Jeavons Syndrome: Clinical Features and Response to Treatment

Accepted Manuscript

Jeavons Syndrome: clinical features and response to treatment Kelsey M. Smith MD , Paul E. Youssef DO , Elaine C. Wirrell MD , Katherine C. Nickels MD , Eric T. Payne MDMPH , Jeffrey W. Britton MD , Cheolsu Shin MD , Gregory D. Cascino MD , Marc C. Patterson MD , Lily C. Wong-Kisiel MD PII: DOI: Reference:

S0887-8994(18)30351-5 10.1016/j.pediatrneurol.2018.06.001 PNU 9360

To appear in:

Pediatric Neurology

Received date: Accepted date:

16 April 2018 1 June 2018

Please cite this article as: Kelsey M. Smith MD , Paul E. Youssef DO , Elaine C. Wirrell MD , Katherine C. Nickels MD , Eric T. Payne MDMPH , Jeffrey W. Britton MD , Cheolsu Shin MD , Gregory D. Cascino MD , Marc C. Patterson MD , Lily C. Wong-Kisiel MD , Jeavons Syndrome: clinical features and response to treatment, Pediatric Neurology (2018), doi: 10.1016/j.pediatrneurol.2018.06.001

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ACCEPTED MANUSCRIPT

Title: Jeavons Syndrome: clinical features and response to treatment [email protected]

Paul E. Youssef DOa

[email protected]

Elaine C. Wirrell MDa

[email protected]

Katherine C. Nickels MDa

[email protected]

Eric T. Payne MD, MPHa

[email protected]

Jeffrey W. Britton MDa

[email protected]

Cheolsu Shin MDa

[email protected]

Gregory D. Cascino MDa

[email protected]

Marc C. Patterson MDa

[email protected]

Lily C. Wong-Kisiel MDa

[email protected]

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Kelsey M. Smith MDa

a. Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN, USA 55905

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Corresponding author: Lily C. Wong-Kisiel 200 First Street SW Rochester, MN 55905 Telephone: 507-266-0774, Fax: 507-284-0727

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Number of text pages 16 Number of words 3005 Number of references 21 Number of figures 2 Number of tables 2 Number of supplementary tables in e-component: 2

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Key words: epilepsy; drug-resistant epilepsy; Jeavons syndrome; eyelid myoclonia with or without absence; generalized epilepsy Author contributions: Conception, design, data collection, data interpretation, drafting, and critical review: K. Smith, P. Youssef, L. Wong-Kisiel; Conception, design, drafting/revising the manuscript,: E. Wirrell; Drafting/revising the manuscript: K. Nickels, E. Payne, J. Britton, C. Shin, G. Cascino, M. Patterson.

ACCEPTED MANUSCRIPT Jeavons syndrome Abstract Background: Jeavons syndrome is an underreported epileptic syndrome characterized by eyelid myoclonia, eyelidclosure induced seizures or electroencephalography paroxysms, and photosensitivity. Drug resistant epilepsy is common, but the prognostic factors and clinical course leading to drug

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resistance have not been well characterized. Methods: We identified 30 patients who met diagnostic criteria of Jeavons syndrome at a single

institution between January 1, 2000 and December 15, 2016. Criteria for Jeavons syndrome included all of the following: (1) eyelid myoclonia with or without absences, (2) eye-closure induced seizures or

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electroencephalography paroxysms, and (3) seizure onset after 12 months of age. We reviewed and described the epilepsy history, antiepileptic drug trials, and response to treatments.

Results: Mean age at seizure onset was 7.3 years and 80% were women. Absence seizures (63%) and generalized tonic-clonic seizures (23%) were most common at onset. Diagnosis was delayed by an

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average of 9.6 years. After a median follow-up of 2 years, 80% of patients had drug resistance epilepsy and 70% experienced generalized tonic-clonic seizures. Generalized tonic-clonic seizures and seizure

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types other than absence seizures increased the risk of drug resistant epilepsy (p-value 0.049 and 0.03, respectively). Valproic acid, lamotrigine, ethosuximide, and levetiracetam were the most effective in

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reducing seizures by >50%.

