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|Year : 2021 | Volume
| Issue : 6 | Page : 1701-1705
Drug-resistant 'Non-Lesional' Visual Sensitive Epilepsies of Childhood – Electroclinical Phenotype–Genotype Associations
Ramshekhar N Menon1, Poornima N Nambiar1, R Ravish Keni1, Jitupam Baishya1, Ashalatha Radhakrishnan1, Ajith Cherian1, Sheela Nampoothiri2, GK Madhavilatha3, Udaya H Kotecha3, Sanjeev V Thomas1
1 Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India
2 Amritha Institute of Medical Sciences, Kochi, Kerala, India
3 MedGenome Labs Ltd, Bengaluru, India
|Date of Submission||04-Sep-2019|
|Date of Decision||01-Dec-2019|
|Date of Acceptance||20-Mar-2020|
|Date of Web Publication||23-Dec-2021|
Dr. Ramshekhar N Menon
Department of Neurology, SCTIMST, Thiruvananthapuram-11, Kerala
Source of Support: None, Conflict of Interest: None
Background: Sporadic nonlesional intractable visual-sensitive epilepsies of childhood represent a challenging subset of epilepsies in terms of management and prognostication given a propensity to evolve as epileptic encephalopathy.
Objective: To study the genetic heterogeneity of drug-resistant visual sensitive epilepsy of childhood.
Methods: A retrospective chart review was conducted on patients in the pediatric age group between 2016 and 2018, with drug-resistant epilepsy (DRE) and video electro encephalography (VEEG) documented reflex photosensitivity, eye-condition sensitivity. Those patients who underwent genetic testing with targeted next-generation sequencing using an epilepsy gene panel were selected.
Results: During the study period, out of 96 patients who underwent genetic testing, 4 patients (4.17%) with sporadic DRE presented with clinical phenotypes ranging from myoclonic-atonic epilepsy, generalized epilepsy with eyelid myoclonia as well as febrile and unprovoked seizures, along with visual sensitivity. Video EEG documented abnormalities ranged from occipital, posterior-cortex and generalized discharges with “eyes-closed state” triggered, self-induced “smart-phone” triggered, photosensitive focal-onset and generalized myoclonic seizures. Accompanying developmental impairment was noted. These patients who were investigated with clinical exome sequencing were detected to have mutations in not only SCN1A genes (pathogenic exonic and intronic variants) but also CHD2 (pathogenic) and CACNA1H genes (a familial febrile-seizure susceptibility variant of unknown significance).
Conclusions: The series highlights the complex genetics of drug-resistant visual-sensitive epilepsy of childhood. Such genotype–phenotype associations throw light on the role of ion-channel and non-ion channel genes on reflex epileptogenesis in this group of patients.
Keywords: Clinical exome sequencing, drug-refractory, EEG, genetics, visual sensitive epilepsy
Key Message: Reflex visual sensitive epilepsies (photosensitive or eye condition sensitive) of childhood may have a monogenic basis and mandate genetic testing, especially in association with developmental impairment and anti-seizure medication resistance.
