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Early Infantile Epileptic Encephalopathy Type 6

DS

Dravet Syndrome, or severe myoclonic epilepsy of infancy, is a severe and often drug-resistant condition characterized by the appearance of intractable generalized or unilateral seizures triggered by fever during the first year of life. Genetic mutations in subunits of voltage-gated sodium channels are established in the vast majority of patients and a definite diagnosis is made by their confirmation. Antiepileptics are the main therapeutic modality.

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Presentation

The clinical presentation of patients with DS is distinguished by the appearance of seizures during the first year of life, most commonly between 2 and 10 months [4]. Initially, tonic-clonic seizures are preceded by increased body temperature, which is why these attacks are often misdiagnosed as febrile convulsions [4], but later on, seizures are polymorphic in nature. Both focal and generalized myoclonus, atypical absence seizures, complex partial seizures, but also "obtundation status" may be encountered in these patients [1]. Clonic and unilateral nonfebrile convulsions that last for a prolonged period of time (status epilepticus may also occur) are typical findings as well [10]. In addition to seizures, psychomotor development becomes affected from the second year of life, together with ataxia and clumsiness, while photosensitivity has been reported as well [10]. In late childhood and adulthood, patients do not suffer from further neuropsychiatric deterioration, but cognitive functions remain below average throughout life [10].

Developmental Delay
  • He presented with intractable and recurrent convulsions, global developmental delay and microcephaly.[ncbi.nlm.nih.gov]
  • They analyzed the influence of age at seizure-onset and age at appearance of developmental delay, and compared their results in two subgroups of patients: those with and those without vaccination-associated seizure onset (defined as seizures appearing[pediatricneurologybriefs.com]
Chronic Infection
  • Common issues associated with Dravet include prolonged seizures, frequent seizures, behavioral and developmental delays, movement and balance issues, orthopedic conditions, growth and nutrition issues, sleeping difficulties, chronic infections, disruptions[gofundme.com]
  • Patients also may experience movement and balance problems, growth or nutrition issues and, chronic infections. There are many other conditions that often co-occur with Dravet syndrome.[dravetsyndromenews.com]
  • Conditions Associated With Dravet Syndrome Several other health conditions have been linked with Dravet syndrome, including: Chronic infection Delayed growth Delayed language and speech acquisition Delays in behavioral, cognitive and emotional development[citiva.com]
  • Some of the symptoms associated with Dravet Syndrome include: Developmental delays Behavioral delays Issues with balance and movement Orthopedic conditions Delayed speech development Growth impediments Nutritional issues Sleep disturbances Chronic infections[disability-benefits-help.org]
  • These conditions include: behavioral and developmental delays movement and balance issues orthopedic conditions delayed language and speech issues growth and nutrition issues sleeping difficulties chronic infections sensory integration disorders disruptions[dravet.eu]
Developmental Disabilities
  • A few types of epilepsy, however, are characterized by seizures which begin very early in childhood and are associated with severe intellectual and/or developmental disabilities.[centerwatch.com]
  • Dravet syndrome is a rare epilepsy that begins in infancy, is lifelong and often leads to developmental disability. [2] It is most often caused by a mutation or deletion in the Scn1a gene, a gene that codes for an important sodium channel whose function[cureepilepsy.org]
  • The majority of children with Dravet syndrome; however, experience some degree of developmental disability that persists.[disabled-world.com]
  • Yet most children with Dravet syndrome have some degree of developmental disability that persists.[epilepsy.com]
  • From around the age of two, the children develop symptoms like developmental disabilities, motor skill difficulties, hyperactivity, communication difficulties and behavioural abnormalities.[mun-h-center.se]
Noncompliance
  • Although the effect of the KD was independent of age at initiation, it had to be withdrawn due to noncompliance more frequently in solid fed older children compared with infants treated with the liquid ketogenic formula.[ncbi.nlm.nih.gov]
Decrease in Height
  • Mean growth parameter measurements were significant for decrease in height z-score of 0.10 (p CONCLUSIONS: Comorbidities in children with Dravet syndrome may involve more systems than previously reported.[ncbi.nlm.nih.gov]
Photosensitivity
  • CONCLUSIONS: Although photosensitivity is well recognized in Dravet syndrome, myoclonic absence seizures have not been previously reported.[ncbi.nlm.nih.gov]
  • In addition to seizures, psychomotor development becomes affected from the second year of life, together with ataxia and clumsiness, while photosensitivity has been reported as well.[symptoma.com]
Seizure
  • It has been reported that children with Dravet syndrome often present with recurrent febrile seizures and vaccination-related seizures.[ncbi.nlm.nih.gov]
  • […] generalized, clonic seizure.[orpha.net]
  • A distinguishing feature of DS is that seizures recur within weeks or months after the first episode and various seizure types may be encountered later on, including generalized or partial myoclonus, absence seizures and partial seizures.[symptoma.com]
Tonic-Clonic Seizure
  • METHODS: Patients with Dravet syndrome having 4 clonic/tonic-clonic seizures per 30 days while on clobazam and valproate (with or without bromide) received add-on stiripentol for 16 weeks.[ncbi.nlm.nih.gov]
  • Dravet syndrome Other names Severe myoclonic epilepsy of infancy, severe polymorphic epilepsy of infancy, borderland SMEI (SMEB), borderline SMEI, intractable childhood epilepsy with generalised tonic clonic seizures (ICEGTCS) Pronunciation dra-vay Specialty[en.wikipedia.org]
Ataxia
  • Danielle.Andrade@uhn.on.ca Abstract Dravet syndrome is a genetically determined severe epilepsy associated with cognitive decline and ataxia. The many types of seizures seen in these patients are typically pharmacoresistant.[ncbi.nlm.nih.gov]
Myoclonic Jerking
  • As the affected children grow up, they develop myoclonic jerking, and their seizures may become refractory to treatment. Synonym: severe myoclonic epilepsy of infancy[medical-dictionary.thefreedictionary.com]
  • Generalized ictal myoclonic jerks: The generalized ictal myoclonic jerks are always preceded by clear-cut spike-wave discharges. Available evidence suggests that they originate from the spread of focal cortical myoclonic activity.[icnapedia.org]
  • Myoclonic seizures, often called myoclonic jerks, are common. Over time seizures occur more frequently without obvious triggers, and resistant to treatment.[secure.ssa.gov]
  • Development during the first year of life is usually normal, but following this a range of seizures appear which include: myoclonic jerks, single or multiple muscle jerks, which may involve one part of the body or the whole body atypical absences with[contact.org.uk]
Febrile Convulsions
  • The diagnosis of DS may be difficult to attain in early infancy, as its clinical presentation is strikingly similar to febrile convulsions and other epileptic disorders.[symptoma.com]
  • However, at this time it can be difficult to differentiate these children from others with briefer febrile convulsions, who do not go on and develop other types of seizure.[epilepsy.org.uk]
  • Dravet Syndrome (previously called severe myoclonic epilepsy of infancy, SMEI), is an epilepsy that usually starts in the first year of life with frequent febrile convulsions that are often prolonged.[epilepsyqueensland.com.au]
  • Not all patients start with febrile convulsions.[epilepsydiagnosis.org]

