Epileptic and Epileptiform Encephalopathies Workup
- Author: Dean Patrick Sarco, MD; Chief Editor: Amy Kao, MD more...
Genetic and metabolic testing should be guided by the clinical scenario. No specific testing can be recommended for all cases, given the variability between these disorders. A more aggressive search is usually undertaken when development is slowing, plateauing, or regressing.
Studies to be considered include EEG monitoring, potentially with video to characterize seizures, and magnetic resonance neuroimaging. Every effort should be made to characterize a patient's epilepsy syndrome so that a more focused evaluation may be undertaken.
Genetic and Metabolic Testing
Testing for specific conditions, particularly treatable ones, should always be performed. Many genetic and metabolic conditions, however, may have similar or nonspecific presentations. Thus, screening metabolic studies may be considered, including the following:
Complete blood count
Serum amino acids
Urine organic acids
Cerebrospinal fluid evaluation
Screening genetic studies to consider would include karyotype, fragile X testing, and chromosomal microarray analysis. When a specific condition is suspected, testing specific to that condition should be performed because screening studies may be inconclusive, potentially more costly, and less sensitive, depending on the condition suspected. When indicated, consultation with a geneticist may aid in diagnosis.
In general, neuroimaging is necessary when evidence of focality is noted on either the clinical examination or the EEG. MRI, preferably at least 1.5-Tesla strength, is recommended. CT imaging may be useful in specific cases, such as when calcification may help clarify a diagnosis.
When epilepsy surgery is a consideration, functional neuroimaging studies may be useful. These include single-photon emission computed tomography (SPECT) and positron emission tomography (PET) scans. SPECT measures cerebral blood flow, and PET measures cerebral metabolism.
Magnetoencephalography (MEG) detects the magnetic field of epileptic discharges, which are superimposed on MR imaging. EEG abnormalities from deeper cortical areas such as language cortex may not reach the surface; therefore, the EEG could potentially be unremarkable, whereas MEG can detect the discharges.
Epileptiform activity may occur only in sleep; therefore, an EEG obtained only in the awake state is considered incomplete. Long-term EEG monitoring (24-h EEG) is considered the best study, but may not be necessary if marked epileptiform activation is seen during sleep, in the routine EEG (eg, electrical status epilepticus of sleep [ESES]). A prolonged EEG may capture a suspicious clinical event, such as a staring spell, and help determine whether it is an actual seizure.
The advantage of quantified EEG (QEEG) with spike localization and steady-state frequency-modulated auditory-evoked response (FMAER) is that spike localization techniques may better map the exact location of the discharge. Steady-state FMAER tests reflect response from the auditory association cortex involved in receptive language function. See the image below.
Early infantile epileptic encephalopathy (Ohtahara syndrome)
Interictal EEG reveals a suppression-burst pattern during wakefulness and in sleep. Bursts of generalized high amplitude slowing with admixed multifocal spike discharges are separated by several seconds of diffuse voltage suppression. Ictal EEG reveals typical generalized electro-decrements during tonic seizures.
Early myoclonic encephalopathy
The interictal EEG reveals a burst-suppression pattern more pronounced in sleep, with longer periods of diffuse voltage suppression lasting up to 10 seconds. The EEG may evolve to hypsarrhythmia or multifocal spike discharges and may then return to a suppression-burst pattern afterwards.
Infantile spasms (West syndrome)
Hypsarrhythmia, the typical interictal EEG finding, consists of a disorganized pattern with asynchronous, very-high-amplitude slowing and frequent multifocal spike and sharp wave discharges. The ictal EEG typically reveals a generalized slow wave followed by diffuse voltage attenuation (electro-decrement), which may associated with a spasm or be only electrographic (without clinical correlate).
Malignant epilepsy with migrating partial seizures in infancy
The interictal EEG reveals multifocal epileptiform activity and slowing. The ictal EEG confirms multifocal onsets, which may shift from seizure to seizure.
Severe myoclonic epilepsy of infancy (Dravet syndrome)
The interictal EEG is initially normal and then deteriorates to a nonspecific pattern of multifocal epileptiform discharges and multifocal or generalized slowing. A photoparoxysmal response may occur early in childhood. Ictal EEG findings depend on the seizure type. The ictal focus may shift during some seizures.
Myoclonic status in nonprogressive encephalopathies
The interictal EEG consists of multifocal epileptiform discharges and background slowing. Epileptiform discharges are potentiated in sleep, in some cases similar to an ESES pattern. Ictal EEG recording may demonstrate generalized slow spike and wave, or an absence pattern, depending on the seizure type.
