Dravet Syndrome course

Dravet syndrome is a rare type of lifelong genetic epileptic encephalopathy. The first signs of this syndrome are the occurrence of epileptic seizures during the first year of life in a normally developing infant (Dravet et al. 2011).

The types and frequency of seizures vary but usually persist throughout the patient’s lifetime. This syndrome also affects psychomotor, motor, cognitive and behavioural development (Dravet et al. 2011).

Clinical course

Dravet syndrome evolves with age. Four stages can be identified, although the ages may vary (Dravet and Guerrini, 2011):

  • THE ONSET PHASE (children under one year of age)
  • THE WORSENING PHASE (children between 1 and 5 years of age)
  • THE STABILISATION PHASE (children over 5 years of age)
  • ADULTHOOD

Clinical course of Dravet Syndrome – Epilepsy

The Onset phase (< 1 year)
The Worsening phase (1 - 5 years)
The Stabilisation Phase (> 5 years)
Adulthood

THE ONSET PHASE (< 1 YEAR)

The child’s development is normal, mostly with no significant previous pathological history and normal neuroimaging (CT scan, MRI). The first epileptic event occurs generally between 4 and 8 months of age, often triggered by a mild fever (<38.5°C) (Dravet et al. 2011).
The seizure is usually clonic, either initially generalised or involving one side of the body (hemiclonic). If the seizure is hemiclonic, it may remain on that side or spread to both sides and become generalised. This first seizure is typically a prolonged seizure that sometimes turns into a status epilepticus (>5 minutes) (Brophy et al. 2012 ; Guilliams et al. 2013 ; Bayrlee et al. 2015).
Over the following weeks or months, the child will undergo other seizures, febrile or afebrile, despite the use of anticonvulsive medications. At this point, the electroencephalogram (EEG) and neuroimaging investigations (CT scan, MRI) are nearly always normal (Dravet et al. 2011).

THE WORSENING PHASE (1 – 5 YEARS)

During the worsening phase, seizures are often extremely frequent, intense and prolonged, resulting in multiple hospitalisations. Seizures can occur with or without fever, and often include episodes of status epilepticus. Alternating hemiclonic seizures are the most characteristic type of seizures (type of unilateral convulsive seizure susceptible to change from one side to the other at different moments). Emergency treatments like rectal Diazepam are not always effective (Dravet et al. 2011).
Other types of seizures appear, such as myoclonic seizures, atypical absence seizures and focal seizures. In addition, more or less prolonged obtundation status (non-convulsive status epilepticus) can also be observed (Dravet et al. 2011).
Seizures may be triggered by internal or external factors. This is largely observed in young patients with Dravet syndrome.
Seizures are a major stress factor for parents who tend to avoid all triggering factors, resulting in the isolation of the child. These stimuli, which are detailed further in the Dravet management section, consist of intermittent flashes of light or specific patterns (designs such as regular geometric patterns, lines, or dots), physical effort, or even excitement (Dravet et al. 2011).

THE STABILISATION PHASE (> 5 YEARS)

From the middle of childhood and into adolescence, seizures progressively improve with a reduction and sometimes disappearance of focal seizures, atypical absence seizures and myoclonic seizures. Although the number of febrile episodes tends to decrease, febrile convulsive seizures usually persist. These convulsive seizures are often clustered together and occur especially at the beginning or at the end of the night (Rilstone et al. 2012).
In most patients, status epilepticus is considerably less frequent.
Sensitivity to fever and infections as trigger factors decreases in approximately half of patients (Dravet et al. 2009).
Few medications are effective and seizure control remains often incomplete and transitory (Dravet et al. 2011).

ADULTHOOD

Although seizures are less frequent than in childhood, young adult and adult patients with Dravet syndrome still have seizures (Darra et al. 2019). These are mainly generalised tonic-clonic and occur during the night.
As with focal seizures, atypical absence seizures and myoclonic seizures, status epilepticus tend to disappear in adulthood.

