Review Article - Neuropsychiatry (2017) Volume 0, Issue 0
Comorbidities of Refractory Epilepsy and the Update Mechanism
- Corresponding Author:
- Guoming Luan, MD
Department of Functional Neurosurgery
Sanbo Brain Hospital of Capital Medical
University, Beijing, Beijing Key Laboratory of Epilepsy
Beijing Institute for Brain Disorders, China
Tel: +86 1062856718
Fax: +86-10- 62856902
Epilepsy is still an issue that perplexes the epileptologists worldwide, with a reported impact on 50 million populations. With the reconceptualization of epilepsy as a disease of brain networks, it is great timing to rethink epilepsy and those associated comorbidities, including cognitive and behavioral comorbidities, psychiatric comorbidities, cardiovascular disease and migraine. In this review, we introduce the state of the art of these comorbidities of refractory epilepsy, including etiology, epidemiology, manifestation and mechanism. As essential comorbidities of epilepsy share the network consistent with epilepsy, a series of recent studies of comorbidities of epilepsy supply a new perspective on epileptic network. It is possible to accelerate the progression of epilepsy by translating those exciting advances in epileptic network into routine clinical practice.
Epilepsy, Comorbidities, Mechanism, Cognitive, Psychiatric, Cardiovascular, Migraine
Epilepsy is a disorder of unprovoked seizures, diagnosing by at least one unprovoked seizure and high risk for another . The majority of patients with refractory epilepsy, which is up to 30% of epilepsy, will suffer a lifetime burden that horrible seizures deteriorate the quality of life with cognitive, psychiatric and (or) other comorbidities . As epilepsy has been regarded as a disease of brain networks, those associated comorbidities, such as cognitive and behavioral comorbidities, psychiatric comorbidities, cardiovascular disease and migraine, are great starting point and refresher for epileptic network [3-8]. Unfortunately, the exact underlying etiology of those comorbidities is not clear. The epilepsy associated comorbidities are often underestimated, consequently, undertreated. Furthermore, cognitive deficits always remain despite seizure greatly control . Increased attention and early management of associated comorbidities is of great significance to improve the quality of life and maximize the opportunity for patients to re-integrate the society. In terms of mechanism, associated comorbidities can be divided into essential comorbidities and secondary comorbidities, according to whether sharing certain same mechanism of seizures . In this review, we focus on comorbidities of refractory epilepsy, discussing their etiology, category, manifestation and current progression of mechanism.
▪ Cognitive and behavioral comorbidities
The cognitive and behavioral comorbidities are more common in refractory epilepsy than those with “pharmaco-sensitive” epilepsy. The common cognitive and behavioral comorbidities, including learning disorders, social cognition disorders and attention deficit-hyperactivity disorder (ADHD), always have a huge influence on the quality of life, even greater than does epilepsy. The etiology of cognitive and behavioral comorbidities still remains unclear.
The refractory epilepsy has explicit impact on pediatric neurodevelopment, especially intellectual disability and learning function. A community-based study showed that children with epilepsy had lower overall cognition function than those without , whereas another study revealed onset age <5 years and symptomatic epilepsy were associated with low cognition function . In aspect of associated learning disorders, they are often found at the onset, and always described as subtle, consequently, difficult to recognize. Both working memory and processing speed are sensitive markers of impaired learning function, can be used as a screening tool for learning disorders . Regardless of AED use, underlying syndrome and remission status, children with epilepsy often have unsatisfied performance in writing, reading and mathematics, even they are within normal range of IQ [11,14]. Generalized epilepsy is often giving a worse performance in arithmetic test than focal epilepsy .
In fact, the definition of social cognition is included autism spectrum disorder (ASD), but often less severe than ASD. The prevalence of epilepsy, both adults and adolescents, with ASD is 20%, at the other hand, 8% of those with epilepsy have ASD, or social cognition deficit less severe than autism . There are serials of studies revealing a higher rate of epilepsy in ASD than general population [17-19].
