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Year : 2007  |  Volume : 10  |  Issue : 5  |  Page : 3-6
 

Epileptic encephalopathy


The Prince of Wales's Prof. of Childhood Epilepsy, Institute of Child Health, London, National Centre for Young People with Epilepsy, Lingfield, Great Ormond Street Hospital for Children, London, United Kingdom

Correspondence Address:
Brian Neville
The Prince of Wales's Prof. of Childhood Epilepsy, Institute of Child Health, London, National Centre for Young People with Epilepsy, Lingfield, Great Ormond Street Hospital for Children, London
United Kingdom
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   Abstract 

Epileptic encephalopathy is applied to loss of skills in all domains of functioning including cognitive, behavioural, communication and motor that occurs with epilepsy and appears to be caused by epilepsy, particularly by subclinical seizure activity. It is particularly common in early onset epilepsies in which deterioration may be catastrophic but milder problem of cognition, attention and behaviour occur in up to half of school age children with epilepsy. Management involves early and vigorous treatment of the epilepsy and the identification and management of the additional impairments.


Keywords: Epilepsy, encephalopathy, acquired impairments, malignant epilepsies of childhood


How to cite this article:
Neville B. Epileptic encephalopathy. Ann Indian Acad Neurol 2007;10, Suppl S1:3-6

How to cite this URL:
Neville B. Epileptic encephalopathy. Ann Indian Acad Neurol [serial online] 2007 [cited 2019 Dec 10];10, Suppl S1:3-6. Available from: http://www.annalsofian.org/text.asp?2007/10/5/3/33491


Epileptic encephalopathy (EE) is the broad name given to alterations in function which are persistent but are regarded as a direct consequence of epilepsy rather than of the causative lesion, if such is identified.[1] As normally used EE refers to both the state of the person suffering it, the pathogenesis of that state and it is also used to describe the specific epilepsy syndrome, e.g., West syndrome, but it is clearer to separate the process from the specifically named epilepsy syndromes. It is believed that many of the impairments associated with epilepsy are acquired either transiently or permanently by this route. However defined, the subject is poorly researched and curiously it has been accepted that people with epilepsy have a range of impairments which are present from early life but how they came by them is often ignored. I shall approach the subject from a paediatric developmental position proposing that this process results in a huge burden of disability and care and constitutes the main problem in epilepsy. For a variety of reasons it appears to be a much more prominent issue in paediatric practice. Within this theoretical framework, I will exclude acquired brain damage and stick firmly to functional impairments associated with epilepsy or what, with our present level of routine imaging, appear to be purely functional.

EE therefore refers to impairments that are acquired coincident with epileptic seizures or subclinical epileptic activity, particularly, it seems, with a high rate of seizure activity in sleep. It can affect all domains of functioning including cognitive, behavioural, motor and visual. Within these domains, one can see arrest of developmental progress, loss of acquired skills or deviant patterns of development. Quite often within epileptic encephalopathy, one can also see fluctuation which gives a diagnostic clue to the pathogenesis. Although no change in routine magnetic resonance imaging or rate of head growth in EE has been accepted, recent findings cast doubt upon this. Patients may have the potential for recovery but more commonly are left with major or minor deficits.

I will exclude from this process other methods by which disability is acquired in epilepsy including the febrile status/mesial temporal sclerosis sequence, head trauma caused by seizures, Rassmussen's encephalitis and the effect of anti-epilepsy drugs, although some would include some of these. I will also pragmatically exclude epilepsy in patients with very severe primary brain damage or malformation such as lissencephaly and spastic tetraplegia because it may be impossible to assess any change in developmental progress. I will also exclude the phenomena of the seizures themselves, the phenomena of transient cognitive impairment, which I would regard as a cognitive seizure and transient post ictal phenomena, for example hemiparesis or aphasia. It is important to note however that such post ictal phenomena are quite common in disorders that cause encephalopathy, for example, Landau-Kleffner syndrome (LKS). I will similarly exclude but discuss minor epileptic status in which the patient reverts to a groggy state with poor performance skills and impaired cognitive state but with observable myoclonic jerks and absences.[2] This latter state could be regarded as an EE and often co-exists with a more long standing series of impairments. The reason for this exclusion is the presence of observable ictal phenomena i.e., with careful observation there should not be any doubt that clinical seizures are occurring.