Conclusions: Diagnosis of Jeavons syndrome is often delayed. Generalized tonic-clonic seizures and

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seizure types other than absence seizures may be predictors for drug resistant epilepsy among patients

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with Jeavons syndrome.

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ACCEPTED MANUSCRIPT Jeavons syndrome 1. Introduction Jeavons syndrome, also known as eyelid myoclonia with or without absences, was first described in 1977 [1]. It is thought to be uncommon, but it is likely under recognized. Prevalence of Jeavons syndrome is reported between 2.7% and 12.9% of generalized epilepsies and between 0.56% and 2.7% of

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all epilepsies [2, 3]. Jeavons syndrome is characterized by eyelid myoclonia with or without absences, eye-closure induced seizures or EEG paroxysms, and photosensitivity. Patients experience daily frequent episodes of upward jerking of the eyelids with upward deviation of the eyes which may be accompanied with head movements [4]. Photosensitivity decreases with age and with antiepileptic drugs (AEDs) [4].

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Generalized tonic-clonic seizures are common. The syndrome has a female predominance, and typically begins between ages 2-14 years with most cases presenting between ages 6-8 years [5]. Many with Jeavons syndrome have drug resistant epilepsy, requiring multiple AED trials. Valproic acid has been commonly used. In addition, levetiracetam has been shown to be efficacious [6,

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7]. Treatment options such as the ketogenic diet and vagus nerve stimulation (VNS) have not been thoroughly explored or documented. Jeavons syndrome is thought to persist lifelong. Due to this, these

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patients will likely be managed by both pediatric and adult epileptologists, making this an important syndrome for all neurologists to recognize. In this study, we describe the natural history and treatment

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response in Jeavons syndrome. 2. Material and methods

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The study was approved by the institutional review board. A total of 8285 patients less than 18 years of age underwent routine outpatient EEG between January 1, 2000-December 15, 2016 at Mayo

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Clinic in Rochester, Minnesota. Patients were identified through the electroencephalography (EEG) database using the following search terms: Jeavons, Jeavons’, eyelid myoclonia, and eyelid myoclonus. Inclusion criteria for Jeavons syndrome included all of the following (1) eyelid myoclonia with or without absences, (2) eye-closure induced seizures or EEG paroxysms, and (3) seizure onset after 12 months of age. The digital video EEGs were re-reviewed for presence of eye-closure induced paroxysms if EEG reports lacked specific mention of eye-closure induced seizures or paroxysms. Although photosensitivity 3

ACCEPTED MANUSCRIPT Jeavons syndrome is a feature of Jeavons syndrome, patients were still included if no photoparoxysmal response was documented on available EEGs because documentation of repetitive photic stimulation was not available in all patients and photosensitivity is known to decrease with age and concurrent AEDs [3]. Clinical information was extracted from the medical record. Abstracted clinical features included

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demographics, seizure history (age of onset, seizure type or types at onset and ever documented, types of pharmacologic and nonpharmacological treatments used and efficacy), developmental delay or learning disability at seizure onset, first or second degree family history of seizures or epilepsy, EEG and

radiographic features, and age of last follow-up. Intelligence quotients (IQs) from formal neuropsyhometric

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testing were used to assess for intellectual disability when available. A developmental quotient (DQ) was calculated where developmental age was divided by chronological age when there were concerns for delays without a documented IQ. Intellectual disability based off of IQ or DQ was defined as follows: absent >69, mild = 50-69, moderate = 35-49, and severe <35. If no IQ was available and there were no concerns for

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intellectual disability in the records, intellectual disability was felt to be absent.