ASSOCIATED COMORBIDITIES

Dravet syndrome evolves similarly in most patients. Developmental delay and intellectual disability are nearly always present (Dravet et al. 2011).

At onset, psychomotor, motor, cognitive and behaviour development are usually normal throughout the first year of life. Cognitive, motor, behavioural and social impairment of different severity then occur in most patients throughout the disease’s course (Dravet et al. 2011).

Adult patients with Dravet syndrome are usually partially dependent or live in special institutions. They attend occupational day centres, sheltered workshops or special professional schools.

Clinical course of Dravet Syndrome – Comorbidities

Behaviour and communication disorders

Behavioural and psychological issues are always observed in patients with Dravet syndrome and impact their family and social life (Dravet et al. 2011).

These issues vary from one child to another and may include:

ATTENTION DEFICIT

Attention deficit is one of the first and most constant traits. It can make life dangerous for these patients as they may fail to perceive certain situations as risky (Dravet and Guerrini, 2011 – Wang et al. 1996).

HYPERACTIVITY

Hyperactivity is one of the first and most constant traits. It can make life dangerous for these patients as they may fail to perceive certain situations as risky (Dravet and Guerrini, 2011 – Wang et al. 1996).

PROBLEMS WITH SOCIAL INTERACTIONS

Their communication problems make social interaction difficult. They may have uneasy eye contact and very little interest in other children. They may prefer the company of adults. Overly trusting and friendly behaviour towards adults may put them at risk in certain situations (Dravet and Guerrini, 2011).

REPETITIVE MOVEMENTS AND BEHAVIOURS

Stereotypical activities (repetitive movements and behaviours) may interfere with structured play as well as with learning activities.

OPPOSITIONAL BEHAVIOUR

Oppositional behaviour can also make patients difficult to manage at home and in public. This may be linked to language impairment and poor communication (Dravet and Guerrini, 2011).

RESISTANCE AND STUBBORNNESS

Oppositional behaviour can also make patients difficult to manage at home and in public. This may be linked to language impairment and poor communication (Dravet and Guerrini, 2011).

AUTISTIC FEATURES

Patients have impaired social competence partly due to autistic traits, but most patients cannot be diagnosed as actually being autistic. This was well demonstrated by a study (Villeneuve et al. 2014) of 21 patients assessed with the Vineland adaptive behavioural scales. The author reported that patients with Dravet syndrome present a particular adaptive and behavioural profile different from that usually found in autistic patients (Villeneuve et al. 2014).

ANXIETY

For some patients, anxiety and depression are associated with Dravet syndrome.

PSYCHOSIS (RARELY)

This comorbidity is observed less frequently.

In their longitudinal retrospective study of two independent cohorts of 34 adolescents and 50 adults, Darra et al observed behavioural problems or psychiatric disorders in most patients (73%).
The behavioural disorders range:

  1. from mild or moderate: attention deficit, anxiety, perseveration, rule breaking, aggressiveness,
  2. to severe: obsessive‐compulsive disorder, autistic features, and sometimes psychosis (Darra et al. 2019).

Behavioural and psychological problems often worsen in adolescence, particularly in patients who do not have severe cognitive impairment and become aware of their differences with those of the same age (Dravet and Guerrini, 2011).

Adult patients are usually calm and passive, searching for affection, contact with others and perseverating in repetitive activities (Dravet and Guerrini, 2011). However, in some patients, different behavioural problems can be present. In their study, Darra et al. 2019, observed behavioural disorders in 52% of the adults. Attention deficit, obsessive and oppositional disorder, autistic traits and psychosis (rarely) may be present.

Finally, pedagogic, behavioural and psychological measures can be used depending on the organisations and specialists present in different countries. For instance, special classes, individual help in mainstream classes, out-of-school social and educational settings, sports practice, and group leisure activities, are possible solutions. In adulthood, some patients can engage in simple work in a sheltered setting. Wherever possible, specialized institutions for patients with intellectual disability can be positively received by patients and ease the burden on families (Dravet and Guerrini, 2011).