Patients with refractory epilepsy have a higher rate of attention-deficit/hyperactivity disorder (ADHD), with a reported prevalence ranged from 28% to 70% , whereas 5-10% in general population . Combined subtype of ADHD is believed to be more common in developmental ADHD, whereas Inattentive ADHD is more common in children with epilepsy . Several epileptic manifestations are positively related to attention skills, such as location of epileptogenic zone, epilepsy duration, frequency, age of onset and the number of AEDs .
▪ Psychiatric comorbidities
In this part, we review the recent progression on epidemiology of common psychiatric comorbidities of refractory epilepsy, depression and anxiety. In terms of mood disorders, depression is common but often misdiagnosed, with 23.1% prevalence reported by a recent metaanalysis . According to a study on Canadian patients, the prevalence of epilepsy patients with depression is about 30%, and patients with epilepsy are more likely to express anxiety than individuals without epilepsy . The cause of psychiatric comorbidities still remains unknown . Psychiatric comorbidities, associated with poor prognosis, decreased medical adhesion and increased medical cost, have even a greater hazard on the quality of life than seizures do . Psychiatric comorbidities are often difficult to diagnose, as it is tough to distinguish depression and anxiety from the side effects of antiepileptic drugs. Even when depression or anxiety draws attention, epileptologists are possible to consider that mood as a natural response of uncomfortable feelings imposed by epilepsy.
▪ Other associated comorbidities
The category of comorbidities of epilepsy is various. Cardiovascular comorbidities of epilepsy include various arrhythmias, structural cardiac disease, transient myocardial ischemia and the Takotsubo syndrome. Most patients with epilepsy have arrhythmias, but often without manifestations. It is worth to mention that ictal asystole has been always considered to be the mechanism of sudden unexpected death in epilepsy (SUDEP).
The relationship between migraine and epilepsy is still controversial. Patients with epilepsy have a higher risk for developing migraine , and vice versa, individuals with migraine are at higher risk of epilepsy . Although the etiology and mechanism is not clear, migraine is associated with epilepsy, especially benign childhood epilepsy with Centro-temporal spikes (BECTS) .
▪ The update mechanism
In aspect of cognitive and behavioral comorbidities, the ion channel dysfunction caused by genetic mutations contributes to epilepsy, disturbing different brain network depend on specific distribution. For example, decreased excitability of GABAergic cerebellar Purkinje cells caused by SCN1A mutation not only contributes to seizure but also can be linked with learning and behavioral dysfunction . Epilepsy and cognitive comorbidities attribute to interictal frequent epileptiform discharges, which impair synaptic plasticity, neurogenesis and memory retrieval by inhibition of action potential firing through spine loss in pyramidal cells in hippocampal CA3 .
Interestingly, epilepsy and ASD share mechanism in level of gene, protein, neurotransmitters, ion channel and synapse. In terms of gene level, DEPDC5, NPRL3 and MTOR have been elucidated that associated with epilepsy and ASD [32-34]. The mutation of subunit of the sodium channel gene, SCN1A, is often found in both patients with dravet syndrome and ASD families [35,36]. In patients with epilepsy, decreased level of GABA contributes to epileptogenesis, whereas GABAA binding sites have been found to be reduced in ASD individuals . In addition, neurexin and synapsin dysfunction can be implicated in epilepsy and ASD comorbidity [38,39]. These findings suggest that the neurobiological and genetic mechanisms of epilepsy and ASD can be reasonably regarded as shared.
Ictal asystole is the most common cardiovascular comorbidity, and attributes to epilepsy activity initiating the autonomic networks, such as cingulate gyrus and amygdala .
For both migraine comorbidity and epilepsy, neuronal hyper excitability is thought to be key point to initiate. In migraine the hyper excitabilities of pyramidal cells result in decreased cortical propagation which in turn generates the pain and aura . Furthermore, the relationship between migraine and epilepsy can also be supported by the evidence that, valproate and topiramate are effective for migraine prevention . Serials of genetic mutations have been reported to be shared in both epilepsy and migraine, such as CACNA1A, ATP1A2, PRRT2, encoding calcium channel, sodium/potassium pump and axonal protein .