Myoclonic-astatic epilepsy (Doose syndrome)
The EEG is initially normal or mildly abnormal, with worsening. Generalized spike and poly-spike wave discharges and excessive theta activity in the central-parietal regions typically develop interictally. Myoclonic seizures demonstrate generalized spike or poly-spike wave discharges, and atonic seizures demonstrate poly-spike wave discharges with electromyogram (EMG) silence.
Lennox-Gastaut syndrome (LGS)
The hallmark interictal EEG finding is generalized slow spike-wave discharges (usually 1.5-2 Hz), often with multifocal epileptiform discharges. Bursts of generalized fast spike discharges (approximately 10 Hz) are common in sleep (see the image below).
Ictal EEG findings depend on the seizure type captured. Tonic seizures demonstrate a diffuse electrodecrement pattern with superimposed low amplitude, fast spike discharges. A slow spike-wave pattern may be seen with atypical absences, and myoclonic seizures may have a diffuse spike or poly-spike wave pattern.
Landau-Kleffner syndrome and epilepsy with continuous spikes-waves during slow sleep
The hallmark EEG finding of Landau-Kleffner syndrome (LKS) and continuous spikes-waves during slow sleep (CSWS) is ESES, consisting of near-continuous, diffuse, epileptiform discharges in non-REM sleep (see the first image below). Often, multifocal and frequent epileptiform activity may also be present (see the second image below).
These discharges are markedly sleep potentiated; however, epileptiform activity is often present during rapid eye movement (REM) sleep and waking as well. ESES was initially described as having an EEG spike wave quantity occupying 85% of non-REM sleep; this is not an absolute requirement, however, as fewer discharges (perhaps 50% spike wave index of sleep) may result in cognitive deficits.[49, 50, 51]
The term ESES is somewhat misleading, since the pattern is not a clear ictal pattern. However, it is believed to cause more impairment than interictal activity in other disorders, thus representing a gray zone between the ictal and interictal states. Ictal EEG findings depend upon the seizure type recorded.
In LKS, the ESES discharges tend to be more posteriorly predominant (temporal or temporal-occipital), whereas in CSWS, frontotemporal or centrotemporal discharges are more common. In CSWS, frontotemporal discharges result in more executive function impairment and autistic behaviors, while a more central EEG focus (posterior frontal lobe involvement) may result in more motor impairment, including dyspraxia, dystonia, and ataxia.
As in LKS, the frequent epileptiform discharges contribute to the cognitive impairments seen. The ictal EEG pattern depends upon the seizure type captured.
Benign childhood epilepsy with centro-temporal spike discharges (benign rolandic epilepsy)
The interictal EEG pattern is characterized by frequent, sleep-potentiated, bilateral or unilateral, centrotemporal, sharp or spike-wave discharges. The EEG pattern may be seen in the absence of clinical seizures and is then termed the benign rolandic epilepsy (BRE) trait.
Preservation of nonverbal skills is an important diagnostic feature of LKS and may help differentiate LKS from other disorders, including autism.
Engel J Jr. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology. Epilepsia. 2001 Jun. 42(6):796-803. [Medline].
Drislane FW. Overlap of Encephalopathies and Epileptic Seizures. J Clin Neurophysiol. 2013 Oct. 30(5):468-476. [Medline].
Coppola G, Plouin P, Chiron C, Robain O, Dulac O. Migrating partial seizures in infancy: a malignant disorder with developmental arrest. Epilepsia. 1995 Oct. 36(10):1017-24. [Medline].
A glossary of terms most commonly used by clinical electroencephalographers. Electroencephalogr Clin Neurophysiol. 1974 Nov. 37(5):538-48. [Medline].
Moruzzi G, Magoun HW. Brain stem reticular formation and activation of the EEG. 1949. J Neuropsychiatry Clin Neurosci. 1995 Spring. 7(2):251-67. [Medline].
Holmes GL, Lenck-Santini PP. Role of interictal epileptiform abnormalities in cognitive impairment. Epilepsy Behav. 2006 May. 8(3):504-15. [Medline].
Shewmon DA, Erwin RJ. Transient impairment of visual perception induced by single interictal occipital spikes. J Clin Exp Neuropsychol. 1989 Oct. 11(5):675-91. [Medline].
Shewmon DA, Erwin RJ. The effect of focal interictal spikes on perception and reaction time. II. Neuroanatomic specificity. Electroencephalogr Clin Neurophysiol. 1988 Apr. 69(4):338-52. [Medline].
Kasteleijn-Nolst Trenité DG. Transient cognitive impairment during subclinical epileptiform electroencephalographic discharges. Semin Pediatr Neurol. 1995 Dec. 2(4):246-53. [Medline].