Either psychotherapy or, at least, psychological support should also be offered. Pharmacological treatment is rarely necessary, except for some children with hyperkinesis and depressed adults (Dravet and Guerrini, 2011).

Cognition and learning disabilities

Even though the evolution of Dravet syndrome is very much specific to the individual, cognitive functions are nearly always impacted. These features are variable from one patient to another and some patients may present with only slightly delayed development up to school age. However, at this time, they reveal difficulties in learning, reading and writing and their skills development will be very slow (Ragona et al. 2011).

Attention deficit is one of the main factors responsible for learning disability (Ragona et al. 2011).

When reaching the stabilisation phase, cognitive disorders persist but tend to stabilise. Development may continue slowly or restart if there have been periods of regression. However, progress is slow and heterogeneous. Intelligence Quotient (IQ) continues to decrease because the gap between children with Dravet syndrome and normal children widens (Ragona et al. 2011).

Permanent intellectual disability varies from moderate to severe, depending on developmental evolution during the previous years. In the study by Darra et al 2019, at last evaluation of adolescent patients, the intellectual disability was moderate or severe in 70.5% of patients. In adulthood, it was moderate or severe in 80% of patients.

Intellectual disability and coordination problems preclude independent living.

Cross-sectional analysis of development status over time (adapted from Brunklaus et al. 2012)

Speech and communication

The acquisition of new words and the ability to associate them is delayed. Sentences are often very short or non-existent. Speech comprehension is better than verbal expression, the latter being impaired by dysarthria. Most children can speak after the age of six but maintain a lower-age linguistic level. Some linguistic functions (articulation, naming test) can improve during the stabilisation phase (Dravet and Guerrini, 2011).

In adulthood, nearly all patients with Dravet syndrome have poor and slow speech. This disorder varies in degree. In 2019, Darra et al. showed that among 50 adult patients :

  • 16% of patients had normal language skills,
  • 14% were able to sustain a simple conversation,
  • 24% used short sentences,
  • 22% were able to produce only isolated words,
  • 24% were incapable of speaking.

Some adults are able to have a conversation on simple topics, others are nonverbal and merely produce isolated syllables, words or sounds. They sometimes do not make sentences and may even present dysarthria that worsens after the age of 40 (Dravet and Guerrini, 2011).

Sleeping disorders

Difficulty falling asleep, maintaining sleep, awaking very early or excessive sleepiness can occur in patients with Dravet syndrome. There are many causes for this, including unrecognised seizures or side effects from some anti-epileptic drugs, which may be improved through dose adjustment and spreading out doses during the day. Sleep-inducer drugs may help falling asleep (Dravet and Guerrini, 2011).

In the study by Licheni et al. 2017, a questionnaire using the Sleep Disturbance Scale for Children was completed by the parents of patients with Dravet syndrome (57).

The authors identified different disorders:

  1. disorders of initiating and maintaining sleep,
  2. sleep–wake transition disorders,
  3. sleep breathing disorders,
  4. disorders of excessive somnolence,
  5. disorders of arousal (rare),
  6. sleep hyperhidrosis – excessive sweating during sleep (rare).

The nature of the sleep disorders was different according to the age of the patient.

This paper shows that “more than 70% of the patients with Dravet syndrome have sleep problems” (Licheni et al. 2017).

Feeding disorders

Feeding disorders can also occur in patients. Chewing/swallowing difficulties, lack of appetite, refusal of food, loss of weight, anorexia or growth failure are observed.

It may be helpful for patients to consult a psychologist. Guidance from a paediatric neurologist is necessary.

Most feeding disorders, such as anorexia or loss of appetite, are a consequence of overdosage of anti-epileptic drug treatment. Dose adjustments might be necessary but not easy to achieve because of the risk of seizure recurrence.

In rare cases, anorexia, failure to thrive or weight loss are independent of anti-epileptic drugs and are so worrying that gastrostomy becomes necessary.

