Atypical multifocal Dravet syndrome lacks generalized seizures and may show later cognitive decline

Authors

  • Young Ok Kim,

    1. Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Melbourne, Australia
    2. Department of Paediatrics, School of Medicine, Chonnam National University, Gwangju, Korea
    Search for more papers by this author
  • Susannah Bellows,

    1. Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Melbourne, Australia
    Search for more papers by this author
  • Jacinta M McMahon,

    1. Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Melbourne, Australia
    Search for more papers by this author
  • Xenia Iona,

    1. Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
    Search for more papers by this author
  • John Damiano,

    1. Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Melbourne, Australia
    Search for more papers by this author
  • Leanne Dibbens,

    1. Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
    Search for more papers by this author
  • Kent Kelley,

    1. NorthShore University HealthSystem, Evanston, IL, USA
    Search for more papers by this author
  • Deepak Gill,

    1. TY Nelson Department of Neurology, The Children's Hospital at Westmead, Sydney, Australia
    Search for more papers by this author
  • J Helen Cross,

    1. UCL-Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
    2. Young Epilepsy, Lingfield, UK
    Search for more papers by this author
  • Samuel F Berkovic,

    1. Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Melbourne, Australia
    Search for more papers by this author
  • Ingrid E Scheffer

    Corresponding author
    1. Epilepsy Research Centre, Department of Medicine, The University of Melbourne, Austin Health, Melbourne, Australia
    2. Florey Institute, Melbourne, Australia
    3. Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Melbourne, Australia
    • Correspondence to Professor Ingrid E Scheffer, Epilepsy Research Centre, 245 Burgundy Street, Heidelberg, Victoria 3084, Australia. E-mail: scheffer@unimelb.edu.au

    Search for more papers by this author

Abstract

Aim

To show that atypical multifocal Dravet syndrome is a recognizable, electroclinical syndrome associated with sodium channel gene (SCN1A) mutations that readily escapes diagnosis owing to later cognitive decline and tonic seizures.

Method

Eight patients underwent electroclinical characterization. SCN1A was sequenced and copy number variations sought by multiplex ligation-dependent probe amplification.

Results

All patients were female (age range at assessment 5–26y) with median seizure onset at 6.5 months (range 4–19mo). The initial seizure was brief in seven and status epilepticus only occurred in one; three were febrile. Focal seizures occurred in four patients and bilateral convulsion in the other four. All patients developed multiple focal seizure types and bilateral convulsions, with seizure clusters in six. The most common focal seizure semiology (six out of eight) comprised unilateral clonic activity. Five also had focal or asymmetric tonic seizures. Rare or transient myoclonic seizures occurred in six individuals, often triggered by specific antiepileptic drugs. Developmental slowing occurred in all: six between 3 years and 8 years, and two around 1 year 6 months. Cognitive outcome varied from severe to mild intellectual disability. Multifocal epileptiform discharges were seen on electroencephalography. Seven out of eight patients had SCN1A mutations.

Interpretation

Atypical, multifocal Dravet syndrome with SCN1A mutations may not be recognized because of later cognitive decline and frequent tonic seizures.

Atypical multifocal Dravet syndrome was first described in our large study of infantile-onset epileptic encephalopathies due to mutations of the sodium channel α1 subunit gene (SCN1A), as severe infantile multifocal epilepsy.[1] We studied 188 patients with early-onset epileptic encephalopathies without structural or metabolic causes, including 102 with the classic and borderline forms of Dravet syndrome.[1-6] In addition, three children had an atypical SCN1A epileptic encephalopathy where seizures began at 4 to 7 months comprising multiple types of focal seizure in the absence of prominent generalized seizure types or generalized spike-wave activity. Developmental slowing occurred considerably later than usually observed in Dravet syndrome.[1] Electroencephalography (EEG) showed multifocal discharges; generalized spike wave activity was not seen.[1] Here we confirm that this atypical multifocal form of Dravet syndrome is distinctive and may escape diagnosis given the later cognitive decline and lack of prominent generalized seizure types and EEG features. Lack of recognition means that patients are at a higher risk of therapies that exacerbate seizures and thereby potentially result in poorer cognitive outcome.

