In this cross-section cohort, we collected data about patients with DS from caregivers in Taiwan, which add to our understanding about the impact of DS patients’ condition and DS on caregivers’ concerns. It is important to avoid specific seizure trigger factors in DS. In our study, we found that the most significant trigger factor as shown in other studies is hyperthermia. Therefore, the patients should avoid the predisposing factors of hyperthermia, such as overexcitement, overexertion, sun exposure, and warm bath [9]. The family members should also be educated to seek for medical assistance whenever facing hyperthermia. We also noticed that photosensitivity and pattern sensitivity were trigger factors of seizure, similar to that of Villas et. al. reported in 2017 [10].
In our study, we found that vaccine-related seizures were reported in 12 (34%) of 35 patients at our cohort. This was consistent with previous studies showing that one third of patients with DS developed seizures after vaccination [7, 8, 11] (Table 4). Because there was no statistically significant difference between language, ambulation or seizure characteristics for those with and without vaccine-related seizures, the vaccination should not be withheld in patient with DS, and all clinicians should provide families with proper information before administering vaccination.
Table 4
Comparison of literature review in vaccination-related seizures in Dravet syndrome
| Study | Present Study | Wong et al. Pediatr Neurol 2016 | Tro-Baumann et al. Epilepsia.2011 | McIntosh et al. Lancet Neurol.2010 |
| Country | Taiwan | Hong Kong | Germany and Austria | Austria |
| Numbers | 38 | 54 | 70 | 40 |
| Ethnic Origin | 100% Chinese | 98% Chinese | Unspecified | Unspecified |
| Percentage of Vaccination-Related Seizures | 34% | 31.5% | 27% | 30% |
| Significance of SCN1A mutations | Patient recruitment consists of 100% patients with DS with SCN1A mutation | The presence of SCN1A mutation found in the vaccination-proximate (94.1%) compared with the vaccination-distant (78.4%) group (P 1⁄4 0.244, no significant difference) | Patient recruitment consists of 100% patients with DS with SCN1A mutation | Patient recruitment consists of 100% patients with DS with SCN1A mutation |
| Major Findings | No statistically significant difference between language, ambulation or seizure characteristics. | Vaccination-proximate patients are more likely to develop status epilepticus and absence seizure as subsequent seizure types across the life span in DS when compared with the vaccination-distant group, but no difference in the clinical outcome and subsequent seizure development | 58% of patients with vaccination-related seizures represented the first clinical manifestation | No differences in intellectual outcome, subsequent seizure type, SCN1A mutation type |
In previous literatures, seizure frequency may decrease with age, which was independent of their SCN1A mutation type [12–15]. We also found a tendency of decreasing seizure frequency with age, although this did not reach statistical significance. In other study, in adolescence and adult groups with DS, fever sensitivity persisted but had less influence [14].
According to previous studies in Dravet mouse model, seizure susceptibility in DS is caused by reducing the sodium currents and electrical excitability of GABAergic interneurons, which lower the seizure threshold [16, 17]. Therefore, the first-line treatments for DS include valproic acid and clobazam, and the second-line treatment may include stiripentol, topiramate and the ketogenic diet [18]. As shown in Table 5, valproate was the most commonly used AEDs. Clobazem, topiramate, and stiripentol were also used frequently. In contrast, levetiracetam was the third common AED treatment in Taiwan.