EEs are common in early onset epilepsies and particularly in those starting in the first 6 months of extra-uterine life. They are usually associated with a high rate of epileptic discharges, particularly in sleep and they commonly have a poor response to routine anti-epilepsy drugs. They constitute some of the major impairments that are associated with early lesions of the brain and our clinical task is to separate the effects of loss of eloquent cortex, downstream effects of cortical loss and those attributable to seizure activity.

In the United Kingdom, with a total population of over 60 million people, one in 200 children have epilepsy. Twenty-five percent have continuing seizures which is a total of 75,000. In the as yet unpublished Lambeth Study thirty to fifty percent have learning and behavioural problems which is therefore about 25,000 children. Ten percent of the total have serious developmental arrest and psychiatric illness which is a total of approximately7,500 children. Within this group there is a significant mortality but many of the children survive to adult life with their impairments but seen rarely to be recognised within the adult population so far as epilepsy services are concerned.

The impairments that occur in childhood epilepsy consist of: seizures, cognitive arrest/regression, psychiatric illness (mood disorders, attention deficit hyperactivity disorder, autism, obsessive compulsive disorder) and motor disorders (apraxia, dystonia, ataxia). However, there is increasing evidence that the type of behavioural impairments that occur with early brain damage and dysfunction, including epilepsy, is in part dependent on the genetic load in the family.

If we take tuberous sclerosis as a starting point, the startling information is the very high rate of cognitive and behavioural impairments, particularly autism spectrum disorder in those children whose epilepsy starts early and the marked freedom from such effects when the first two years of life are spared epilepsy. If we then look at surgery for tuberous sclerosis the aims of surgery are:

  1. To stop seizures.
  2. To allow the rest of the brain to develop free from the noxious influence of epilepsy.


When we look at our surgical patients with tuberous sclerosis, despite achieving the aim of a high rate of seizure freedom in carefully selected patients, our current practice of surgical resection does not have any impact upon the early encephalopathies, particularly that associated with infantile spasms. There may be some amelioration of the severity of an autism spectrum disorder but it remains largely unchanged.

The disorders which accompany the early developing brain regularly show a lower IQ if epilepsy coexists. This is a feature of congenital hemiplegia where those without epilepsy have an IQ approaching the normal range whilst those with seizures have an IQ of around 15-20 points lower.[3] An identical outcome was found in the follow-up of preterm babies in which those without seizures had IQs within the normal range where those who had seizures had IQs which were more than 20 points lower.[4] The general message which arises from these studies is that epilepsy, cognitive impairment and behaviour disorders occur together very commonly and appear to form a triad indicating early cortical grey matter damage. However, whether they constitute an active process driven by earlier or current epilepsy, i.e. an epileptic encephalopathy, is unknown. If that were the case the high rate of subclincal seizures would have had to have been at an earlier stage because they currently do not usually have a high rate of seizure activity in sleep.

The malignant epilepsies or catastrophic epilepsies, include the following:[5]

  1. early onset with hemimegalancephaly
  2. early onset temporal dysembryoplastic lesions
  3. infantile spasms/West syndrome
  4. Lennox-Gastaut syndrome
  5. Landau-Kleffner syndrome
  6. infantile polymorphic epilepsy / severe myoclonic epilepsy of infancy/Dravet's syndrome
  7.  Sturge- Weber syndrome More Details More Details


These forms of epilepsy are typically those associated with regression of cognitive and behavioural functions, which are commonly not relieved by antiepilepsy treatment and in which the severity of the epileptic encephalopathy is usually unaffected by treatment. Of these, the most obvious but rare condition is the Landau-Kleffner Syndrome in which the core features consist of a period of at least two years of normal development including speech, followed by the appearance of either seizures or a severe epileptiform EEG and marked regression of receptive language which, at its purest level, is an auditory agnosia.[6] The behavioural components of the disorder are often very prominent. It is also our experience that motor impairments are very common in LKS. These motor impairments in children with epileptic encephalopathy include apraxia, dystonia and ataxia.[7] Interestingly, they are commonly cortico-steroid responsive. Treatment with cortico-steroids and multiple subpial transections for LKS is only partially successful in a proportion.[8] It is of interest that children with benign rolandic epilepsy commonly show a language processing disorder despite the benign nature of the seizure disorder. Thirteen out of twenty subjects that we studied showed such abnormalities and at school reported difficulties in reading, spelling and auditory-verbal learning.[9] Although EEs are usually regarded as causing severe regression, milder and more selective varieties exist but it may be difficult to demonstrate that they are acquired.