Method

Patients

From our cohort of patients with focal epileptic encephalopathies of unknown aetiology, we selected those who fulfilled the following inclusion criteria: normal early development; seizure onset below 2 years of age; multiple types of focal seizure; and later developmental slowing. We analysed clinical data, EEG, brain imaging, and metabolic and genetic results. Three patients were previously briefly reported as having severe infantile multifocal epilepsy.[1] This study was approved by the Human Research Ethics Committee of Austin Health, Melbourne. Signed informed consent for study participation was obtained from the participants or, for minors or adults with intellectual disability, from their parents or legal guardians.

Mutation screening

All 26 SCN1A (GenBank accession number AB093548) exons and exon–intron junctions were analysed by bi-directional Sanger sequencing (ABI 3730xl) after polymerase chain reaction. Copy number variations were detected by multiplex ligation-dependent probe amplification (MRC-Holland, Amsterdam, the Netherlands).[6] In the previously reported three children, SCN1A mutations were identified by denaturing high-performance liquid chromatography and confirmed by sequencing. Mutations or rare variants were distinguished from coding single-nucleotide polymorphisms using 1000 genomes and dbSNP databases. Parental DNA was tested to distinguish between de novo and inherited variants and, in the case of patient 8, her monozygotic twin was also sequenced for SCN1A mutations.

Results

Seizure characteristics

Eight patients with atypical multifocal Dravet syndrome were identified (five new, three previously reported); all were female, aged 5 to 26 years. The median age of seizure onset was 6.5 months (range 4.5–19mo). Seizures began between 4 months and 10 months in seven children, and one had later onset at 19 months. The first seizure was brief in all patients except for one who presented with status epilepticus. In four patients, the initial seizure was focal (two febrile), whereas four presented with a bilateral convulsive seizure (one febrile). Although fever was only present in three patients at onset, it proved to be a major trigger for six of the eight (Table 1).

Table 1. Electroclinical data for patients with atypical multifocal Dravet syndrome
CharacteristicPatient 1aPatient 2aPatient 3aPatient 4Patient 5Patient 6Patient 7Patient 8
  1. Three patients were previously briefly reported.

  2. ↑, an increase in seizures; VGB, vigabatrin; TGB, tiagabine; GBP, gabapentin; ID, intellectual disability; EDs, epileptiform discharges; MFEDs, multifocal epileptiform discharges; GSW, generalized spike-wave; MRI, magnetic resonance imaging; CT, computed tomography; LGS, Lennox–Gastaut syndrome; MAE, myoclonic astatic epilepsy.

