The goal of this review is to discuss the comorbidities reported in specific epilepsy syndromes to examine possible underlying causes or associations and to present data on current therapies for these conditions. Comorbid conditions including cognitive impairment, neuropsychiatric problems, and social difficulties are common in children with epilepsy, and often more disabling than the seizures themselves. Biological factors associated with a greater risk of comorbidity in epilepsy include younger age at seizure onset, cognitive impairment, temporal or frontal lobe onset, and intractability. Social factors correlating with greater risk include lower socioeconomic status, lower parental education level, and poorer family function. These comorbid conditions not only have a significant impact on the child but also are a source of increased stress and burden for families. Increased awareness and early diagnosis of these conditions may affect therapeutic intervention and long-term outcome as well as assist in better understanding of potential risk factors and biological mechanisms
Camfield CS, Camfield PR, Gordon K., Wirrell E., Dooley JMIncidence of epilepsy in childhood and adolescence: a population-based study in Nova Scotia from 1977 to 1985. Epilepsia. 1996;37:19-23.
2.
Camfield CS, Camfield PRLong-term social outcomes for children with epilepsy. Epilepsia . 2007;48(suppl):3-5.
3.
Sillanpaa M. , Jalava M., Kaleva O., Shinnar S.Long-term prognosis of seizures with onset in childhood. N Engl J Med. 1998;338:1715-1722.
4.
Sillanpaa M. , Schmidt D.Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study. Brain. 2006;129(pt 3):617-624.
5.
Feinstein A.The pretherapeutic classification of comorbidity in chronic disease. J Chronic Dis. 1970;2:455-468.
6.
Gaitatzis A. , Carroll K., Majeed A.W.Sander J.The epidemiology of the comorbidity of epilepsy in the general population. Epilepsia. 2004 ;45:1613-1622.
7.
Mirsky AF, Primac DW, Marsan CA, Rosvold HE, Stevens JRA comparison of the psychological test performance of patients with focal and nonfocal epilepsy. Exp Neurol. 1960;2:75-89.
8.
Mirsky AF, Vanburen JMOn the nature of the ``absence'' in centrencephalic epilepsy: a study of some behavioral, electroencephalographic and autonomic factors. Electroencephalogr Clin Neurophysiol. 1965;18:334-348.
9.
Duncan C.Application of event-related brain potentials to the analysis of interictal attention in absence epilepsy. In: AF Mirsky, M Myslobodsky eds. Elements of Petit Mal Epilepsy. New York: Peter Lang; 1988:341-364.
10.
Mirky A., Duncan C.Neuropsychological studies in idiopathic generalized epilepsy. In: I Jambaque, M Lasssonde, O Dulac eds. Neuropsychology of Childhood Epilepsy. New York: Kluwer Academic /Plenum; 2001:141-150.
11.
Mirsky A.Behavioral and psychophysiological effects of petit mal epilepsy in the light of a neuropsychologically-based theory of attention. In: AF Mirsky, M Myslobodsky eds. Elements of Petit Mal Epilepsy. New York: Peter Lang;1988:311-340.
12.
Janz D., Christian W.Impulsiv-Petit mal. Dtsch Z Nervenheik. 1957 ;176:346-386.
13.
Perini GI, Tosin C., Carraro C., et al. Interictal mood and personality disorders in temporal lobe epilepsy and juvenile myoclonic epilepsy. J Neurol Neurosurg Psychiatry . 1996;61:601-605.
14.
Devinsky O. , Gershengorn J., Brown E., Perrine K., Vazquez B., Luciano D.Frontal functions in juvenile myoclonic epilepsy . Neuropsychiatry Neuropsychol Behav Neurol. 1997;10:243-246.
15.
Croona C., Kihlgren M., Lundberg S., Eeg-Olofsson O., Eeg-Olofsson KENeuropsychological findings in children with benign childhood epilepsy with centrotemporal spikes. Dev Med Child Neurol. 1999;41:813-818.
Baglietto MG , Battaglia FM, Nobili L., et al. Neuropsychological disorders related to interictal epileptic discharges during sleep in benign epilepsy of childhood with centrotemporal or Rolandic spikes. Dev Med Child Neurol . 2001;43:407-412.
18.
Staden U., Isaacs E., Boyd SG, Brandl U., Neville BGLanguage dysfunction in children with Rolandic epilepsy. Neuropediatrics. 1998;29:242-248.
