Comorbidities in Dravet Syndrome and Lennox–Gastaut Syndrome

This study aims to describe the main cognitive and behavioral comorbidities of Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS), their impact on the health-related quality of life (QOL) of patients and their caregivers, and provide a summary of the neuropsychological tools available for the evaluation of these comorbidities. The cognitive and behavioral comorbidities in patients with DS and LGS have a profound effect on the QOL of affected individuals and their caregivers and, as patients grow, tend to surpass the impact of the seizures. DS is a genetic condition associated with loss-of-function mutations in the SCNA1 sodium channel gene; LGS is an etiologically heterogeneous condition that is often secondary to structural brain abnormalities. The first seizures associated with DS typically present in the first year of life, and developmental delay becomes progressively evident thereafter. LGS usually starts between the ages of 3 and 8 years, with cognitive impairment becoming clinically evident in most patients within 5 years from the onset. In both DS and LGS, cognitive impairment is generally moderate to severe and is often accompanied by behavioral problems such as hyperactivity and inattention. In addition to optimal seizure control, regular assessment and active management of cognitive and behavioral comorbidities are required to meet the complex needs of patients with DS or LGS.

LGS occurs most often as a result of a structural brain abnormality, such as tuberous sclerosis complex, cerebral malformation, or hypoxic-ischemic injury, and very rarely as a result of a progressive metabolic disorder [2,[9][10][11][12].
LGS accounts for an estimated 1-10% of childhood epilepsies, and the reported incidence of DS is between 1 in 15,700 and 1 in 40,000 live births, so these are rare diseases [2,3,13,14]. However, the morbidity associated with LGS This article is part of the Topical Collection on Medicine * Pasquale Striano strianop@gmail.com; pasqualestriano@gaslini.org and DS leads to disproportionately large costs to the healthcare system and society in general [7,13]. Treatment of DS and LGS focuses on alleviation of seizure burden, but some patients may have treatment-resistant seizures. In addition, DS and LGS are associated with multiple comorbidities, which present further management challenges [4,10,[15][16][17]. Despite their different etiologies, DS and LGS share several comorbid features, including developmental delays in several domains: social-emotional, cognitive, motor, adaptive, and communicative [18][19][20][21][22]. Thorough and accurate early assessment and diagnosis, including careful assessment of clinical and electroencephalography (EEG) features, are important to ensure that patients receive the most appropriate treatment and support as soon as possible, to optimize longterm neurodevelopmental outcome [4,19,23].
In this review, we describe the most common cognitive and behavioral comorbidities of DS and LGS and their impact on the health-related quality of life (HRQOL) of patients and their caregivers. Management implications and neuropsychological tools for the evaluation of cognitive and behavioral aspects of LGS and DS are also discussed.

Cognitive and Behavioral Comorbidities of Dravet Syndrome and Lennox-Gastaut Syndrome
Cognitive Impairment Moderate-to-severe cognitive impairment is common in DS and LGS and is a diagnostic feature of both disorders [2][3][4]15]. Cognitive delay generally occurs earlier in life with DS than with LGS [2,19], but cognitive impairment is not necessarily apparent at the onset of seizures in either syndrome [1,21,24].

Dravet Syndrome
Intellectual disability (ID) is a comorbidity of DS, but it is still unclear if ID results from damage caused by seizures, the abnormal levels of Na v 1.1 protein, the use of inappropriate medications, such as sodium channel inhibitors, or a combination of these factors [25]. DS typically presents in the first year of life in children with no pre-existing developmental problems [3,21,26,27]. It was generally thought that DS patients show typical cognitive development until the second year of life, followed by a gradual decline which leads to moderate or severe ID by 6 years of age ( Fig. 1) [26][27][28][29][30][31][32]. However, recent data indicate variability in cognitive development among DS children tested before 24 months of age, suggesting that cognitive delay may begin before 2 years of age in some patients [33]. A study by Nabbout et al. [31] in 67 children with DS showed that, after 6 years of age, IQ decreased with age, but patients continued acquiring new skills during the first decade. Therefore, the progression of developmental delay seen from 2 years of age [22,26,27,[31][32][33][34][35] could reflect an early arrest of cognitive development, followed by an increasing discrepancy between developmental age and chronological age [26], rather than consistent cognitive regression.
In the literature, many authors have found that seizure frequency and severity, the presence of status epilepticus (SE), or EEG activity may influence the cognitive outcome in patients with DS [28,29,31,32,36,37]. However, in other studies, there was no significant correlation between the severity of cognitive delay and seizure activity [31,38]. Preclinical  [28] studies suggest that SCN1A mutation by itself may play a role in determining the final cognitive outcome [26,31]. The pattern of cognitive deficits observed in patients with DS is consistent with cerebellar cognitive syndrome, as language comprehension tends to be better preserved than language production and visuospatial functions [22,31,34,35,37,39,40].

