "spot-checked" than the broad testing the question referred to.
When Dravet patients are identified as having an SCN1A mutation, other healthy "controls" are then tested. This is often family, or healthy people close to the individual who've volunteered to undergo testing. When they test these healthy controls, they usually don't sequence the entire gene: they just look at specific regions known to be mutated in Dravet patients. (Sometimes, in the case of family, it's a very small region they look at. Other times, in broader studies, they may sequence more of the gene, but usually not the entire thing.)
This method can quickly and cheaply identify the disease- associated mutation, but it obviously doesn't determine an overall mutation rate in the general population. The problem is that healthy controls may harbor their own mutations that are not pathogenic and not in the same spot as where they are tested, thus can go unnoticed.
In general, they've found about a 1% mutation rate in healthy controls just by this spot-checking method. The study that was cited (Klassen) goes on to say that, amazingly, the only deletion found in the study was actually in a control.
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