Aarts JH, Binnie CD, Smit AM, Wilkins AJ. Selective cognitive impairment during focal and generalized epileptiform EEG activity. Brain. 1984 Mar. 107 ( Pt 1):293-308. [Medline].
Binnie CD. Cognitive impairment during epileptiform discharges: is it ever justifiable to treat the EEG?. Lancet Neurol. 2003 Dec. 2(12):725-30. [Medline].
Binnie CD. Significance and management of transitory cognitive impairment due to subclinical EEG discharges in children. Brain Dev. 1993 Jan-Feb. 15(1):23-30. [Medline].
Binnie CD, Kasteleijn-Nolst Trenité DG, Smit AM, Wilkins AJ. Interactions of epileptiform EEG discharges and cognition. Epilepsy Res. 1987 Jul. 1(4):239-45. [Medline].
Aldenkamp AP, Overweg J, Gutter T, Beun AM, Diepman L, Mulder OG. Effect of epilepsy, seizures and epileptiform EEG discharges on cognitive function. Acta Neurol Scand. 1996 Apr. 93(4):253-9. [Medline].
Nicolai J, Aldenkamp AP, Arends J, Weber JW, Vles JS. Cognitive and behavioral effects of nocturnal epileptiform discharges in children with benign childhood epilepsy with centrotemporal spikes. Epilepsy Behav. 2006 Feb. 8(1):56-70. [Medline].
Massa R, de Saint-Martin A, Carcangiu R, Rudolf G, Seegmuller C, Kleitz C, et al. EEG criteria predictive of complicated evolution in idiopathic rolandic epilepsy. Neurology. 2001 Sep 25. 57(6):1071-9. [Medline].
Nabbout R, Dulac O. Epileptic encephalopathies: a brief overview. J Clin Neurophysiol. 2003 Nov-Dec. 20(6):393-7. [Medline].
Morrell F. Secondary epileptogenesis in man. Arch Neurol. 1985 Apr. 42(4):318-35. [Medline].
Morrell F, Whisler WW, Smith MC, Hoeppner TJ, de Toledo-Morrell L, Pierre-Louis SJ, et al. Landau-Kleffner syndrome. Treatment with subpial intracortical transection. Brain. 1995 Dec. 118 ( Pt 6):1529-46. [Medline].
Kobayashi K, Murakami N, Yoshinaga H, Enoki H, Ohtsuka Y, Ohtahara S. Nonconvulsive status epilepticus with continuous diffuse spike-and-wave discharges during sleep in childhood. Jpn J Psychiatry Neurol. 1988 Sep. 42(3):509-14. [Medline].
Guzzetta F, Battaglia D, Veredice C, Donvito V, Pane M, Lettori D, et al. Early thalamic injury associated with epilepsy and continuous spike-wave during slow sleep. Epilepsia. 2005 Jun. 46(6):889-900. [Medline].
Hrachovy RA, Frost JD. Severe Encephalopathic Epilepsy in Infants: Infantile Spasms (West Syndrome). In: Pellock JM, Bourgeois BFD, Dodson WE. Undefined. Pediatric Epilepsy. Third Edition. New York, NY: Demos Medical Publishing; 2008:16.
Saitoh M, Shinohara M, Hoshino H, Kubota M, Amemiya K, Takanashi JL, et al. Mutations of the SCN1A gene in acute encephalopathy. Epilepsia. 2012 Feb 6. [Medline].
} Dalla Bernardina B, Fontana E, Darra F. Myoclonic status in non-progressive encephalopathies. International Leauge Against Epilepsy. Available at http://www.ilae.org/ctf/myoclon_stat_nonpro_enceph.html. Accessed: February 15, 2011.
Morita DA, Glauser TA. Lennox-Gastaut Syndrome. In: Pellock JM, Bourgeois BFD, Dodson E. Third. Undefined. Pediatric Epilepsy: Diagnosis and Therapy. New York, NY: Demos Medical Publishing; 2008:Chapter 21.
Takeoka M, Riviello JJ Jr, Duffy FH, Kim F, Kennedy DN, Makris N, et al. Bilateral volume reduction of the superior temporal areas in Landau-Kleffner syndrome. Neurology. 2004 Oct 12. 63(7):1289-92. [Medline].
Strug LJ, Clarke T, Chiang T, Chien M, Baskurt Z, Li W, et al. Centrotemporal sharp wave EEG trait in rolandic epilepsy maps to Elongator Protein Complex 4 (ELP4). Eur J Hum Genet. 2009 Sep. 17(9):1171-81. [Medline]. [Full Text].