Lennox-Gastaut Syndrome
In contrast to DS, 20-60% of LGS patients have cognitive impairment before the onset of seizures, particularly when LGS is a consequence of an identifiable etiology [15,19,41]. Children with LGS of unknown origin may seem to develop normally before the appearance of the first seizures [15,19]. In general, cognitive impairment becomes progressively evident over time [1,2,15], and the proportion of patients with serious ID may increase to 75-95% at 5 years after the onset of seizures [42]. The cognitive outcome of patients with LGS is variable [43], and there is no evidence that it correlates only with epilepsy severity. LGS is characterized by alterations in specific thalamocortical networks, which normally support a broad range of cognitive functions [44]. Disruption of normal interactions within and between brain networks that support key cognitive processes has been reported in an EEGfunctional magnetic resonance imaging study of 15 adult patients with LGS [45]. It has been proposed that epileptic activity in LGS, which intersects with cognitive networks, may initiate sustained abnormal network behavior, and the persistence of these abnormal cognitive network interactions in the absence of detectable epileptic activity potentially contributes to impaired cognition [45]. The relatively preserved cognitive status observed in late-onset LGS may, in part, be because these patients did not experience epileptic activity during sensitive periods of neurodevelopment when cognitive networks are most vulnerable to disrupted maturation [36,[45][46][47].

Behavioral Problems
In DS and LGS, cognitive impairment is frequently associated with social-emotional problems, but there is not necessarily a linear relationship between the severity of the cognitive disability and the frequency of behavioral difficulties [4,20,[48][49][50]. Attention and hyperactivity problems, as well as autistic traits, are commonly observed in both DEEs [2-4, 15, 16, 51].

Dravet Syndrome
Behavioral difficulties in children with DS usually include attention disorders and hyperactivity, aggressive behavior, and social problems [16,33]. These problems, which do not appear to be related to the severity or frequency of epilepsy, seem to increase in childhood, peak in adolescence, and then plateau or decrease in adulthood, while autistic traits tend to persist [28,49,[52][53][54]. Parents and caregivers often report high levels of attention difficulties in patients affected by DS, which have been confirmed in several studies, but the prevalence of ADHD among children with DS is unknown [16,50,53].
DS patients may display autistic traits, such as stereotyped, repetitive and disinhibited behavior, obsessions, and poor peer relationships [38, 50-52, 54, 55], but the prevalence of autism spectrum disorder (ASD) in DS varies significantly across studies. One reason may be that communicative skills are relatively preserved, leading to an underestimation of ASD prevalence among patients with DS [38,[50][51][52]. When gold-standard ASD assessment tools were used, ASD prevalence ranged from 22 to 39% [16,51]. Studies in mice show that impairment of sodium channel function and the resulting GABAergic signaling dysfunction likely contribute to behavioral and cognitive impairment in DS [8,56,57].

Lennox-Gastaut Syndrome
Hyperactivity/inattention, anxiety, agitation, depression, and aggression are commonly seen in patients with LGS [1,2,15,42,58,59]. Autistic behavior has also been reported, but only in a few cases of LGS, and is less common in LGS than DS, despite the similar prevalence and severity of IDs in the two forms of encephalopathy [42]. It has been suggested that factors other than cognitive impairment are involved in the pathogenesis of autistic traits in LGS and DS [42], such as epilepsy itself, abnormal brain neural network characteristics, and the effect of medications [1].

