Dravet Syndrome (DS)

Dravet syndrome (DS) is a rare, severe epileptic and developmental encephalopathy with an infantile onset. The majority of patients with DS carry a mutation in the sodium channel gene SCN1A that leads to neurological dysfunction, such as prolonged seizures. Because the condition is lifelong and progressive, its manifestations evolve as patients age.^1,2

The clinical features of DS typically include refractory seizures, developmental and behavioral delay, cognitive impairment, motor dysfunction and gait difficulties, orthopedic conditions, delayed language and speech difficulties, growth and nutrition problems, sleep cycle disruptions, frequent respiratory tract infections, sensory integration disorders, and dysautonomia.^2,3

The mortality rate is high in infants with DS, but some survive through adulthood with persistent motor and cognitive dysfunction. In general, DS has a mortality rate of 15% to 20%; status epilepticus and sudden unexpected death in epilepsy (SUDEP) are the most common causes of death.^1,4

Neurological Features of DS

Seizure Presentation

The first symptoms in patients with DS are epileptic seizures, which appear during infancy or early childhood in a previously normal child. Seizure onset is typically between the ages of 2 months and 15 months; in rare cases, it may be as early as 1 month or as late as 20 months. The seizures are generally frequent, prolonged, and difficult to manage with current medications. The seizure presentation varies with age. Although the initial seizures are typically generalized or focal clonic, a variety of seizure types (pleomorphic epilepsy) appear later in the disease course.^5-7

Initial Seizures

Initial seizures are typically generalized tonic-clonic or focal clonic (sometimes hemiclonic), recurrent, and often prolonged (lasting over 5 minutes). The results of magnetic resonance imaging (MRI) of the brain and interictal electroencephalography (EEG) are usually normal before 12 months of age. The initial seizure may or may not be triggered by factors such as fever, infection, immunization or vaccination, environmental heat (including hot baths), sunlight, visual pattern stimulation, exercise, and overexertion.^5-7 

In approximately 50% of cases, the first seizure is febrile. Later, the seizures may evolve to status epilepticus, a state in which a continuous seizure lasting 5 to 30 minutes requires emergency medical intervention.^5-7

Read more about DS signs and symptoms

Progressive Seizures

During the later part of the first year and the second year of life, other types of seizures (myoclonic, atypical absence, focal impaired awareness, clonic, atonic, tonic seizures, and obtundation status) appear that are predominantly brief.^5-7 

Sleep/nocturnal tonic and tonic-clonic seizures may appear in clusters at approximately 4 to 5 years of age and increase during adulthood. The main triggers of seizures in this age group are fever, physical activity, change in environmental temperature, excitement, stress, and lights, particularly flashing lights. Although status epilepticus may occur frequently before 5 years of age, status epilepticus and obtundation status become less frequent with time and are generally not evident in adolescence and young adulthood.^5-7

Characteristic EEG Patterns

Typically, an interictal EEG background after the age of 2 years is slow and often associated with epileptiform discharges (focal, multifocal, and generalized). Interictal frontal discharges are often seen in patients with sleep cluster seizures. In some cases, photoparoxysmal responses may occur at onset and increase over time.^5-7

Read more about DS testing

MRI Results

MRI may show variable degrees of cortical atrophy and hippocampal sclerosis as the patient ages.^5-7

Neurological and Motor Impairments

Hypotonia, impaired dexterity, and problems with movement, balance, and gait may become apparent as children develop, becoming progressively more pronounced as they age. Gait abnormalities including ataxia or crouch gait are noted in approximately half of school-age children (6 to 11 years) and in most teens and young adults with DS. Most adults with DS have problems that resemble parkinsonian features, including rigidity, bradykinesia, parkinsonian gait (stiff, stooped, unsteady), and postural instability.^7-9

Read more about DS comorbidities

Dysautonomia

Dysautonomia, or disruption of the autonomic nervous system, occurs commonly in DS, but the underlying cause is not well understood. In patients with DS, the regulation of certain autonomic processes, such as body temperature, sweating, heart rate, blood pressure and digestive processes, is dysfunctional.^9,10

Clinical Features of Developmental Delay in DS

Development is usually normal before 18 months of age. However, subtle delays in development are commonly seen in children between the ages of 18 and 36 months. By the age of 3 years or older, most children exhibit intellectual disability that worsens with time; most teens and adults with DS have moderate to severe intellectual disability that affects learning, cognition, speech, language, visual perception, and motor development. Motor system dysfunction manifests as ataxia, tremors, dysarthria, and pyramidal and extrapyramidal signs.^7-9

Read more about DS life expectancy

Clinical Features of Behavioral Disturbance in DS

The most common behavioral disturbances in DS are autistic-like traits, attention-deficit disorder (ADD), attention-deficit/hyperactivity disorder (ADHD), preservation, obsessiveness about specific things, aggressiveness, irritability, agitation, relational difficulties, opposition, and hoarding behavior.^7-9 

Motor and cognitive impairment also influence behavioral changes, significantly affecting social life and adaptive behavior. As children with DS reach adolescence and adulthood, depression and anxiety become more prevalent and can be seen in most adults.^7-9

Read more about DS prognosis

References

1. Dravet syndrome. NORD. Updated July 24, 2020. Accessed March 15, 2023.
2. Dravet syndrome. NIH | National Institute of Neurological Disorders and Stroke. Accessed March 15, 2023.
3. What is Dravet syndrome. Dravet Syndrome Foundation. Accessed March 15, 2023.
4. Cardenal-Muñoz E, Auvin S, Villanueva V, et al. Guidance on Dravet syndrome from infant to adult care: road map for treatment planning in Europe. Epilepsia Open. 2022;7(1):11-26. doi:10.1002/epi4.12569
5. Zuberi SM, Wirrell E, Yozawitz E, et al. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022;63(6):1349-1397. doi:10.1111/epi.17239
6. The diagnosis and treatment of Dravet syndrome. Dravet Syndrome Foundation. Accessed March 15, 2023. 
7. Wirrell EC, Hood V, Knupp KG, et al. International consensus on diagnosis and management of Dravet syndrome. Epilepsia. 2022;63(7):1761-1777. doi:10.1111/epi.17274
8. Anwar A, Saleem S, Patel UK, Arumaithurai K, Malik P. Dravet syndrome: an overview. Cureus. 2019;11(6):e5006. doi:10.7759/cureus.5006
9. Comorbidities in Dravet syndrome. Dravet Syndrome Foundation. Accessed March 15, 2023.
10. Berg AT, Coffman K, Gaebler-Spira D. Dysautonomia and functional impairment in rare developmental and epileptic encephalopathies: the other nervous system. Dev Med Child Neurol. 2021;63(12):1433-1440. doi:10.1111/dmcn.14990

Reviewed by Hasan Avcu, MD, on 3/16/2023.

---

Erum Naqvi, PhD

Erum Naqvi obtained her Ph.D. in Molecular Medicine from Hannover Medical School (Germany) after completing her Masters in Biomedical Science and Bachelors in Microbiology from University of Delhi (India). She has several years of experience as a science writer.