Epileptic Encephalopathies: An OverviewSonia Khan 1 ,* and Raidah Al Baradie 2

Epilepsy Res Treat. 2012; 2012: 403592.

Published online 2012 November 20. doi:  10.1155/2012/403592

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3508533/

Epileptic encephalopathies are an epileptic condition characterized by

epileptiform abnormalities associated with progressive cerebral

dysfunction. In the classification of the International League Against

Epilepsy eight age-related epileptic encephalopathy syndromes are

recognized. These syndromes include early myoclonic encephalopathy and

Ohtahara syndrome in the neonatal period, West syndrome and Dravet

syndrome in infancy, myoclonic status in nonprogressive encephalopathies,

and Lennox-Gastaut syndrome, Landau-Kleffner syndrome, and epilepsy

with continuous spike waves during slow wave sleep in childhood and

adolescences. Other epileptic syndromes such as migrating partial seizures

in infancy and severe epilepsy with multiple independent spike foci may be

reasonably added. In this paper, we provide an overview of epileptic

encephalopathies including clinical neurophysiological features, cognitive

deterioration, and management options especially that these conditions

are generally refractory to standard antiepileptic drugs.

Epileptic encephalopathy is defined as a condition in which epileptiform abnormalities are believed to contribute to the progressive disturbance in cerebral function, but this definition may be ambiguous [1]. The report of the International League Against Epilepsy (ILAE) Task Force on classification and terminology includes 8 syndromes under epileptic encephalopathies: early myoclonic encephalopathy, Ohtahara syndrome, West syndrome, Dravet syndrome, myoclonic status in nonprogressive encephalopathies, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, and epilepsy with continuous spike waves during slow-wave sleep [1]. To these syndromes, the migrating partial seizures in infancy and severe epilepsy with multiple independent spike foci may be reasonably added [2].

A common feature is that these disorders are usually refractory to standard antiepileptic drugs (AEDs) [3]. As a result, more aggressive use of AEDs considered effective in suppressing interictal epileptiform discharges (e.g., benzodiazepines, valproic acid, and lamotrigine), immunomodulatory therapies (e.g., corticosteroids, intravenous immunoglobulin (IVIG), and plasmapheresis), ketogenic diet, and surgical options is often considered [3]. In this paper, epileptic encephalopathies will be dealt with in the following concept: a particular group of usually age-related and extremely intractable epilepsies with characteristic generalized minor seizures and massive epileptic EEG abnormalities, both of which cause stagnation or deterioration in mental and cognitive functions in addition to the preexisting developmental deficit due to organic brain damage [1–3].

Early Infantile Epileptic Encephalopathy (Ohtahara Syndrome)

Ohtahara syndrome is the earliest form of the age-dependent neonatal epileptic encephalopathies and was first described by Ohtahara and colleagues in 1976 [4]. It is often defined as “Early Infantile Epileptic Encephalopathy (EIEE) with burst-suppression” or “early myoclonic encephalopathy (EME)” [4]. Symptoms appear within the first 3 months of birth and usually within the first 10 days. Often symptoms will appear with the first few hours after birth, and in some cases mothers have felt possible seizures activity in utero. Onset is acute in previously normal children [4]. Main seizure pattern is tonic spasms; other patterns include tonic/clonic, clonic, myoclonic, atonic, absences, partial, complex partial (with or without secondary generalization), gelastics, and Jacksonians. Seizures can appear in clusters or singly and patterns are likely to change with time. It is not uncommon for patterns to reappear at a later stage [4]. EEG pattern is characterized as burst suppression during both waking and sleeping states. This means that the EEG (electroencephalogram) tends to show periods of very little electrical brain activity followed by a burst of high spiky activity before returning to very low activity again. Sometimes, one side of the brain seems to be affected more than the other [5]. Seizures are intractable; although in some cases they can be improved through treatment. In general prognosis is poor with severe psychomotor retardation and significant learning difficulties. Frequently cases will progress to West syndrome or partial epilepsy (usually during infancy). Later a much smaller number develops to Lennox-Gastaut syndrome. Psychomotor development may be slightly better if the infants do not develop West or Lennox-Gastaut syndrome. Half of the children are likely

to die in infancy or childhood [5, 6]. Although the disorder in incurable, much can be done to improve the lives not only of the children but also of the families. Seizure control is the main aim and will be attempted either through optimized dosages of anticonvulsants such as vigabatrin (Topamax), Dilantin, Zonegran, and Phenobarbitone, or through steroid therapies using ACTH and Prednisone. AEDs can be taken in either mono- or polytherapies. The quest for seizure control can be a slow and frustrating process. There is also the possibility of utilizing such treatments as the ketogenic diet, the VNS, or more invasive surgery, such as a partial resection or complete hemispherectomy. Physiotherapy and occupational therapies can help improve motor skills, while hippotherapy can help improve general mobility, strength, and endurance [7].

