Retracing the natural history of Dravet syndrome: Report and review of literature
Dravet syndrome (DS) is an epileptic encephalopathy dominated by polymorphic seizures, which are typically myoclonic, atypically absent, but can also be complex partial and generalized tonic–clonic. Their onset occurs in the first year of life. They may be febrile as well as afebrile seizures. The precipitation of seizures may occur due to the administration of vaccination, may be associated with a high incidence of status epilepticus, and their worsening may occur by the administration of sodium channel blockers, especially lamotrigine. Identification of variegate mutations of the sodium channel-1 A has led to a better understanding of the roots of this genetically determined epilepsy. The natural history of DS in adults has been studied systematically by investigators from southeast Asia and Europe. However, there is no worthwhile data regarding the changing seizure patterns and other clinical and electrographic aspects from India.,,,,, The story of a 25-year old girl who overcame the challenge of this severe epilepsy is presented to discuss these aspects, which are relevant for neurologists and treating physicians who are likely to encounter this entity in their clinical practice.
A young lady 25 years of age from the hill country of Nainital, India, was evaluated recently at our center for intractable epilepsy. She was born of non-consanguineous union as the first of two siblings, by normal vaginal delivery at full term; she cried immediately after birth and had an uneventful perinatal period. At 3 months, 12–16 h after the diphtheria, pertussis (whooping cough), and tetanus [DPT] vaccination, she had fever followed by a cluster of sudden jerky movements of limbs. Two months later, she had febrile generalized tonic–clonic/clonic seizures. She was started on phenobarbitone, on which she remained seizure free for 2 years. An attempted taper of the drug caused an episode of right hemiclonic seizures, which prompted escalation of the drug dosage. Some Ayurvedic medicines were also tried. The parents could recall only occasional myoclonic seizures. Things went well until she reached 3.5 years of age; while travelling in the bus on a hot and humid day, she had one episode of a generalized tonic–clonic seizure (GTCS) lasting approximately 2 min. The next seizure episode occurred when she had attained the age of 5 years, again with the febrile undertone, while gathered with friends around a bonfire. The seizure frequency increased exponentially after this age with approximately 1–2 seizures/month by the time she had attained the age of 6 years. She continued to attend school and her academic performance was average. Carbamazepine, valproate, phenytoin, and clonazepam were tried in maximum tolerable doses without significant decline in the frequency of seizures. The seizure semiology after the age of 6 years was focal with secondary generalization – the focal component being head version/clonic movement of the upper limb of either side. By 12–13 years of age, the events came down to once every 2–3 months. At this point, she also experienced experiential and visual aura in the form of persistent visual imagery or jumbled words, vertiginous sensation before the onset of head version or tonic/clonic movements. These events were at times precipitated by reading or tasks requiring mental concentration. There was no further scholastic decline; however, behavioural symptoms such as irritability and aggressiveness were reported. Approximately a few months before presenting to us, the patient had a worsening in the seizure frequency, with withdrawal, and at times, confused behaviour after lamotrigine was added by the treating physician. After discontinuation of the drug, the patient still had prominent behavioural symptoms, which we attributed to the administration of drugs, especially phenobarbitone. In addition, she was also on carbamazepine, valproate, and clobazam; the latter two medications were gradually withdrawn. We added topiramate (200 mg) and lacosamide (200 mg) to carbamazepine (800 mg), which achieved sustained seizure freedom (a 5-month follow-up was available) and a steady improvement in her behavioural symptoms. She is presently stable and on the way to completing her graduation. She had no family history of seizures or any significant neurological insult to account for her symptoms.
On examination, she appeared bright with normal attention, language, and cognitive functions. A reduced speed of response was the only shortcoming observed. Rest of the neurological and systemic examination was normal. A 1.5 Tesla MRI of the brain, the epilepsy protocol, as well as the endocrinal and blood work-up were normal. The records available with her included a normal reported electroencephalogram (EEG) at the age of 2 years and the presence of generalized spike and wave discharges at the age 8 years (however, the graphs were not available). A 32-channel EEG performed using the Nicolet machine revealed mild background slowing of 6.5–7 Hz frequency with partial response to eye opening. No spikes, sharp waves, focal slowing, or photosensitivity were observed. Sleep spindles were well formed and symmetric.
DS, which owes its name to the French psychiatrist and epileptologist Charlotte Dravet, who first described it, is as a unique epileptic syndrome of infantile onset with a characteristic evolution of seizure semiology and frequency, which can continue into adulthood. Typically, it announces itself as an early-onset febrile seizure which can have an atypical (sometimes hemiclonic) semiology. The initially infrequent seizures become rampant in early childhood, the atypical absence and myoclonic seizures being the predominant types. As the disease progresses, the trajectory may change favourably, although most of the victims are left with significant disability.,,,,,
In this report, we attempt to examine four aspects pertaining to disease evolution in DS: Seizure semiology; seizure frequency and response to antiepileptic drugs; the associated cognitive and neurobehavioural effects; and, electrography.
