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Clinical aspects in Dravet syndrome, what do we know 40 years after first description

Autor: Mihaela-Adela Vințan
Distribuie pe:

SUMMARY
Dravet syndrome was described 40 years ago (1978) by Charlotte Dravet under the name of severe myoclonic epilepsy in infancy (SMEI). It is an epileptic encephalopathy characterized by seizures, beginning in the first year of life in the form of prolonged febrile seizures; in a child with no previous personal history of neurological disease; epilepsy or febrile convulsions are present in family history. Other type of seizures appear later in evolution and other neurological symptoms: ataxia, pyramidal signs, intellectual deficiency and personality disorders. It is a genetic, resistant form of epilepsy and it has high impact on the child, families and medical system. Its management needs a multidisciplinary team, due to complex symptoms and high risk of morbidity and mortality. Dravet syndrome must be kept in mind in every infant presented in ER with previous mentioned symptoms, correct diagnosis could avoid fatal mistakes and assure the most proper management for these children.
Keywords: Dravet syndrome, encephalopathy, childhood, adult

BACKGROUND
Synonims:
Dravet syndrome (DS),
Epilepsy with polymorphic seizures, Polymorphic epilepsy in infancy (PMEI), Severe myoclonic epilepsy in infancy (SMEI).
Dravet syndrome spectrum:
– Dravet syndrome
– Febrile seizures
– Genetic epilepsy with febrile seizures plus (GEFS+)
– Epilepsy with mental retardation limited to females (EMRF)
– Intractable childhood epilepsy with GTCs (ICE-GTC)
– Severe myoclonic epilepsy borderline (SMEB)
DEFINITIONS
Dravet syndrome was described in 1978 by Charlotte Dravet under the name of severe myoclonic epilepsy in infancy (SMEI) [1]. Later, it was showed that epilepsy was not limited to infancy or childhood, but continued through adulthood, so the name ‘‘Dravet syndrome’’ was proposed (Commission on Classification and Terminology of the International League Against Epilepsy, 1989) [2]. In the latest ILAE
classification for epilepsies and epileptic syndromes (2017), DS is included in generalized epilepsies with genetic etiology [3]. Bordeline DS is defined as
„epilepsy with clinical characteristics as those in DS but lacking epileptic myioclonic seizures and atypical absence seizures” [4].
Sites
OMIM 54 607208
Disease Ontology 12 DOID:0060171
Orphanet 56 ORPHA3306ICD10 via Orphanet 34 G40.4
MedGen 40 C0751122 C3501832 MeSH 42 D004831
Is DS an epileptic encephalopathy?
DS has been considered ‘epileptic encephalopathy’ in previous International League Against Epilepsy classification [5].
The term epileptic encephalopathy is defined by
Berg et al. (2010) “as where the epileptic activity itself contributes to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone (e.g., cortical malformation). Global or selective cognitive impairments can worsen over time.These impairments can be seen along a spectrum of severity and across all epilepsies and can occur at any age” [6].
The latest ILAE classification on epilepsies and epileptic syndromes (2017) maintain, even modified the term of developmental and epileptic encephalopathies, as epileptic syndromes where “the abundant epileptiform activity interferes with development resulting in cognitive slowing and often regression, and sometimes is associated with psychiatric and behavioral consequences”. The epileptiform activity can induce regression while a previous normal development or developmental delay prior to epilepsy onset. “A key component of the concept is that amelioration of the epileptiform activity may have the potential to improve the developmental consequences of the disorder” [3].
Many developmental and epileptic encephalopathies have genetic etiology and “also have developmental consequences arising directly from the effect of the genetic mutation, in addition to the effect of the frequent epileptic activity on development” [3]. There were debates as if the seizures and/or interictal discharges themselves are responsible for the
cognitive decline in DS [7].
There are several reports where almost all patients with DS showed severe to moderate mental deficit [8], but deterioration was not observed [7].
A large study on children with typical DS, where they have been assessed for cognitive development, showed that mental retardation worsened with age, but there were no loss of abilities and children progressed slow but constant along the first decade; these evidences preceded the new defined term of developmental and epileptic encephalopathy [9].