Other Comorbidities of Dravet Syndrome and Lennox-Gastaut Syndrome
Patients with DS often develop disabling motor impairment, involving all motor domains (balance, coordination, visuomotor integration, power, and locomotion) [60]. As a result, walking becomes increasingly ataxic, and gait tends to worsen with age [3,17,20,21,28,30,50,[61][62][63], such that, from adolescence, many patients require the use of a wheelchair for longer distances [20]. A "crouch gait" (defined as the increased ankle, knee, and hip flexion during the whole gait cycle, plus rotations of the femur and/or tibia, and muscle retraction) is not specific to DS but often appears by 13 years of age [61,63]. In fact, a study by Di Marco et al. [64] showed that the crouch gait pattern could appear as early as 4 years of age in patients with DS. By adolescence (age > 13 years), some patients have developed a flexed gait pattern with passive knee extension deficit and bony malalignment. In adulthood, extrapyramidal signs and Parkinsonian gait become evident [17,18,[61][62][63]. Gitiaux et al. proposed that to understand gait disturbance, w e s h o u l d c o n s i d e r D S a s a s o d i u m c h a n n e l interneuronopathy causing complex clinical presentations of varying nature [17]. So depending on the site or structure where the voltage-gated sodium channel type 1 (Na V 1.1) is expressed, different movement disorders are induced. In particular, motor neuron dysfunction could partially explain the gait features observed at first as mild distal motor deficits, followed by proximal (crouch-like) deficits. In a genetic mouse model of DS, ataxia was caused by deficits in the cerebellar Purkinje neurons conveying output information on movement, coordination, and balance from the cerebellar cortex [65]. In contrast, mobility problems in LGS are often a direct result of seizures, particularly drop attacks, which are physically demanding and often result in injury [10,48].
Sleep disturbances, which are common in DS and LGS, may contribute to cognitive, behavioral, and psychological issues [10,48,50,55,[66][67][68]. Tonic seizures occurring during sleep, with the potential to disrupt the sleep cycle, are characteristic of LGS [48]. DS children and adults have more nighttime awakenings, reflective of poor quality of sleep [25]. SCNA1 mutations dysregulate neurological sleep networks [8,66], as demonstrated in a mouse model, in which Na V 1.1 channels encoded by SCN1A are expressed in the GABAergic neurons in the hypothalamus, thalamic reticular nucleus, and cortex [69]. In both DS [66] and LGS [70], nocturnal seizures, polypharmacy, developmental delay, and environmental factors (such as co-sleeping) may also contribute to a high frequency of sleep disturbances.
Epilepsy patients have a 24-to 28-fold higher rate of sudden death compared with the general population [71]. It has been proposed that channelopathy common to both epilepsy and cardiac disease may contribute to the increased risk of death via a lethal cardiac arrhythmia [72,73]. Patients with DS have a genetic predisposition to cardiac autonomic dysfunction, heart rate abnormalities, and arrhythmias, reflecting SCN1A expression in the heart and contributing to a high risk of sudden unexpected death in epilepsy [74][75][76].

Impact of Comorbidities on Patients and Caregivers
Comorbidities of DS and LGS increase the complexity of the patient's care needs and can disrupt daily activities, limit educational and social progress, and have a profound impact on the HRQOL of patients with DS or LGS and their families (Fig. 2) [20, 48-50, 54, 77-80]. Cognitive impairment and behavioral problems both independently predict reduced HRQOL, but behavioral problems can be particularly burdensome [20,49,53,54,81]. With their impact on mobility, motor impairments further detract from HRQOL [20,78,81].
Whereas the nature of seizures can change and seizure burden can decrease, the burden of comorbidities in DS and LGS does not improve and increases with age [25,29,48,50,59]. Although seizures remain a prominent problem, cognitive, behavioral, and physical comorbidities can eclipse seizures as a higher management priority in adolescent and adult patients with LGS, reflecting the importance of education, independence, and the ability to work, interact with peers, and form relationships [15,48,59].