 Lennox-Gastaut Syndrome LGS

Childhood epileptic encephalopathy, or Lennox-Gastaut syndrome (LGS), is a devastating pediatric epilepsy syndrome constituting 1–4% of childhood epilepsies. The syndrome is characterized by multiple seizure types; mental retardation or regression; abnormal findings on electroencephalogram (EEG), with paroxysms of fast activity and generalized slow spike and wave discharges (1.5–2 Hz) (Figure 4). The most common seizure types are tonic-axial, atonic, and absence seizures, but myoclonic, generalized tonic-clonic, and partial seizures can be observed (see clinical presentation). An EEG is an essential part of the workup for LGS. Neuroimaging is an important part of the search for an underlying etiology. LGS can be classified according to its suspected etiology as either idiopathic or symptomatic. Patients may be considered to have idiopathic LGS if normal psychomotor development occurred prior to the onset of symptoms, no underlying disorders or definite presumptive causes are present, and no neurologic or neuroradiologic abnormalities are found. In contrast, symptomatic LGS is diagnosed if a likely cause can be identified as being responsible for the syndrome. Population-based studies have found that 70–78% of patients with LGS have symptomatic LGS. Underlying pathologies in these cases include encephalitis and/or meningitis, tuberous sclerosis, brain malformations (e.g., cortical dysplasias), birth injury, hypoxia-ischemia injury, frontal lobe lesions and trauma. Overall, LGS accounts for 1–4% of patients with childhood epilepsy but 10% of patients with onset of epilepsy when younger than 5 years. The prevalence of LGS in Atlanta, GA, USA, was reported as 0.26 per 1000 live births. LGS is more common in boys than in girls. The

prevalence is 0.1 per 1000 population for boys, versus 0.02 per 1000 population for girls (relative risk, 5.31). The mean age at epilepsy onset is 26–28 months (range, 1 d to 14 y). The peak age at epilepsy onset is older in patients with LGS of an identifiable etiology than in those whose LGS has no identifiable etiology. The difference in age of onset between the group of patients with LGS and a history of West syndrome (infantile spasm) and those with LGS without West syndrome is not significant. The average age at diagnosis of LGS in Japan was 6 years (range, 2–15 y). Epidemiologic studies in industrialized countries (e.g., Spain, Estonia, Italy, and Finland) have demonstrated that the proportion of epileptic patients with LGS seems relatively consistent across the populations studied and similar to that in the United States. The prevalence of LGS is 0.1–0.28 per 1000 population in Europe. The annual incidence of LGS in childhood is approximately 2 per 100,000 children. Among children with intellectual disability, 7% have LGS, while 16.3% of institutionalized patients with intellectual disability have LGS. Long-term prognosis overall is unfavorable but variable in LGS. Longitudinal studies have found that a minority of patients with LGS eventually could work normally, but 47–76% still had typical characteristics (mental retardation, treatment-resistant seizures) many years after onset and required significant help (e.g., home care, institutionalization). A variety of therapeutic approaches are used in LGS, ranging from conventional antiepileptic agents to diet and surgery. Unfortunately, much of the evidence supporting these approaches is not robust, and treatment is often ineffective. The medical treatment options for patients with LGS can be divided into the following 3 major groups: The medical treatment options for patients with LGS include the use of antiepileptic drugs such as valproic acid and benzodiazepines such as clonazepam, nitrazepam and clobazam, vigabatrin, zonisamide, lamotrigine, topiramate and rufinamide proven effective by double-blind placebo-controlled studies (e.g., lamotrigine, topiramate, felbamate, and rufinamide). The ketogenic diet may be useful in patients with LGS refractory to medical treatment. Surgical options for LGS include corpus callosotomy, vagus nerve stimulation, and focal cortical resection [18–21].

Figure 4

EEG in Lennox-Gastaut syndrome with paroxysms of fast activity and generalized slow spike and wave discharges (1.5–2 Hz) (arrows).