Table 5
Review of real-world evidence on medicine utilization of patients with Dravet syndrome in publish data
| Study | Present study | Schubert-Bast et al. Epilepsy Behav 2019 | Villas et al. Epilepsy Behav 2017 | Lagae et al. Dev Med Child Neurol 2018 | Aras et al. Epilepsy Behav 2015 |
| Year of survey | 2019/2020 | 2017/18 | 2016 | 2016 | 2014 |
| Country | Taiwan | Germany | Worldwide | Worldwide | Europe-wide |
| Numbers | 38 | 93 | 256 | 584 | 274 |
| Age (years) | Mean:10.6 | Mean:10.1 | Median:7–10 | Mean:10.6 | Median:4–8 |
| Most used AEDs | 1. Clobazam (68%) 2. Valproic acid (66%) 3. Levetiracetam (55%) 4. Topiramate (29%) 5. Stiripentol(26%) 6. Clonazepam (18%) | 1. Valproate (66%) 2. Bromide(44%) 3. Clobazam(41%) 4. Stiripentol(35%) 5. Topiramate(15%) | 1. Valproate (89%) 2. Clobazam (79%) 3. Topiramate (75%) 4. Lamotrigine (44%) 5. Stiripentol (94%) | 1. Valproate (76%) 2. Clobazam (53%) 3. Stiripentol (47%) 4. Topiramate (34%) 5. Bromide(10%) | 1. Valproate (86%) 2. Clobazam (55%) 3. Topiramate (44%) 4. Stiripentol (42%) 5. Levetiracetam (22%) |
About the side effect of AEDs, drowsiness, cognition problem, and unsteady gait were most common in our study. In contrast, hematologic side effects, such as thrombocytopenia, neutropenia, or anemia, did not reach significance in our study. Nephrocalcinosis caused by topiramate accounted for 3% of the patients, which was similar to other studies [10]. Appetite disturbance and constipation were also noted in our patients, which might be due to AEDs or DS itself.
The characteristic symptoms of DS in our study include nocturnal seizures, hypotonia, drowsiness, cognition problem, unsteady gait, constipation, and psychiatric issues like ADD or ADHD problem, corresponding to previous literatures [10, 19]. In our study, caregivers’ reports of nocturnal seizure were 51%, the same as one previous study [20], and was less compared with another study, which reported 77% of nocturnal seizure [10]. It indicated that nocturnal seizures are a major concern for most caregivers. Awareness and attention between DS with SCN1A mutations and heart rate/rhythm and abnormalities are increasing in recent years. Cardiac dysfunction leading to sudden death may be a major concern for caregivers [21]. Although cardiac arrhythmia was noted in some of our patients, no one was found to have sudden death due to cardiac problem.
There was limited discussion about the possible pathogenic mechanisms leading to different comorbidities in the past. Dravet syndrome, which is primarily caused by heterozygous loss of function mutation in the SCN1A gene that encodes voltage-gated sodium channel type-1, termed Nav 1.1. Nav1.1, is a member of a family of voltage-sensitive sodium channels expressed primarily in the brain, including Nav1.1, Nav1.2, Nav1.3, and Nav1.6. As Nav1.1 expression is very low in neonates, other alpha subunits such as Nav 1.2 and Nav 1.3 may compensate for reduced Nav 1.1 function during this early stage of development [22]. Therefore, as shown in mouse model, a physiologic decline in Nav 1.3 channel expression in brain development, coupled with the failure of increase in functional Nav 1.1 channels in Dravet syndrome, may lead to wide spread dysfunction of neuronal networks, intractable seizures, and comorbidities, including ataxia, sleep quality and autistic-like behaviors and spatial learning and memory [23].
Electrophysiological studies showed that Nav 1.1 plays a crucial role in the excitability of cerebellar Purkinje neurons, with major contributions to peak, persistent, and resurgent forms of sodium current and to sustained action potential firing. Loss of these channels in Purkinje neurons of mutant mice may cause loss of excitability of Purkinje neurons leading ataxia, as shown in other study [24].
Patients with DS had reported sleep problems, including disturbance of sleep time, impaired sleep quality and increased incidence of nocturnal seizures [25]. In DS mouse model, the mechanism of sleep disorders is related to mutation of Nav1.1 channel in forebrain GABAergic interneurons without involvement of drug treatment and may correlated with cell-specific loss of sodium current and excitability of reticular nucleus of the thalamus GABAergic interneurons. This result confirms that impaired action potential firing of these GABAergic interneurons is responsible for the defect in sleep quality [26]. Regarding other sleep problems, DS children also have a circadian rhythm defect, which influences their sleep-wake cycle [25]. Although our result did not show significant finding in this field, DS mice had an abnormally long circadian cycle length, defects in phase shift after change of their light-dark cycle, and impaired light-induced shifts of their sleep-wake cycle [25]. In heterozygous Scn1a+/− mice study, it showed that reduced Nav1.1 channel activity impairs suprachiasmatic nucleus of the hypothalamus, the primary site of the circadian clock [27]. This finding supports the relationship between decreased GABAergic transmission and circadian defect [27]. Therefore, some symptoms of DS sleep problems may be treatable by enhancement of GABAergic neurotransmission [27].
