Course of Dravet syndrome

Dravet syndrome is a rare type of lifelong epilepsy. The first signs of this syndrome are the occurrence of epileptic seizures during the first year of life in a normally developing infant.

The seizure types and frequency vary but usually persist throughout the patient’s lifetime. This syndrome also affects cognitive, motor and behavioural development.

1/ Clinical Course

Dravet syndrome has an age-dependent evolution. Three stages may be identified:

  • The onset phase (children under one year of age)
  • The worsening phase (children between about one and five years of age)
  • The stabilisation phase (children over about five years of age)

A/ THE ONSET PHASE

  • The child has normal development, mostly with no significant previous pathological history and normal neuroimaging (CT scan, MRI ). The first epileptic event generally occurs between age 4 and 8 months, triggered by a mild fever (<38.5°C).
  • Usually it is a clonic seizure, either initially
    generalisedSeizure that affect all the body
    or involving one side of the body (
    hemiclonicClonic seizures that only affect half of the body
    ). If it is on one side, it may remain on that side or spread to both sides and become generalised. The first seizure is typically a prolonged seizure (>15 minutes) that sometimes turns into a
    status epilepticusSeizures lasting for more than 30 minutes
    (>30 minutes).
  • Over the following weeks or months the child will undergo other seizures,
    febrileWith fever
    or
    afebrileWithout fever
    , despite the use of anticonvulsive medications. At this point, the electroencephalogram (
    EEGElectroencephalography
    ) and neuroimaging investigations (CT scan,
    MRIMagnetic Resonnance Imaging
    ) are nearly always normal.

B/ The worsening phase

  • During this period the seizure frequency increases. Seizures can occur with or without fever, and often include episodes of
    status epilepticusSeizures lasting for more than 30 minutes
    . The alternating
    hemiclonicClonic seizures that only affect half of the body
    seizures are the most characteristic ones. Rectal Diazepam is not always effective.
  • Other types of seizures appear:
    myoclonic seizuresSudden, very brief movements, sometimes repeated, similar to "jumping" (the physical reaction to being startled).
    ,
    atypical absencesAbsences difficult to recognise because they start and end gradually
    and
    focal seizuresSeizures involving only a limited area of the brain.
    . More or less prolonged obtundation status can also be observed.
  • Seizures may be triggered by internal or external stimuli. This is largely observed in the young Dravet syndrome patient. Seizures are a major stress factor for parents who tend to avoid all triggering stimuli, 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.
  • During this phase seizures are often extremely frequent, intense and prolonged, resulting in multiple hospitalisations.

C/ THE STABILISATION PHASE

  • From the middle of childhood and into adolescence, generally seizures progressively improve, with a reduction and sometimes disappearance of
    focal seizuresSeizures involving only a limited area of the brain.
    ,
    atypical absencesAbsences difficult to recognise because they start and end gradually
    and
    myoclonic seizuresSudden, very brief movements, sometimes repeated, similar to "jumping" (the physical reaction to being startled).
    .
    FebrileWith fever
    convulsive seizuresSeizures including more or less violent motor phenomena (hypertonia, convulsions…)
    usually persist, although the number of febrile episode tends to decrease.
  • These convulsive seizures often cluster together, especially at the beginning or at the end of the night.
  • In the majority of patients,
    status epilepticus Seizures lasting for more than 30 minutes
    is considerably less frequent.
  • Few medications are effective, and often seizure control remains incomplete and transitory.

2/ Psycho-motor & cognitive course

  • Dravet syndrome has a characteristic developmental evolution. Developmental delay and
    intellectual disabilityDefined by the WHO as a significantly reduced ability to understand new or complex information and to learn and apply new skills (impaired intelligence). This results in a reduced ability to cope independently (impaired social functioning), and begins before adulthood, with a lasting effect on development.
    are nearly always present.
  • Just as in the clinical course of seizures, three stages may be identified, although the ages may vary:
  • The onset phase (children under one year of age)
  • The worsening phase (children between about 1 and 5 years of age)
  • The stabilisation phase (childhood and adolescence)

A/ THE ONSET PHASE

Psychomotor development is usually normal throughout the first year of life.