Epidemiology
DS is found in 1 per 20,000 to 1 per 40,000 members of a population [7]. Recent studies have shown an overall incidence = 1:28 600 [10]. An epidemiological study showed an incidence of DS around 1:22,000 [11].
DS was reported being responsible for 1.4% of all epileptic children age under 15 years, in a study realized in Navara, Spain in 2007 [12].
A male-to-female ratio of 1.27 to 1 was reported [10].
Family history
A family history of febrile seizures or epilepsy in relatives of DS children, was identified being present in 15-35% of cases, the most common phenotype seen is GEFS+ [4]. Monozygotic twins and rarely in zygotic twins have been found in DS families. There are few reports of two or more affected children in the same family. Mosaicism is reported in 7% of families with DS [12].
DS could appear both in families with positive history of febrile seizures and de novo SCN1A mutations, suggesting a polygenic mode of inheritance and modifier genes such as SCN9A was related to the phenotype severity [13].
Personal history
Neurological status is normal at onset. There is no significant neurological personal history. Could be present though antecedents of sufferance during pregnancy and delivery in 22–40% of the cases [14].
There were identified other rare associated disorders: Rud syndrome (AR, congenital ichthyosis, epilepsy, dwarfism, sexual infantilism, polyneuritis, and macrocytic anemia), type I neurofibromatosis [7], congenital cardiac defect, growth hormone deficit, and hemophilia [15].
Neurological development, prior seizures onset, is apparently normal, even in the patients with pathological history.
Epilepsy onset
Seizures onset is around 5 – 8 months (ranges from 2 to 10 months); onset after the age of 1 year has been exceptionally reported, the seizure onset, up to age of 15 months may occur [14].
Typically, the first seizure is clonic, bilateral, or unilateral, triggered by fever and lasting longer than a simple febrile seizure (longer than 20 minutes) [7,14]. In 25% – 49% of the cases, seizure evolve into status epilepticus. There are also reported the onset seizures occurring without fever in 28% – 61% of the
patients [7,14].
Afebrile seizures occur though during an infectious episode, after exposure to warm water (after bath) or after a vaccination later, these children still associate febrile triggered seizures. Seizures triggered by vaccination occur earlier than fever triggered seizures but, it was proved that vaccination itself had no impact on the developmental outcome [15].
Sometimes, isolated focal myoclonic episodes could be present in prior days or even weeks before the first convulsive seizure.
The first convulsive episode is often evaluated as an accidental, isolated seizure or a simple febrile seizure, that’s why usually no investigations are performed, and no treatment is given. Later, usually after 2 weeks (or up to 2 months), another convulsive episode triggered by fever occur. In time, between the age of 1 to 4 years, other seizure types occur, associated with developmental delay.
Type of seizures
In DS seizures are polymorphous:
1. convulsive seizures – generalized onset motor seizures – clonic or tonic–clonic, or alternating unilateral clonic seizures. Convulsive seizures are most of them focal to bilateral; usually there is a brief focal onset, or they are ‘‘unstable from one hemisphere to the contralateral” [16]. In younger patients dominate unilateral clonic seizures that tend to be prolonged to status epilepticus; in older patients, seizures are shorter, with unilateral motor semiology (clonic or tonic-clonic) but associated with contralateral tonus changes and, often with post-ictal transitory hemiparesis. Unilateral clonic seizures can be on either side or alternating pattern – that is a clue for the diagnosis of DS [15].
2. myoclonic seizures – appear after the age of 1 year, up to the age of 5 years (mean age 1.5 years), bilateral, sometimes barely discernible. It may associate an atonic phase “head nodding”. Myoclonic seizures can appear isolated or grouped in bursts of 1 – 3 sec. Sometimes they are present only with minutes or hours in the preceding of a convulsive seizure. In DS children myoclonic seizures could be triggered by photic stimulation (light intensity variation, eyes closure, or patterns). Seldom, myoclonic status could appear and it lasts more than 24 hours.