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3508533/

EVOLUCIÓN DEL SÍNDROME GASTAUT EN LA EDAD ADULTA

Sara Rodríguez-Rodríguez, Javier Salas-Puig, Juan C. Álvarez-Carriles, Teresa Temprano-

Fernández,

Celia Antón González, Alberto García-Martínez

http://www.neurologia.com/pdf/Web/5205/bf050257.pdf

Lennox-Gastaut Syndromeby Edwin Trevathan, M.D., M.P.H.Dr. Trevathan is Associate Professor of Neurology & Pediatrics at Washington University School of Medicine and Director of the Pediatric Epilepsy Center at St. Louis Children's Hospital .

http://neuro.wustl.edu/patientcare/clinicalservices/pediatricepilepsycenter/

patientfamilyphysician/lennoxgastautsyndrome/

_________________________________________________________________________

Hypsarrhythmia, which is an EEG pattern, and infantile spasms do not have an absolutely

constant relationship and are not interchangeable terms. Typical and modified hypsarrhythmia

occurs in two thirds of the EEGs of infants with infantile spasms, whereas the remaining one

third show generalized slow spike wave discharges (described below).[86] Besides various

pathologic conditions associated with a severe cortical insult, hypsarrhythmic pattern is often

encountered in infants suffering from tuberous sclerosis or genetically determined metabolic

conditions such as non-ketotic hyperglycenemia.[87]Children with Aicardi's syndrome (agenesis

of corpus callosum, mental retardation, infantile spasms, choreoretinal lesions) show a

markedly asymmetric hypsarrhythmic pattern with virtually complete interhemispheric

asynchrony of a suppression-burst-like background.[88]

The hypsarrhythmic pattern is a maturational pattern most commonly

expressed between the ages of 4 and 12 months. As the infant grows older,

beyond the age of 2 years, it is rare to encounter typical hypsarrhythmia,

although infantile spasms may still continue. Hypsarrhythmia is replaced by

different EEG patterns such as a diffusely slow tracing, slow spike wave

discharges as seen with Lennox-Gastaut syndrome, IMSD, and, rarely, a

normal tracing.

Adrenocorticotrophic hormone therapy often has a dramatic effect on

infantile spasms as well as the hypsarrhythmic EEG pattern, which may

virtually disappear in a matter of a few days to a few weeks after initiation of

therapy. However, despite these clinical and EEG improvements, the long-

term neurocognitive development remains subnormal.

Lennox-Gastaut syndrome (childhood epileptic encephalopathy) is another

common form of SGE manifesting in early childhood with developmental

delay, neurocognitive deficits, and frequent generalized seizures including

tonic seizures. The EEG shows generalized, slow spike wave discharges

(1.5 to 2.5 Hz) superimposed on abnormally slow background activity (Fig.

24).[89,90] It is important to distinguish these EEG findings from those seen with

primary generalized epilepsy where the background activity is normal for age

and the generalized spike wave discharges are usually of faster frequency (3

to 5 Hz). Although appearing widespread and bilaterally synchronous, the

slow spike wave activity is usually higher in amplitude over the anterior head

regions (in 90% of patients); less commonly the amplitude is highest over

the occipital areas. The duration of the paroxysms varies widely from

isolated complexes to almost continuous slow spike wave activity, commonly

without an identified behavioral or awareness change. Hence, the slow spike

wave activity in Lennox-Gastaut syndrome is considered an interictal

pattern, although it must be understood that subtle changes of behavior in

retarded and uncooperative children are hard to recognize.

Figure 24 EEG of a 16-year-old child with mental retardation and tonic seizures, showing slow spike wave activity superimposed on a slow background.

When one encounters prolonged episodes of slow spike wave activity lasting

several seconds to minutes, the interpretative challenge is to decide if these

electrographic events represent an ictal pattern (atypical absences or

nonconvulsive status) or they simply represent more pronounced interictal

pattern. A history of similar long episodes of slow spike wave activity in one

or more previous EEGs would support an interictal finding. Also, giving a

small dose of lorazepam intravenously will have no affect on an interictal

pattern but will usually abort an ictal pattern, at least temporarily.

If a tonic seizure is recorded during the EEG of a patient with Lennox-

Gastaut syndrome, the characteristic finding is an electrodecrement or

"flattening" lasting several seconds. In addition, high-frequency rhythmic

activity in the alpha-beta frequency range commonly occurs during the

electrodecrement.

Another distinctive EEG pattern of a symptomatic generalized epilepsy

syndrome is IMSD characterized by the presence of three or more

independent and noncontiguous foci of spike or spike wave activity with at

least one focus in one hemisphere (Fig. 25).[91,92] As expected, the

background activity is invariably disorganized and slow in frequency.