|How to cite this article:|
Menon RN, Nambiar PN, Keni R R, Baishya J, Radhakrishnan A, Cherian A, Nampoothiri S, Madhavilatha G K, Kotecha UH, Thomas SV. Drug-resistant 'Non-Lesional' Visual Sensitive Epilepsies of Childhood – Electroclinical Phenotype–Genotype Associations. Neurol India 2021;69:1701-5
|How to cite this URL:|
Menon RN, Nambiar PN, Keni R R, Baishya J, Radhakrishnan A, Cherian A, Nampoothiri S, Madhavilatha G K, Kotecha UH, Thomas SV. Drug-resistant 'Non-Lesional' Visual Sensitive Epilepsies of Childhood – Electroclinical Phenotype–Genotype Associations. Neurol India [serial online] 2021 [cited 2022 Jan 18];69:1701-5. Available from: https://www.neurologyindia.com/text.asp?2021/69/6/1701/333508
The MRI negative drug-resistant epilepsy (DRE) syndromes of posterior cortex origin in childhood represent a peculiar subset with a propensity for frequently intractable visual-sensitive seizures, persistence into adolescence, genetic predisposition as opposed to the “benign”/idiopathic subtypes such as late-onset childhood occipital epilepsy-Gastaut subtype. We have recently reported variants of visual-sensitive epilepsy (eye closure, eye-closed sensitivities, and photosensitivity), including pharmaco-resistant subtypes, with a predilection for the pediatric age group, although genotype–phenotype correlations were not elucidated. While progressive symptomatic etiologies such as progressive myoclonus epilepsies, celiac disease, mitochondrial disorders merit consideration, understanding of genetic mechanisms behind these “non-lesional” epilepsies (which often fall under the rubric of “unknown” or “presumed genetic” etiology) has compounded in the past decade. The seizure burden in terms of refractoriness to standard antiepileptic drugs (AED) and developmental implications can mimic epileptic encephalopathies (EE). Photosensitive epilepsies are also known to be associated with EE, such as Dravet syndrome (DS) and encephalopathy associated with a mutation in CHD2. Often, correlation of electroclinical phenotypes akin to an EE requires elucidation of well-described genotypic associations which often point to inherited ion channelopathies. Recognition of novel gene mutations in such phenotypes has potential therapeutic and prognostic implications. In the prototypical EE, DS, a genetic cause of de novo SCN1A mutation was first identified in 2001. Subsequently, it has been found that >80% of cases of DS have SCN1A mutations. However, other genes like PCDH19 and GABRA1 account for a small number of cases. With the advent of novel techniques like chromosomal microarray and next-generation parallel sequencing of multiple genes, cases of de-novo genetic developmental encephalopathies are identified, and further studies are required to confirm the role of the newly recognized genes as causative for drug-resistant 'cryptogenic' epilepsies with distinctive reflex features. This case series investigates genotype-–phenotype associations in paediatric patients with drug-resistant focal-onset and generalized visual-sensitive epilepsy without demonstrable focal lesions on 3 T MRI brain epilepsy protocol.
| » Methods|| |
From the computerized database of a comprehensive epilepsy care center at a tertiary hospital in the South Indian city of Trivandrum, patients in the pediatric age group <12 years with DRE or EE of unknown etiology who underwent genetic testing as part of the diagnostic algorithm were screened for diagnosis of visual-sensitivity. Visual-sensitivity was defined based on the presence of photosensitivity (PS) (including television and video game triggered seizures), fixation-off sensitivity and eye-condition sensitivity (eyes closed, eye closure) based on criteria as detailed by us recently. The patients who were documented to have visual-sensitivity on video electroencephalography (VEEG) were included in this descriptive study which was carried out based on their clinical, video EEG, and genetic data. The study was conducted with approval from the Institute Ethics Committee (IEC and informed consent of patient's family members is taken with regard to use of data before admission to our VEEG unit 1296/2018).
| » Results|| |
Out of 96 patients in the pediatric age-group with DRE/EE of unknown etiology in childhood who underwent genetic testing 4 (4.17%) met our inclusion criteria for visual sensitivity. The electroclinical data of the patients are as described below.