3. atypical absences and obtundation status – the onset is between 4 months and 6 years associated with myoclonic seizures. They could appear later, in childhood, up to the age of 12 years. The absences seizures last from 3 – 10 sec, and are characterized by impaired awareness; they are isolated or accompanied by myoclonias, “eye fluttering”, “head nodding”. The “obtundation status” is a characteristic symptom for DS patients, present in 30 to 40% of them and it could last for hours or even several days. It is sustained by eye closure, pattern fixation (TV screen, “dotted lines on the walls”). Strong sensorial stimulation could improve the awareness but, not completely [7,16].
4. focal seizures or focal to bilateral seizures – occur in up to 78,6% of patients [7]. The onset is between age of 4 months to 4 years. They are focal seizures with motor onset (tonic versive or focal clonic limited to a limb or part of the face, automatisms, eyelid myoclonias or limb myoclonias) or with more complex semiology, including significant autonomic symptoms (pallor, cyanosis, respiratory changes, drooling, sweating) [7,14].
5. tonic seizures – are not characteristic for DS but could appear; they resemble the axial tonic seizures from
Lennox-Gastaut syndrome, sometime myoclonyas are associated. Usually they are sporadic [7].
Seizures triggering factors
1. It is a well-known fact that in DS patients, seizures are triggered or exacerbated by external factors, such as:
2. Environmental temperature variations, hot baths;
3. Infections, even without fever;
4. Environmental light and pattern exposure;
5. Physical exercise, that could induce body overheating;
6. Noisy environments, music;
7. Emotions positive or negative (birthday or new year parties).
Sensitivity to these stimuli is present all along the life span, sometimes determines auto- stimulation (simply by eyes closure) [7,14]. The high convulsive susceptibility is considered a factor of pharmacoresistance [15].
Developmental and cognitive features
In the first neuropsychological study of DS patients, performed in Marseille, the global developmental quotient (DQ) declined quickly: to 60 – 95 in children aged 1 to 3 years and to severe deficit, 25 – 40 in children older than 6 years. The impairment degree was correlated with the severity of epilepsy at onset (in the first 2 years of life) [15].
Motor development appears to be in normal ranges in the first year of life with a later decline; walking is gained at a normal age but it becomes unsteady; “crouch gait with increased flexion from hip and knee and dorsiflexion of the ankle in sagittal plane in the stance phase, accompanied by medial femoral torsion, lateral tibial torsion and feet valgus abductus in medial plane” is developed in time [17]. Because of this, periodic orthopedic evaluation it is recommended for DS children.
Language is also normal developed in the beginning, but many DS children do not gain the ability to construct elementary sentences; fine motor abilities are also deficient due to segmental myoclonus and poor eye-hand coordination. They are not able to draw a design and could write only using printing letters even when milder cognitive impairment is present [15].
We could say that persons with DS develop a particular psychological profile (suggesting a frontal lobe disfunction/ immaturity) characterized by:
– lack of attention, with significant impact on learning disabilities that appear later,
– restlessness and hyperactivity, impulsivity,
– most of the time they do not listen to adults and are not interested to participate in usual activities related to their age group, sometimes they could develop recalcitrant behavior,
– they have perseverative responses,
– executive function is impaired and have deficient planning,
– DS children prefer stereotype activities – to complete puzzles and watch cartoons repetitively,
– sleep disorders are often present [10],
– associated, reduced sensitivity to pain is reported [18],
– autistic features are repeatedly reported, language may be less affected in some patients, though. There were reported studies that included psychological evaluation of DS patients, socialization skills assessed using the Vineland scale, were significantly better than communication skills and autistic features previous reported were not confirmed [13].
In an animal study, the mouse models of DS demonstrated hyperactivity, stereotypic behavior and cognitive deficits from ADHD and autistic spectrum, due to reduced expression of GABAergic interneurons in the forebrain. In mice studies, where SCN1A activity was selectively reduced, the animals did not develop seizures, but cognitive deficits appeared, showing that Nav1.1 dysfunction plays an important role on cognitive decline, independent on seizures severity [13].