SexFemaleFemaleFemaleFemaleFemaleFemaleFemaleFemale
Age at last visit5y24y23y8y 8mo7y 11mo8y 8mo7y 11mo26y
Age at seizure onset and initial seizure (mo)4.5 (focal)5 (bilateral, febrile)7 (bilateral, febrile)5 (focal)19 (focal, febrile)6 (bilateral)10 (bilateral)8 (focal)
Seizure type
 FocalYesYes (↑ by VGB)Yes (↑ by VGB, TGB)YesYesYesYesYes
ClonicYesYesRareYesNoYesYesYes
TonicNoYesYesYesYesNoYesNo
 MyoclonicNoRare (3y – not known)Transient (7y with VGB, 14y with GBP)Rare (5mo–3y)Rare (19mo–5y)Transient (10–18mo with VGB)Rare (not known)No
Provoking factorsNoFever, stress, fatigue, foodFever, excitement, menstruationFever, viralFever, excitement, hot weatherNoFever, viralFever, viral, excitement
Age at onset of status epilepticus3y22mo7y (by TGB)9mo4y9mo10mo4y 7mo
Age at onset of developmental slowing16mo3y 6mo6y4y3y18mo4y 6mo8y
IntellectMild ID (at 3y)Moderate ID (at 12y)Moderate ID (at 13y)Moderate ID (at 8y 6mo)Mild ID (at 6y 6mo)Severe ID (at 8y)Moderate ID (at 7y)Mild ID (at 18y)
ElectroencephalographyFocal EDs 4.5mo, MFEDs 3yNormal until 22mo, brief GSW 2y 6mo, focal EDs 2y 10mo, MFEDs 9y 10moNormal until 5y, MFEDs 7yNormal or focal slowing 4yNormal or focal slowing 3y 5mo, MFEDs 4y 4moNormal 1y, focal EDs from 1y, MFEDs 2y 7moNormal 3y, MFEDs 5y 6moNormal 4y 4mo, Asymmetric diffuse slowing 6y 6mo
Brain image studyNormal (MRI)Normal (CT, MRI)Normal (MRI)Normal (MRI)Normal (MRI)Mild ventricular dilatation (MRI)Left hippocampal volume loss (MRI)Normal (CT)
SCN1A mutation (transmission)p.Phe1543Ser (maternal)p.Arg1596Cys (de novo)p.Phe575SerfsX48 (de novo)p.Arg101Gln (de novo)c.IVS13+5G>A (not available)p.Leu373PhefsX6 (not available)p.Asn275Lys (not available)No
Neurological signsNoAtaxiaAtaxia, crouch gait, spasticityAtaxiaAtaxiaAtaxiaAtaxiaNo
Family historyNoEpilepsy (LGS, aunt; MAE, cousin)Febrile seizure (cousin)Epilepsy, autism, dyslexia (cousins)NoSeizures (cousin and grandfather)NoEpilepsy and febrile seizure (monozygotic twin)

In all patients, multiple types of focal seizure developed over time and evolved to bilateral convulsive seizures. In six patients, there were frequent clusters of focal seizures. Status epilepticus occurred between 3 years and 7 years of age in four individuals and below 2 years in the remaining four. The most common focal seizure semiology (six out of eight) was clonic activity of one extremity or one side associated with loss of awareness, often with head and eye deviation. Todd's paresis was seen after seizure clusters in five patients. Mirror image seizures, in which identical semiology was seen involving alternate sides of the body, occurred in all. The second most common focal seizure semiology (five out of eight) comprised unilateral or bilateral asymmetric tonic seizures sometimes preceded by facial grimacing or deviation of the head or eyes. They frequently occurred during sleep before awakening. Six had transient or rare myoclonic seizures (Table 1).

Seizure exacerbation due to vigabatrin, tiagabine, and gabapentin was observed. One female had focal motor status epilepticus after tiagabine and myoclonic status epilepticus triggered by vigabatrin; myoclonic seizures were also brought on by gabapentin in this patient. Another patient had myoclonic seizures during treatment with vigabatrin. Carbamazepine, prescribed in six patients, did not trigger myoclonic seizures.

Seizures were resistant to multiple antiepileptic drugs. Although one patient was responsive to the ketogenic diet, it was ineffective in four. Vagal nerve stimulation was not effective in one patient although it did improve her alertness.

Five patients had a family history of epilepsy (four out of eight probands), febrile seizures (one out of eight), and developmental disorders (two out of eight). Patient 8 had a monozygotic twin sister with a milder phenotype, not fulfilling our criteria for atypical multifocal Dravet syndrome. The twin had onset at 9 months of febrile left hemiclonic seizures, sometimes preceded by giggling and visual hallucinations, which remitted at 9 years and occurred in the setting of normal intellect.

Development

In all children, developmental slowing and regression occurred at a median age of 3 years 10 months, well after seizure onset and later than usually observed in Dravet syndrome. In six children, slowing began between 3 years and 8 years, and in two patients around 18 months. Slowing typically followed frequent clusters of seizures or status epilepticus. Cognitive outcome was variable: one had severe, four moderate, and three mild intellectual disability. Six patients had mild ataxia. Patient 3 had a crouch gait with mild spasticity[7] (Table 1).