Children with DS also exhibit autistic-like behaviors [10]. DS mice also have substantial deficit in social interactions. This deficit may be explained by the specific deletion of Nav1.1 channel in forebrain inhibitory neurons, which may reduce action potential firing in inhibitory neurons. Besides, treating with low doses clonazepam may rescue the autistic-like behaviors in DS mice, caused by channel dysfunction rather than the epileptic activity itself as contributor [28]. Furthermore, another study also showed that GABAergic interneurons may include parvalbumin-(PV+) or somatostatin-expressing (SST+) interneurons [29]. Therefore, deletion of Nav 1.1 in PV + interneurons may cause social interaction deficit rather than hyperactivity; however, deletion of Nav 1.1 in SST + interneuron may cause hyperactivity behavior. In contrast, synergistic effect of PV + and SST + interneurons were found to impair long-term spatial memory [29]. In these studies, they demonstrated that autistic-related phenotypes and spatial learning deficits resulted from decreasing Nav 1.1 activity in GABAergic interneurons in hippocampus and cortical interneurons [17, 28, 30].
As we known, sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in intractable epilepsies, but the physiological mechanisms leading to SUDEP are unknown [20]. Although we did not document these events in our study, recent works suggested that SUDEP was caused by parasympathetic hyperactivity following hyperthermia-induced tonic-clonic seizures, which resulted in severe bradycardia and death in the Scn1a+/− mouse model of DS [31]. DS mice had been shown to have ventricular myocytes problems via alterations in neuronal excitability and cardiac electrophysiologic abnormalities, which may contribute to the susceptibility for arrhythmogenesis and SUDEP [32]. Furthermore, reductions in Nav1.1 expression may indirectly affect Nav 1.5 activity and cardiac electrical function [32], leading cardiac problems.
Therefore, regaining the impaired GABAergic neurotransmission may not only lead to improved seizure control but also improved function form prefrontal cortex to cerebellar networks, as has been shown in mice [28, 29, 33] (Fig. 3).
In recent literatures, more and more studies have focused on caregivers of patients with DS owing to different aspects of stress, and, therefore, may need multidisciplinary team to care about the patients. In our study, caregivers viewed additional household tasks, symptoms observation, further medical plan and financial problems as significant factors. A cohort study in Children's Hospital Colorado, they found caregivers suffered from emotional exhaustion and anxiety related to “fear of the next seizure” and “the seizure that kills my child”. Besides, caregivers need to quit their jobs or careers to care for their child with DS due to the severity of condition [34]. In another study in Canada, persistent severe seizures, accompanied with developmental, cognitive, behavioral, and sleeping issues increased caregivers’ burden [25]. Most caregivers may also concern about sleep deprivation, reduced mental health, deterioration of social relationships, and financial burden problem [35].
Caregivers in this study ranked their top 3 major concerns in the future, including lack of independence/constant care, seizure control, speech and communication problem and sibling impacts (long-term care when parents are gone). In another study, caregivers ranked their top 4 concerns, as speech and communication challenges, the impact of the patient with DS on siblings, cognitive/developmental delay, and behavioral issues including violence and autistic traits [10]. Therefore, recent studies have begun to raise the attention about caregivers’ need and offer further additional support services for the relief the burden of caring for patients with DS in the hope for improving caregivers physical and financial well-being.
There were several limitations in our study. Not all patients with DS from Taiwan were enrolled in the present study. In addition, the most common seizure pattern in adolescents and adults was generalized tonic-clonic, and mostly nocturnal and in cluster [14, 36]. However, in our study, we did not record the serial seizure changes. We could also not prove that broken bones and scoliosis were positively related to DS or other etiologies, such as vitamin D deficiency, due to no related blood tests in patients.
In conclusion, comorbidities are very common in patients with DS. They are related to the involvement of different regions in the brain. Therefore, detailed evaluation of the patients with DS for possible association of different comorbidities may direct the neurologists to correct treatment in addition to seizures.