Dravet syndrome as Presented to NORD

Dravet syndrome

Michelle Welborn, PharmD

written for:  National Organization for Rare Diseases

March 2009

Synonyms of Dravet syndrome

  • Severe Myoclonic Epilepsy in Infancy (SMEI)
  • Polymorphic Epilepsy in Infancy (PMEI)
  • Epilepsy with polymorphic seizures

Disorder Subdivisions

  • Febrile Seizures
  • Genetic Epilepsy with Febrile Seizures Plus (GEFS+) – formerly Generalized Epilepsy with Febrile Seizures Plus
  • Severe Myoclonic Epilepsy Borderline (SMEB)
  • Intractable Childhood Epilepsy with Generalized Tonic Clonic Seizures (ICE-GTC)

General Discussion
Dravet syndrome is a rare genetic epileptic encephalopathy with onset during the first year in an otherwise healthy infant.  Mutations of sodium channels in the brain, specifically SCN1A mutations,  cause  79% of diagnosed cases of Dravet syndrome.    Frequently referred to as a sodium channelopathy, this intractable epilepsy is characterized by unilateral (one-sided) clonic  or tonic clonic (grand mal) seizures that are prolonged (> 5 minutes) or progress to status epilepticus (>30 minutes) and require emergency management.   Myoclonic seizures, often called myoclonic jerks, are common and over time seizures present without fever, illness or heat triggers. Seizures are frequent and resistant to treatment.  Often the first seizure is associated vaccine administration at six months of age. Between one and four years of age, children develop other seizure types including atypical absence, eyelid myoclonia and non-convulsive seizures. All seizure types may be prolonged or lead to status epilepticus.  Seizures are treatment resistant and combination 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 and ataxia is common.  Confirmation of diagnosis, appropriate and aggressive seizure management, and implementation of global therapies are necessary to improve the outcome of children affected with Dravet syndrome.

Genetics of Sodium Channel Epilepsy Disorders

Sodium channel related seizure disorders encompass a spectrum that ranges

from simple febrile seizures (FS) and genetic epilepsy with febrile seizures plus

(GEFS+) at the mild end to Dravet syndrome (Ds) at the severe end.

FS——–GEFS+————-ICE-GTC—————SMEB—————-SMEI

Three hundred and thirty various SCN1A mutations have been associated with Dravet syndrome .  Type or location of the mutation is not well correlated to severity of illness or cognitive outcome; however, truncation mutations including frameshift and nonsense and de novo (mutation not passed from parent) mutations are more likely to be associated with more severe disease and impaired cognition than missense mutations.  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.

Epidemiology

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.

Ds 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.

Sodium Channel Related Epilepsy in Children

Febrile seizures (FS, FS+): childhood seizures that occur only

in association with fever

• Onset between ages 3 months and 6 years

• Fever usually higher than 38° C (without evidence of CNS infection)

• Autosomal dominant inheritance with reduced penetrance , which means 1) either sex child can inherit the gene; 2) 50% of offspring of affected individual will also carry the gene and 3)a person can carry the gene but not have seizures

• Mutations associated with febrile seizures:

FEB1, FEB2, FEB4,  SCN1B,  SCN1A, GABAA and GABRG2

• FEB4 may be the most common mutation in FS

• Treatment with drugs is not usually necessary unless seizures are prolonged

• 2008 International League Against Epilepsy (ILAE)[i] classification for FS: FS+ is classified under Genetic and Developmental Epilepsy syndromes by age of onset and is defined as a seizure disorder that is not traditionally given the diagnosis of epilepsy

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

• Onset before age one year

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

• Autosomal dominant inheritance, variable expressivity, incomplete penetrance

• 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, environmental, or

multi-genetic variability

• 2008 ILAE classification revisions

o “Genetic” replaces “Generalized” Epilepsy with Febrile Seizure-Plus (GEFS+)

o GEFS+ does not fit the current understanding of a syndrome as disorder with

relative phenotypic homogeneity that can be recognized on an individual level

o GEFS+ is now termed its “own cluster” or ”phenomenon” and is listed under

Genetic and Developmental Epilepsy syndromes

• SCN1A, SCN2A, GABAA, GABRG2 mutations, mostly in the form of missence

mutations are associated with GEFS+

Dravet Syndrome and Derivatives

Severe Myoclonic Epilepsy of Infancy Borderland2 (SMEB), a variety of definitions

for SMEB exist in the literature, and often SMEB is interchangeable with ICE-GTC;