EEG

Initial EEG studies were normal or showed focal slowing in most patients (Table 1). Epileptiform activity typically became evident in the third year or later (2y 6mo–7y), with only two patients showing focal discharges earlier at 4.5 months and 1 year. Multifocal discharges were seen in six children from 2 years 7 months to 9 years 10 months, although EEG studies were not performed at regular intervals (Fig. 1a–d). Two patients never had epileptiform activity captured on EEG, although few studies were performed. No generalized spike-wave or photosensitivity was noted with the exception of patient 2, who, at 2 years 6 months, had two brief paroxysms of generalized spike-wave during one of 10 EEG recordings.

Figure 1.

Electroencephalography excerpts showing interictal multifocal epileptiform discharges and an ictal recording in patient 2 at age 20 years. (a–d) Interictal epileptiform discharges emanating from the (a) left temporal, (b) right frontal, (c) right centro-parietal, and (d) left frontal regions. (e) An ictal recording with a high-voltage bifrontal spike followed by diffuse low-voltage fast activity. The open arrow denotes clinical seizure onset with right upper-limb elevation and tonic posturing.

Five patients (1, 2, 3, 5, 7) had ictal recordings emanating from different cortical foci in different seizures; however, intraictal migration of focal seizures was not observed. Three patients had electrographic seizures captured without a clinical correlate. During tonic seizures (patients 2, 3), paroxysmal diffuse fast activity was seen (Fig. 1e).

Brain imaging

Brain imaging (magnetic resonance imaging [MRI] or computed tomography) was normal in six children. One showed mild ventricular dilatation and another had left hippocampal volume loss (Table 1).

SCN1A study

Seven patients had a SCN1A mutation: four missense (two de novo; one maternal, one parental DNA unavailable), two truncation (one de novo; eight parental DNA unavailable), and one splice site mutation (parental DNA unavailable; Table 1). Patient 8 and her monozygotic twin did not have a SCN1A mutation.

Discussion

Atypical multifocal Dravet syndrome is a slowly progressive infantile-onset epileptic encephalopathy with multiple types of focal seizure and later developmental slowing. Our large study of infantile-onset SCN1A epileptic encephalopathies identified this phenotype as severe infantile multifocal epilepsy, but no further cases have been reported.[1] Some of these patients may have been previously subsumed in the group of borderline Dravet syndrome; however, our concern is that, in many instances, their lack of generalized seizures and EEG patterns means that an atypical form of Dravet syndrome would not have been considered.[2-6]

Here we ask whether this is an identifiable SCN1A epileptic encephalopathy that may be at risk of misdiagnosis as it misses many of the cardinal features of Dravet syndrome (Table 2). These absent features include prominent generalized spike-wave activity on EEG, generalized seizure types, and developmental slowing between 1 year and 2 years of age. Moreover, this atypical form is often associated with tonic seizures, which are rare early in Dravet syndrome but are more frequently observed in adult life.[2-6]

Table 2. Key differences between the typical and atypical forms of Dravet syndrome
CharacteristicDravet syndrome[1-6, 8]Atypical multifocal Dravet syndrome[1],a
  1. a

    This study.

  2. EEG, electroencephalography.

Typical age at seizure onset~6mo~6mo
Seizure types
 FocalYesYes
 GeneralizedYesNo
 TonicLateYes
EEG patterns
 Focal epileptiform dischargesYesYes
 Generalized spike waveYesNo
Age at cognitive slowing1–2y1–6y
Fever with first seizureFrequentUncommon
Status epilepticus with first seizureFrequentRare

First, we reviewed our original five patients regarded as having severe infantile multifocal epilepsy.[1] We excluded two patients with further information: a male had spasms that were not part of atypical multifocal Dravet syndrome; he also never had the cardinal feature of multiple types of focal seizure. A female presented in the neonatal period with seizures associated with birth asphyxia and subsequent right hemispheric atrophy; the onset was too early for Dravet syndrome and the MRI findings were in keeping with the history of birth asphyxia rather than Dravet syndrome. Second, we report an additional five patients and review our experience of this distinctive phenotype.