Figure 25 EEG of a 7-month-old child, showing independent multifocal spike discharges.

Figure 25.

EEG of a 7-month-old child, showing independent multifocal spike discharges.

There is a close correlation between the three EEG patterns of

hypsarrhythmia, slow spike wave, and IMSD associated with SGE. All of

them are associated with diffuse or multifocal cerebral abnormalities and

have similar clinical correlates of mental retardation, multiple and medically

intractable seizure types, and a high incidence of neurologic deficits.[91] Furthermore, serial studies over time may show a change of one pattern

to the other in the same patient. Also, in the same EEG study, more than

one of these patterns may coexist (e.g., IMSD during wakefulness and slow

spike wave activity during sleep). It is very well known that at least 20% of

infants with hypsarrhythmia may show slow spike wave usually by the

second to fourth year of life. Both of these patterns may further change to

IMSD in early childhood. Thus, these three EEG patterns have a common

physiopathologic basis and are probably dependent more on cerebral

maturation than on a particular kind of cerebral pathologic process.[91]Hypsarrhythmia is usually seen in the later half of the first year of life in

response to a cerebral insult prenatally, perinatally, or in the immediate

postnatal period. It rarely results from cerebral insults after the second year

of life. The slow spike wave pattern associated with Lennox-Gastaut

syndrome is commonly observed between the ages of 2 and 5 years. The

IMSD pattern is seen commonly throughout the first decade of life.

A unique EEG pattern of GPFA is seen predominantly during sleep

consisting of high-frequency, 12 to 25 Hz repetitive spike discharges

occurring synchronously over both hemispheres (Fig. 26).[93] It is associated

most commonly with SGE (usually Lennox-Gastaut syndrome) but it may

rarely occur also with PGE or in patients with focal seizures, particularly with

a frontal lobe focus. This EEG pattern is usually not associated with an

obvious clinical change, although subtle tonic seizures (opening of eyes and

jaw, eye deviation upward) may be missed. In rare patients with PGE and 3

Hz generalized spike wave, the awake EEG may appear rather benign but

the presence of GPFA during sleep is a warning that more severe

encephalopathy may be present. In such patients, motor seizures are

common and the disorder is likely to persist in adulthood.[94]

Figure 26 EEG of an 11-year-old patient with Lennox-Gastaut syndrome, showing generalized paroxysmal fast activity (B).

When one encounters prolonged episodes of slow spike wave activity lasting

several seconds to minutes, the interpretative challenge is to decide if these

electrographic events represent an ictal pattern (atypical absences or

nonconvulsive status) or they simply represent more pronounced interictal

pattern. A history of similar long episodes of slow spike wave activity in one

or more previous EEGs would support an interictal finding. Also, giving a

small dose of lorazepam intravenously will have no affect on an interictal

pattern but will usually abort an ictal pattern, at least temporarily.

If a tonic seizure is recorded during the EEG of a patient with Lennox-

Gastaut syndrome, the characteristic finding is an electrodecrement or

"flattening" lasting several seconds. In addition, high-frequency rhythmic

activity in the alpha-beta frequency range commonly occurs during the

electrodecrement.

EG IN STATUS EPILEPTICUSStatus epilepticus (SE) is usually defined as continuous seizure activity persisting for more than 30 minutes or more than one sequential seizure without full recovery of consciousness between seizures. A very common reason for ordering an emergency EEG is for the diagnosis and management of SE. A simplified classification of SE includes: (1) generalized convulsive status, characterized by motor seizures with loss of consciousness; (2) simple partial or focal status, characterized by focal motor seizures repeating frequently or epilepsia partialis continua with the patient remaining fully conscious; and (3) nonconvulsive status (NCSE) characterized by a variable alteration of consciousness with minimal or no motor activity.

NCSE poses many challenging nosologic, diagnostic, and therapeutic problems. NCSE includes: (1) absence status, occurring in the setting of generalized epilepsy (idiopathic or symptomatic) and (2) complex partial status associated with focal or partial epilepsy of frontal or temporal onset. In both types, the patient may present with mental status alteration (e.g., slowness in behavior and mentation, confusion, and, rarely, stupor or coma). Then, there are patients who after treatment of generalized convulsive status continue to be obtunded or comatose and show epileptiform discharges in their EEG. These patients are often designated as having "subtle" SE or lumped under NCSE.