Response to antiepileptic treatment, dietary therapy, and VNS was defined as effective when there

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was a sustained greater than 50% reduction of seizure frequency after introduction of a new treatment regimen. Childhood onset epilepsy was defined by age of second unprovoked seizure at 10 years of age

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or less. Juvenile onset epilepsy was defined by onset of seizures between 11 and 18 years old. Drug resistant epilepsy was defined as failure to achieve seizure control despite trials of more than two

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appropriate AEDs used at adequate doses. The term “myoclonic seizures” was used to describe extremity or appendicular myoclonus and not those with eyelid myoclonia alone.

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Descriptive statistics included means and standard deviations or medians and interquartile ranges

(IQR), as appropriate. For bivariate comparisons, t tests and Fisher exact test were used as appropriate. Analysis was performed using the JMP statistical software package (version 9; SAS Institute Inc). All tests were two-sided, and p-values 0.05 were considered statistically significant.

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ACCEPTED MANUSCRIPT Jeavons syndrome 3. Results 3.1. Study population A total of 30 patients with Jeavons syndrome were included. Two patients were excluded due to incomplete clinical data. Four patients met criteria for inclusion but did not carry a clinical diagnosis of

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Jeavons syndrome at the time of data collection. 3.2. Clinical Features

Of the 30 patients, 24 (80%) were female (Table 1). The age of seizure onset ranged from 1.5-16 years, with the mean of 7.3 years. The most commonly reported seizure type at onset was absence

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seizures in 19 patients (63.3%) followed by generalized tonic-clonic seizures in 7 patients (23.3%).

Presentation with eyelid myoclonia as the only seizure type was infrequent and reported in only 3 patients (10%). One patient reported multiple seizure types at onset. Family history of epilepsy in first or second degree relatives was present in 10 patients (33.3%), and family history of febrile seizures in 2 patients

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(6.7%). Only 1 patient (3.3%) had a personal history of febrile seizures. Intellectual disability was present in 6 patients (23.3%): mild in 5 patients and moderate in 1 patient.

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Patients were followed for a median of 2 years (IQR 0.2-4.3 years). Over the course of their epilepsy, 21 patients (70%) had generalized tonic-clonic seizures, 10 patients (33.3%) had myoclonic

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seizures, 1 patient (3.3%) had tonic seizures, and 4 patients (13.3%) had atonic seizures. Eighty percent of patients had drug resistant epilepsy. The clinical diagnosis of Jeavons syndrome was delayed until 9.6

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years after seizure onset (IQR 5.8-13.4) when patients were at a mean age of 17 years (IQR 14.2-20.4). All patients had eye-closure induced EEG paroxysms or seizures captured on EEG (Figure 1). Among 29

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patients with repetitive photic stimulation performed, 23 had a photoparoxysmal response. 3.3. Etiology

MRI of the brain were normal or showed nonspecific findings not contributing to epilepsy in 29

of 30 patients. One patient had a lesion consistent with a differential diagnosis of low-grade glial or glial neuronal tumor, low grade infiltrating astrocytoma or multinodular and vacuolating neuronal tumor.

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ACCEPTED MANUSCRIPT Jeavons syndrome Genetic testing was pursued in 15 patients (50%) but resulted in no probable pathogenic mutation relevant for presumed generalized genetic epilepsy (Supplementary Table 1 and 2). 3.4. Treatment The median number of AEDs trialed was 5.5 (IQR 4-9). One patient remained off AEDs

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because of side effects from a single medication. This patient only had eyelid myoclonia without a history of absence seizures. Eyelid myoclonia was found incidentally due to changes seen on an EEG during a sleep study done for concerns of non-restorative sleep. Only 4 patients (13.3%) achieved seizure freedom on monotherapy. Of these, 2 patients (6.7%) were on ethosuximide and 2 patients (6.7%) on

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levetiracetam monotherapy. An additional patient was seizure free for >6 months on rufinamide monotherapy after trialing 8 other AEDs.