19.
Yung AW, Park YD, Cohen MJ, Garrison TNCognitive and behavioral problems in children with centrotemporal spikes. Pediatr Neurol. 2000;23:391-395.
20.
Binnie CD, Marston D.Cognitive correlates of interictal discharges. Epilepsia. 1992;33(suppl):S11-S17.
21.
D'Alessandro P., Piccirilli M., Tiacci C., et al. Neuropsychological features of benign partial epilepsy in children. Ital J Neurol Sci. 1990;11:265-269.
22.
Piccirilli M. , D'Alessandro P., Sciarma T., et al. Attention problems in epilepsy: possible significance of the epileptogenic focus. Epilepsia. 1994;35:1091-1096.
23.
Piccirilli M. , D'Alessandro P., Tiacci C., Ferroni A.Language lateralization in children with benign partial epilepsy. Epilepsia. 1988;29:19-25.
24.
Weglage J., Demsky A., Pietsch M., Kurlemann G.Neuropsychological, intellectual, and behavioral findings in patients with centrotemporal spikes with and without seizures. Dev Med Child Neurol. 1997;39:646-651.
25.
Deonna T., Zesiger P., Davidoff V., Maeder M., Mayor C., Roulet E.Benign partial epilepsy of childhood: a longitudinal neuropsychological and EEG study of cognitive function. Dev Med Child Neurol. 2000;42:595-603.
26.
Metz-Lutz MN , Kleitz C., de Saint Martin A., Massa R., Hirsch E., Marescaux C.Cognitive development in benign focal epilepsies of childhood. Dev Neurosci. 1999;21:182-190.
27.
Dongier S., Charles C., Chabert F.Sémiologie psychiatrique et psychometrique. In: H Gastaut, J Roger, R Soulager, et al. eds. L'Encephalopathie Myoclonique Infantile avec Hypsarythmie (Syndrome de West). Paris: Masson.
28.
Guzzetta G. , Cristafulli A., Crino M.Cognitive assessment in infants with West syndrome: how useful is it for diagnosis and prognosis? Dev Med Child Neurol. 1993;35:379-387.
29.
Jambaque I.Neuropsychological aspects. In: O Dulac , HT Chugani, BD Dalla Bernardina, eds. Infantile Spasms and West Syndrome . London: WB Saunders; 1994:82-87.
30.
Dulac O., Plouin P., Jambaque I.Predicting favorable outcome in idiopathic West syndrome. Epilepsia. 1993;34:747-756.
31.
Lerman P., Kivity S.The efficacy of corticotropin in primary infantile spasms. J Pediatr. 1982;101:294-296.
32.
Lombroso CTA prospective study of infantile spasms: clinical and therapeutic correlations. Epilepsia. 1983 ;24:135-158.
33.
Chevrie JJ, Aicardi J.[Psychiatric prognosis of infantile spasms treated by ACTH or corticoids. Statistical analysis of 78 cases followed for more than one year]. J Neurol Sci. 1971;12: 351-357.
34.
Riikonen R.Long-term outcome of patients with West syndrome . Brain Dev. 2001;23:683-687.
35.
Riikonen R. , Amnell G.Psychiatric disorders in children with earlier infantile spasms. Dev Med Child Neurol. 1981 ;23: 747-760.
36.
Saemundsen E., Ludvigsson P., Rafnsson V.Autism spectrum disorders in children with a history of infantile spasms: a population-based study. J Child Neurol. 2007;22:1102-1107.
37.
Hunt A., Dennis J.Psychiatric disorder among children with tuberous sclerosis. Dev Med Child Neurol. 1987;29:190-198.
38.
Bolton PF, Park RJ, Higgins JN, Griffiths PD, Pickles A.Neuro-epileptic determinants of autism spectrum disorders in tuberous sclerosis complex. Brain. 2002;125(pt 6):1247-1255.
39.
Kieffer-Renaux V., Kaminska A., Dulac O.Cognitive deterioration in Lennox-Gastaut and Doose epilepsy. In: I Jambaque, M Lasssonde, O Dulac eds. Neuropsychology of Childhood Epilepsy. New York: Kluwer Academic/Plenum ; 2001:185-190.
40.
Roger J., Remy C., Bureau M., et al. [Lennox-Gastaut syndrome in the adult]. Rev Neurol (Paris). 1987;143:401-405.