SMEB is defined as variations of SMEI and often represents SMEI without

myoclonic seizures or SMEI void of one or more clinical characteristic

• Onset before age one year

• 69% have an SCN1A mutation5

• 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

• Lossin further divides SMEB into subcategories

• Not listed in ILAE classification system outside of Ds

Intractable childhood epilepsy with generalized tonic-clonic seizures

(ICE-GTC) is distinguished by the absence of other generalized seizures,

specifically myoclonic seizures

• Onset before age one year

• Seizures are frequent, prolonged, GTC seizures evolve to status epilepticus

frequently, fever and illness are triggers

• 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 (SMEI), is considered the most severe of the

SCN1A related epilepsies

• Onset before age one year

• Up to 79% diagnosed have a truncating (frameshift or nonsense) or

missense SCN1A mutation; additional deletions and splice sense mutations

have been identified

• Initial EEGs are usually normal, epileptiform activity appears over time –

generally by age 4 years

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

• Modest hyperthermia (low grade fever,bath, physical exertion), vaccines, illness,

excitation, and light fractionation are common triggers

Hemiconvulsive, 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

polypharmacy is necessary for acceptable seizure control

• Dravet et al have named a seizure type “obtundation status”1, implying

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

• In most cases sy age two, slowing in psychomotor development is noted;

regression of acquired skills and/or developmental delay usually appear in

varying degrees

• 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)

• 2008 ILAE classification revisions:

o In the 1989 ILAE classification, Dravet syndrome was listed as a

cryptogenic disorder with both focal and generalized features. 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 (what might have been called “idiopathic” in 1989),

and also perhaps a part of the GEFS+ spectrum. Ds is also classified in the

2008 revision as a Genetic and Developmental Epilepsy syndrome.

SCN1A phenotype overlap5 with known epilepsy syndromes

Cryptogenic generalized epilepsy

• Harkin et al reported a 24% rate of SCN1A mutation in children diagnosed

with a cryptogenic generalized epilepsy

Cryptogenic focal epilepsy

• Harkin et al reported a 22% rate of SCN1A mutation in children diagnosed

with a cryptogenic focal epilepsy; three out of five children in this study had a

diagnosis of severe infantile multifocal epilepsy and presented with early onset

multifocal seizures and later cognitive decline

Differential Diagnosis

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. Consideration of differential diagnosis in

positive family history of epilepsy including benign familial neonatal seizures,

benign familial infantile seizures, benign childhood epilepsy with centrotemporal

spikes, childhood occipital epilepsy, absence epilepsies is worthwhile.  A study published in the Lancet Neurology, a medical journal, in 2006  reported SCN1A mutations in 11 of 14 patients with alleged vaccine  related seizures and brain dysfunction (encephalopathy).

Consider SCN1A testing to confirm clinical diagnosis of Ds when

infant < 12 months presents or medical history reveals:

Differentiation of the spectrum of SCN1A related epilepsies and overlapping

epilepsy syndromes is difficult. Hattori et al developed a scored Ds

prediction tool for infants less than 12 months. An age of onset of febrile

seizure < 7 months, a total number of seizures > 5, and prolonged seizures

lasting more than 10 minutes were regarded as significant risk factors for Ds.

Other factors highly predictive of Ds were hemiconvulsions, partial seizures,

myoclonic seizures, and hot water–induced seizures.

I: Infant onset (<12 months); initial development,

EEG, MRI, metabolic studies normal

C:       Clonic hemiconvulsions common; modest temperature

elevation and illness are seizure triggers

E: Episodes frequent, prolonged, and treatment resistant

Knowledge of SCN1A mutation where EEG, MRI, or other objective data

suggest overlapping diagnosis of sodium channel mutation related AND other

known epilepsy syndrome such as West syndrome, Lennox Gastaut Syndrome,

temporal lobe epilepsy or frontal lobe epilepsy is useful for pharmacotherapy

guidance to avoid drugs that exacerbate seizures when SCN1A mutation exists;

understanding over overlapping encephalopathies will help define the spectrum of sodium channel related epilepsies.