Drug resistant epilepsy was present in 24 patients (80%). Eight patients (26.6%) were minimally responsive to treatment. Drug resistant epilepsy correlated with the presence of seizures other than

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absence seizures (p-value 0.03) and generalized tonic-clonic seizures (p-value 0.049). Predictors of drug resistant epilepsy are shown in Table 2. Of the patients who had an effective response at any time to an

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AED treatment, polypharmacy with three or more medications was commonly required. Figure 2 shows the number of patients for each AED or treatment ever tried and the prevalence of effective response.

by >50%.

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Valproic acid, lamotrigine, ethosuximide, and levetiracetam were the most effective in reducing seizures

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VNS was placed in 4 patients, and 3 experienced a >50% seizure reduction. A total of 8 patients

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underwent diet therapy for epilepsy (3 classic ketogenic diet, 6 modified Atkins diet or low glycemic index treatment). Compliance with ketogenic diet was limited. Diet therapy was effective in 2 of 3 patients on a conventional ketogenic diet and 3 of 6 patients on the modified Atkins diet or low glycemic index treatment. Mean duration of dietary therapy was 14.3 months (range 2-85 months), including one patient managed on the ketogenic diet before transitioning to the modified Atkins diet. 4. Discussion

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ACCEPTED MANUSCRIPT Jeavons syndrome A female predominance in Jeavons syndrome has been well described. Our data supports this with 24 patients identified being female (80%). The average age of seizure onset was 7.3 years which is consistent with prior literature, where the average age of onset is between 6-8 years [5]. Despite most patients having childhood onset epilepsy, a clinical diagnosis of Jeavons syndrome was delayed by 9.6

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years, with a mean age of Jeavons syndrome diagnosis at 17 years. In fact, there were 4 patients who met criteria for inclusion who did not carry a clinical diagnosis of Jeavons syndrome at the time of data

collection. This large gap in seizure onset and clinical diagnosis of Jeavons syndrome argues that this is a diagnosis which continues to be under recognized. It has been argued that a diagnosis of Jeavons

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syndrome may be delayed as eyelid myoclonia may be labeled as tics or a behavior action [8]. In fact, in a prior study, only 3 out of 26 patients carried a diagnosis of Jeavons syndrome despite meeting diagnostic criteria [9]. Also, in a study of 31 patients with pure Jeavons syndrome, there was a mean delay in diagnosis of 10.3 years [10]. Generalized tonic-clonic seizures were also common. Patients had

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generalized tonic-clonic seizures variably throughout their lifetime, with some patients originally presenting with generalized tonic-clonic seizures and some not having any until after a diagnosis of

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Jeavons was made. Additional generalized seizure types, including atonic, myoclonic, and tonic seizures, were identified in some patients. Atonic and myoclonic seizures have been previously described in

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patients with Jeavons syndrome, which expands on the clinical variability [11, 12]. From family studies of probands and cases of concordant monozygotic twins, Jeavons syndrome

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is thought to have a genetic etiology [5, 13, 14]. In a previous study looking at seizures in family members of patients with Jeavons syndrome, 83% of patients had a family history of seizures, with nearly

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all affected relatives with generalized seizures and 62% of affected relatives to have genetic epilepsy with febrile seizures plus [5]. The role of genetics in Jeavons syndrome is likely of complex genetic heterogeneity. Attention has been drawn to copy number variants in chromosome 15q26 and to CHD2 (chromodomain helicase DNA binding protein 2) gene. CHD2 was the only shared gene among several reported cases of photosensitivity epilepsy with deletions in the chromosome 15q26.1 region, and the frequency of unique variations in CHD2 was the highest in Jeavons syndrome compared to other epilepsy 7

ACCEPTED MANUSCRIPT Jeavons syndrome syndromes [15]. In our series, the 33% family history of seizures in first or second degree relatives was lower than previously reported and may be the result of ascertain bias because familial information was abstracted retrospectively and based on documentation from the index case. Genetic testing was unrevealing in our study, and likely due to variable and limited genetic evaluations in this cohort. Further