Workup

The diagnosis of DS may be difficult to attain in early infancy, as its clinical presentation is strikingly similar to febrile convulsions and other epileptic disorders. This may be even more difficult in the setting of a normal EEG and brain imaging studies, which is not uncommon in the initial stages of the disease. During disease progression and increased seizure frequency, however, EEG findings eventually reveal both focal and multifocal anomalies, including generalized spike-and-wave discharges and slowed background activity [1] [4]. To confirm the diagnosis, genetic testing for SCN1A mutations may be performed, yielding positive results in approximately 80% of patients [4], but the diagnosis still rests on clinical criteria (recurrent seizures in infancy that are refractory to therapy with mild cognitive decline) [6].

Spike-and-Slow-Waves
  • Trevor Resnick, MD: Lennox-Gastaut [syndrome] is an epileptic encephalopathy—[it’s] very, very difficult to control the condition—that’s characterized by an abnormal pattern on the EEG [electroencephalogram] with a slow spike and slow wave pattern of[neurologylive.com]
  • Four children had generalized spike and slow wave or polyspike and slow wave.[neurology.org]
Generalized Spike-and-Slow-Waves
  • Four children had generalized spike and slow wave or polyspike and slow wave.[neurology.org]

Treatment

Significant challenges exist when it comes to treatment of patients suffering from DS, as the hallmark of this epileptic disorder is resistance to AEDs [9]. Benzodiazepines and valproate, which are considered as first-line therapy for many seizures, are not effective, whereas phenobarbital, lamotrigine and carbamazepine are avoided because they can further aggravate existing seizures [7]. Current therapeutic options include stripentol, one of the very few drugs that shows marked efficacy in reducing the burden of seizures and is often used in combination with valproate and clobazam [6] [7]. Despite all available AEDs, seizures cannot be completely abolished in DS patients and the search for optimal therapy is ongoing.