Comorbidities
1. Walking disorder that develops once the walking is acquired, is associated with osteopenia that worsened with patient age. Repeated fractures could appear, also worsened with age, being more prevalent in teenagers and adults comparing with infant and toddlers [18]. For DS patients it is recommended periodic orthopedic evaluation
2. Cardiac involvement: long Q-T intervals are reported in SCN1A patients; they are related with cardiac arrest in SUDEP. Even heart structure abnormalities were reported. Bradycardia and tachycardia were identified in these patients (13% and 30%, respectively) [19]. For DS patient periodic cardiological evaluation it is mandatory.
3. Feeding disorders with appetite disturbances, metabolism and growth issues – needing periodic nutritional evaluation by a dietician. It has been shown that feeding disorders become more severe after age of 4–6 years; it could be a medication side effect, or it is due to Dravet syndrome itself [18].
4. Prone to frequent infections, like otitis, bronchitis, pneumonia, or chronic infections, there could be associated immunity issues and allergies, aspect that raise the need of periodic allergology and immunology evaluation [18].
5. Precocious puberty was reported in 9% of DS children, same as is delayed puberty (9%), these patients needing periodic endocrinological evaluation also [18]. There are studies showing that DS patients SCN1A-negative were more likely to experience delayed puberty [18,10].
6. Nephrocalcinosis was another co-morbidity shown to be present in DS patients, raising the need of nephrological evaluation. Nephrocalcinosis was more often reported in patients without SCN1A mutations than in patients with SCN1A mutations [18].
7. Autonomic disorders such as temperature dysregulation, was reported in a high proportion of DS patients (80%, according to Villas et al, 2017); it seems to appear around the age of one to three years and it remains steady throughout the older age [18].
THE COURSE OF THE DISEASE
There are three stages described in Dravet syndrome:
1. the febrile or diagnostic stage – in the first year
of life, characterized by prolonged febrile seizures, evolving to status epilepticus; it’s the time when usually, the diagnosis is done [7], [14].
2. the worsening (preferred to ‘‘catastrophic’’) stage
– between 1 and 5 years – it is a period with many seizures and episodes of febrile status epilepticus, behavioral deterioration; it’s the stage when other neurologic signs and symptoms occur;
3. the stabilization stage – after the age of 5 years,
convulsive seizures occur mainly during sleep and diminish in frequency and intensity; myoclonic and absence seizures decrease and even can disappear, focal seizures persist or decrease; mental development and behavior tend to improve but cognitive impairment it is still present in variable degree. Worsening of epilepsy and cognitive status could still appear after the age of five.
Losito&Nabout (2017) put things together and set the three stages of Dravet syndrome including cognitive evolution, presented in Table I:
Table I. The course of Dravet syndrome in three stages with the clinical and cognitive states at each stage. (Losito & Nabout, 2017)

First stage or “febrile stage” (1 – 12 months)
Convulsive seizures, mainly febrile, hemiclonic and long lasting are characteristic for Dravet syndrome
Normal EEG and MRI
Normal psychomotor development but early visual functions impairments are present
Second stage (12-15 months – 5 years)
Polymorphous resistant seizures: myoclonias, atypical absences, tonic/clonic focal seizures
Gait disturbances
Normal EEG or showing a slowing in the background activity and multifocal epileptiform abnormalities Slowing in cognitive development with attention deficit, behavior disorders and autistic spectrum disorders in some patients
Third stage (>6 years)
Pharmacorezistant seizures persisting with few seizures’ free patients
Nocturnal seizures might be more frequent than diurnal Persistence of fever sensitivity
Definite intellectual disability, stagnation without regression Executive function deficit
Language output more impaired than comprehension Persistent deterioration of visual function
Hattori et al (2008) proposed a risk score for a screening test in children with clinical characteristics of DS [20] – presented in Table II.
Dravet syndrome genetics
More than 500 mutations have been associated with DS and there are randomly distributed along the SCN1A gene, encoding the a1 subunit of the sodium channel (SCN1A). Up to 70 – 80% of the patients are positive for SCN1A mutation, there were reported Table II. Risk score for screening test in children suspected of Dravet syndrome

Predictive factors Risk score
Clinical score
– Onset ≤ 7 months 2
– Total number of seizures ≥ 5 3
– Hemiconvulsions 3
– Focal seizures 1
– Myoclonic seizures 1
– Prolonged seizures 3
– Hot water-induced seizures 2
Genetic score
– SCN1A missense mutation 1
– SCN1A truncated mutation 2
First phase:
If the calculated clinical risk score is ≥6 genetic testing should be considered.