With the rapid development of neuroscience, the mechanism of epileptogenensis still remains uncertain. The research of comorbidities of epilepsy reveals a new perspective on epileptogenesis. As epilepsy is regarded as a disease of brain network, the manifestation of comorbidities implies which network is involved. The core of exploring the relationship between epilepsy and those associated comorbidities is to identify similarities and differences of neurobiological and genetic mechanism of populations with epilepsy-only or other disorders-only. Consequently, it is hopeful that several new markers and precise treatment will emerge in the future.
- Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 55(4), 475-482 (2014).
- Loughman A, Bendrups NA, D'Souza WJ. A Systematic Review of Psychiatric and Psychosocial Comorbidities of Genetic Generalised Epilepsies (GGE). Neuropsychol. Rev 26(4), 364-375 (2016).
- Shmuely S, van der Lende M, Lamberts RJ, et al. The heart of epilepsy: Current views and future concepts. Seizure 44(1), 176-183 (2017).
- Richard AE, Scheffer IE, Wilson SJ. Features of the broader autism phenotype in people with epilepsy support shared mechanisms between epilepsy and autism spectrum disorder. Neurosci. Biobehav. Rev 75(1), 203-233 (2017).
- Gill SJ, Lukmanji S, Fiest KM, et al. Depression screening tools in persons with epilepsy: A systematic review of validated tools. Epilepsia 58(5), 695-705 (2017).
- Papavasiliou AS, Bregianni M, Nikaina I, et al. Pediatric Headache and Epilepsy Comorbidity in the Pragmatic Clinical Setting. Neuropediatrics 47(2), 107-111 (2016).
- Nickels KC, Zaccariello MJ, Hamiwka LD, et al. Cognitive and neurodevelopmental comorbidities in paediatric epilepsy. Nat. Rev. Neurol 12(8), 465-476 (2016).
- Gogou M, Haidopoulou K, Eboriadou M, et al. Sleep apneas and epilepsy comorbidity in childhood: a systematic review of the literature. Sleep. Breath 19(2), 421-432 (2015).
- Reilly C, Atkinson P, Das KB, et al. Neurobehavioral comorbidities in children with active epilepsy: a population-based study. Pediatrics 133(6), e1586-93 (2014).
- Wilson SJ, Baxendale S. Reprint of: The new approach to classification: Rethinking cognition and behavior in epilepsy. Epilepsy. Behav 64(Pt B), 300-303 (2016).
- Beghi M, Cornaggia CM, Frigeni B, et al. Learning disorders in epilepsy. Epilepsia 47(Suppl 2), 14-18 (2006).
- Rai D, Kerr MP, McManus S, et al. Epilepsy and psychiatric comorbidity: a nationally representative population-based study. Epilepsia 53(6), 1095-1103 (2012).
- Gottlieb L, Zelko FA, Kim DS, et al. Cognitive proficiency in pediatric epilepsy. Epilepsy. Behav 23(2), 146-151 (2012).
- Berg AT, Langfitt JT, Testa FM, et al. Residual cognitive effects of uncomplicated idiopathic and cryptogenic epilepsy. Epilepsy. Behav 13(4), 614-619 (2008).
- Jackson DC, Dabbs K, Walker NM, et al. The neuropsychological and academic substrate of new/recent-onset epilepsies. J. Pediatr 162(5), 1047-1053 (2013).
- Kohane IS, McMurry A, Weber G, et al. The co-morbidity burden of children and young adults with autism spectrum disorders. PLoS. One 7(4), e33224 (2012).
- Woolfenden S, Sarkozy V, Ridley G, et al. A systematic review of two outcomes in autism spectrum disorder-epilepsy and mortality. Dev. Med. Child. Neurol 54(4), 306-312 (2012).
- Mouridsen SE, Rich B, Isager T. Epilepsy in individuals with a history of Asperger's syndrome: a Danish nationwide register-based cohort study. J. Autism. Dev. Disord 43(6), 1308-1313 (2013).
- Jokiranta E, Sourander A, Suominen A, et al. Epilepsy among children and adolescents with autism spectrum disorders: a population-based study. J. Autism. Dev. Disord 44(10), 2547-2557 (2014).