Motor and Gait impairment

A delay in fine and gross motor skills become evident before 2 years of age in patients with Dravet syndrome. Gait tends to worsen with patients’ age (Wyers et al. 2019). Fine motor skills are impacted from the first years, making children clumsy, especially if they have ictal and interictal myoclonic jerks (Dravet and Guerrini, 2011).

At least 15%-30% of patients need support from another person to walk outside their home and some of them use a wheelchair (up to 20%). This accentuates the lack of autonomy and independence of patients. This is frequently a major concern for parents and caregivers as patients are dependent on others for many daily activities (Wyers et al. 2019).

By adolescence (age ≥ 13), part of the patients have developed a flexed gait pattern with passive knee extension deficit and skeletal malalignment (Wyers et al. 2019).. For these patients, gait deterioration is not typical and out of synchrony. It tends to deteriorate from about nine to ten years of age, associated with pes valgus and, sometimes, cyphoscoliosis (Rodda et al. 2012).

Crouch gait is a special crouch pattern gradually developed by the most severely affected adolescent and adult patients when they walk. The picture below illustrates this specific gait defined as “excessive ankle dorsiflexion with excessive hip and knee flexion during stance phase” making it difficult to walk long distances (Wyers et al. 2019).

Figure extracted from Rodda et al. 2012. Crouch gait is characterized by increased hip and knee flexion and ankle dorsiflexion in the sagittal plane throughout the stance phase and is accompanied by bony malalignment in the transverse plane of medial femoral torsion, lateral tibial torsion, and planoabductovalgus of the feet.

 

In their publication, Darra et al confirmed this data. In the adolescent group, motor abnormalities were present in most patients. In all cases, they appeared during childhood, usually before the age of 6. In the adult group, most of the patients presented motor impairment with pyramidal signs, extrapyramidal signs and ataxia.

The walking abilities and motor problems of patients with Dravet syndrome may be improved by orthopaedic interventions and rehabilitation programs. Psychomotricity therapy and physiotherapy can also attenuate this motor impairment (Wyers et al. 2019). Other motor problems such as parkinsonism, extrapyramidal signs, cerebellar gait, neurological signs, spasticity, dysarthria and intentional tremor are also observed (Wyers et al. 2019).

Finally, in 2012 Brunklaus et al. showed that moderate to severe intellectual disabilities, autistic features, motor disorders and behavioural disorders increase with age. This is illustrated in the charts below.

Cross-sectional analysis of acquired autistic features, behavioural and motor disorder over time (adapted from Brunklaus et al. 2012)

 

It is important that health care professionals and caregivers are aware of all these comorbidities. They must take time to listen to patients and families, without forgetting siblings. They must help them to find the best possible solutions and to accept the disease (Brunklaus et al. 2012).

MORTALITY

The mortality rate for patients with all types of epilepsy is two to three times higher than in the general population (Tomson et al. 2000).

Dravet syndrome is characterized by high epilepsy-related premature mortality (up to 21%) and a marked young age at death. The two most common causes for premature death in Dravet syndrome are Sudden Unexplained/Unexpected Death in Epilepsy (SUDEP) and status epilepticus (SE) accounting for about 80% of the premature deaths (Shmuely et al. 2016). SUDEP can be defined as “a sudden, unexpected death in a person with epilepsy, with or without evidence for a seizure preceding the death, in which there is no evidence of other disease, injury, or drowning that caused the death” (Nashef et al. 2012). The cause of the excess premature mortality in patients with Dravet syndrome remains elusive but may be explained by epilepsy severity, as well as genetic susceptibility to SUDEP (Shmuely et al.2016).

A lot of research is ongoing to understand the cause and how it could be prevented. SUDEP in Dravet syndrome occurs mainly in childhood with a mean age at 8.7 years (Shmuely et al. 2016) but the majority of patients with Dravet syndrome live into adulthood.

Age distribution for all causes of death in 142 Dravet syndrome cases (adapted from Shmuely et al. 2016)

DS=Dravet syndrome; SUDEP=sudden unexpected death in epilepsy; SE=status epilepticus