It is relatively easy to diagnose NCSE associated with focal epilepsy when there are frequent electrographic focal seizures with an ictal EEG pattern that evolves over time with change in the amplitude, frequency, and spatial distribution. However, it is quite common for the ictal EEG pattern associated with complex partial status associated with focal epilepsy to be generalized spikes or sharp waves repeating at 1 to 6 Hz frequency. Such a generalized EEG pattern is similar to that seen in typical absence status associated with idiopathic generalized epilepsy (absence

epilepsy) and atypical absence status in children with secondary generalized epilepsy of the Lennox-Gastaut type. To complicate the situation even further, patients with Lennox-Gastaut syndrome interictally have generalized 1.0 to 3.0 cps spike wave discharges that may be very frequent, and one needs to decide if they represent an ictal pattern (hence atypical absence status) or simply represent a prominent interictal pattern. Some waxing or waning of such generalized epileptiform discharges may not help in the distinction because this may be simply related to state changes.

Some helpful criteria are proposed by Young et al[122] in patients who show almost continuously occurring generalized, nonevolving epileptiform discharges in their EEGs, including repetitive generalized or focal epileptiform discharges (spikes, sharp waves, and spike waves) that repeat at a rate faster than three per second, very likely represent an ictal pattern. Such repetitive discharges at a frequency slower than three per second are likely to be ictal if significant clinical and/or EEG improvement is demonstrated following small doses of intravenous lorazepam or diazepam. Rhythmic sinusoidal waves of any frequency (ranging from β to δ frequency) may represent an ictal pattern if there is an evolving pattern at the onset (increasing amplitude and/or decreasing frequency) or a decrement pattern at the termination (decremental amplitude or frequency) or postdischarge slowing or voltage attenuation.

In a patient with obtundation or mental status change of recent onset, an EEG is indicated to rule out NCSE. If repetitive generalized epileptiform discharges are recorded in the EEG, 1 to 2 mg of lorazepam or 5 to 10 mg of diazepam are injected intravenously while the EEG is running. A marked clinical improvement of obtundation and disappearance of generalized paroxysmal activity in the EEG would strongly support the diagnosis of NCSE (Figs. [36] and [37]). Such a rewarding experience is most common in typical absence status and less common in other forms of NCSE.

Reviewing the previous EEG and obtaining follow-up EEG studies also provide a helpful distinction between ictal and interictal basis for the repetitive generalized spike wave discharges seen in children with Lennox-Gastaut syndrome. A period of frequent repetitive generalized spike wave discharges associated with clinical deterioration of mental status is more likely an episode of atypical absence status, particularly if the previous EEGs or follow-up EEGs display dramatically fewer epileptiform abnormalities.

"Subtle" SE commonly includes patients who had a known episode of convulsive or generalized tonic-clonic status, brought under control by intravenous antiepileptic therapy (e.g., phenytoin, lorazepam, and barbiturates), but continue to remain obtunded or comatose without significant motor activity. EEG of such patients often show repetitive discharges, which may include lateralized periodic discharges (e.g., PLEDs or BiIPLEDS) or generalized periodic discharges (PEDs). Some epileptologists[123] are of the opinion that progressive sequential EEG changes occur during generalized convulsive SE with an "intermediary" pattern of PEDs and PLEDs (unilateral or bilateral) before disappearance of all paroxysmal EEG activities, and that the presence of these "intermediary" EEG patterns necessitate further aggressive therapeutic measures (e.g., inducing pentobarbital coma, etc.). Such views are not universal. Many, on the other hand, consider PED and PLED patterns observed during the course of convulsive status not an ictal pattern but suggestive of a severe epileptic encephalopathy reflective of a neuronal dysfunction from underlying brain damage.[124]

Refractory SE is usually treated by continuous intravenous anesthesia maintained by pentobarbital, propofol, or medazolam. The dose is regulated such as to control all clear-cut clinical or electrographic seizures and to maintain a suppression-burst pattern in the EEG. Therefore, continuous bedside EEG is monitored. There is no consensus as to the duration of

"burst" and "flat" periods for optimal dosing. Most consider that establishing and maintaining any degree of suppression-burst pattern is adequate.

One final note of caution is that focal motor seizures including epilepsia partialis continua may not show ictal changes in the EEG because of the limited size of neuronal tissue involved during the epileptic seizure or because the ictal pattern in the EEG may be obscured by artifacts. Careful review of the EEG using different montages (especially a transverse bipolar montage going through the midline electrodes) and use of appropriate muscle filters may reveal a low-amplitude ictal pattern.