Deonna T, Roulet E. Autistic spectrum disorder: evaluating a possible contributing or causal role of epilepsy. Epilepsia. 2006. 47 Suppl 2:79-82. [Medline].
Kramer U, Nevo Y, Neufeld MY, Fatal A, Leitner Y, Harel S. Epidemiology of epilepsy in childhood: a cohort of 440 consecutive patients. Pediatr Neurol. 1998 Jan. 18(1):46-50. [Medline].
Aicardi J, Ohtahara S. Severe neonatal epilepsies with suppression-burst pattern. In: Roger J, Thomas P, Bureau M, Hirsch D, Dravet C, et al. Undefined. Syndromes in Infancy, Childhood and Adolescence. Fourth Edition. John Libbey Eurotext; 2005:Chapter 3.
Hurst DL. Epidemiology of severe myoclonic epilepsy of infancy. Epilepsia. 1990 Jul-Aug. 31(4):397-400. [Medline].
Guerrini R, Parmeggiani L, Bonanni P, Kaminska A, Dulac O. Myoclonic astatic epilepsy. In: Roger J, Bureau M, et al. Undefined. Syndromes in Infancy, Childhood and Adolescence. Fourth Edition. Montrouge, France: John Libbey Eurotext; 2005:Chapter 8.
Oguni H, Hayashi K, Imai K, Funatsuka M, Sakauchi M, Shirakawa S, et al. Idiopathic myoclonic-astatic epilepsy of early childhood--nosology based on electrophysiologic and long-term follow-up study of patients. Adv Neurol. 2005. 95:157-74. [Medline].
Oguni H, Hayashi K, Osawa M. Long-term prognosis of Lennox-Gastaut syndrome. Epilepsia. 1996. 37 Suppl 3:44-7. [Medline].
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 Oct. 39(10):646-51. [Medline].
Staden U, Isaacs E, Boyd SG, Brandl U, Neville BG. Language dysfunction in children with Rolandic epilepsy. Neuropediatrics. 1998 Oct. 29(5):242-8. [Medline].
Nicolai J, van der Linden I, Arends JB, van Mil SG, Weber JW, Vles JS, et al. EEG characteristics related to educational impairments in children with benign childhood epilepsy with centrotemporal spikes. Epilepsia. 2007 Nov. 48(11):2093-100. [Medline].
Saint-Martin AD, Seegmuller C, Carcangiu R, Kleitz C, Hirsch E, Marescaux C, et al. [Cognitive consequences of Rolandic Epilepsy]. Epileptic Disord. 2001. 3 Spec No 2:SI59-65. [Medline].
Metz-Lutz MN, Filippini M. Neuropsychological findings in Rolandic epilepsy and Landau-Kleffner syndrome. Epilepsia. 2006. 47 Suppl 2:71-5. [Medline].
Ohtahara S, Yamatogi Y. Ohtahara syndrome: with special reference to its developmental aspects for differentiating from early myoclonic encephalopathy. Epilepsy Res. 2006 Aug. 70 Suppl 1:S58-67. [Medline].
Riviello JJ, Hadjiloizou S. The Landau-Kleffner Syndrome and Continuous Spike-Waves during Sleep. In: Pellock JM, Bourgeois BFD, Dodson WE. Pediatric Epilepsy: Diagnosis and Therapy. Third Edition. New York, NY: Demos Medical Publishing; 2008:Chapter 24.
Tuchman R, Rapin I. Epilepsy in autism. Lancet Neurol. 2002 Oct. 1(6):352-8. [Medline].
Levisohn PM. The autism-epilepsy connection. Epilepsia. 2007. 48 Suppl 9:33-5. [Medline].
Laufs H. Functional imaging of seizures and epilepsy: evolution from zones to networks. Curr Opin Neurol. 2012 Feb 8. [Medline].
Patry G, Lyagoubi S, Tassinari CA. Subclinical "electrical status epilepticus" induced by sleep in children. A clinical and electroencephalographic study of six cases. Arch Neurol. 1971 Mar. 24(3):242-52. [Medline].
Van Hirtum-Das M, Licht EA, Koh S, Wu JY, Shields WD, Sankar R. Children with ESES: variability in the syndrome. Epilepsy Res. 2006 Aug. 70 Suppl 1:S248-58. [Medline].
Smith MC, Hoeppner TJ. Epileptic encephalopathy of late childhood: Landau-Kleffner syndrome and the syndrome of continuous spikes and waves during slow-wave sleep. J Clin Neurophysiol. 2003 Nov-Dec. 20(6):462-72. [Medline].