- Berl MM, Terwilliger V, Scheller A, et al. Speed and complexity characterize attention problems in children with localization-related epilepsy. Epilepsia 56(6), 833-840 (2015).
- Willcutt EG. The prevalence of DSM-IV attention-deficit/hyperactivity disorder: a meta-analytic review. Neurotherapeutics 9(3), 490-499 (2012).
- MacAllister WS, Vasserman M, Vekaria P, et al. Neuropsychological endophenotypes in ADHD with and without epilepsy. Appl. Neuropsychol. Child 1(2), 121-128 (2012).
- Engle JA, Smith ML. Attention and material-specific memory in children with lateralized epilepsy. Neuropsychologia 48(1), 38-42 (2010).
- Sajobi TT, Jette N, Zhang Y, et al. Determinants of disease severity in adults with epilepsy: Results from the Neurological Diseases and Depression Study. Epilepsy. Behav 51(1), 170-175 (2015).
- Tellez-Zenteno JF, Patten SB, Jette N, et al. Psychiatric comorbidity in epilepsy: a population-based analysis. Epilepsia 48(12), 2336-2344 (2007).
- Barry JJ, Ettinger AB, Friel P, et al. Consensus statement: the evaluation and treatment of people with epilepsy and affective disorders. Epilepsy. Behav 13(Suppl 1), S1-S29 (2008).
- Wang XQ, Lang SY, Zhang X, et al. Comorbidity between headache and epilepsy in a Chinese epileptic center. Epilepsy. Res 108(3), 535-541 (2014).
- Keezer MR, Bauer PR, Ferrari MD, et al. The comorbid relationship between migraine and epilepsy: a systematic review and meta-analysis. Eur. J. Neurol 22(7), 1038-1047 (2015).
- Clarke T, Baskurt Z, Strug LJ, et al. Evidence of shared genetic risk factors for migraine and rolandic epilepsy. Epilepsia 50(11), 2428-2433 (2009).
- Bender AC, Natola H, Ndong C, et al. Focal Scn1a knockdown induces cognitive impairment without seizures. Neurobiol. Dis 54(1), 297-307 (2013).
- Chapman KE, Specchio N, Shinnar S, et al. Seizing control of epileptic activity can improve outcome. Epilepsia 56(10), 1482-1485 (2015).
- Moller RS, Weckhuysen S, Chipaux M, et al. Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy. Neurol. Genet 2(6), e118 (2016).
- Dibbens LM, de Vries B, Donatello S, et al. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat. Genet 45(5), 546-551 (2013).
- Kuwano Y, Kamio Y, Kawai T, et al. Autism-associated gene expression in peripheral leucocytes commonly observed between subjects with autism and healthy women having autistic children. PLoS. One 6(9), e24723 (2011).
- Mullen SA, Scheffer IE. Translational research in epilepsy genetics: sodium channels in man to interneuronopathy in mouse. Arch. Neurol 66(1), 21-26 (2009).
- Sanders SJ, Murtha MT, Gupta AR, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485(7397), 237-241 (2012).
- Guptill JT, Booker AB, Gibbs TT, et al. [3H]-flunitrazepam-labeled benzodiazepine binding sites in the hippocampal formation in autism: a multiple concentration autoradiographic study. J. Autism. Dev. Disord 37(5), 911-920 (2007).
- Penagarikano O, Abrahams BS, Herman EI, et al. Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 147(1), 235-246 (2011).
- Corradi A, Fadda M, Piton A, et al. SYN2 is an autism predisposing gene: loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth. Hum. Mol. Genet 23(1), 90-103 (2014).
- Sevcencu C, Struijk JJ. Autonomic alterations and cardiac changes in epilepsy. Epilepsia 51(5), 725-737 (2010).
- Leniger T, von den Driesch S, Isbruch K, et al. Clinical characteristics of patients with comorbidity of migraine and epilepsy. Headache 43(6), 672-677 (2003).
- Nye BL, Thadani VM. Migraine and epilepsy: review of the literature. Headache 55(3), 359-80 (2015).