55 Kenosia Avenue
Danbury, CT 06810
Phone: 203.744.0100
Toll Free: 1.800.999.6673
http://rarediseases.org

Dravet Syndrome Spectrum

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Copyright 2009, 2012

NORD is very grateful to Michelle Welborn, PharmD, President/CEO of Intractable Childhood Epilepsy Alliance for the creation of this report; Charlotte Dravet, MD and Dr. Catherine Chiron, for assistance in the review of this report.

Synonyms of Dravet Syndrome Spectrum

Disorder Subdivisions

General Discussion

Dravet syndrome spectrum disorders are rare genetic epileptic encephalopathies (dysfunction of the brain) with onset during the first year of life in an otherwise healthy infant. There is a spectrum of severity ranging from no clinical symptoms, to simple febrile seizures, and extending to Dravet syndrome, which is the most severe. Mutations of the SCN1A gene cause 79% of diagnosed cases of Dravet syndrome. Frequently referred to as a sodium channelopathy, this intractable (uncontrollable) epilepsy is characterized by unilateral (one-sided) clonic or tonic clonic (grand mal) seizures that may be prolonged (> 5 minutes) or progress to status epilepticus (>30 minutes). Myoclonic seizures, often called myoclonic jerks, are common but not always present. Over time seizures present without fever, illness or heat triggers. Seizures are frequent and resistant to treatment. The first seizure is often associated with vaccine administration at six months of age. Infants eventually develop other seizure types including atypical absence, eyelid myoclonia and non-convulsive seizures. Multiple drug therapy is necessary for acceptable seizure control. Some anti-epileptic drugs exacerbate seizures and should be avoided. In most cases, surgery is not indicated. The initial EEG is normal but within the second or third year of life, brief generalized spike, polyspike, or polyspike-wave paroxysms appear. MRI and metabolic studies are normal. Developmental delays appear to varying degrees in most patients by age two years and ataxia (abnormal gait) is common. Appropriate and aggressive seizure management, and implementation of global therapies are necessary to improve the outcome of children affected with Dravet syndrome spectrum disorders.

Symptoms

Febrile seizures (FS, FS+): childhood seizures that occur only in association with fever:

· Onset between ages 3 months and 6 years

· Seizures only with fever usually higher than 38° C (without evidence of CNS infection)

· Gene mutations associated with febrile seizures: FEB1, FEB2, FEB4, SCN1B, SCN1A, GABAA and GABRG2

· FEB4 may be the most common gene mutation in FS

· Treatment with drugs is not usually necessary unless seizures are prolonged, child typically outgrows prior to adolescence. Development is normal.

· 2008 International League Against Epilepsy (ILAE) classification for Febrile Seizures: seizure disorder that is not traditionally given the diagnosis of epilepsy. Febrile Seizures+ (FS+) is classified under Genetic and Developmental Epilepsy Syndromes. Children with FS+ may have prolonged seizures with fever or atypical seizures outside of generalized tonic clonic seizures during fever. Development is typically normal and child usually outgrows seizures by adolescence.


Genetic epilepsy with febrile seizures plus (GEFS+): refers to a family rather than an individual:

· Onset in infancy or early childhood (before 36 months)

· Often presents as severe or atypical febrile seizure (FS+)

· Occasional tonic, clonic, myoclonic, or absence seizures

· Usually responsive to medication, seizures remit by late childhood or early adolescence

· Good prognosis for cognitive development in most cases; however, spectrum of intellectual ability exists

· Offspring of affected parent, siblings, or identical twins may express different phenotypes implying genetic mosaicism (parent may carry mutated genes in DNA other than blood including egg or sperm), environmental, or multi-genetic variability

· In the 2008 International League Against Epilepsy (ILAE) classification revisions
"Genetic" replaces "Generalized" Epilepsy with Febrile Seizure-Plus (GEFS+) and is classified under "Genetic and Developmental Epilepsy Syndromes"

· GEFS+ does not fit the current understanding of a syndrome as disorder with relative phenotypic homogeneity that can be recognized on an individual level

· GEFS+ is now termed its "own cluster" or "phenomenon" and is listed under Genetic and Developmental Epilepsy syndromes

· SCN1A, SCN2A, SCN1B, GABAA, GABRD, GABRG2 gene mutations are associated with GEFS+


Epilepsy with mental retardation limited to females (EMRF):

EMRF is a recently discovered disease that shares many Dravet syndrome features but occurs only in females. Scientists are working to understand the full spectrum of this disorder and to discover improved treatment.

· X-linked disorder affecting females and sparing males (father carries the gene but is unaffected, transmits it to female offspring)

· Caused by mutation in protocadherin 19 gene (PCDH19)

· Seizure onset in first three years

· Multiple seizure types, including febrile seizures, drug resistant

· Intellectual ability varies from normal to severely delayed, but most (67%) patients have borderline intellectual ability (typically a better prognosis vs. Dravet Syndrome). Autistic traits are common.