41.
Ohtsuka Y., Amano R., Mizukawa M., Ohtahara S.Long-term prognosis of the Lennox-Gastaut syndrome. Jpn J Psychiatry Neurol. 1990;44:257-264.
42.
Oller-Daurella L.Lennox Gastaut syndrome. Clinicoelectroencephalographic aspects of its diagnosis. Arq Neuropsiquiatr. 1972;30:271-287.
43.
Oguni H., Tanaka T., Hayashi K., et al. Treatment and long-term prognosis of myoclonic-astatic epilepsy of early childhood. Neuropediatrics. 2002;33:122-132.
44.
Wolff M., Casse-Perrot C., Dravet C.Severe myoclonic epilepsy of infants (Dravet syndrome): natural history and neuropsychological findings. Epilepsia. 2006 ;47(suppl):45-48.
45.
Nickels K., Wirrell E.Electrical status epilepticus in sleep. Semin Pediatr Neurol . 2008;15:50-60.
46.
Mantovani JF , Landau WMAcquired aphasia with convulsive disorder: course and prognosis. Neurology. 1980;30:524-529.
47.
Mira L., Oxilia B., Lierde AVCognitive assessment of children with CSWS syndrome: a critical review of data from 155 cases submitted to a Venice colloquium. In: A Beaumanoir, M Bureau, T Deonna, L Mira, CA Tassinari eds. Continuous Spikes and Waves During Slow Sleep. London: John Libbey;1995:229-242.
48.
Praline J., Hommet C., Barthez MA, et al. Outcome at adulthood of the continuous spike-waves during slow sleep and Landau-Kleffner syndromes. Epilepsia. 2003;44:1434-1440.
49.
Robinson RO , Baird G., Robinson G., Simonoff E.Landau-Kleffner syndrome: course and correlates with outcome. Dev Med Child Neurol. 2001;43:243-247.
50.
Oguni H., Andermann F., Rasmussen T.The natural history of the syndrome of chronic encephalitis and epilepsy: a study of the NNHI series of forty-eight cases. In: F Anderman, ed. Encephalitis and Epilepsy: Rasmussen's Syndrome . London: Butterworth-Heinemann ; 1991:7-35.
51.
Andermann F. , Farrell K.Early onset Rasmussen's syndrome: a malignant, often bilateral form of the disorder. Epilepsy Res.2006;70(suppl):S259-S262.
52.
Kossoff EH, Vining EP, Pillas DJ, et al. Hemispherectomy for intractable unihemispheric epilepsy etiology vs outcome. Neurology. 142003;61:887-890.
53.
Joinson C., O'Callaghan FJ, Osborne JP, Martyn C., Harris T., Bolton PFLearning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex. Psychol Med. 2003;33:335-344.
54.
Jozwiak S., Goodman M., Lamm SHPoor mental development in patients with tuberous sclerosis complex: clinical risk factors. Arch Neurol. 1998;55:379-384.
55.
Shepherd CW , Houser OW, Gomez MRMR findings in tuberous sclerosis complex and correlation with seizure development and mental impairment. Am J Neuroradiol. 1995;16:149-155.
56.
Jones AC, Daniells CE, Snell RG, et al. Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis . Hum Mol Genet. 1997;6:2155-2161.
57.
Jones AC, Shyamsundar MM, Thomas MW, et al. Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. Am J Hum Genet. 1999;64:1305-1315.
58.
Prather P., de Vries PJBehavioral and cognitive aspects of tuberous sclerosis complex. J Child Neurol. 2004;19:666-674.
59.
Hunt A., Shepherd C.A prevalence study of autism in tuberous sclerosis. J Autism Dev Disord. 1993;23:323-339.
60.
DeVries P.Attention and the Psychopathology of Tuberous Sclerosis. Cambridge, UK: University of Cambridge;2001.
61.
DeVries P.Tuberous sclerosis. In: P Hsowlin, O Udwin eds. Outcomes in Neurodevelopmental and Genetic Disorders. Cambridge, UK: Cambridge University Press;2002:272-298.
62.
Smalley SL, McCracken J., Tanguay P.Autism, affective disorders, and social phobia. Am J Med Genet . 271995;60:19-26.
63.