[Guideline] Hirtz D, Ashwal S, Berg A, Bettis D, Camfield C, Camfield P, et al. Practice parameter: evaluating a first nonfebrile seizure in children: report of the quality standards subcommittee of the American Academy of Neurology, The Child Neurology Society, and The American Epilepsy Society. Neurology. 2000 Sep 12. 55(5):616-23. [Medline].
[Guideline] Karis JP, Seidenwurm DJ, Davis PC, Brunberg JA, De La Paz RL, Dormont PD, et al. ACR Appropriateness Criteria epilepsy. Epilepsy. [Full Text].
Cusmai R, Martinelli D, Moavero R, Dionisi Vici C, Vigevano F, Castana C, et al. Ketogenic diet in early myoclonic encephalopathy due to non ketotic hyperglycinemia. Eur J Paediatr Neurol. 2012 Jan 17. [Medline].
Chiron C, Marchand MC, Tran A, Rey E, d'Athis P, Vincent J, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group. Lancet. 2000 Nov 11. 356(9242):1638-42. [Medline].
Sasagawa M, Kioi Y. [A successful treatment with intravenous high doses of gamma globulin for a minor status in a patient with Doose syndrome]. No To Hattatsu. 1997 May. 29(3):261-3. [Medline].
LANDAU WM, KLEFFNER FR. Syndrome of acquired aphasia with convulsive disorder in children. Neurology. 1957 Aug. 7(8):523-30. [Medline].
Deuel RK, Lenn NJ. Treatment of acquired epileptic aphasia. J Pediatr. 1977 Jun. 90(6):959-61. [Medline].
Aeby A, Poznanski N, Verheulpen D, Wetzburger C, Van Bogaert P. Levetiracetam efficacy in epileptic syndromes with continuous spikes and waves during slow sleep: experience in 12 cases. Epilepsia. 2005 Dec. 46(12):1937-42. [Medline].
De Negri M, Baglietto MG, Battaglia FM, Gaggero R, Pessagno A, Recanati L. Treatment of electrical status epilepticus by short diazepam (DZP) cycles after DZP rectal bolus test. Brain Dev. 1995 Sep-Oct. 17(5):330-3. [Medline].
Hadjiloizou SM, Bourgeois BFD, Duffy FH, et al. Childhood-onset epileptic encephalopathies with sleep activated EEG (EESA_EEG) and high dose diazepam treatment (HDDT): Review of a 5-year experience at Children's Hospital Boston. Undefined. Epilepsia. Suppl. 8; 2005;46:150-151.
Marescaux C, Hirsch E, Finck S, Maquet P, Schlumberger E, Sellal F, et al. Landau-Kleffner syndrome: a pharmacologic study of five cases. Epilepsia. 1990 Nov-Dec. 31(6):768-77. [Medline].
Lerman P, Lerman-Sagie T, Kivity S. Effect of early corticosteroid therapy for Landau-Kleffner syndrome. Dev Med Child Neurol. 1991 Mar. 33(3):257-60. [Medline].
Chez MG, Loeffel M, Buchanan CP, et al. Pulse high-dose steroids as combination therapy with valproic acid in epileptic aphasia patients with pervasive developmental delay or autism. Undefined. Ann Neurol. 1998;44(3):539.
Tsuru T, Mori M, Mizuguchi M, Momoi MY. Effects of high-dose intravenous corticosteroid therapy in Landau-Kleffner syndrome. Pediatr Neurol. 2000 Feb. 22(2):145-7. [Medline].
Sinclair DB, Snyder TJ. Corticosteroids for the treatment of Landau-kleffner syndrome and continuous spike-wave discharge during sleep. Pediatr Neurol. 2005 May. 32(5):300-6. [Medline].
Dagar A, Chandra PS, Chaudhary K, Avnish C, Bal CS, Gaikwad S, et al. Epilepsy Surgery in a Pediatric Population: A Retrospective Study of 129 Children from a Tertiary Care Hospital in a Developing Country along with Assessment of Quality of Life. Pediatr Neurosurg. 2011. 47(3):186-93. [Medline].
Morrell F, Whisler WW, Bleck TP. Multiple subpial transection: a new approach to the surgical treatment of focal epilepsy. J Neurosurg. 1989 Feb. 70(2):231-9. [Medline].
Grote CL, Van Slyke P, Hoeppner JA. Language outcome following multiple subpial transection for Landau-Kleffner syndrome. Brain. 1999 Mar. 122 ( Pt 3):561-6. [Medline].
Irwin K, Birch V, Lees J, Polkey C, Alarcon G, Binnie C, et al. Multiple subpial transection in Landau-Kleffner syndrome. Dev Med Child Neurol. 2001 Apr. 43(4):248-52. [Medline].