The following electroclinical syndromes are within the Dravet syndrome spectrum:
Severe myoclonic epilepsy of infancy borderline (SMEB):

A variety of definitions for SMEB exist in the literature, and often SMEB is interchangeable with intractable childhood epilepsy with generalized tonic clonic Seizures (ICE-GTC). Children with SMEB do not have myoclonic seizures or other clinical characteristics associated with Dravet syndrome.

· SMEB and ICE-GTC are associated with the same gene mutations as Dravet syndrome, including SCN1A, SCN1B, SCN2A, GABRD, GABRG2. SCN1A is the predominant gene mutation responsible for disease.

· Onset before age one year

· 69% have an SCN1A mutation

· Seizures may be frequent, prolonged, and include status epilepticus or may present on the milder end of the spectrum

· SMEB does not imply a more favorable cognitive prognosis

· Not listed in ILAE classification system outside of DS


Intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC):
ICE-GTC is distinguished by the absence of other generalized seizure types, specifically myoclonic seizures.

· Onset before age one year

· Seizures are frequent, prolonged, GTC seizures evolve to status epilepticus frequently, fever and illness are triggers. Myoclonic seizures are not present.

· Poor prognosis for cognitive development; distinction from DS is difficult; alternating hemi-convulsions and or myoclonic seizures suggest a DS diagnosis.

· 2008 ILAE classification system: not listed

· SCN1A mutation in 79% reported cases; GABAA and GABRG2 mutations are also reported.


Dravet syndrome:

Dravet syndrome is considered the most severe of the SCN1A related epilepsies.
· Onset before age one year

· Up to 79% diagnosed have an SCN1A mutation

· Initial EEGs are usually normal, but become abnormal over time - generally by age 4 years

· Early seizures are often prolonged febrile seizures, or status epilepticus (>30 min)

· Modest temperature elevation (low grade fever, warm bath, physical exertion), vaccines, illness, excitation, and light fractionation are common triggers

· Hemi convulsive, myoclonic, GTC, absence, atypical absence seizures, and non-convulsive seizures with or without fever appear over time: "eye blink seizures" which may be myoclonic or atypical absence commonly appear in the toddler years; prolonged seizures, status epilepticus, and non-convulsive status epilepticus is common; seizures are treatment resistant and a multiple drug regimen is necessary for acceptable seizure control.

· A seizure type "obtundation status", implying non-convulsive seizures with impairment of consciousness with variable intensity lasting hours to days; EEG shows diffuse dysrhythmia of slow waves with focal and diffuse spikes.

· Infants are typically developing prior to seizure onset

· Slowing in development noted by age 2 in most cases and regression of acquired skills and/or developmental delay usually appear in varying degrees; however, there are reports of normal development in children diagnosed with Dravet syndrome. Autistic spectrum disorder, attention deficit disorder, and other behavioral disorders are common as are sleep disturbances.

· Painful orthopedic conditions may result from low motor tone, pronation, and abnormal gait.

· Neurologic symptoms such as ataxia or tremor appear over time.

· Mortality rate is up to 20% by age 20 years, due to accident or sudden unexpected death (SUDEP)

· The 2008 ILAE revision classifies DS as an epileptic encephalopathy with onset during the first year of life and of a fundamental genetic basis, most frequently a sodium channelopathy, and also perhaps a part of the GEFS+ spectrum. DS is also classified in the 2008 revision as a Genetic and Developmental Epilepsy syndrome.

Causes

Mutations of the SCN1A gene cause 79% of diagnosed cases of Dravet syndrome. To date, more than 400 SCN1A mutations have been identified. The type or location of the mutation is not well correlated to severity of illness or cognitive outcome, however, de-novo mutations (mutation not passed from parent) are more likely to be associated with more severe disease and impaired cognition than mutations passed from a parent. The course of disease or clinical outcome in a child that has inherited an SCN1A mutation from a parent with a less severe clinical presentation is not clear cut as multi-genetic variability has been reported in the literature and the spectrum of this genetic epilepsy is not completely elucidated.

Genetic and environment factors contributing to this spectrum are not fully understood.

Affected Populations

Dravet syndrome is a rare disorder with an incidence estimated between 1:20,000 and 1:40,000 representing about 7% of all severe epilepsies starting before the age of 3 years. Prevalence of SCN1A related seizure disorders, syndromes, and encephalopathies are currently difficult to estimate as the commercial availability of genetic testing is recent.

Febrile seizures affect 2- 5% of children in North America and Europe and 6-9% of children in Japan. Thirty five percent of first and 33% of recurrent febrile seizures had one or more complex features such as focal onset (affecting one side of the brain), duration 10 minutes or greater, or multiple seizures during the illness. Epidemiologic studies of GEFS+ are lacking; no comprehensive epidemiology reports are found in the literature.