Prognosis

Previous mortality rates from DS were estimated at 10-15%, with main causes of death being drowning, prolonged convulsions and sudden unexpected death, but due to improvement in care and overall management of epilepsy patients, recent studies estimate a 5% mortality rate [6]. Unfortunately, long-term prognosis of DS patients is not good, as seizures are refractory and often resistant to antiepileptic drugs (AEDs), but also because mental retardation and other neuropsychiatric complaints persist in early life and necessitate life-long monitoring and care of both patients and their families [4] [6].

Etiology

Mutations of SCN1A gene that code for voltage-gated sodium channels in neural tissue is the principal mechanism of diseases in DS and about 80% of cases are confirmed by genetic testing [1]. Specifically, the α-subunit of the sodium channel is coded by the gene located on chromosome 2 [2], and more than 95% of SCN1A mutations arising de novo [1]. The remaining 5% have shown a familial component, in which case a strong suspicion of generalized epilepsy with febrile seizures plus (GEFS+), a variant of SMEI, is made [3]. Other reports, however, suggest that familial cases represent as high as 25% of all DS patients [5]. Consequently, other genetic factors presumably play a role in the pathogenesis on this condition, the most prominent candidate being mutations of GABA A receptor subunit mutations [3].

Epidemiology

Incidence rates of 1 in 20,000-40,000 children suggest that DS is a disorder that is rarely encountered in clinical practice [9]. It is estimated that 3-8% of all seizures during the first year of life may be attributed to DS, while gender predilection toward males was established across different studies (male-to-female ratio of 2:1) [4] [9]. Factors that provoke an increase in body temperature, such as overt physical activity, infection, or sun exposure are known to induce seizure activity [6]. Ethnic predilection is currently not established.

Sex distribution
Age distribution

Pathophysiology

Under physiological circumstances, the voltage-gated sodium channels play an integral role in nerve conduction signaling and the action potential cascade. In the case of DS, the α subunit of the channel is altered by mutations in the gene responsible for its formation [1], SCN1A, most commonly through truncation mutations, but also deletions, splicing and missense mutations [5]. Because of its abnormal activity, patients are predisposed to epileptic seizures that are refractory to therapy and present as a significant challenge for the physician.

Prevention

Because seizures in DS patients are known to be induced by increased body temperature, especially during infancy, various effective strategies exist for reducing the risk of their appearance. Fever, when present, should be immediately managed through use of antipyretics, whereas the overall health of the child through adequate nutrition and vaccination should aid in minimizing the risk for infections [6]. Cooling baths and avoidance of extensive sun exposure through use of protective clothing, such as hats and sunglasses (in the case of photosensitivity) are also recommended strategies [6]. Despite the fact that numerous situations during the day may increase body temperature in children, including playing or running or any form of physical activity, prevention of dehydration and ensuring a cold environment as much as possible can be of significant help so that the affected individual is not deprived of a normal childhood.

Summary

Initially known as severe myoclonic epilepsy in infancy (SMEI), Dravet syndrome (DS) is a form of severe epilepsy and encephalopathy developing in the first year of life [1]. This disorder stems from genetic mutations of SCN1A gene, which codes for voltage-gated sodium channels in the neural tissue [2]. This mutation was identified in 67%-86% of patients across different studies [1], while mutations in gamma-aminobutyric acid (GABA) A receptors have also been discovered in a subset of patients [3]. Epidemiology studies show that DS is a rare disorder, occurring in approximately 1 per 20,000-40,000 children, with a slight predilection toward male gender (2:1 male-to-female ratio) [4]. However, it was established that DS is responsible for 3-7% of all seizures in the first year of life, suggesting that it is an important cause of epilepsy [1] [4]. Familial occurrence has been described in up to 25% of cases and the clear association remains unknown, as almost 95% of SCN1A mutations arise de novo [5]. Seizures begin during the first year of life and present as either generalized or unilateral convulsions of various types [1]. The clinical presentation almost invariably involves tonic-clonic seizures triggered by fever (caused by infections, hot baths or some other activity that increased body temperature), which is why it is often misdiagnosed as febrile convulsions [4]. In addition to seizures, progressive neurocognitive decline is evident in the majority of children, peaking in the second year of life [1]. Electroencephalography (EEG), like in all epileptic disorders, is the initial diagnostic method of choice, but initial findings may be normal in DS. As seizures accumulate, however, multifocal spikes or spike and waves are encountered on EEG [4]. Magnetic resonance imaging (MRI) is important in excluding other causes of epilepsy (eg. tumors), but in the case of DS, it yields no effect, as a normal endocranial MRI is seen in virtually all patients [4]. To confirm DS as the underlying cause of symptoms, clinical criteria such as retractable seizures in weeks or months aggravated by fever, without an obvious cause, should be supported by genetic testing, which is commercially available in some countries, including the United states [6]. Confirmation of SCN1A mutations, however, may not occur in up to 20% of cases despite clinical findings that are highly suggestive of DS [4]. The improvement in general care and introduction of antiepileptic drugs have reduced the mortality rate of DS and clonazepam, together with recently created topiramate and stiripentol have shown good long-term efficacy in managing children suffering from this type of epilepsy [7] [8]. Unfortunately, seizures are often refractory and DS is resistant to virtually all antiepileptics in many patients. Moreover, the condition is life-long and continuous medical and emotional support is necessary to reduce the burden of the disease on both the patient and his/her family.