A 4½-year-old girl, born off nonconsanguineous parentage with normal birth and developmental history, had one simple febrile seizure (FS) at 2½ years of age followed a year later by unprovoked episodes of brief focal nonmotor seizures with impaired awareness followed by head drops. Following 2 episodes of fever provoked generalized seizures at 3 years 9 months of age, she was started on AED. After 3 months she developed episodes of recurrent eye blinks and generalized clonic seizures with admissions for fever provoked convulsive status epilepticus. Developmental delay, maximal in the language and social domains was noted. Her father had a history of febrile seizures in childhood. Her neurological examination showed no focal deficits. Video-EEG [VEEG; [Figure 1]] showed occipital dominant generalized polyspikes and attempted eyes-closed state triggered one episode of generalized clonic seizure. The early age of onset, the presence of fever-provoked and unprovoked seizures with head drops and generalized seizures, DS leading to visual-sensitive epilepsy was considered. The disabling seizure subtypes included myoclonic-atonic and generalized seizures with eyelid myoclonia. Clinical exome sequencing revealed a heterozygous variant in the chromodomain helicase DNA-binding protein 2 (CHD2) gene at exon 35 (c.4489G >T, p.Glu1497Ter variant). This mutation results in a stop codon and premature truncation of the protein at codon 1497. She was further optimized on a combination of valproate and zonisamide and currently has only brief episodes of eyelid myoclonias daily.
|Figure 1: EEG of patient 1 (a and b) Average reference montage, sensitivity 20 μV/mm generalized polyspike and wave discharges in sleep; (c) Average reference montage, sensitivity 10 μV/mm and d bipolar montage, 10μV/mm “eyes-closed” state triggered focal yet bilateral onset parieto-occipital seizures with rapid secondary generalization|
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A 3-year-old girl, with no antecedent or family history of note, presented with fever provoked generalized tonic-clonic seizures (GTCs) from the age of 5 months along with multiple episodes of febrile hemiclonic status epilepticus and language delay. From 1 year of age, she started experiencing eyelid myoclonias and generalized myoclonic jerks without associated absences or unprovoked GTCS. Examination revealed a developmental age of 1 year 6 months with the persistence of eyelid myoclonus with occasional autoinduction on exposure to sunlight. VEEG was consistent with photosensitive occipital lobe epilepsy with reflex eyelid myoclonias and focal onset nonmotor seizures with impaired awareness [Figure 2]. With a clinical suspicion of reflex photosensitive epilepsy as a spectrum of DS phenotype, genetic analysis was done which revealed a heterozygous dominant variant of unknown significance on exon 20 of the CACNA1H gene (chr16:1260631G > A; c. 4018G > A; p.Val1340Met). She currently experiences only eyelid myoclonias on a combination of zonisamide, valproate, levetiracetam, and clonazepam with rare fever provoked exacerbations of myoclonic and generalized seizures.
|Figure 2: EEG of patient 2 in bipolar montage, sensitivity 15 μV/mm– (a and b) Reflex eyelid myoclonia followed by complex partial seizure noted on photic stimulation at 30 Hz (grade IV photoparoxysmal response) with ictal onset noted predominantly over bilateral posterior temporo-parieto-occipital regions, evolving better over the right hemisphere; (c) Eye-closed sensitivity with evidence of parieto-occipital paroxysms; (d) predominant right posterior temporo-parieto-occipital poly spikes noted during sleep|
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A 3-year-old boy, who was born of non-consanguineous parentage, with no antecedent events or family history and initially normal development, experienced polymorphic febrile followed by a febrile seizures from the age of 6 months. These included GTCS, focal motor, and nonmotor seizures with impaired awareness and atonia. Over the next year, he developed daily episodes of eyelid myoclonias with absences often followed by generalized seizures along with prominent heliotropism. Regression in language milestones with mild ataxia was noted subsequently. The VEEG [Figure 3] documented focal occipital and occipital dominant generalized discharges with peculiar photosensitive myoclonic seizures, noted while viewing the smart-phone without activation on photic stimulation. Following optimization on a combination of Topiramate, valproic acid and clonazepam, the GTCS stopped with the persistence of photosensitive seizures, language delay and improvement in gait. Genetic testing identified a well-documented heterozygous variant (chr2:166911147C>T; c.602 + 1G>A)-the essential splice donor site, in intron 4 of the SCN1A gene. The family could not afford to import stiripentol.