When this early-onset severe epileptic syndrome chooses to step into later life, it generally lets go of many of its signature manifestations such as myoclonus, atypical absence seizures, and status epilepticus. Fever may continue to exert its influence on a modest level with the majority of seizures being afebrile. Focal with secondary generalized seizures emerge as the dominant phenotype. Conflicting data exists regarding the persistence of complex partial seizures with reports varying from 4% to 50%.,,,,, This transformation is probably a reflection of the different ways the maturing brain and evolving epileptic networks deal with the underlying pathology, which in turn is genetic in origin. Reflex seizure induced by an increase in body temperature, visual stimulation (intermittent photic, pattern, or light stimulation), and music are known triggers in DS; the visual phenomenology that was precipitated by reading, a prominent seizure type in our patient, has never been reported. However, the electrographic onset from the occipital lobe has been depicted previously in ictal recordings of patients with DS.,
As per the available literature, the seizure frequency in DS tends to plateau by early adulthood and may even decrease after the mid-twenties. Probably this denotes the natural history of the disease or the improved efficacy of antiepileptic drugs with advancing age. In our patient, we could achieve a significant decline in seizure frequency with sustained remission for the past 5 months on a combination of lacosamide, topiramate, and carbamazepine. The effective control of seizures in adults is potentially attainable as exemplified in a series by Akiyuma et al., who achieved a seizure-free period of more than 1 year in 16.1% of the patients. Genton et al., had 2 patients in their cohort of adult DS who enjoyed seizure freedom for more than 2 years and who attributed their success to the addition of topiramate. In the adult age group, the administration of newer antiepileptic drugs could be a viable option, especially in the wake of non-availability of conventional anti-epileptic drugs (AEDs) used in Dravet syndrome, like the administration of stiripentol. Stiripentol is an allosteric modulator of gamma amino butyric acid (GABA)-A receptor, which has been found to be effective in reducing the incidence of prolonged seizures in DS. Ketogenic diet is as effective as AED treatment in DS with the overall response rates of 60–70%. The patient also showed deterioration with lamotrigine – an established phenomenon in DS; however, other sodium channel blockers such as carbamazepine continued to be tolerated and exerted their role well in the combination regimen. The term 'borderline severe myoclonic epilepsy of infancy' (SMEI) is applied to a subtype of patients who lack myoclonic and atypical absence seizures. The former is associated with a better prognosis. Although our patient had myoclonic seizures during the initial part of the illness, they were not very disabling and atypical absence was not noticed.
Cognition and behaviour get affected in DS as early as the second year of life and worsen during childhood; and, a relative improvement occurs later in the course of illness usually by the second decade. Only a small minority of patients in the published literature had an independent life, and residual cognitive, behavioural, and social impairment is the rule.,,,,,, The cognitive abilities of our patient were relatively well preserved, as evidenced by the fact that she has entered the final year of her graduation. Except for the fact that she had a slow and subdued demeanour and a tendency to be irritable or anxious at times, she arguably classified as 'near-normal' with respect to cognition and behaviour. Such an excellent outcome is unusual in DS and correlates well with the good control of seizures and absence of interictal epileptiform discharges.,,, Slow but well-formed occipital alpha rhythm may also be regarded as an indicator of better neurocognitive/psychiatric outcome, as was observed in our patient. Multiple episodes of convulsive status (>3) are yet another harbinger of cognitive disability; these episodes were also averted in her, again as a result of early and efficacious management. In the majority of cases, the convulsive status occurs in the first decade but has been reported in patients up to 28 years of age., Nonconvulsive status epilepticus (NCSE) is even more infrequent. A specific entity called 'obtundation status', characterized by a fluctuating sensorium with intermittent loss of postural tone and myoclonic status has been described in DS. Our patient could have suffered from NCSE after the introduction of lamotrigine, although it was not documented well in her clinical records. Wolff et al., observed that a seizure frequency >5 per month was associated with significant mental subnormality. Hence, efforts to combat seizures should be an ongoing endeavour in this epileptic debacle, if one were to attain sustained and meaningful long-term results. Nevertheless, the contribution of other factors such as the presence and nature of SCN1A mutations cannot be discounted.
DS can have a normal EEG at both ends of its natural history – at the beginning and towards the end with a flurry of abnormalities in between.,,,, Our patient carried reports of abnormal EEGs with generalized IEDs (interictal epileptiform discharges); however, no graphs could be retrieved to verify the same. The present EEG showed mild generalized slowing only [Figure 1]. The absence of IEDs and focal abnormalities plays well with the rest of the clinical picture, as elaborated in the existing literature. The photosensitivity in DS tends to disappear before the age of 20 years, as reported by several authors., It is interesting to note that, in DS, the photoparoxysmal response is dependent more on the quantity of light than its wavelength. The spikes also tend to become more focal as the disease evolves.
Through this illustrative case and discussion, an effort is made to examine the natural history of DS with emphasis on the clinical, prognostic, and therapeutic aspects. Apart from being the first such report from India, this case also stands out because of the excellent clinical outcomes both in terms of seizure control and cognitive improvement, which underscores the importance of an early diagnosis, careful selection of the antiepileptic drugs, and a regular follow-up.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
We acknowledge the Director of St Stephen's Hospital and the Hospital management for allowing us to publish this Report.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.