Introduction

Epilepsy is a neuronal disease characterised by a sudden and significant increase in electrical discharge from neurons in the brain, leading to seizures. Seizures are recurrent and, depending on which part of the brain is affected, symptoms can manifest in different ways. The World Health Organisation estimates that every 7.6 per 1000 persons is likely to develop epilepsy, and a worldwide prevalence of 50 million people is currently affected by epilepsy.¹

Epilepsy and seizures

Seizure types in epilepsy are classified broadly as either focal or general (Table 1). Focal seizures occur when a localised section or lobe of the brain is affected and the manner in which a person reacts is dependent on which part of the brain is affected. A severe focal seizure can cause the overstimulation to migrate from one location of the brain to another. A general seizure on the other hand, will affect the entirety of the brain and the person is usually unconscious when this happens.

Seizures can be provoked by a range of stimuli inclusive of stress, alcohol consumption, drugs (both legal and illegal), lack of sleep or tiredness, and flashing lights or high contrast patterns (photosensitive epilepsy). 

Table 1:Types of epileptic seizures

Developmental and epileptic encephalopathies (DEEs)

DEEs is an umbrella classification term used to describe neurological disorders that comprise both epileptic encephalopathies (EEs) and developmental encephalopathies (DEs). EEs, as defined by the International League Against Epilepsy (ILAE) Commission, is the detection of frequent epileptiform activity (a specific pattern associated with an electroencephalogram evaluation) which significantly disrupts normal development in an individual.⁴ DEs refer to developmental delays or intellectual disabilities brought on by the existence of a non-progressive brain disorder. Since people with DEs are known to have a higher risk of developing epilepsy, it has been theorised that these developmental delays and intellectual abilities may invariably be the cause of epilepsy.⁵ In growing children, developmental or intellectual disabilities which may have been considered negligible or slight, can increase in severity as they get older.

DEEs therefore encompass a class of severe symptoms such as delay or regression in development, cognitive impairment, as well as seizures. In concert, the patient and caregiver are significantly affected by the burden of disease and lowered quality of life.⁵

Dravet syndrome

Dravet syndrome is a type of epileptic encephalopathy (DEE). It is a rare developmental disease, occurring in 1 out of every 15,700 births in the US.⁶ A significant number of patients (approximately 80%) with Dravet syndrome carry a mutation on the sodium channel alpha subunit 1 (SCN1A) gene, which plays an important role in neuronal excitation.^6,7

The onset of Dravet syndrome occurs in early infancy, with initial seizures being experienced between the age of 0–2 years⁶. Patients experience severe prolonged and frequent polymorphic seizures. That is, two or more types of seizures can occur.  Nominally triggered by a fever or infection, seizures in Dravet syndrome are resistant to current drug therapies used to treat epilepsies and are significantly difficult to manage. In addition, people with Dravet syndrome experience significant developmental, intellectual and motor function impairments, putting them at high risk of early mortality. The leading cause of death in people with Dravet syndrome is sudden unexpected death in epilepsy (SUDEP).⁵

Clinical features and presentation

Seizures in Dravet syndrome manifest early in life, usually in neonates between 2 and 15 months and their onset is triggered by changes in temperature, such as that instigated by a fever, infection or a bath.^6,8 Seizures that then follow through early childhood are lengthy (> 5 minutes), frequent (every few weeks), and polymorphic.

Polymorphic seizures in Dravet syndrome can  be hemi-clonic, affecting only one side of the body.  In approximately 25% of patients, seizures are triggered by visual stimuli⁹, and in most other cases they are unprovoked.⁸ Seizure incidence then tends to modify with age, occurring mainly during or around sleep.

Although characterised by seizures, non-seizure symptoms associated with Dravet syndrome cause just as significant concern as seizures since these tend to have significant emotional, social and economic burdens which negatively affect overall quality of life for both the child and caregiver. Non-seizure symptoms include lack of sleep or inability to establish good sleeping patterns, nutritional imbalance leading to growth impairment, motor and sensory issues, cognitive impairment and slowed speech development.⁶

Genetics and aetiology

A significant number of developmental and epileptic encephalopathies, inclusive of Dravet syndrome, are caused by mutations to genes responsible for neuronal activities such as neuronal and synaptic signalling and ion-channel function or regulation. Up to 80% of patients with Dravet syndrome have a pathological mutation to the sodium channel encoding SCN1A gene. Approximately 90% of these Dravet syndrome cases are  new mutations to the individual, while the remaining 10% are hereditary.¹⁰ Mutations in SCN1A, while common, are not exclusive to Dravet syndrome. Mutations in the genes CHD2, HCN1, GABRA1, GABRG2, SCN1B, SCN9A and STXBP1 have also been reported.¹¹ Infants with recurrent fever-induced seizures have a significant risk (approximately 50%) of developing Dravet syndrome. However, the likelihood of a child with a gene mutation developing Dravet syndrome is also thought to be age dependent. The risk of developing Dravet syndrome is estimated to be 85% in children up to 0.5 years, 51% up to 1 year and nil after 1 year.⁷

It is also worthwhile noting that mutations in SCN1A do not always lead to the development of Dravet syndrome  and mutations of this gene are also present in other disorders such as familial hemiplegic migraine type 3 (FHM3), epilepsy of infancy with migrating focal seizures (EIMFS) familial febrile seizures (FS) and genetic epilepsy with febrile seizures plus (GEFS+).¹²

