Dravet syndrome (DS) is a well-recognized developmental and epileptic encephalopathy associated with SCN1A mutations and 15% mortality by 20 years. Although over half of cases succumb to sudden unexpected death in epilepsy, the cause of death in the remainder is poorly defined. We describe the clinical, radiologic, and pathologic characteristics of a cohort of children with DS and SCN1A mutations who developed fatal cerebral edema causing mass effect after fever-associated status epilepticus. Cases were identified from a review of children with DS enrolled in the Epilepsy Genetics Research Program at The University of Melbourne, Austin Health, who died after fever-associated status epilepticus. Five children were identified, all of whom presented with fever-associated convulsive status epilepticus, developed severe brain swelling, and died. All had de novo SCN1A mutations. Fever of 40°C or greater was measured in all cases. Signs of brainstem dysfunction, indicating cerebral herniation, were first noted 3 to 5 days after initial presentation in 4 patients, though were apparent as early as 24 hours in 1 case. When MRI was performed early in a patient’s course, focal regions of cortical diffusion restriction were noted. Later MRI studies demonstrated diffuse cytotoxic edema, with severe cerebral herniation. Postmortem studies revealed diffuse brain edema and widespread neuronal damage. Laminar necrosis was seen in 1 case. Cerebral edema leading to fatal brain herniation is an important, previously unreported sequela of status epilepticus in children with DS. This potentially remediable complication may be a significant contributor to the early mortality of DS.
- CT —
- computed tomography
- DS —
- Dravet syndrome
Dravet syndrome (DS) is a severe infantile-onset epilepsy syndrome, typically presenting with hemiclonic or generalized febrile status epilepticus in the first year after birth, followed by developmental plateau or regression and emergence of other seizure types.1 Approximately 80% of patients have a mutation of SCN1A (Online Mendelian Inheritance in Man #182389), the gene encoding neuronal voltage-gated sodium channel subunit Nav1.1. Children with DS commonly present with recurrent febrile status and, though most recover fully, variable degrees of developmental regression are often observed.2,3
The mortality in DS is high with 15% dying by 20 years,4,5 which is much higher than epilepsy overall, but comparable to rates for other epileptic encephalopathies.6 Death is attributed to sudden unexpected death in epilepsy in over 50%, with 36% due to status epilepticus with complications such as multiorgan failure.5,7,8
Acute encephalopathy after status epilepticus with moderate to severe sequelae is described in DS, but fatal outcomes are rare.9 Cytotoxic edema, both focal and generalized, has been described immediately after status epilepticus,10,11 including in DS.2,8,9,12,13 In these cases, follow-up MRI usually demonstrates an evolution to mild then moderate atrophy of the affected brain regions. Cerebral edema causing mass effect and death has not previously been described in DS.
We identified patients with DS who died after status epilepticus with fever and had been recruited to The University of Melbourne, Austin Health Epilepsy Genetics Research Program. Over 17 years, 153 individuals with DS have been recruited, regardless of severity, from around Australia and we have ongoing contact with the families. A retrospective study was undertaken in which records, neuroimaging, and pathology of these individuals were reviewed. The Human Research Ethics Committee of Austin Health approved the study (Project No. H2007/02961); written informed consent was obtained from parents or legal guardians of all participants.
Five children died between 10 months and 11 years of age; 4 had classic DS and case 4 had atypical multifocal DS.14 All but 1 had histories of recurrent febrile status epilepticus as is typically seen in DS. Genetic testing revealed a de novo SCN1A mutation in each case; however, these results were not available until after death in cases 4 and 5 (Table 1).15 Baseline brain MRI revealed no significant abnormalities in any of the children. In all cases, seizure control had been relatively good before the acute presentation.
All children had fever-associated convulsive status epilepticus (temperature 40–43.7°C) with suspected or confirmed viral infection. Status duration was 75 minutes to 4 hours despite early initiation of home rescue benzodiazepine, timely involvement of emergency medical personnel, and initiation of routine status epilepticus protocols in hospital. All children required intubation and ventilation, and multiorgan dysfunction was apparent within 24 hours in 4 cases (Table 2).
All children developed signs of brainstem dysfunction consistent with herniation, typically on days 3 to 5 after their initial status presentation, but as early as 28 hours in case 5. Interventions aimed at reversing increased intracranial pressure including mannitol (3), hypertonic saline (1), cooling (3), hyperventilation (2), and external ventricular drainage (1) were unsuccessful, though case 2 showed transient clinical improvement. Supportive care was withdrawn 8 to 9 days after status epilepticus in 4 cases and at 36 hours in case 5; all children died within 24 hours of withdrawal of intensive care.
Interestingly, case 3 had a similar, but less severe, presentation with status epilepticus lasting an estimated 6 hours at 9 years of age, requiring an 8-week hospital stay. MRI acutely revealed bilateral restricted diffusion, primarily in the frontal lobes. After status, she developed right hemiparesis, cognitive regression, and behavioral change, but returned to premorbid function in 8 months.
Early neuroimaging studies were ordered to investigate persistent decreased level of consciousness, while later studies were for prognostication including decisions regarding withdrawal of supportive therapies. Three children had computed tomography (CT) on day 2, which was normal or revealed only mild edema. Later studies (days 4–7) revealed diffuse edema with tonsillar herniation, often with the cerebellar reversal sign (hyperdense cerebellum relative to cerebrum), indicating severe irreversible brain injury.