The importance of subclinical seizure activity, particularly subclinical status during sleep, is also well illustrated by a number of children with hemispheric lesions. Indeed clinical seizures may have stopped but they fail to make developmental progress until the seizure activity stops and this is usually by hemispherectomy. A particularly regressive variety of epilepsy we found in young children presented with right temporal dysembryoplastic lesions in which seizures were associated with rapid psychosocial regression which was, for practical purposes, never retrieved. After examining our epilepsy surgery patients, it was clear that more than half had a psychiatric disorder which fulfilled DSM criteria.[10] These include oppositional disorder, mood disorder, autism spectrum and a range of other diagnoses. This extremely high rate is quite out of proportion to that which occurs in children with other severe illnesses outside the nervous system.[11] It is commonly combined with learning impairments. It is particularly related to early onset epilepsy and therefore the assumption must be that epilepsy is largely responsible for this group of impairments.

The commonest of the regressive types of epilepsy is the syndrome of infantile spasms where the normal age of seizure onset is between 3 and 7 months and there is rapid developmental arrest and regression, particularly of visual responsiveness and communication and ultimately deviant development particularly along the autism spectrum. Overall, 75-80% of children with infantile spasms suffer mental retardation, continuing epilepsy and autism spectrum disorder.[12]

There is now accumulating evidence of temporal lobe dysfunction in the early onset severe epileptic regressions reported above. These include our right temporal lobe data linking both the dysembryoplastic lesions in the temporal lobe and the more general link between the right temporal lobe epilepsy of early onset and autism. Work on tuberous sclerosis has also indicated a higher rate of autism in association with temporal lobe tubers.[13] The localisation of the EEG abnormality in Landau-Kleffner syndrome is very commonly in the temporal lobe and autism features are commonly seen. Where Tuberous sclerosis and autism coexist, FDG PET studies point to hypometabolism in the temporal lobe.[14] We have studied event related potentials to novel stimuli in children with infantile spasms and demonstrated functional abnormality early in infantile spasms which points to a disturbance in the "wiring" within the temporal lobe which is compatible with a disorder localised to the posterior superior temporal gyrus.[15] These responses are both delayed and blunted. This type of phenomena may account for the permanent nature of most of the impairments that occur with this group of disorders despite apparently successfully stopping the seizures, i.e. that in the first six months of life the damage is permanent.

The hypotheses that follow from the above are:

  1. The combined autism/cognitive regression syndrome seen in early onset epilepsies is primarily mediated through disruption of communication pathways for language and social information in the temporal lobe.
  2. Epileptogenic foci in the R temporal lobe seem to be particularly potent in this respect.
  3. Under 6 months of age there is a high risk of this regression being permanent and this may represent a fixed defect in the dendritic pruning process.
  4. Over 6 months of age there is considerable but not guaranteed potential for recovery.
  5. Non-convulsive status epilepticus in sleep is a prominent feature of the process.
  6. This disruption can be demonstrated by auditory Event Related Potentials.
  7. If this phenomenon can be proven to exist early there is a case for emergency ascertainment and intervention.
  8. The primary aim of intervention would be to disconnect one temporal lobe from the source of the epileptic encephalopathy. This presumes that the encephalopathy prevents relocalisation or persistence of these functions in either temporal lobe.


The permanent or irreversible EE examples, therefore, include a cognitive and behavioural outcome of early onset epilepsies including infantile spasms, severe myoclonic epilepsy of infancy, hemimegalencephaly and right temporal DNETs. This includes some patients with Landau-Kleffner syndrome and benign epilepsy with centro-temporal spikes and the cognitive decline in learning that occurs in several epilepsy syndromes, particularly severe temporal lobe epilepsy and the Lennox-Gastaut syndrome. Examples of reversible encephalopathies include the immediate visual and social regression in infantile spasms, some patients with LKS and late regression in surgically treatable lesional epilepsy.