Related Disorders

More common diagnoses such as trauma, hypoxia, sequelae of meningitis or hemorrhage, infectious or autoimmune cerebritis, vasculitis, paraneoplastic syndrome, toxins (including
drug withdrawal), endocrinopathy, endocrinopathy pyridoxine-dependent seizures and B6-related epilepsies, folinic acid-responsive seizures, inborn errors of metabolism, including mitochondrial dysfunction, and glucose transporter type 1 deficiency should be ruled out before less obvious genetic mutations are implicated as cause of seizure activity.

If there is a family history of epilepsy including benign familial neonatal seizures,
benign familial infantile seizures, benign childhood epilepsy with centrotemporal
spikes, childhood occipital epilepsy, absence epilepsies it is worthwhile to determine if child has one of these epilepsy types.

SCN1A mutations have also been reported in children diagnosed with a cryptogenic generalized epilepsy and cryptogenic focal epilepsy.

Standard Therapies

Diagnosis
Dravet syndrome often presents around age six months, near the time of six month vaccinations. The vaccine, a cold or a fever, are triggers for seizures. If a child presents with a seizure around the time of 6 month vaccination and has a subsequent seizure (especially if seizures prolonged) with or without a trigger prior to the first birthday, SCN1A gene testing may be indicated.

Consider SCN1A testing to help clinical diagnosing of Dravet syndrome when it is not certain and medical history reveals:

I: Infant onset (<12 months); initial development, EEG, MRI, metabolic studies normal; subsequent developmental delays

C: Clonic hemi-convulsions (one-sided seizure) common; modest temperature elevation and illness are seizure triggers

E: Episodes may be frequent, prolonged, and are treatment resistant

Differentiation of the spectrum of SCN1A related epilepsies and overlapping epilepsy syndromes is difficult. Hattori et al developed a scored Dravet syndrome prediction tool for infants less than 12 months:

· An age of onset of febrile seizure < 7 months
· Total number of seizures > 5
· Prolonged seizures lasting more than 10 minutes were regarded as significant risk factors for DS. Other factors highly predictive of DS were hemi-convulsions, partial seizures,
myoclonic seizures and hot water - induced seizures.

Treatment
The following drugs should be avoided in children with a diagnosis of Dravet syndrome OR in patients with a confirmed SCN1A gene mutation because they are likely to WORSEN seizures.

Phenytoin (Dilantin), fosphenytoin (Cerebyx, Prodilantin), carbamazepine (Tegretol), oxcarbazapine (Trileptal), lamotrigine (Lamictal), vigabatrin (Sabril), rufinamide (Banzel) and tiagabine (Gabatril) . Phenytoin or fosphenytoin are likely to be administered in the emergency department during a prolonged seizure - avoid these drugs in emergency management of children with Dravet syndrome.

Parents should be provided with instructions from the neurologist on how to treat fever and should have a written protocol for emergency management of prolonged seizures (> 5 minutes) including instructions for parents, paramedics, and emergency department staff regarding avoiding phenytoin and fosphenytoin. EEG monitoring in the emergency room setting may be necessary to determine if the child is in non-convulsive status epilepticus.

Dravet syndrome is extremely resistant to treatment. In clinical studies, the most well documented and proven combination of drugs for Dravet syndrome include valproic acid, clobazam, and stiripentol (Diacomit). Clobazam has been available for more than 25 years outside of the US and was FDA approved in 2011. Stiripentol is not FDA approved in the US, but may be obtained by importing for compassionate use. Please visit www.ICE-Epilepsy.org for more information about obtaining stiripentol. Topirimate (Topamax), zonisamide (Zonegran), levetiracetam (Keppra), and the ketogenic diet have evidence of efficacy in this syndrome. Use of more than one drug is necessary to get adequate control of seizures in most cases. Felbamate (Felbatol), ethosuximide (Zarontin), and bromides have been useful for controlling certain seizure types. To date, none drug therapy has shown equal efficacy to the stiripentol, valproic acid, and clobazam combination in published clinical trials.

DS often leaves children cognitively and developmentally impaired. Developmental assessments should begin as early as possible and be repeated regularly. Early implementation of global therapies is essential. Children with DS should receive physical, occupational, speech, and social/play therapies and an enriched environment is encouraged.

Expressive and receptive language is often impaired in children with DS and early intervention with speech therapy optimizes potential for improvement.

Pronation of feet often goes unnoticed leading to painful orthopedic conditions by adolescence including ataxia and gait abnormalities. Physical therapy and preventative orthotics may correct or prevent these problems. Low muscle tone is prevalent.

Chronic infection, low humoral immunity, growth, nutrition, and sleep disorders are common. Dysautonomias have been associated and are being studied.