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Figure 26 EEG of an 11-year-old patient with Lennox-Gastaut syndrome, showing generalized paroxysmal fast activity (B).

https://www.thieme-connect.com/ejournals/html/10.1055/s-2003-40750

EG in Lennox-Gastaut syndrome with paroxysms of fast activity and generalized slow spike and wave discharges (1.5–2 Hz) (arrows).

________________________________________________________________________________

2. SINDROME DE WEST

West syndrome usually occurs in the first year of life and consists of the triad of infantile spasms, developmental deterioration, and a hypsarrhythmia pattern on EEG [11]. The epileptic spasms are brief, generalized seizures involving extension and/or flexion axially, and of the extremities. An individual spasm lasts for seconds, often longer than typical myoclonic seizures, though not as long as most tonic seizures. The spasms may be subtle and may be isolated at onset, typically clustering later in the course. Several clusters per day, particularly in drowsiness, are characteristic [11, 12]. 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 (Figure 2). The ictal EEG typically reveals a generalized slow wave followed by a diffuse voltage attenuation (electro-decrement) (Figure 3), which may associate with a spasm or be only electrographic (without clinical correlation) [12]. No clear etiology is found in approximately 40% of cases. There is a broad range of potential causes, including cerebral

malformations, infection, hemorrhage, hypoxic-ischemic injury, metabolic disorders, and genetic conditions, such as Down syndrome [12, 13]. Variation in studying methodologies prohibits a clear recommendation for first line treatment; however, ACTH and vigabatrin are usually used in practice. Corticosteroids may be less efficacious than ACTH, although they are effective. Vigabatrin may be more efficacious in tuberous sclerosis. Other agents that are efficacious include valproate, levetiracetam, topiramate, zonisamide, lamotrigine, and benzodiazepines [11]. The ketogenic diet is helpful in most cases [12]. Focal cortical resection or hemispherectomy may be considered for cases that are lesional and medically intractable [11–13]. Development remains unaffected only in a minority. Most children experience slowing, plateauing, or regression of their developmental trajectory. The developmental prognosis partially depends on the etiology. No specific AED has been shown to affect long-term developmental outcome. An extensive literature review revealed that 16% had normal development, and 47% had continued seizures at an average followup of 31 months. When classified by etiology, normal development was described in 51% of cryptogenic cases versus only 6% of symptomatic cases. Approximately 17% of cases evolved into Lennox-Gastaut syndrome [12].

Figure 2Hypsarrhythmia, the typical interictal EEG finding, consists of a disorganized pattern with asynchronous, very high amplitude slowing and frequent multifocal spike and sharp wave discharges (arrows).

Figure 3The ictal EEG in West syndrome typically reveals a generalized slow wave followed by diffuse voltage attenuation (electrodecrement), which may associate with a spasm or be only electrographic without clinical correlate (arrows).

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3508533/

Electroencefalograma durante la fase REM del sueño. El diagnóstico de síndrome de West se realiza mediante la detección de hipsarritmias en el EEG, desapareciendo estas durante esta fase del sueño.

http://es.wikipedia.org/wiki/S%C3%ADndrome_de_West

Alteraciones del EEG

Los hallazgos electroencefalográficos más específicos del SW son el enlentecimiento y la

desorganización de la actividad eléctrica cerebral, en forma de trazado caótico con mezcla de

puntas y ondas lentas independientes. A este patrón característico se le denomina hipsarritmia.

Wikipedia

TEP. Las áreas en rojo indican alta actividad cerebral http://es.wikipedia.org/wiki/S%C3%ADndrome_de_West

Fig. 5. MRI showing (a) T2WI periventricular white matter hyperintensities, (b) cerebral

atrophy.

http://www.sciencedirect.com/science/article/pii/S0387760404001135

http://www.chp.edu/CHP/infantile+spasms

3.down síndrome

Epilepsy in adult patients with Down syndrome: a clinical-video EEG studyEpileptic

Disorders. Volume 13, Number 2, 125-32, Juin 2011Aglaia Vignoli, Elena Zambrelli, Valentina Chiesa, Miriam Savini, Francesca La Briola, Elena Gardella, Maria Paola Canevini

http://www.epilepticdisorders.com/e-docs/00/04/67/E4/document_article.phtml?cle_video_associee=288773

________________________________________________________________________

Down Syndrome and Epilepsy

By A. Nascimento and C. Ortez-Gonzalez

DOI: 10.5772/18314

Medicine » Medical Genetics » "Genetics and Etiology of Down Syndrome", book edited by Subrata Dey, ISBN 978-953-307-631-7, Published: August 29, 2011 under CC BY-NC-SA 3.0 license