Diagnosis

In making an initial diagnosis of epilepsy, an electroencephalogram (EEG) is the most relied on method for determining brain activity and confirming epileptic encephalopathies. This test illustrates electrical activity in the brain and measures epileptiform activity by way of spike and wave patterns that are specifically associated with seizures.¹³

When compounded with developmental difficulties, either pre-existing or due to EE, a physician may have cause to suspect Dravet syndrome and refer for further testing.¹⁴

Genetic testing for mutations in a panel of genes inclusive of SCN1A, is of particular importance in early diagnosis, as children with Dravet syndrome typically do not initially present with any obvious physical or mental dysfunction. Genetic testing for suspected cases of Dravet syndrome can be carried out by a physician if the following conditions have been met:

• The child has a has a history of seizures within 18 months of age
• Experienced a hemi-clonic seizure and prolonged seizure by 12 months

Clinical presentation of Dravet syndrome tends to differ from one patient to the next. This presents a challenge when acquiring a correct diagnosis. For example, epileptiform activity does not always present in children experiencing the initial febrile seizure, regardless of the severity.¹⁵ Symptom overlap with other DEEs such as Lennox Gastaut or ‘epilepsy limited to females with mental retardation’ (caused by a mutation to protocadherin 19 gene or PCDH19) often lead to misdiagnosis as differences between these syndromes are subtle.^6,16 Nonetheless, specific features will indicate that a physician or neurologist should suspect and not rule out testing for Dravet syndrome. Some of these features  include:^6,17

• There is a family history of epilepsy or febrile convulsions
• Cognitive and motor development is considered normal prior to seizure onset
• There is slowed development of intellectual and psychomotor skills from the second year of life, leading to crouch gait or pyramidal signs
• Seizures in the first year of life are in the first instance, febrile clonic and following this, are typically myoclonic. Two or more of these seizures are prolonged (> 10 minutes)
• Seizures are resistant to all forms of therapeutic treatment^5,6,17

Management & treatment of dravet syndrome

Seizures in patients with Dravet syndrome are often resistant to available antiepileptic medication, so focus may be given to managing and reducing the frequency and severity of convulsive seizures. This can go some way to improving  patients’ quality of life, reducing the risk of SUDEP and overall mortality. Identification and reduction of exposure to potential triggers, such as photosensitivity and sudden temperature changes is recommended. The use of antibiotics as a prophylaxis against fever may also be recommended.⁵

Pharmacological agents             

To achieve appreciable seizure control, patients with Dravet syndrome are normally administered at least two therapeutic drugs. Valproate and clobazam are traditionally the first two drugs prescribed for Dravet syndrome. The two drugs are prescribed as a combined therapy, since single administration is ineffective.¹⁸ However, the administration of valproate and clobazam does not meet expectations for many patients.¹⁹

Although associated with sodium ion channel dysfunction, treatment of Dravet syndrome with known sodium channel blockers used to treat epilepsies such as phenytoin or oxcarbazepine can worsen the condition. Others like Iamotrigene however, are thought to have some beneficial application, with seizures only becoming aggravated when withdrawing treatment.¹²

Recently approved drugs for managing seizures in Dravet syndromes are fenfluramine, stiripentol and cannabidiol.^5,12

Ketogenic diet

Patients on a ketogenic diet have been reported to have a significant reduction in the frequency and severity of seizures. The diet aims to mimic the body’s response to starvation in order to provide ketone bodies instead of glucose as the main energy source for the brain. The diet is high in fat, low in carbohydrate with a sufficient amount of protein. Additionally, it is thought that this diet can be beneficial in mitigating some developmental and behavioural dysfunctions¹⁹.

Vagus nerve stimulation                 

Although not overwhelmingly conclusive, there seems to be some evidence that electrical stimulation of the left cervical vagus nerve in patients with Dravet syndrome leads to a > 50% reduction in seizures in about 53% of all patients.²⁰

Advances in treatments for dravet syndrome

The next few years may yet prove to be exciting in terms of treatment advances for Dravet syndrome. Table 2 summarises treatments for Dravet syndrome which are currently undergoing clinical trials. At present, a number of novel therapeutics are in various stages of investigation and development with promising initial reports reducing seizure occurrence and severity. Successes from treatments developed for neurological disorders such as spinal muscular atrophy, Huntington’s disease and Batten’s disease has prompted researchers to investigate gene therapies with respect to Dravet syndrome¹² where early animal models have shown that viral vector gene therapy targeting increased expression of SCNA1 significantly reduced seizure frequency, severity and mortality risk.¹⁹  

Table 2 Clinical trials for treatment of dravet syndrome (ongoing)¹²

Conclusion

Dravet syndrome is a rare form of epilepsy characterised by both epileptic seizures and developmental dysfunctions. Disease onset is usually between 6 and 12 months of age and continues into adulthood. Comorbidities that develop through disease progression, such as intellectual and motor disabilities, as well as behavioural disorders, makes Dravet syndrome a high burden disease for both the patient and caregiver.

Treatment of Dravet syndrome is particularly challenging as symptoms can differ in individuals, it is resistant to currently available anti-epileptic drugs and its clinical presentation overlaps with a number of other neurological disorders which can often lead to misdiagnosis. Novel drugs offer promise in improving the management of seizures and therefore improving the quality of life for patients with Dravet syndrome. As an outlook, opting for a precision medicine approach with regards to gene therapies also has the potential to further drive effective treatments for patients.