Three MRI studies on days 6 to 9 demonstrated severe cerebral and cerebellar edema with uncal and tonsillar herniation resulting in brainstem compression (Fig 1). Subcortical white matter demonstrated more extensive diffusion restriction than cortex with variable involvement of deep white matter. Magnetic resonance angiography was normal in 2 cases; however, the day 9 study of case 1 revealed absence of intracerebral arterial flow. Magnetic resonance spectroscopy was performed in 2 cases, and revealed increased lactate and decreased N-acetylaspartate peaks.
Case 1 had 2 MRI studies during the acute presentation, revealing a distinctive pattern of evolution (Fig 1A). On day 4, focal bilateral symmetric perirolandic and left medial parietal cortical restricted diffusion was observed. Follow-up study on day 9 revealed resolution of cortical diffusion changes, and development of severe diffuse cerebral edema with tonsillar and uncal herniation. The subcortical and deep white matter revealed severe diffusion restriction. The latter pattern is mirrored in the later images of patients 3 and 4 (Fig 1 C and D).
Postmortem analysis revealed widespread anoxic-ischemic neuronal injury in all 4 cases examined (Fig 2). Case 5, who died 12 hours after brainstem signs were apparent, had severe white matter edema, transtentorial herniation, and associated uncal grooving. Significant edema was not observed in the other 3 cases, who had much longer intervals between herniation and death. Cortical zones of laminar and border zone infarction were noted in case 3. The same patient had postmortem liver and muscle biopsies, which revealed normal respiratory chain enzyme activity. Extensive bilateral hippocampal damage was noted in 2 cases.
There were no signs of meningoencephalitis in any case. The postmortem examinations in cases 1, 4, and 5 revealed findings in keeping with multiorgan dysfunction including pneumonia/pneumonitis in all 3 children, renal tubular necrosis in 2, liver necrosis in 2, and focal adrenal hemorrhage in 1.
Five children with DS and SCN1A mutations presented with high fever (≥40°C) and status epilepticus complicated by severe brain swelling and death. All demonstrated dramatic cerebral and cerebellar edema, far more severe than imaging changes typically seen after convulsive status epilepticus,10 suggesting this phenomenon may be specific to DS. Though focal and generalized cerebral edema have been previously reported after status epilepticus in DS,2,8,9,12,13 these are the first cases demonstrating mass effect resulting in death.
The reason the children in our series developed such profound diffuse edema is unclear. Hypoxic-ischemic injury likely contributes to their presentation, supported by multiorgan failure in 4/5 cases and postmortem neuropathological analysis. However, the MRI patterns of restricted diffusion of cases 1, 2, and 4 are not consistent with the border zone (watershed) or basal ganglia patterns typical of global hypoxic-ischemic injury. The cortical diffusion restriction and T1 and T2 signal change are in keeping with laminar cortical necrosis, confirmed on postmortem.
Extreme hyperthermia may explain the dramatic severity of presentation, given that all children presented with high fever. The impact of temperature on the NaV1.1 channel has been clearly demonstrated in murine models of DS. Environmental hyperthermia is sufficient to increase frequency of epileptiform electroencephalography discharges and elicit seizures, indicating that elevated temperature alone has a deleterious effect on sodium channel function, independent of inflammatory processes accompanying fever.16
Ion channel dysfunction likely underlies development of severe cerebral edema, supported by observations in other genetic channelopathies. Mutations of CACNA1A, encoding the P/Q type voltage-gated calcium channel subunit α-1A can cause fatal cerebral edema in association with minor trauma or hemiplegic migraine (Online Mendelian Inheritance in Man #601011).17,18 Hemiplegic migraine can also be caused by SCN1A mutations,19 demonstrating the clinical overlap between CACNA1A and SCN1A phenotypes.
Mitochondrial dysfunction is another potential contributing factor, particularly as overlap of mitochondrial pathology with DS has been observed, including POLG1 variants associated with acute MRI revealing cytotoxic edema.2
Although these are the first reports of fatal brain edema causing herniation after status epilepticus in DS, this entity may not be rare. An excellent article on acute encephalopathy in DS by Okumura et al9 includes 3 children with brain edema who died; mass effect was not reported but may have developed later. Together with our series, we suggest that herniation may often be the mechanism of death in patients with DS who die of acute encephalopathy after status epilepticus.
As patients with DS present frequently with status epilepticus, brain imaging is often not performed at all. When CT is used, studies are frequently normal during the early stages of edema. Other cases may have been attributed to an unwitnessed severe hypoxic-ischemic event or septic shock.
In addition, children who die relatively young may not yet have a DS diagnosis or SCN1A testing performed. Within our cohort, cases 4 and 5 did not have their SCN1A mutation identified until after death. Given this, SCN1A testing should be considered in all children with fever-associated status epilepticus who go on to develop severe cerebral edema, even if the swelling is not fatal.
Profound status-induced brain edema is a severe, previously unrecognized fatal entity in DS. Children with a history suggestive of DS and SCN1A mutation presenting in status epilepticus should be monitored closely for signs of catastrophic cerebral edema in the following days. Failure to awaken in a timely manner after status should not necessarily be attributed to medication effect or infection, when other causes may be present. Neurologic vital signs including brainstem reflexes should be closely monitored and imaging studies done emergently if recovery from status appears atypical. It remains to be proven whether early recognition of cerebral edema with aggressive intervention to counteract increasing intracranial pressure could be life-saving.
- Accepted November 2, 2016.
- Address correspondence to Ingrid E. Scheffer, MD, PhD, Epilepsy Research Centre, Level 2, Melbourne Brain Centre, Austin Health, 245 Burgundy St, Heidelberg, VIC 3084, Australia. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: This study was supported by funding from an Australian National Health and Medical Research Council (NHMRC) Program Grant; Dr Scheffer also has an NHMRC Practitioner Fellowship.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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- Copyright © 2017 by the American Academy of Pediatrics