1. Introduction

Down syndrome (DS) is associated with many neurological complications including cognitive deficits,

early-onset dementia -which resembles Alzheimer’s disease- and seizures. Although seizures and

epilepsy were not mentioned in the original description of DS (Down, 1886) the prevalence of seizures

in individuals with DS is now known to be higher than in the general population, but lower than in

patients with some other types of mental retardation (Corbett et al., 1975). Reported rates of epilepsy in

DS range from 1 to 13% (see table 1) (Tatsumo et al., 1984). Individual series are difficult to compare

because of differences in inclusion criteria and study populations. The increased seizure susceptibility in

DS has been attributed to inherent structural and molecular anomalies of the brain or to associated

medical complications, such as cardiovascular abnormalities and recurrent infections.

Medical interventions in DS have resulted in increased longevity, with estimated life expectancy of

people with DS in developed countries increasing from an average of 12 years in the 1940s to an average

of 57,8 years for women and 61,1 years for men (Bittles et al., 2007). Epilepsy onset in people with

DS is age-specific; therefore, because certain complications will arise in childhood and

others in adulthood, their occurrence is relevant to paediatric and adult neurologists. This

chapter will provide a critical overview of epilepsy in DS.

Authors No. of patients Percentage (%)

Romano et al. 113 13.00

Pueschel et al. 405 8.10

Stafstrom et al. 737 6.40

TABLE 1.

Reported incidence of seizures in patients with Down syndrome in the 1990s

2. Epidemiology

Patients with DS show a higher incidence of febrile and non febrile seizures than non-DS individuals.

Seizures occur in a bimodal distribution in DS, with 40% of individuals first developing seizures before

1 year of age and another 40% having an onset in their thirties or later (Pueschel et al., 1991). Boys tend

to have an earlier age onset, regardless of seizure type, although this may reflect the general male

predominance in the infantile spasm group aged less than 1 year at onset. The prevalence of epilepsy

increases with age and reaches 46% in those over 50. In general, about 8% of patients with DS have

seizure disorders: 47% of them develop partial seizures, 32% infantile spasms and 21% generalized

tonic-clonic seizures.

3. Pathophysiology

The mechanisms underlying the increased seizure susceptibility in DS have not yet been completely

elucidated. Seizures in infancy have been linked to inherent structural brain abnormalities, such as fewer

inhibitory neurons, abnormal cortical lamination, persistent fetal dendritic morphology, and

underdeveloped synaptic profiles (Kemper et al., 1988). Concentrations of carbonic anhydrase II, which

potentially increases seizure susceptibility, are upregulated in the brains of young children with DS and

in a mouse model of the disorder. (Palminello et al., 2008) (Tatsuno et al., 1984).

Altered membrane potassium permeability, which may lead to a decreased voltage threshold for spike

generation, smaller hyperpolarization following spikes, or increased action potential duration, has also

been documented in patients with DS. Indeed, in the mouse model of trisomy 16, the experimental

model of DS, a rapid spike rise and fall was recorded from the dorsal root ganglia neurons (Scott et al.,

1981)

In DS there is an overexpression of the 21st chromosome. Many enzymes that are encoded on the extra

21st chromosome are known to be actively transcribed, which results in overexpression of the enzymes,

overconsumption of enzymatic substrates and overproduction of metabolic end-products. For example,

the superoxide dismutase-1 gene on the 21st chromosome is approximately 50% overexpressed, which

decreases levels of superoxide (the enzyme’s substrate) and increases levels of hydrogen peroxide (the

enzyme’s metabolite, end product or output). These primary consequences of genetic overexpression

may then produce secondary metabolic adaptations as homeostatic systems attempt to compensate. Thus,

decreased levels of superoxide might alter levels of nitric oxide, peroxynitrate, and nitric oxide

synthetase, or they may impair aromatic hydroxylation enzymes and thereby impair neurotransmitter

synthesis. For another example, increased levels of hydrogen peroxide might induce glutathione

peroxidase production and thereby increase selenium requirements. Such genetically driven enzymatic

and metabolic disturbances may help explain why individuals with DS appear to be more likely to

develop various forms of epilepsy and intractable epilepsy (Smigielska-Kuzia et al. 2009).