Patient Information

Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy (SMEI), is a form of epilepsy that develops during the first year of life as a result of genetic mutations involving sodium channels in the nervous system. Namely, sodium is one of the most important electrolytes involved in generation and transduction of nerve signaling and aberrations in one of the subunits of channels responsible for its utilization is the main cause of disease. The exact reason why these mutations occur is unknown, and approximately 95% of all mutations arise de novo (meaning that there is no previous familial component of the disease). DS is considered to be a rare condition, affecting 1 in 20,000-40,000 children throughout the world and a small but significant predilection toward males has been observed. DS is characterized by the appearance of one-sided or generalized seizures during the first year of life (most commonly between 2-10 months) that are provoked by increased body temperature, which is why it is often misdiagnosed as febrile convulsions or other types of epilepsy. A distinguishing feature of DS is that seizures recur within weeks or months after the first episode and various seizure types may be encountered later on, including generalized or partial myoclonus, absence seizures and partial seizures. In addition to epilepsy, cognitive development is slightly impaired in the first few years of life, whereas photosensitivity, clumsiness and loss of body movement control (known as ataxia) may be reported in these patients as well. To make the diagnosis, the physician must obtain a proper patient history including the onset and course of the disease, while electroencephalography (EEG) and magnetic resonance imaging (MRI) are useful diagnostic tools. To confirm DS, however, genetic testing for SNC1A mutations may be performed, but not all patients are identified through genetic testing. Unfortunately, DS is highly resistant to antiepileptic therapy and drugs such as valproate and benzodiazepines pose little effect on patients. Moreover, lamotrigine, phenobarbital and carbamazepine, which are used for various types of seizures, are contraindicated as they may further aggravate seizures. Recent studies have shown that stripentol, in combination with valproate and clobazam, provides significant reduction of the disease burden in patients, but at this moment, seizures cannot be stopped by therapy. Avoidance of extensive sun exposure, prompt management of infections and use of drugs that reduce fever (antipyretics) are crucial preventive strategies for minimizing the risk of seizure occurrence. The overall mortality rates from this condition have been lowered from 10-15% to 5% through significant improvement in medical care, but the long-term prognosis of patients is not good, as seizures persist throughout life and most patients suffer from some degree of intellectual disability. Nevertheless, it is imperative to recognize this condition as a cause of epilepsy in infants and young children so that adequate care can be initiated as early as possible.

References

Article

  1. Millichap JJ, Koh S, Laux LC, Nordli DR. Child Neurology: Dravet syndrome: When to suspect the diagnosis. Neurology. 2009;73(13):e59-e62.
  2. Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet. 2001;68:1327–1332.
  3. Harkin LA, Bowser DN, Dibbens LM. Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus. Am J Hum Genet. 2002;70:530-536.
  4. Incorpora G. Dravet syndrome. Italian Journal of Pediatrics. 2009;35:27.
  5. Harkin LA, McMahon JM, Iona X, et al. The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain 2007;130:843–852.
  6. Ceulemans, B. Overall management of patients with Dravet syndrome. Dev Med Child Neurol. 2011;53:19–23.
  7. Chiron C. Current therapeutic procedures in Dravet syndrome. Dev Med Child Neurol. 2011;53(2):16–18.
  8. Inoue Y, Ohtsuka Y, Oguni H, et al. Stiripentol, open study in Japenese patients with Dravet’s Syndrome. Epilepsia. 2009;50:362-368.
  9. Kassai B, Chiron C, Augier S, Cucherat M, Rey E, Gueyffier F, et al. Severe myoclonic epilepsy in infancy: A systematic review and a meta-analysis of individual patient data. Epilepsia. 2008;49(2):343–348.
  10. Wolff M, Cassè-Perrot C, Dravet C. Severe myoclonic epilepsy of infants (Dravet Syndrome): natural history and neuropsychological Findings. Epilepsia. 2006;47(2):45-48.

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Last updated: 2019-07-11 21:52