Overall results:
If the total calculated risk score is ≥7 should be strongly suspected a diagnosis of Dravet syndrome [20].

truncating (40%) and missense mutations (40%), the remaining being splice site mutations (insertions, deletions or changes of the number of nucleotides in the specific site at which splicing takes place during the processing of precursor messenger RNA into mature messenger RNA) [21].
Acute encephalopathy
Acute encephalopathy was defined by Mizuguchi et al., as acute brain dysfunction that is usually preceded by an infection. Impaired consciousness, signs of intracranial pressure, often associated with seizures are the characteristic symptoms. AE has been reported in the literature related to various causes, the most frequent being viral (influenza).
Okumura et al. published a series of 15 Japanese cases in 2012. The authors defined AE as a sudden onset of brain dysfunction usually after an infection and fever. It is characterized by loss of consciousness, alone or associated with seizures, involuntary movement, and behavior disorders lasting more than 24 hours [23].
The pathophysiologic mechanisms are not fully known. Several hypotheses were suggested like a selective vulnerability of the cerebellum to injury, excitotoxicity and anoxic ischemia induced by barbiturates, mitochondrial dysfunction, inappropriate antiepileptic drug treatment with large doses of benzodiazepines and secondary respiratory depression [23].
Mortality in Dravet syndrome
DS is associated with high mortality rate, up to 15% by the age of 20 years [7], 16% die before age of 18 [4]. Sudden unexpected death in epilepsy (SUDEP) is frequent present in DS patients; studies in Dravet mice models showed that SUDEP is related with an increased parasympathetic activity that appears after a convulsive generalized seizure, with secondary lethal bradycardia and electrical ventricular dysfunction. This abnormality has been seen in mice with the SCN1A mutations selectively targeted to affect the brain, but not if the SCN1A mutations were selectively targeted to affect the heart only, and it was proposed the hypothesis that SUDEP is due to an autonomic defect that secondary affect the heart after a seizure [24].
Cheah et al (2013) proposed a mechanism of this disorder, a natural decline of Nav1.3 channel expression without increasing of Nav1.1 channel expression that leads to a disinhibition of neuronal circuits and secondary resistant epilepsy with high risk of premature death [25].
Bagnall et al (2017) proposed a list of genes associated with sudden unexpected death in epilepsy (SUDEP) [19], presented in Table III.
DIAGNOSIS CRITERIA
ILAE, 1983 (at that time still called Severe Myoclonic Epilepsy of Infancy)
1. family history of epilepsy or febrile convulsions;
2. no previous personal history of disease;
3. seizures beginning in the first year of life in the

form of generalized or unilateral febrile clonic seizures;
4. secondary appearance of myoclonic jerks and often partial seizures;
5. EEG showing bilateral spike-wave (SW) and polyspike-wave (PolySW), photosensitivity and focal abnormalities;
6. retarded psychomotor development from the second year of life;
7. simultaneous ataxia, pyramidal signs, and interictal myoclonus;
8. resistance to all forms of treatment;
9. intellectual deficiency and personality disorders in all affected children.
(Commission on Classification and Terminology of the International League Against Epilepsy, 1989) [26].
ILAE, 2010:
1. one family history of epilepsy or febrile convulsions is not constant but variable according to the authors (25–71%) [26];
2. the initial seizures are not always generalized or unilateral clonic but may be focal or myoclonic; they are not always febrile and the clonic seizures often evolve to status epilepticus;
3. not only myoclonic jerks and focal seizures appear secondarily but also atypical absences and obtundation statuses;
4. photosensitivity may be associated with pattern- sensitivity;
5. neurological signs are not always present but are frequently observed: ataxia (60%), pyramidal signs (20%) and interictal myoclonus (36– 85%) [26];
6. the MRI is normal at the onset;
7. cognitive deficiency and personality disorders are present in all affected children during the disease, but they are of variable degrees, from slight to severe, and may be detected only at the age when entering elementary school [27,26].