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studies to understand the role genetics plays in Jeavons syndrome are needed. A possible approach to genetic testing in patients presenting with photosensitive epilepsy might include chromosome analysis, array-based comparative genomic hybridization, and an epilepsy gene panel. If these are unrevealing, whole exome sequencing could be considered. This approach could increase the diagnostic yield of

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genomic abnormalities, broaden the discovery of novel genotype-phenotype correlations, and differentiate Jeavons syndrome from other photosensitivity epilepsy syndromes with known genetic association, such as Dravet syndrome due to SCN1A mutations and mutations seen in progressive myoclonic epilepsies [16].

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MRI findings in this cohort were normal or showed nonspecific findings unrelated to epilepsy. One patient had an extensive temporal-parietal-occipital lesion, which may contribute to a visual system

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initiated generalized epilepsy network. Viravan et al. (2011) suggested that Jeavons syndrome could be an occipital cortex initiating a generalized epilepsy network including thalamocortical and transcortical

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pathways and the brainstem [17].

Previous work to delineate cognitive ability among those with Jeavons syndrome has shown a

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below average global IQ in 6 patients [2]. Despite a lower than average IQ, no patient in this prior study was felt to have impairment severe enough to be considered intellectually disabled [2]. Intellectual

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disability has been described in other patients with Jeavons syndrome. One study described a unique group of 18 patients with Jeavons syndrome, decline in intellectual function after seizure onset, and an ictal EEG pattern with discharges of fast generalized polyspike-waves and polyspike-and-waves [4]. Throughout the course of follow-up, intellectual disability was identified in 6 patients (23%) in our cohort. Multiple patients had uncontrolled seizures which led to missed school days and increasing school difficulty. Due to inconsistent documentation, it is difficult to comment on changes of intellectual 8

ACCEPTED MANUSCRIPT Jeavons syndrome ability over time. Further work needs to be done to understand the effects of Jeavons syndrome on cognitive ability. Seizures commonly persist through a patient’s lifetime, and many patients remain drug resistant throughout life [7]. There is little information in the literature about pharmacologic treatment of Jeavons

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syndrome; therefore, AEDs are usually selected empirically. Valproic acid, ethosuximide, and benzodiazepines are common choices [7]. However, the well-known side effects of endocrine

abnormalities limit the use of valproic acid in females of childbearing age. Some AEDs have been

reported to worsen the clinical picture, including carbamazepine, vigabatrin, and phenytoin [7]. The data

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from this study support that many patients with Jeavons syndrome have drug resistant epilepsy. Many patients (80%) identified in this study had tried and failed multiple AED medications due to side effects and ineffectiveness. The wide range of AEDs tried, supports that patients have a varied response to treatment. The most effective AED in our cohort were valproic acid, lamotrigine, ethosuximide, and

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levetiracetam. Although not individually better than the leading effective AED therapies, the benzodiazepine class of AEDs were effective in 5 of 20 patients (25%).

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Among the 30 patients identified in this study, only 4 patients (13.3%) were successfully managed on AED monotherapy throughout the follow-up period, and one additional patient was off of

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AEDs due to a mild clinical picture. Of these 4 patients, 2 patients (6.7%) were on ethosuximide monotherapy and 2 patients (6.7%) were on levetiracetam. Ethosuximide is generally ineffective in

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generalized tonic-clonic seizures but is first line treatment for absence seizures. The two patients successfully treated with ethosuximide had never experienced a generalized tonic-clonic seizure; in fact,

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these patients had only ever experienced absence seizures. Both patients had child onset epilepsy and were noted to have normal cognition at seizure onset and at last follow-up. Levetiracetam is a broader spectrum AED than ethosuximide with a favorable safety profile and

efficacy in generalized tonic-clonic seizures, myoclonic seizures and focal seizures [18]. A pilot study examining the efficacy of levetiracetam in Jeavons syndrome showed promise [7]. In this study of 35 patients, 80% responded to levetiracetam treatment over a 12 week period [7]. Levetiracetam was the 9