General Management Implications
Although seizures must be controlled, management of DS and LGS should focus not only on pharmacologic seizure control but should also address comorbidities [2,4,10,20,21,48,50,79,82]. Seizures may aggravate the cognitive and behavioral comorbidities of DS and LGS, and therefore, pharmacologic treatment should be tailored to each patient based on the type of seizure, age, and clinical history [83]. Moreover, currently used antiepileptic drugs (AEDs) may also contribute to cognitive impairment and behavioral disorders in these patients, and few data are available on the most appropriate antiepileptic therapy for patients with LGS or DS. Comorbidities and the risk of AED-related adverse events (AEs) can also influence the therapeutic choice [4,10,20,41,53,79,83,84].
Valproic acid (VPA) is used in both syndromes; it is a broad-spectrum AED and is highly unlikely to aggravate seizures [10,83]. In the pediatric LGS population, VPA has been associated with cognitive AEs (such as confused state or attention disturbances) or behavioral AEs (such as aggression or agitation); it is rarely associated with AEs such as abnormal behavior or hyperactivity [10]. However, VPA is known to be associated with two types of hepatotoxicity: dose dependent and reversible elevation of serum liver enzymes (type I), and rare but often fatal, idiosyncratic hepatotoxicity (type II) [85]. The risk of VPA-related hepatotoxicity is increased in children below 2 years of age and in patients receiving other anticonvulsants [86][87][88][89]. Also, VPA has been reported to cause some coagulopathies (von Willebrand's disease, factor XIII deficiency, thrombocytopenia); however, their clinical relevance remains uncertain [85]. Clobazam (CLB) is a benzodiazepine with antiepileptic properties and is also used in both syndromes. It has been associated with cognitive and behavioral AEs, including slowed reaction time, confusion, irritability, and numbed emotions [10]. Stiripentol (STP) is an orally active unique AED, indicated for use with CLB and VPA as adjunctive therapy for refractory seizures in DS [90,91]. AEs associated with STP treatment include somnolence and motor impairment such as ataxia or tremor. Felbamate (FLB), which is licensed in some European countries as adjunctive therapy in patients with LGS, showed adverse effects on cognition (abnormal thinking) in 6.5% of pediatric patients; behavioral AEs associated with FLB include agitation, aggression, or psychological disturbance [10]. Lamotrigine (LTG) was approved by the US Food and Drug Administration (FDA) in 1998 as an adjunctive treatment for patients with LGS aged > 2 years [83,92]. It is considered a second-line AED after the failure of VPA. Common AEs associated with LTG include ataxia, rash, headache, anorexia, and drowsiness [83], or very rarely, confusion or hallucinations [10]. Behavioral AEs, such as aggression, irritability, and agitation, may also occur [10]. Rufinamide (RUF) was approved by the European Medicines Agency (in 2007) and by the US FDA (in 2008) as adjunctive seizure therapy in patients with LGS older than 4 years of age [93]. Anxiety is a common behavioral AE associated with RUF [10,94,95]. Topiramate (TPM) was approved by the US FDA in 2001 as adjunctive therapy for the treatment of seizures in patients with LGS aged ≥ 2 years [83]. Its tolerability profile in the pediatric population is characterized by AEs occurring early in the treatment course, and most are CNS related, including somnolence and psychomotor impairment [83]; depression has also been commonly observed [10].
In addition to optimal seizure control, long-term treatment goals should focus on maximizing developmental potential and HRQOL [4,11,19,96].
Given the various comorbidities of DS and LGS, comprehensive multidisciplinary management involving different healthcare professionals is required to ensure that individual patients' medical, educational, psychological, and social needs are met throughout their lives (Fig. 3) [4,10,11,48,50,54,77,97]. Transitioning from pediatric to adult care can be particularly challenging as the provision of care becomes more dispersed and there are generally fewer resources available for adults compared with pediatric patients [10,48,50,77,96]. To ensure as smooth a transition as possible, patients and their families should receive appropriate educational and psychosocial support [19,48].
Cannabidiol (CBD), a nonpsychoactive compound derived from Cannabis plants, is a recent addition to the treatment options for patients with DS and LGS [98]. In the USA, CBD (Epidiolex®, Greenwich Biosciences, Inc., Carlsbad, CA, USA) has been approved for the treatment of seizures associated with LGS or DS in patients aged ≥ 2 years [99]. In the EU, CBD (Epidyolex®, GW Pharmaceuticals, Cambridge, UK) has been approved for the adjunctive treatment (in combination with CLB) of seizures associated with LGS or DS in patients aged ≥ 2 years [100] and for seizures associated with tuberous sclerosis complex in patients aged ≥ 1 year [101]. There is some evidence that, in addition to reducing the frequency and severity of seizures, CBD improves mood and quality of life in patients with treatment-resistant epilepsy [87,102]. In this population, long-term use of CBD does not appear to be associated with negative effects on cognitive functioning [103].