Autistic spectrum, attention deficit hyperactivity disorder (ADHD) and other behavioral disorders, familial autism, as well as headache and psychiatric disorders have been linked to SCN1A, SCN2A and SCN3A mutations.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Organizations related to Dravet Syndrome Spectrum

NORD offers an online community for this rare disease. RareConnect was created by EURORDIS (European Rare Disease Organisation) and NORD (National Organization for Rare Disorders) to provide a safe space where individuals and families affected by rare diseases can connect with each other, share vital experiences, and find helpful information and resources. You can view these international, rare disease communities at www.rareconnect.org.

References

TEXTBOOK
Scheffer I, Berkovic S. Generalized (genetic) Epilepsies with Febrile Seizures Plus. In: Engel J, Pedley T. Epilepsy: A Comprehensive Textbook. Philadelphia, PA: Lippincott, Williams & Wilkins; 2007: 2553-2662.

Dravet C, Bureau M, Oguni H, et al. Severe myoclonic epilepsy in infancy. In: Roger J, Bureau M, Dravet C, Genton P, eds. Epileptic Syndromes in Infancy, Childhood and Adolescence, 4th ed. Montrouge, France: John Libbey Eurotext; 2005:81-103.

JOURNAL ARTICLES
Lossin. A catalog of SCN1A variants. Brain Dev. 2009;31(2):114-30.

Sijbet AE, Sithinamsuwan P, et al. Does an SCN1A gene mutation confer earlier age of onset of febrile seizures in GEFS+? Epilepsia. 2009;50(4):953-56.

Scheffer IE, Turner SJ, et al. Epilepsy and mental retardation linked to females: an under-recognized disorder. Brain. 2008;131(4):918-27.

Korff C, Laux L. Dravet syndrome: a Retrospective study of 16 patients. Jour Child Neur. 2007; 22:185-94.

Harkin LA, McMahon JM. The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain. 2007;130(Pt 3):843-52.

Gardiner M. Molecular genetics of infantile nervous system channelopathies. Early Hum Dev. 2006;82(12):775-9.

Berkovic SF, Harkin L, McMahon JM, et al. De-novo mutation of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study. Lancet Neurol. 2006;5(6):488-92.

Stephani U. The natural history of myoclonic astatic epilepsy (Doose syndrome) and Lennox-Gastaut syndrome. Epilepsia. 2006;47(2):53-5.

Guerrini R, Dravet C, et al. Lamotrigine and Seizure Aggravation in Severe Myoclonic Epilepsy. Epilepsia. 2005;39:508-512.

Caraballo R, Cersosimor R. et al. Ketogenic Diet iin patients with Dravet syndrome. Epilepsia. 2005;46:1539-44.

Scheffer I, et al., Neonatal epilepsy syndromes and GEFS+. Epilepsia. 2005;46(10):41-7.
Kimura K, Sugawara T. A missense mutation in SCN1A in brothers with severe myoclonic epilepsy in infancy (SMEI) inherited from a father with febrile seizures. Brain & Dev. 2005;27:424-430.

Grosso S. et al. Efficacy and safety of topiramate in refractory epilepsy of childhood: long-term follow up study. Jour of Child Neur. 2005;20(11):893-97.

McIntyre, J Robertson S, et al. Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomized controlled tiral. Lancet. 2005; 366:205-210.

Nabbout R, Gennaro E, et al. Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy. Neurology. 2003;60:1961-7.

Kutlu NO, Dogrul M, Yakinci C, Soylu H. Buccal midazolam for treatment of prolonged seizures in children. Brain Dev. 2003 Jun;25(4):275-8.

Fisgin T, Gurer Y. Effects of intranasal midazolam and rectal diazepam on acute convulstions in children: prospective and randomized study. J Child Neurol. 2002;17:123-6.

Iwasaki N, Nakayama J. Molecular Genetics of Febrile Seizures. Epilepsia. 2002;43:32-35.

Hurst D. Epidemiology of Severe Myoclonic Epilepsy of Infancy. Epilepsia. 2001;42:796-803.

Pellock JM. Tiagabine (Gabitril ) Experience in Children. Epilepsia. 2001;42(3):49-51.

Chiron C, Marchand MC, Tran A, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group. Lancet. 2000;356(9242):1638-42.

Scheffer I, Berkovic S. Generalized Epilepsy with Febrile Seizures Plus: A genetic disorder with heterogeneous clinical phenotypes. Brain. 1997;120:479-490.

Yakoub M, et al., Early diagnosis of severe myoclonic epilepsy in infancy. Brain Dev. 1992;14;299-303.

INTERNET
Miller IO, Sotero de Menezes MA. (Updated November 10, 2011). SCN1A-Related Seizure Disorders. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2011. Available at http://www.genetests.org. Accessed April 24, 2012.

Report last updated: 2012/09/06 00:00:00 GMT+0