|Figure 3: EEG of patient 3 (a) Bipolarmontage, sensitivity 15 μV/mm-normal reactive background activity with a single burst of generalized discharge towards the end of the page; (b) Average reference montage, sensitivity 30 μV/mm revealing bilateral posterior temporo-pariteto-occipital and generalized spikes correlating with reflex myoclonic jerks triggered by viewing the smartphone as shown in the video capture (c)|
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A 3-year-old girl, born of a non-consanguineous marriage, presented with fever-provoked and unprovoked right hemiclonic seizures since 5 months of age with occasional myoclonic jerks triggered by exposure to sunlight from 12 months age. Global developmental delay was noted from 9 months of age. Neurological examination revealed mild gait ataxia with language development at 12 months level. She experienced a run-up in seizures on a combination of lamotrigine and sodium valproate. The initial EEG documented photosensitive eyelid myoclonia with absences with ictal onset over the occipital regions across all frequencies of photic stimulation [Figure 4]a and [Figure 4]b In the absence of response to topiramate, zonisamide, phenobarbitone and due to inability to procure stiripentol, she was optimized on levetiracetam, valproate and clonazepam with a reduction in febrile hemiclonic seizures, the persistence of myoclonic jerks and improved neurological development. A follow-up VEEG revealed the disappearance of PS on this AED combination with the persistence of occipital discharges during sleep [Figure 4]c and [Figure 4]d. Clinical exome sequencing documented a unique pathogenic heterozygous nonsense variation in exon 13 of the SCN1A gene (chr2: 166897892A > C; Depth: 72x) that results in a stop codon and premature truncation of the protein at codon 755 (p.Leu755Ter).
|Figure 4: EEG of patient 4 (a and b) bipolar montage, sensitivity 30μV/mm-normal reactive background with photo convulsive response at 18 HZ intermittent photic stimulation followed by temporo-parieto-occipital polyspikes; (c and d) follow-up EEG, average reference montage, sensitivity 15 μV/mm, bilateral occipital spikes noted during sleep|
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| » Discussion|| |
The phenotypes in all 4 patients reported were homogenous in terms of temperature-sensitivity akin to DS/FS plus syndromes initially, followed by visual-sensitive epilepsy with 3 demonstrating PS (including the unique description of “smart-phone” sensitive epilepsy, which is a form of PS, given the LED screens inbuilt in the modern mobile phones). These genetic variants leading to eye condition sensitive and photosensitive seizures of childhood are distinctive in the fact that the epilepsy was highly intractable with demonstrable eyelid myoclonias, limb myoclonia, focal onset and generalized seizures, and EEG demonstrating occipital, as well as occipital dominant generalized discharges with no family history, except for FS in one patient. Refractory photosensitive absence-like seizures have previously been described in families with PS, and ours is a unique description of sporadic cases with disease-causing genetic variants. All four patients had variable responses to polypharmacy with combinations comprising of broad-spectrum AED such as sodium valproate, zonisamide, levetiracetam, topiramate, and benzodiazepines, with associated developmental impairment. CHD2-related disorders are a recently described entity, comprising of autosomal dominant conditions with age of onset from 6 months to 5 years of life, clinical phenotypes dominated by EE, generalized epilepsy with multiple seizure types (absences, myoclonus, atonic, tonic, myoclonic–atonic, tonic–clonic seizures, convulsive and nonconvulsive status epilepticus) and striking clinical PS. It is frequently associated with cognitive impairment and autism. CHD2 gene has been described as a photosensitive epilepsy gene, and the PS may be “self-induced” by television, but need not always have a photoparoxysmal response on EEG (as was evident in patient 1 who had seizures triggered by eye closure), probably impacted by AED. There have been previous reports of CHD2 mutations in pediatric patients with myoclonic atonic epilepsy (MAE), DS, Lennox-Gastaut syndrome, eye-lid myoclonia with absences and other EE.,,, De-novo CHD2 mutation or deletions are an important contributor to both the absence seizures and eyelid myoclonia in pediatric patients with EE., It is uncertain from functional studies with regard to the causation of PS with this variant gene as it does not encode for an ion-channel as opposed to the 3 other patients who harbored ion channel mutant genes, although partial CHD2 knockdown model in zebrafish leading to PS has provided functional proof of this causation.