Neuropsychological Assessment in the Management of Cognitive and Behavioral Problems
Comprehensive care of patients with DS or LGS must involve a careful assessment of comorbidities, routine monitoring of development and behavior at clinic visits, a formal developmental or cognitive assessment before starting school or earlier if there are clinical concerns about development, regular school assessments, and reassessment when transitioning from pediatric to adult care [4,48]. Table 1 summarizes the timepoints for conducting neuropsychological testing in pediatric patients with DS or LGS.
Active management of cognitive and behavioral problems is a high priority, but there are no neuropsychological assessment tools specifically for the evaluation of DS or LGS patients, and characterization of cognitive performance and behavior in these patients is challenging [15,51]. General standardized assessment tools should be c h o s e n a c c o r d i n g t o t h e p a t i e n t ' s a g e a n d neurodevelopmental level, and the neuropsychological components that are typically compromised in children with DS or LGS (i.e., speech, attention, spatial, sensory-motor, and executive function). Many of the same tests are appropriate for use in both DS and LGS ( Table 2).
The Wechsler Intelligence Scale for Children (WISC) and the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) are useful for an initial general   LGS [40,84]. The Leiter-R test is a nonverbal assessment of intellectual functioning, comprising visualization and reasoning, and attention and memory components [104], and is also recommended as an initial test at diagnosis/ onset. The Griffiths or Bayley Scales can be used for very young DS children up to 3 years of age [40,84]. From 3 years, the Visual-Motor Integration Test can be used to assess visual function, which is particularly compromised in DS and precedes detectable cognitive decline [22,35,40]. Other tests that can be used to assess specific skills in patients with DS or LGS include the Corsi Test for visuospatial memory, Bell's Cancellation Test for attention, the Boston Naming Test for language, the Tower of London procedure for executive function [40] in patients with minimal cognitive impairment, and the MacArthur-Bates Communicative Development Inventories for assessment of language [105]. Behavior assessment may be performed using tools such as the Child Behavior Checklist (CBCL) for children aged 1-5 years (CBCL/1-5) or older children and adolescents (CBCL/6-18) [40]. The CBCL questionnaire is completed by parents/caregivers, thereby acknowledging the importance of the role of the caregiver in evaluating the patient. Another generalized behavior assessment tool that is suitable for use in patients with DS or LGS [38,51] is the Vineland Adaptive Behavioral Scales (Vineland-3), which focus on age-dependent adaptive behavior, including communication, daily living, and socialization skills [106].

DS and
LGS are multifaceted diseases with a range of clinical comorbidities that are not purely the result of poorly controlled seizures. Moderate-to-severe cognitive impairment and general behavioral problems are characteristic comorbidities in both DS and LGS. The profound impact of cognitive and behavioral comorbidities on the lives of patients with DS or LGS and their caregivers and families highlights the importance of active multidisciplinary management, careful treatment choice, and appropriate educational and psychosocial support systems. In particular, psychoeducation (e.g., cognitive behavioral therapy or mood management) and community support may help patients and their family/caregivers in coping and adapting to the distress of pervasive and severe behavioral comorbidities of DS and LGS. Therefore, in addition to the medical management of seizures, comprehensive assessment and careful management of comorbidities should be a core aspect of care (Table 3).

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Conflict of Interest P.S. has received speaker fees and participated at advisory boards for Biomarin, Zogenyx, and GW Pharmaceuticals and has received research funding from ENECTA BV, GW Pharmaceuticals, Kolfarma srl., and Eisai. The other authors declare that they have no conflict of interest.  Rufinamide [112] Adjunctive therapy in the treatment of seizures associated with LGS in patients 1 year of age and older 100 mg, 200 mg, and 400 mg film-coated tablets Headache, dizziness, fatigue, and somnolence Topiramate [113] Adjunctive therapy in children aged 2 years and above, adolescents and adults with partial-onset seizures with or without secondary generalization or primary generalized tonic-clonic seizures and for the treatment of seizures associated with LGS LGS, Lennox-Gastaut syndrome Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.