Atypical multifocal Dravet syndrome shares many features with Dravet syndrome (Table 2). The term Dravet syndrome is used here to encompass both the classic and borderline forms.[2, 8] The age at seizure onset of 4 to 10 months is the same, with the exception of one patient here with onset at 19 months, which is older than that usually accepted for Dravet syndrome. The initial seizure was either focal or generalized, which is also typical, yet only one of our cohort presented with status epilepticus, a common presentation for Dravet syndrome. Similarly, fever often triggers the initial seizure in Dravet syndrome, but was only apparent in three of our eight patients. The hallmark of this atypical form is the presence of multiple types of focal seizure, which is also part of Dravet syndrome.

Why is it important, then, to distinguish atypical multifocal Dravet syndrome? The principal reason is the lack of generalized spike-wave and generalized seizures, as many clinicians do not think of a genetic aetiology without these generalized epilepsy ‘signatures’ of Dravet syndrome. Tonic seizures were frequently seen in our cohort but are uncommon in Dravet syndrome in infancy and childhood. Furthermore, SCN1A testing may not be sought for children who show later cognitive decline than the typical slowing at 1 to 3 years that is part of the Dravet phenotype.[2-6] In six patients, developmental slowing occurred between 3 years and 8 years and intellectual disability was universal, albeit mild, in three patients. It is well recognized that rare patients with Dravet syndrome may be of normal intellect, so this less severe outcome is not surprising but the later age of decline is unusual.[9-11] It is important that clinicians recognize that SCN1A epileptic encephalopathies can present with later decline as diagnosis will influence selection of antiepileptic therapy. If drugs specifically targeting focal (or multifocal) epilepsies are chosen, such as carbamazepine, vigabatrin, or tiagabine, then seizure exacerbation may occur and detrimentally affect cognitive outcome.

Here, we extend our previous observation that atypical multifocal Dravet syndrome is a distinctive phenotype often associated with SCN1A mutations. It can also be distinguished from epilepsy of infancy with migrating focal seizures, which is a much more severe early infantile focal epileptic encephalopathy. We, and others, recently found SCN1A mutations in a small proportion of cases with this rare syndrome.[12, 13] The hallmark of this syndrome is that there is intraictal migration of focal seizures between hemispheres, which is not seen in atypical multifocal Dravet syndrome. Onset is earlier, beginning at a median age of 3 months (range 0–6 mo). Profound early global developmental delay is typical and acquired microcephaly at less than 1 year is observed.[14, 15]

Focal seizures associated with SCN1A mutations are seen in a spectrum of epilepsy syndromes that vary in severity. Severe SCN1A focal epilepsies include atypical multifocal Dravet syndrome and epilepsy of infancy with migrating focal seizures where both syndromes present with multiple types of focal seizure. SCN1A mutations have also been associated with mild focal epilepsies including temporal lobe epilepsy and Panayiotopoulos syndrome in individuals with normal intellect.[16, 17]

Although the multifocal EEG manifestations in our cohort share some similarities with an entity described by Japanese authors, severe epilepsy with multifocal independent spike foci,[18] the phenotypes are quite different. Severe epilepsy with multifocal independent spike foci has (1) predominantly generalized seizures with a mean onset of 11.6 months (first day to 2y 10mo), (2) extensive pathology on neuroimaging in 70% of patients, (3) significant motor deficits, (4) can evolve to West syndrome or Lennox–Gastaut syndrome, and (5) multifocal independent spike foci can be seen from 2 months.[18]

SCN1A is the most relevant gene in epilepsy today as mutations are found in 70% to 80% of patients with Dravet syndrome[1, 3] and 10% of the much milder familial epilepsy syndrome, genetic epilepsy with febrile seizure plus.[19, 20] Although SCN1A is widely regarded as important in generalized epilepsies, SCN1A testing is rarely considered for infantile epileptic encephalopathies characterized by focal seizures alone, where a structural basis is often presumed. Atypical multifocal Dravet syndrome expands the clinical spectrum of epileptic encephalopathies associated with SCN1A mutations.

Acknowledgements

We thank the patients and their families for participating in our research. This study was funded by the National Health and Medical Research Council of Australia. Young Ok Kim was supported by a grant (CRI09073-1) from Chonnam National University Hospital Research Institute of Clinical Medicine, Republic of Korea.

Ancillary