Dravet syndrome (DS) is a rare, severe form of epilepsy beginning in infancy, often classified as a developmental and epileptic encephalopathy. It is characterized by drug-resistant seizures that are notoriously difficult to control with medication. While many individuals survive into adulthood, DS significantly increases the lifelong risk of premature mortality compared to the general population.
The Genetic Origin and Early Manifestation
The underlying cause of Dravet syndrome in approximately 80% of cases is a mutation in the SCN1A gene. This gene provides instructions for making the NaV1.1 subunit of the voltage-gated sodium channel. The mutation generally results in a loss-of-function, meaning the channels do not work correctly or are not produced sufficiently. Since these channels are highly concentrated in inhibitory neurons, their dysfunction reduces inhibitory signaling, causing hyperexcitability and frequent seizures.
The onset of Dravet syndrome typically occurs within the first year of life, often between four and twelve months of age. Initial seizures are frequently prolonged, lasting more than ten minutes, and are often triggered by fever or high body temperature. These early seizures may appear as generalized tonic-clonic seizures, affecting the entire body, or as hemiclonic seizures, affecting only one side. The initial presentation in an otherwise healthy infant often makes diagnosis challenging.
Understanding Mortality Risk and Causes
Premature mortality affects an estimated 15% to 20% of patients before adulthood. The leading cause of death is Sudden Unexpected Death in Epilepsy (SUDEP), accounting for nearly half of all DS-related fatalities. SUDEP is the sudden, unexpected death of a person with epilepsy, typically occurring during sleep, where no other cause is found upon autopsy. The risk of SUDEP is approximately 15 times higher in children with Dravet syndrome compared to those with other childhood epilepsies.
The high incidence of SUDEP is likely due to uncontrolled, generalized tonic-clonic seizures combined with the underlying SCN1A gene mutation. Seizures disrupt vital functions, such as breathing and heart rhythm. The other primary cause of death is status epilepticus, defined as a single seizure lasting longer than five minutes or a series of seizures without recovery. Status epilepticus is a medical emergency that can cause brain damage and death.
Seizure-related accidents also contribute to mortality, including drowning or injuries sustained during a convulsive episode. The mean age of death is often young, with a large percentage occurring before the age of ten. Proactive management of seizure control is paramount.
Comprehensive Impact on Development and Daily Life
Dravet syndrome extends beyond seizures, impacting a child’s overall development and quality of life. While initial development may appear normal during the first year, a slowing of skill acquisition and regression often becomes noticeable around the second year. The majority of individuals experience intellectual disability, ranging from moderate to severe. This cognitive impairment affects learning, speech, and language abilities, requiring extensive support.
Non-seizure-related comorbidities contribute to the complexity of daily life. Difficulties with movement are common, including issues with balance and coordination, often described as ataxia. Sleep disturbances are also highly prevalent, with many patients struggling to maintain a regular sleep pattern.
Behavioral issues are frequently reported, including features that resemble the autism spectrum. Attention Deficit Hyperactivity Disorder (ADHD) and problems with irritability or aggressive behavior are also observed as children grow older. Managing these developmental, motor, and behavioral challenges requires a dedicated multidisciplinary approach.
Current Treatment Approaches and Ongoing Research
Treating Dravet syndrome is challenging because the seizures are often refractory to standard anti-epileptic drugs (AEDs). The standard of care involves using multiple AEDs in combination, with valproate and clobazam frequently used as initial therapies. Three adjunct AEDs approved for Dravet syndrome are fenfluramine, stiripentol, and cannabidiol.
A distinct feature of treatment is the necessity to avoid certain AEDs that can worsen seizure control. Sodium channel blocking medications, such as carbamazepine, lamotrigine, and phenytoin, are generally contraindicated for maintenance therapy. These drugs can exacerbate symptoms by further inhibiting the already-compromised sodium channels. For seizure emergencies, a benzodiazepine is typically prescribed as an at-home rescue medication to quickly stop prolonged episodes.
Beyond medication, non-pharmacological therapies play a significant role in management, especially for addressing developmental and cognitive impairments. These approaches include the ketogenic diet and, in some cases, Vagus Nerve Stimulation (VNS), considered after pharmacological options have failed. Research is actively exploring therapies that target the underlying genetic cause, such as gene therapy and antisense oligonucleotide (ASO) treatments. These offer a promising, though still experimental, avenue for disease modification.