Physical Characteristics

There are no physical characteristics of children with Ds reported in the

literature other than atypical dysmorphic traits in some children with

SCN1A deletions, thought to be associated with adjacent chromosomes

rather than the SCN1A region. Careful observation by the author of this guide

in over 200 exposures to children with Ds has uncovered strikingly similar

symmetrical facial features. Multi-nationally, children with Ds have large,

wide-set, almond shaped eyes; flat nasal bridge; marked low facial muscle

tone; small delicate nose; and soft chin with relatively heart shaped face. This

“baby face look” continues into adulthood.

Interdisciplinary Management

Ds leaves children cognitively and developmentally impaired— often severely.

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. Ds are in the early stages of investigation.

Children with Ds may be at increased risk for:

• Expressive and receptive language is often impaired;

early intervention with speech therapy optimizes potential

• Pronation of feet often goes unnoticed leading to painful orthopedic

conditions by adolescence; Ataxia and gait abnormality; 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, ADHD and other behavioral ers; familial autism as well

as headache and psychiatric disorders have been linked to SCN1A, SCN2A

and SCN3A mutations

Knowledge of SCN1A mutation where EEG, MRI, or other objective data

suggest overlapping diagnosis of sodium channel mutation related AND other

known epilepsy syndrome such as West syndrome, Lennox Gastaut Syndrome,

temporal lobe epilepsy or frontal lobe epilepsy is useful for pharmacotherapy

guidance to avoid drugs that exacerbate seizures when SCN1A mutation exists;

understanding over overlapping encephalopathies will help define the spectrum of sodium channel related epilepsies.

Pharmacotherapy of Sodium Channel Epilepsies Orphan and Compassionate Use Drugs

Stiripentol (Diacomit) Stiripentol (Diacomit-Biocodex, France) is authorized in the European Union in January, 2007 for use in conjunction with clobazam and valproate as adjunctive therapy of refractory generalized tonic-clonic seizures in patients with severe myoclonic epilepsy in infancy (SMEI or Dravet syndrome) whose seizures are not adequately controlled with clobazam and valproate.  On November 11, 2008, the FDA accepted stiripentol as an Orphan Drug. This acceptance was initiated and supported by the leadership of the Intractable Childhood Epilepsy Alliance (www.ICEpilepsy.org).

Stiripentol works indirectly as a cytochrome P450 coenzyme inhibitor, linearly increasing the area under the curve of drugs with major metabolism through this pathway. It also has weak GABA-ergic activity. The drug interactions associated with stiripentol delayed acceptance of this drug by the EMA until studies showed significant efficacy of STP+VPA+CBZ in children with Dravet syndrome. It is important to note the proven clinical utility to date of stiripentol in Dravet syndrome is for: 1) Children who have not reached adolescence; 2) Decreasing frequency and/or duration of seizures, particularly status epilepticus; and 3) Dravet syndrome in combination with clobazam and valproic acid. Clinical studies do not support the use of stiripentol outside of this combination. Further, caution should be exercised when adding stiripentol to CBZ and VPA due to significant increases in active drug and metabolites which may lead to toxicity. STP: 50 mg/kg/day with careful monitoring of VPA levels and adverse effects due high CLB levels;  increase to 100 mg/kg/day with a max of 4 g/day per seizure control and tolerance;  divide BID – TID with meals.

Clobazam (Frisium-Ovation, Chicago) is an atypical benzodiazepine with activity at the 1,5 BZD receptor.  Traditional BZDs bind to the 1,4 BZD receptor.  Clobazam is less sedationg and less likely to blunt cognition compared to traditional BZDs.  Nor-clobazam (N-CBZ), is a potent active metabolite. Blood levels of traditional BZDs such as clonazepam (CZP) or lorazepam will increase when STP is associated; however, active metabolites of these compounds are not as potent as N-CBZ and controlled clinical trials of STP with traditional BZDs are lacking.  CBZ may be used alone or with STP combination therapy for Ds. CLB (clobazam): 0.2 – 2 mg/kg/day divided BID or TID; reduce CLB by 50% when STP is added to avoid toxicity expressed by aggressive behavior, hyperactivity, insomnia, or lethargy – titrate as necessary for seizure control as tolerated.

Though not exact, about a 1:10 relative dose proportion exists between CZP:CLB; when converting CZP to CLB it is prudent to introduce CLB as CZP is weaned to avoid precipitation of SE. Ovation Pharmaceuticals has received Orphan Drug status for CLB use in LGS and is pursuing full FDA approval.

