Dravet Syndrome (DS)

Dravet syndrome (DS) is a rare form of severe childhood epileptic encephalopathy, characterized by frequent, refractory seizures of varying types, cognitive impairment, developmental and speech delays, motor deficits, and behavioral problems. Seizure onset occurs in infancy, often within the first year of life.¹

Etiology

In around 80% of cases, DS is caused by mutations in the SCN1A gene. Of these mutations, approximately 90% arise de novo and up to 10% are inherited in an autosomal-dominant pattern. Other genes have also been found to contribute to the development of DS or DS-like phenotypes. These genetic mutations lead to the biosynthesis of faulty voltage-gated sodium channels, which are normally responsible for initiating and propagating action potentials along neurons.²

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Diagnosis

By the age of 2, individuals with DS demonstrate abnormal electrical activity in the brain on electroencephalography (EEG). EEG can differentiate between multiple seizure types that often become difficult to manage with available antiseizure medications.³ 

EEG can also document paroxysmal discharges of cerebral neurons causing seizures and long-lasting behavioral changes due to nonconvulsive status epilepticus, periodic bedwetting due to nocturnal seizures, and clumsiness on awakening due to myoclonic jerks, absence seizures, and neonatal seizures.³

In a minority of patients with DS, magnetic resonance imaging (MRI) or computed tomography (CT) scans may reveal some structural abnormalities, although most patients with DS demonstrate no gross structural abnormalities of the brain on early imaging. Slight, moderate, or diffuse atrophy of the cerebrum or cerebellum and white matter signal hyperintensities may be present on imaging. Focal structural abnormalities such as arachnoid cysts or hippocampal sclerosis may also occur.⁴

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Histology

According to the literature, there are no existing histopathological hallmarks of DS. Following postmortem examination of adults with DS, histologists discovered well-preserved networks of neurons and interneurons in the cortex, especially the temporal, frontal, and occipital lobes, and the hippocampus, regardless of the duration of repeated, poorly managed seizures. Other subcortical structures, including the thalamus, basal ganglia, and amygdala, also remained intact upon postmortem examination.⁵

However, routine histological staining and calbindin and parvalbumin immunohistochemistry revealed cerebellar atrophy, particularly Purkinje cell loss and gliosis, in all adults examined post mortem.⁵

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Clinical Studies on DS Histology

A murine study revealed histological changes in retinal glial cells of knock-in mice with DS. The researchers discovered increased activation of retinal microglial and astroglial cells without apoptosis of retinal ganglion cells or GABAergic amacrine cells. These findings suggest that retinal histological changes may be useful as a biomarker for individuals with DS.⁶

Another murine study also detected higher levels of neuroinflammation and glial reactivity of the prefrontal cortex and dentate gyrus as evidenced by higher glial fibrillary acidic protein (GFAP) and Iba-1 immunoreactivity during immunofluorescence studies.⁷ GFAP is an intermediate filament protein specifically found in astrocytes in the central nervous system.⁸ Iba-1 is a protein expressed in activated microglial cells.⁹

The researchers also detected higher granule cell dispersion and increased numbers of cells that were positive for Ki67, a marker of cell proliferation, in the dentate gyrus of mice with DS. This potentially suggested reactive gliogenesis.⁷

Researchers investigated histopathological findings in the brain tissue of patients with pharmacoresistant focal epilepsy, which may include DS. Frequent observations included cortical dyslamination next to glial or glioneuronal tumors or vascular malformations, focal cortical dysplasia, hippocampal sclerosis, and cortical lamination abnormalities near brain lesions sustained early in life. The most common tumors among children with refractory, focal epilepsy were glioneuronal tumors.¹⁰ 

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References

1. Anwar A, Saleem S, Patel UK, Arumaithurai K, Malik P. Dravet syndrome: an overview. Cureus. 2109;11(6):e5006. doi:10.7759/cureus.5006
2. Ding J, Li X, Tian H, et al. SCN1A mutation—beyond Dravet syndrome: a systematic review and narrative synthesis. Front Neurol. 2021;12:743726. doi:10.3389/fneur.2021.743726
3. Panayiotopoulos CP. Epileptic encephalopathies in infancy and early childhood in which the epileptiform abnormalities may contribute to progressive dysfunction. In: The Epilepsies: Seizures, Syndromes and Management. Oxfordshire, UK: Bladon Medical Publishing; 2005. Accessed March 14, 2023.
4. Guerrini R, Striano P, Catarino C, Sisodiya SM. Neuroimaging and neuropathology of Dravet syndrome. Epilepsia. 2011;52(s2):30-34. doi:10.1111/j.1528-1167.2011.02998.x
5. Catarino CB, Liu JYW, Liagkouras I, et al. Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology. Brain. 2011;134(10):2982-3010. doi:10.1093/brain/awr129
6. Salazar JJ, Satriano A, Matamoros JA, et al. Retinal tissue shows glial changes in a Dravet syndrome knock-in mouse model. Int J Mol Sci. 2023;24(3):2727. doi:10.3390/ijms24032727
7. Satta V, Alonso C, Díez P, et al. Neuropathological characterization of a Dravet syndrome knock-in mouse model useful for investigating cannabinoid treatments. Front Mol Neurosci. 2021;13:602801. doi:10.3389/fnmol.2020.602801
8. Yang Z, Wang KKW. Glial fibrillary acidic protein: from intermediate filament assembly and gliosis to neurobiomarker. Trends Neurosci. 2015;38(6):364-374. doi:10.1016/j.tins.2015.04.003
9. Shi FJ, Xie H, Zhang CY, et al. Is Iba-1 protein expression a sensitive marker for microglia activation in experimental diabetic retinopathy? Int J Ophthalmol. 2021;14(2):200-208. doi:10.18240/ijo.2021.02.04
10. Metodiev D, Minkin K, Penkov M, Dimova P, Nachev S. Histopathological findings in brain tissue of patients with pharmacoresistant focal epilepsy. J Neurol Neurobiol. 2022;8(1). doi:10.16966/2379-7150.186

Reviewed by Debjyoti Talukdar, MD, on 3/24/2023.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.