DIFFERENTIAL DIAGNOSIS
Dravet syndrome must be differentiated from other childhood epilepsies and epileptic encephalopathies, in order to choose the best management and set the most probable prognosis. Main epileptic syndromes Dravet syndrome need to be differentiated are listed in Table IV.
Transition to adulthood
Childhood-onset epilepsy persisting into adulthood can have one of the three possible outcomes.
Well-controlled epilepsy in cognitively normal patients – the group of IGE=idiopathic generalized epilepsies from old clasification;
Difficult to treat epilepsy in cognitively normal patients – most commonly with focal onset – temporal lobe epilepsy (TLE);
Resistant epilepsy associated with cognitive deficits.
Patients with Dravet syndrome survive into adulthood. It is essential for neurologists to know Dravet syndrome characteristics for proper management, in this regard a good ‘transition’ is important.
Transition has been defined as a “purposeful planned process that addresses the medical, psychosocial, and educational/vocational needs of young people with chronic physical and medical conditions as they move from child-centered to adult-oriented health care systems” [28].
A transition clinic could be helpful, there is a place where the patient and family are seen for several
visits jointly by the adult neurologist together with the pediatric neurologist. Alternately, transition to an adult center that is specialized in rare epilepsies may also be very successful solution.
Also, adult emergency room physicians need to become involved in the transition process.
Considering it is a childhood epileptic encephalopathy, Dravet syndrome is under-diagnosed and under-reported in adulthood. The diagnosis should be considered in all adults presenting with infantile-onset resistant epilepsy, by reevaluation of childhood history and SCN1A testing [29].
DS in adulthood
DS seizures in adulthood
Generalized convulsive seizures, mostly reported as generalized tonic–clonic seizures (GTCS), were the only seizure type observed in almost all the patients [15].
Convulsive status epilepticus had never occurred in any of the patients after age 10 [4].
Fever’s impact on seizure frequency and severity is milder than in infancy. Fever-related
seizures in adults do not evolve into SE or seizure clusters [4].
Myoclonic seizures and atypical absences disappear before the age of 20 in up to 93% of patients [4].
Photosensitivity and pattern sensitivity also showed a tendency to disappear before the age of 20 [4], [8].
Neurologic status in DS adult
Cerebellar features: ataxia, dysarthria, intention tremor, and eye movement disorder are more
prominent. Pyramidal symptoms, features of Parkinsonism with bradykinesia, asymmetric rigidity and cogwheeling, non-epileptic myoclonus are present. Orthopedic signs like: kyphosis, kyphoscoliosis, flat feet, or claw feet are present. Minor symptoms during childhood – worsened during and after adolescence, despite physiotherapy. Walking – markedly impaired, there is the need for wheelchair. Neurological deterioration continued throughout life in all patients, with further impairment of speech, mobility and
ability for daily activities.
Mental disability is moderate to severe [4]. Autism spectrum disorders persist in adult patients with DS,

while certain characteristics associated with behavioral problems, such as hyperactivity or the need for using of psychoactive medication, are be less prominent than in childhood [30], [31].
Most of the adult patients live in residential care or at home, with support for daily activities. The oldest age reported for living Dravet patient was 60 years of age [31].
In adult DS patients, the lack of occipital alpha rhythms on the follow-up EEGs was significantly correlated with a severe mental disability and it is thought that slow EEG background must represent brain dysfunction.
No SCN1A mutation was related with seizure or mental outcome in adult DS patients.
WHAT DO WE KNOW 40 YEARS LATER (OR, INSTEAD OF CONCLUSIONS)?
1. Dravet syndrome may be better viewed as a disease of the central nervous system with epileptic and non-epileptic manifestations rather than merely an epilepsy syndrome
2. Dravet syndrome is not limited to pediatric age
3. It is a resistant form of epilepsy
4. Early diagnosis means the opportunity for a better management and possible a better prognosis
5. Proper management needs multidisciplinary team and a well-established protocol of coordinated evaluations.

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