The phenotype in the second case was that of febrile hemiclonic seizures and photosensitive occipital lobe epilepsy with myoclonus resembling DS and genetic testing was done suspecting SCN1A disease-causing variants. Only a small number of DS cases have been shown to be due to mutations in non-SCN 1A genes, such as SCN1B, SCN2A, or GABRG2, so the unexplained cases may be due to de-novo mutations in additional genes or may have polygenic aetiologies., Here, we report a variant of unknown significance in the calcium channel gene. This gene has been described in families with genetic generalized epilepsy (GGE), including childhood absence epilepsy, FS, temporal lobe epilepsy thereby suggesting that CACNA1H could represent a susceptibility rather than causative gene considering the polygenic nature of these disorders. As the child's asymptomatic mother also exhibited an identical mutation, the susceptibility matrix can only be proven by functional studies. In vitro, functional expression studies demonstrated that a variant mutation resulted in a depolarizing shift in the half-inactivation potential and increased recovery from inactivation, consistent with a gain of function and increased channel activity. However, in one report, only 1 of 2 affected individuals in a family with genetic generalized epilepsy carried the variant. The phenotypes were variable and included FS and MAE. It may be hypothesized that the sporadic mutation reported may render accelerated channel activation at potentials which are more electropositive and enable accelerated inactivation, thus allow for greater channel availability compared to wildtype. From both patients with SCN1A positive epilepsy, it is apparent that though the genetics of PS is complex with several susceptibility loci,, determination of this ion channel variation is paramount in drug-resistant visual-sensitive epilepsy of childhood. The identified intronic variant has been previously reported in DS literature. This hypothetically causes splicing defects owing to the introduction of a new splice site, resulting in a frameshift, consequent premature termination of the protein and subsequent loss-of-function. The unique variant identified in the fourth child with refractory eyelid myoclonias and absences has not been reported in literature; however, it is well known that truncation mutations in DS phenotypes are often the most refractory ones. Pathogenic variants involving deletions in the SCN1A gene have been shown to be associated with a spectrum ranging from FS and generalized epilepsy with febrile seizures plus (GEFS+) at the mild end to DS and intractable childhood epilepsy with generalized tonic-clonic seizures at the severe end. This should also include visual sensitive and often self-induced occipital epilepsy which is described with variable prevalence in DS. In the absence of family history in both patients, it may be hypothesized that novel variants (de novo), germline mosaicism, incomplete penetrance and phenotypic variability, as has been reported in SCN1A mutations, may lead to photosensitive occipital epilepsy which is much more refractory than idiopathic photosensitive occipital epilepsy (IPOE). This is correlated to the severity of the disorder in terms of early age at onset, intellectual disability and frequent spontaneous occipital spikes, with a propensity to worsen with sodium channel blockers as seen in the fourth patient. De novo or inherited variants can only be established by further segregation analysis which we could only perform in the child with the CACNA1H variant, which established its familial basis.
| » Conclusions|| |
This case series highlights detailed electro-clinical phenotype–genotype associations in sporadic drug-resistant focal and generalized epilepsy of childhood with visual sensitivity and electro-clinical features closely mimicking DS. With the well-described SCN1A syndrome accounting for half the cases, novel non-ion channel genes such as CHD2 and febrile seizure/GGE-susceptibility genes such as CACNA1H genes accounted for the remaining cases indicating potential genetic heterogeneity of this ostensibly homogeneous electroclinical phenotype. Despite the electroclinical data being similar to IPOE, the identification of monogenic subtypes, DRE and associated developmental consequences necessitate the consideration of the terminology “genetic visual sensitive epilepsy” of childhood.
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.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]