B/ The worsening phase

  • After the first or the second year of age a general slowdown in development is often observed. Intellectual and behavioural disorders appear. Their severity may vary from one child to another.
  • Attention deficit and
    hyperkinesisSaid of a child who can’t stay still, always moving
    are the first and most constant traits. Then speech and language are impacted. Acquisition of new words and the ability to associate them are delayed and often sentences are very short or do not exist. Speech comprehension is better than verbal expression, the latter being impaired by dysarthria.
  • Most other areas of development are gradually affected, such as gross and fine motor functions with ataxia, clumsiness, and/or impaired visuomotor coordination.
  • Children become resistant, stubborn, and obstinate. Their communication problems make social interaction difficult. They may have uneasy eye contact and very little interest in other children. They will prefer interactions with any adult.
  • Sleep and feeding disorders have also been described.
  • However, these features are variable from one patient to another and some of them can present with only a slightly delayed development up to school age. But, at this time, they reveal difficulties in learning, reading and writing and their skills will be very slow.

C/ The stabilisation phase

  • When reaching this phase, cognitive disorders tend to stabilise. Development may continue slowly or restart if there have been periods of regression. However, progress is slow and heterogeneous and the Intelligence Quotient (IQ) still decreases.
  • Permanent
    intellectual disabilityDefined by the WHO as a significantly reduced ability to understand new or complex information and to learn and apply new skills (impaired intelligence). This results in a reduced ability to cope independently (impaired social functioning), and begins before adulthood, with a lasting effect on development.
    varies from moderate to severe, depending on developmental evolution during the previous years.
  • Communication often remains difficult; most children are able to speak after the age of six but maintain a lower age linguistic level. Comprehension remains better than verbal expression. Some linguistic functions (articulation, naming test) improve.
  • Visual attention, visual motor integration, visual perception as well as executive functions are the most impaired abilities. Oculomotor coordination skills are limited. Graphic skills are low and patients are not interested in drawing. Reproducing a simple geometrical figure will result in a drawing at the level of a 3- to 4- year-old child.
  • Patients have impaired social competence partly due to
    autistic traitsDifferent manifestations of the child's behaviour evoke autism but there is no real autism: difficulty in communication through language or look (evasive look), restricted interest in others (children and adults), stereotyped, repetitive play and activities.
    , but the majority of patients cannot be diagnosed as actually being autistic. This was well demonstrated by a study of 24 patients assessed with the Vineland adaptive behavioural scales. The author reported that socialisation was almost always better than the overall scale results, and only two children were autistic.
  • Despite the persistence of behavioural opposition (stubbornness), attention will increase and
    hyperkinesisSaid of a child who can’t stay still, always moving
    will decrease or even disappear, giving way to slowness and repetitive behaviour.

3/ Long-term outcome

Based on the clinical experience of a number of expert physicians, early appropriate management of Dravet syndrome seems to result in a better outcome regarding long-term evolution and life expectancy in comparison to published data.

A/ MORTALITY RATE

  • The mortality rate for patients with all types of epilepsy is higher than in the general population.
  • Dravet syndrome-related mortality is estimated to be 10 -15%, with most deaths occurring in children or young adults. The causes of death vary and include infections, accidents (such as falls or drowning), but are mainly
    status epilepticusSeizures lasting for more than 30 minutes
    and unexplained reasons also called
    SUDEPAccording to the World Health Organization SUDEP is defined, as the sudden, unexpected, unexplained, witnessed or unwitnessed, nontraumatic, and nondrowning death in patients with epilepsy, with or without evidence of a seizure.
  • However, the majority of people with Dravet syndrome live well into adulthood.

B/ Recognizing an adult Dravet syndrome

  • In adulthood nearly all patients with Dravet Syndrome present with a handicap, which can express itself through slow movements, poor and slow language, sometimes without making sentences, with even dysarthria that worsens after the age of 40.
  • Although seizures are less frequent than in childhood, adult Dravet patients still have seizures, which are mainly the generalized tonic clonic type occurring during the night. Intellectual and coordination problems preclude independent living.
  • Motor impairment also impacts the Dravet adult population such as ataxia, tremor, myoclonus, clumsiness. Most patients are dependent on others for assistance with many activities of daily living.
  • Many have problems walking with planoabductovalgus of the feet, cyphoscoliosis and a special crouched gait. Some require a wheelchair for mobility.