Hernandez MT, Sauerwein HC, Jambaque I., et al. Attention, memory, and behavioral adjustment in children with frontal lobe epilepsy. Epilepsy Behav. 2003 ;4:522-536.
64.
Prevost J., Lortie A., Nguyen D., Lassonde M., Carmant L.Nonlesional frontal lobe epilepsy (FLE) of childhood: clinical presentation, response to treatment and comorbidity. Epilepsia. 2006;47:2198-2201.
65.
Cormack F., Cross JH, Isaacs E., et al. The development of intellectual abilities in pediatric temporal lobe epilepsy. Epilepsia. 2007;48:201-204.
66.
Gonzalez LM , Anderson VA, Wood SJ, Mitchell LA, Harvey ASThe localization and lateralization of memory deficits in children with temporal lobe epilepsy. Epilepsia . 2007;48:124-132.
67.
Rzezak P., Fuentes D., Guimaraes CA, et al. Frontal lobe dysfunction in children with temporal lobe epilepsy . Pediatr Neurol. 2007;37:176-185.
68.
Austin JK, Dunn DW, Huster GAChildhood epilepsy and asthma: changes in behavior problems related to gender and change in condition severity. Epilepsia. 2000;41:615-623.
69.
Austin JK, Harezlak J., Dunn DW, Huster GA, Rose DF, Ambrosius WTBehavior problems in children before first recognized seizures. Pediatrics. 2001;107:115-122.
70.
Dunn DW, Austin JK, Huster GABehaviour problems in children with new-onset epilepsy. Seizure . 1997;6:283-287.
71.
Oostrom KJ, Schouten A., Kruitwagen CL, et al. Behavioral problems in children with newly diagnosed idiopathic or cryptogenic epilepsy attending normal schools are in majority not persistent . Epilepsia. 2003;44:97-106.
72.
Oostrom KJ, Smeets-Schouten A., Kruitwagen CL, Peters AC, Jennekens-Schinkel A; Dutch Study Group of Epilepsy in Childhood. Not only a matter of epilepsy: early problems of cognition and behavior in children with ``epilepsy only''-a prospective, longitudinal, controlled study starting at diagnosis. Pediatrics. 2003;112(6 pt 1):1338-1344.
73.
Guimaraes CA , Franzon RC, Souza EA, et al. Abnormal behavior in children with temporal lobe epilepsy and ganglioglioma. Epilepsy Behav. 2004;5:788-791.
74.
Nestler EJ, Barrot M., DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LMNeurobiology of depression. Neuron. 2002;34: 13-25.
75.
Jobe PC, Dailey JW, Wernicke JFA noradrenergic and serotonergic hypothesis of the linkage between epilepsy and affective disorders. Crit Rev Neurobiol. 1999;13:317-356.
76.
Toczek MT, Carson RE, Lang L., et al. PET imaging of 5-HT1A receptor binding in patients with temporal lobe epilepsy. Neurology. 112003;60:749-756.
77.
Dunn D., Austin J., Harezlak J., Amrosius W.ADHD and epilepsy in childhood. Dev Med Child Neurol. 2003;45:50-54.
78.
Hermann B., Jones J., Dabbs K., et al. The frequency, complications and aetiology of ADHD in new onset paediatric epilepsy. Brain. 2007;130(pt 12):3135-3148.
79.
Castellanos FX, Lee PP, Sharp W., et al. Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. JAMA. 2002;288: 1740-1748.
80.
Giedd JN, Blumenthal J., Molloy E., Castellanos FXBrain imaging of attention deficit/hyperactivity disorder. Ann N Y Acad Sci. 2001;931:33-49.
81.
Dickstein SG , Bannon K., Castellanos FX, Milham MPThe neural correlates of attention deficit hyperactivity disorder: an ALE meta-analysis. J Child Psychol Psychiatry. 2006;47: 1051-1062.
82.
Roth RM, Saykin AJExecutive dysfunction in attention-deficit/ hyperactivity disorder: cognitive and neuroimaging findings. Psychiatr Clin North Am. 2004;27:83-96, ix.
83.
Khalilov I. , Holmes GL, Ben-Ari Y.In vitro formation of a secondary epileptogenic mirror focus by interhippocampal propagation of seizures. Nat Neurosci. 2003;6:1079-1085.
84.
Cohen I., Navarro V., Clemenceau S., Baulac M., Miles R.On the origin of interictal activity in human temporal lobe epilepsy in vitro . Science. 2002;298:1418-1421.