There are several implications to this discussion. In a number of types of epilepsy, there are mixed structural and functional impairments, for example, Rassmussen's syndrome and Sturge-Weber syndrome. In the acute phase of the encephalopathy, a high rate of seizure activity in sleep is very common but the chronic phase is not consistently associated with seizure activity implying a very short time window for possible intervention. The semiology of the seizure and/or the encephalopathy is often quite close, particularly in BECTS and LKS. It is uncertain whether the reduced IQ found in children with congenital hemiplegia associated with epilepsy is an EE or not. It seems likely that the motor and behavioural aspects of an encephalopathy are commonly ignored. Quite a number of EEs are steroid responsive, but often not treated. The risk of late (15 years +) psychosis particularly with temporal lobe lesions may be a different variety of encephalopathy and is not associated with a high rate of epileptiform activity at the time of the psychosis it would appear that genetic loading is quite important in developing a psychosis.

The EEs, therefore, are a crucial part of our understanding and management of childhood epilepsy with many service implications. The latter includes the need for community based early ascertainment of epilepsy. We need clinical and neurophysiological systems for the early identification of deviant development. Motor disability assessment and management involving paediatric neurology, neurodisability, behavioural and psychiatric skills, psychology, therapy, specialist nursing and multiagency coordination are required, some of them for the person's whole life. In a sense, therefore, seizures are not as important in childhood epilepsy as the accompanying encephalopathy and that EEGs, particularly sleep EEGs in children with epilepsy and cognitive and behavioural problems, may be crucial in our understanding of the pathogenesis and for management.

 
   References Top

1.Engel J Jr; International League Against Epilepsy (ILAE). A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: Report of the ILAE Task Force on Classification and Terminology. Epilepsia 2001;42:796-803.  Back to cited text no. 1    
2.Brett EM. Minor epileptic status in children. J Neurol Sci 1966;3:52-75.  Back to cited text no. 2  [PUBMED]  
3.Vargha-Khadem F, Isaccs E, van der Werf S, Wilson J. Development of intelligence and memory in children with hemiplegic cerebral palsy. The deleterious consequences of early seizures. Brain 1992;115:315-29.  Back to cited text no. 3    
4.Amess PN, Baudin J, Townsend J, Meek J Roth SC, Neville BG, Wyatt JS, et al . Epilepsy in very preterm infants: Neonatal cranial ultrasound reveals a high-risk subcategory. Dev Med Child Neurol 1998;40:724-30.  Back to cited text no. 4    
5.Arzimanoglou A, Guerrini R, Aicardi J. Aicardi's epilepsy in children. 3rd ed. Lippincott Williams and Wilkins.  Back to cited text no. 5    
6.Landau WM, Kleffner FR. Syndrome of acquired aphasia with convulsive disorder in children. Neurology 1957;7:523-30.  Back to cited text no. 6  [PUBMED]  
7.Neville BG. Steroid responsive motor disorders associated with epilepsy. In : Epilepsy and movement disorders. Guerrini R, Aicardi J andermann F, Hallet M, editors. Cambridge University Press: Cambridge; 2002.  Back to cited text no. 7    
8.Morrell F, Whister WW, Bieck TP. Multiple subpial transaction: A new approach to the surgical treatment of focal epilepsy. J Neurol 1989;70:231-9.  Back to cited text no. 8    
9.Staden U, Isaacs E, Boyd SG, Brandl U, Neville BG. Language dysfunction in children with Rolandic epilepsy. Neuropaediatrics 1998;29:242-8.  Back to cited text no. 9    
10.Taylor DC, Neville BG, Cross JH. Autistic spectrum disorders in childhood epilepsy surgery candidates. Eur Child Adolesc Psychiatry 1999;8:189-92.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.Rutter M, Graham L, Yule W. A neuropsychiatric study in childhood. Clinics in Developmental Medicine nos 35/36 SIMP Heineman Medical: London; 1970.  Back to cited text no. 11    
12.Riikonen R. Long term outcome of West Syndrome: A study of adults with a history of infantile spasms. Epilepsia 1996;37:367-72.  Back to cited text no. 12  [PUBMED]  
13.Bolton PF, Griffiths PD. Association of tuberous sclerosis of temporal lobes with autism and atypical autism. Lancet 1997;349:392-5.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.Asano E, Chugani DC, Muzik O, Behen M, Janisse J, Rothermel R, et al . Autism in tuberous sclerosis complex is related to both cortical and subcortical dysfunction. Am Acad Neurol 2001;57:1269-77.  Back to cited text no. 14    
15.Werner K, Scott R, Baldweg T, Boyd S, Neville BG. Auditory evoked potential abnormalities in infants with infantile spasms. Dev Med Child Neurol Supp 2005;101:47.  Back to cited text no. 15    




 

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