Epistatus (buccal midazolam maleate-Special Products, London) is available as a special product in the UK.  This novel compound is a patented maleate midazolam salt with optimal pH for mucosal membrane absorption.  Special Products of London owns this compound and will seek acceptance of regulatory authorities and approval multi-nationally in time.  In the most recent Cochrane Reviw of managing acute tonic-clonic convulsions in children including status epilepticus, Appleton et al concluded “where intravenous access is unavailable there is evidence from one trial that buccal midazolam is the treatment of choice”.  Standardized doses of buccally or nasally administered midazolam are not accepted by any regulatory agency at this time; however, 0.3 mg/kg/dose has been utilized in most published clinical studies.

Trials are lacking for use of STP combination in conjunction with ketogenic diet (although this combination is being utilized); appetite suppression is common; macrolide antibiotics are commonly prescribed and should be avoided when possible due to drug interaction – caution parents to be aware of interactions with other AEDs, natural supplements, and drugs and to ask before giving to child.

STP, CLB and Epistatus are not available in the US and have limited availability in other parts of the world outside of Europe; however compassionate use policies allow import with appropriate process for each country. STP may be obtained directly through Biocodex Pharmaceuticals, France pursuant to compassionate use regulations specific to each country. Contact Biocodex at www.biocodex.com.

STP, CLB, and Epistatus may also be obtained through Caligor Pharmacy in NY for patient s living in the United States. In the US, Caligor Pharmacy in New York serves as an imported for compassionate use products and can obtain STP and CLB. Contact Caligor Pharmacy at 212.369.6000 or FAX: 212.879.8415. Patients may choose to obtain medications from overseas pharmacies or through websites. Obtaining compassionate use products by these methods are not in compliance with US FDA governance and product quality may be questionable. For information or guidance on compassionate use or Orphan Drugs for intractable epilepsy, please contact us at info@ICEpilesy.org.  ICEpilepsy does not promote the use or market  non regulated drugs in the United States or other other countries.  ICEpilepsy serves the child with intractable epilepsy by providing peer reviewed literature, research, advocacy, and resources for the child neurologist to optimize treatment in Dravet syndrome and other intractable childhood epilepsy syndromes.

TPM (topirimate):  5-9 mg/kg/day (up to 25 mg/kg/day have been reported necessary for seizure control in some patients with Ds) divided BID per manufacturer; higher doses have been reported and may be necessary for acceptable seizure control; cognition and language impairment should be monitored and dose minimized when possible; hypohidrosis or anhydrosis are side effects and may increase sensitivity to heat; TPM used with VPA may cause ammonia induced encephalopathy –check ammonia levels in this combination if behavioral changes occur.

VPA (valproate): 30-50 mg/kg/day divided appropriately; serum concentration target 70-100 mg/L; higher serum concentration may be necessary for acceptable seizure control if tolerable; baseline and regular monitoring of LFTs in young children is prudent due to risk of liver toxicity in children under 2 years; supplementation with L-Carnitine 50 -100 mg/kg/day may reduce risk of liver toxicity from carnitine depletion; reduction of VPA by 30% when baseline serum concentration in lower range and up to 50% when baseline serum level is on higher range when adding STP is added due to CP450 interactions – baseline and weekly VPA levels during STP titration will help avoid VPA toxicity.

CZP (clonazepam): 0.03 – 0.1 mg/kg/day divided BID or TID

References

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Written and submitted by:  Michelle Welborn, PharmD, President/CEO Intractable Childhood Epilepsy Alliance

Thanks to Dr. Charlotte Dravet for her generous review and contribution to this article.  Thanks to Dr.  Catherine Chiron for her input.

Organizations related to Dravet syndrome

  • Intractable Childhood Epilepsy Alliance (ICEpilepsy)

e-mail: info@icepilepsy.org

Home page:  www.ICEpilepsy.org


[i]ILAE  is the world’s preeminent association of physicians and other health professionals working towards a world where no persons’ life is limited by Epilepsy. Its mission is to provide the highest quality of care and well-being for those afflicted with the condition and other related seizure disorders.  Naming and classification of seizure types and syndromes are orchestrated by this organization.

http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Dravet%20Syndrome

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