ACCEPTED MANUSCRIPT Jeavons syndrome most commonly trialed AED in our study. It has been suggested that Jeavons syndrome should be considered a type of myoclonic epilepsy that is limited to the eyelids rather than a primary absence epilepsy [7]. In fact, there have been patients reported that appear to demonstrate an overlap between juvenile myoclonic epilepsy and Jeavons syndrome by meeting the diagnostic criteria for both [12]. It

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argues that in these patients levetiracetam would be a good treatment option to explore. Both patients in our study who were successfully managed on levetiracetam monotherapy had seizure types other than absences: generalized tonic-clonic seizures in one patient, generalized tonic-clonic seizures and

myoclonic seizures in the other patient. Also worth noting, there was one additional patient who after

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trialing 8 AEDs was found to be seizure free for > 6 months at last follow-up on rufinamide monotherapy. There is limited evidence for use of diet therapy in the treatment of patients with drug-resistant Jeavons syndrome. In an open label prospective study of the modified Atkins diet for adults with idiopathic generalized epilepsy, one patient was reported as having Jeavons syndrome [19]. However,

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this patient dropped out of the study after 2 weeks of participation [19]. Compliance with a diet as a treatment modality can be difficult. In our study, the ketogenic diet, modified Atkins diet, and low

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glycemic index treatment all showed response in at least 1 patient, suggesting that with proper training and motivation, diet therapy may be treatment options to explore with patients not responding to AEDs.

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Lens therapy and VNS were other treatment options tried in our group of patients. VNS seemed effective in decreasing seizures by >50% in 3 of the 4 patients who had them placed. There were two

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patients who attempted lens therapy in this study. However, response is not well documented, so it is unknown how effective this was at reducing seizures. Lens therapy has been shown to be efficacious in

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epilepsy patients with photoparoxysmal response [20, 21]. A particular blue lens with an ultraviolet filter, called Z1, was shown to lead to the elimination of photoparoxysmal response in 78% and 75% of patients in two previous studies [20, 21]. In general, lens therapy is well tolerated. Given the predominate feature of photosensitivity in Jeavons syndrome, lens therapy may have a therapeutic role. However, there are no studies looking at lens therapy in Jeavons syndrome specifically. Further work needs to be done to investigate VNS and lens therapy in the treatment of Jeavons syndrome. 10

ACCEPTED MANUSCRIPT Jeavons syndrome The study was retrospective in nature and relied on clinical notes and documentation. The clinical effectiveness noted was subjective and follow-up on effectiveness of medications was not systematically documented in all cases. Referral bias due to cases identified being from a tertiary medical center raises the concern that the more difficult to treat cases of Jeavons syndrome were included. In this

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cohort, the diagnosis of Jeavons syndrome was delayed and the majority of patients had drug resistant epilepsy. Seizures other than absences were identified in the majority of patients. Further work to

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understand the pathophysiology of Jeavons syndrome and the most appropriate treatment is needed.

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ACCEPTED MANUSCRIPT Jeavons syndrome Figure legends

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Figure 1: EEG showing eye-closure induced paroxysms and eyelid myoclonia

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ACCEPTED MANUSCRIPT Jeavons syndrome Figure 2: Treatments tried and effective. This shows the number of patients who tried each treatment and the number of patients who found the treatment effective at reducing seizure frequency. MAD: Modified Atkins Diet, LGIT: Low glycemic index treatment. *1 patient transitioned from the ketogenic diet to the

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MAD.