85.
Haut SR, Veliskova J., Moshe SLSusceptibility of immature and adult brains to seizure effects. Lancet Neurol. 2004;3:608-617.
86.
Ben-Ari Y., Holmes GLEffects of seizures on developmental processes in the immature brain. Lancet Neurol. 2006 ;5: 1055-1063.
87.
Ben-Ari Y.Excitatory actions of GABA during development: the nature of the nurture. Nat Rev Neurosci. 2002;3:728-739.
88.
Cheung C., Wirrell E.Adolescents' perception of epilepsy compared with other chronic diseases: ``through a teenager's eyes''. J Child Neurol. 2006;21:214-222.
89.
de Souza EA , Salgado PCA psychosocial view of anxiety and depression in epilepsy. Epilepsy Behav. 2006;8:232-238.
90.
Hermann B., Jones J., Sheth R., Dow C., Koehn M., Seidenberg M.Children with new-onset epilepsy: neuropsychological status and brain structure . Brain. 2006;129(pt 10):2609-2619.
91.
Brent DA, Crumrine PK, Varma RR, Allan M., Allman C.Phenobarbital treatment and major depressive disorder in children with epilepsy . Pediatrics. 1987;80:909-917.
92.
Hellstrom B. , Barlach-Christoffersen M.Influence of phenobarbital on the psychomotor development and behaviour in preschool children with convulsions . Neuropadiatrie. 1980;11: 151-160.
93.
Canadian Study Group for Childhood Epilepsy.Clobazam has equivalent efficancy to carbamazepine and phenytoin as mono-therapy for childhood epilepsy. Epilepsia . 1998;39:952-959.
94.
Briggs DE, French JALevetiracetam safety profiles and tolerability in epilepsy patients. Expert Opin Drug Saf. 2004;3: 415-424.
95.
Post RM, Denicoff KD, Frye MA, et al. A history of the use of anticonvulsants as mood stabilizers in the last two decades of the 20th century. Neuropsychobiology . 1998;38:152-166.
96.
Mula M., Sander JWNegative effects of antiepileptic drugs on mood in patients with epilepsy . Drug Saf. 2007;30:555-567.
97.
Hammad TA, Laughren T., Racoosin J.Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry. 2006;63:332-339.
98.
US Food and Drug Administration.Relationship between psychotropic drugs and pediatric suicidality: review and evaluation of clinical data. Available at: www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-10-TAB08-Hammads-Review.pdf
99.
Dunn DW, Harezlak J., Ambrosius WT, Austin JK, Hale B.Teacher assessment of behaviour in children with new-onset seizures. Seizure. 2002;11:169-175.
100.
Hesdorffer DC , Ludvigsson P., Olafsson E., Gudmundsson G., Kjartansson O., Hauser WAADHD as a risk factor for incident unprovoked seizures and epilepsy in children. Arch Gen Psychiatry. 2004;61:731-736.
101.
Jones JE, Watson R., Sheth R., et al. Psychiatric comorbidity in children with new onset epilepsy . Dev Med Child Neurol. 2007;49:493-497.
102.
Berg AT, Smith SN, Frobish D., et al. Special education needs of children with newly diagnosed epilepsy . Dev Med Child Neurol. 2005;47:749-753.
103.
Hermann BP , Seidenberg M., Bell B.The neurodevelopmental impact of childhood onset temporal lobe epilepsy on brain structure and function and the risk of progressive cognitive effects. Prog Brain Res. 2002;135:429-438.
104.
Stefan H., Pauli E.Progressive cognitive decline in epilepsy: an indication of ongoing plasticity . Prog Brain Res. 2002;135: 409-417.
105.
Barry JJ, Ettinger AB, Friel P., et al. Consensus statement: the evaluation and treatment of people with epilespy and affective disorders. Epilepsy Behav. 2008;13:S1-S29.
106.
Thome-Souza MS, Kuczynski E., Valente KDSertraline and fluoxetine: safe treatments for children and adolescents with epilepsy and depression. Epilepsy Behav. 2007;10:417-425.
107.
Cushner-Weinstein S., Berl M., Salpekar JA, et al. The benefits of a camp designed for children with epilepsy: evaluating adaptive behaviors over 3 years. Epilepsy Behav. 2007;10: 170-178.