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ACCEPTED MANUSCRIPT Jeavons syndrome

All patients (n=30) 24 (80%) 22 (73%) 10 (33%) 7.3 (3.9-11) 17 (14.1-20.4) 8 (27%)

Female (%) Childhood onset (=<10 years) Family history of epilepsy Age at seizure onset, years Age at diagnosis of Jeavons syndrome Eyelid myoclonia with or without absence only Drug resistant epilepsy Number of AED trials

24 (80%) 5.9 (4-9)

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Data presented as N (%), or mean (interquartile range, IQR)

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Table 1. Patient characteristics and clinical features.

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ACCEPTED MANUSCRIPT Jeavons syndrome Table 2. Predictors of Drug Resistance Epilepsy in Jeavons syndrome

2 2 1

DRE (N=24) 19 1 18 16

0.03*

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0.049* 0.63

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1.0 1.0 0.65 0.63

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*Statistically significant p-values ° Total 29 patients given 1 patient without predominant seizure type at onset DRE: drug resistant epilepsy

p-value

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Female History of febrile seizures Childhood (=<10 years) onset Absence seizures only at epilepsy onset° Seizure type ever Any types other than absences / Eyelid myoclonia with absences Generalized tonic-clonic seizures Myoclonic seizures

Not DRE (N=6) 5 0 4 3

ACCEPTED MANUSCRIPT Jeavons syndrome References: 1.

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2.

Caraballo, R.H., et al., A study of 63 cases with eyelid myoclonia with or without absences: type of seizure or an epileptic syndrome? Seizure, 2009. 18(6): p. 440-5.

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Capovilla, G., et al., Eyelid fluttering, typical EEG pattern, and impaired intellectual function: a

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homogeneous epileptic condition among the patients presenting with eyelid myoclonia. Epilepsia, 2009. 50(6): p. 1536-41. 5.

Sadleir, L.G., et al., Family studies of individuals with eyelid myoclonia with absences. Epilepsia, 2012. 53(12): p. 2141-8.

Parissis, D., P. Ioannidis, and D. Karacostas, Levetiracetam as alternative treatment in Jeavons

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syndrome. J Neurol Sci, 2014. 341(1-2): p. 147-9. Striano, P., et al., A pilot trial of levetiracetam in eyelid myoclonia with absences (Jeavons

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syndrome). Epilepsia, 2008. 49(3): p. 425-30. Wang, X.L., et al., Jeavons syndrome in China. Epilepsy Behav, 2014. 32: p. 64-71.

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ACCEPTED MANUSCRIPT Jeavons syndrome 13.

Yang, T., et al., Absence status epilepticus in monozygotic twins with Jeavons syndrome. Epileptic Disord, 2008. 10(3): p. 227-30.

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Adachi, M., et al., Eyelid myoclonia with absences in monozygotic twins. Pediatr Int, 2005. 47(3): p. 343-7. Galizia, E.C., et al., CHD2 variants are a risk factor for photosensitivity in epilepsy. Brain, 2015.

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138(Pt 5): p. 1198-207. 16.

Pearl, P.L., Epilepsy Syndromes in Childhood. Continuum (Minneap Minn), 2018. 24(1, Child Neurology): p. 186-209.

Viravan, S., et al., Jeavons syndrome existing as occipital cortex initiating generalized epilepsy. Epilepsia, 2011. 52(7): p. 1273-9.

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Abou-Khalil, B.W., Antiepileptic Drugs. Continuum (Minneap Minn), 2016. 22(1 Epilepsy): p. 132-56.

Kverneland, M., et al., A prospective study of the modified Atkins diet for adults with idiopathic

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generalized epilepsy. Epilepsy Behav, 2015. 53: p. 197-201. Capovilla, G., et al., Effectiveness of a particular blue lens on photoparoxysmal response in

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photosensitive epileptic patients. Ital J Neurol Sci, 1999. 20(3): p. 161-6. Capovilla, G., et al., Suppressive efficacy by a commercially available blue lens on PPR in 610

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photosensitive epilepsy patients. Epilepsia, 2006. 47(3): p. 529-33.

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