Seizures can also be regarded as complications of congenital cardiovascular anomalies in children with

DS (Marsh et al., 2009). Moyamoya’s disease is a rare vascular complication which seems to occur with

a higher frequency in children with DS than in those without it. Moyamoya’s disease is characterised by

a chronic occlusive cerebrovascular alteration of unknown pathogenesis in which there is progressive

stenosis of the supraclinoid portions of the internal carotid arteries. Associated with this stenosis is the

formation of convoluted arterial collaterals at the base of the brain. Although the presentation of

Moyamoya’s disease in adults is haemorrhagic, the presenting symptoms in children are typically

ischaemic, with a fixed unilateral neurological deficit or alternating hemiplegia. Some children with

Down’s syndrome who have Moyamoya’s disease also develop seizures or involuntary movements.

(Nascimento et al. 2006).

Adult-onset seizures in the absence of dementia are rare in people with DS but might become more

frequent in the future because of the extension of the lifespan of people with the disorder. Late-onset

seizures in people with DS seem to be associated with a propensity to dementia resembling Alzheimer’s

disease. The cause of seizures in adults with DS who do not have dementia is not yet clear (Puri, 2001)

Once seizures occur in the course of dementia in patients with DS, functional decline is often rapid, to

the point where floor effects preclude further cognitive testing. Seizures are common in people with

early-onset Alzheimer’s disease associated with genetic defects, including mutations that result in

overexpression of amyloid-β, such as those involving presenilin 1 genes. Animals with overexpression

of the APP gene have a lower threshold to induced seizures. High concentrations of amyloid-β caused by

APP overexpression result in epileptiform activity in vivo, even in the absence of neurodegeneration,

suggesting that these high concentrations are a direct cause of epilepsy. (T. Llot 2010).

4. Clinical and electrophysiological features

Epilepsy in DS showed a bimodal distribution; in the younger age group, infantile spasms and tonic-

clonic seizures with myoclonus are the main finding, whereas older patients often have partial simplex

or partial complex seizures as well as tonic-clonic seizures (Pueschel et al., 1991).

4.1. SEIZURES IN INFANCY AND CHILDHOOD

It is currently known that there is a higher incidence of seizures, particularly infantile spasms, in DS

compared to the general population. Few children with DS have their first epileptic attacks after the age

of 3. These patients often have partial simplex or partial complex seizures as well as tonic-clonic

seizures.

Infantile spasms are an age-dependent epilepsy that most frequently appears in the first year of life, with

ictal episodes consisting of spasms that usually occur in clusters (Dulac et al., 1994). There is a

characteristic chaotic and high-voltage interictal electroencephalography (EEG) pattern, which, when

typical, is called hypsarrhythmia. West’s syndrome is the term employed when such spasms are

concomitant with delayed psychomotor development and EEG hypsarrhythmia. It has been reported that

6.4% of 737 patients with DS had epilepsy, and 12.8% of epileptic patients with DS had West syndrome.

In addition, it has been reported that 8.1% of 405 patients with DS had epilepsy in childhood, and 18%

of the epileptic patients were diagnosed as having infantile spasms.

Infantile spasms, which often indicate poor prognosis in the general population, do not seem to be

associated with difficulties in long-term seizure control in children with DS. However, in children with

DS who have infantile spasms, there seems to be a substantial association between treatment and

developmental quotient as well as progression to autistic features. There are no long-term studies of the

intellectual outcome of children with DS in whom infantile spasms were successfully controlled. In our

experience, patients with Down syndrome with infantile spasms and abnormal but non-hypsarrhythmic

EEG may have poor disease progression (figure 1 a and b& Figure 2 a and b), with persistence of

seizures and severely impaired psychomotor development (Nascimento & Ortez 2009).

FIGURE 1.

EEG of an 8m21d boy with DS. a) In a sleep stage, no physiological graphoelements were observed and

there were very frequent multifocal paroxysms in the form of high-voltage spike-wave complexes;

paroxistic alterations persisted during the waking stage. b) There was an electroclinical episode

consisting of the emergence of a high-voltage spike-wave complex clinically accompanied by extension

and abduction of the upper limbs and a slight extension of the lower limbs. Note the contraction

recorded over both deltoid muscles.

FIGURE 2.

EEG of a 3-year-old girl with DS initially affected by West’s syndrome who then evolved to Lennox-

Gastaut syndrome. a) Tonic seizure: Ictal electroencephalography (EEG) shows a diphasic, mid-voltage

slow wave, followed by recruiting low-voltage fast activity, replaced by spike and polyspike and wave

discharges; tonic contraction was recorded over both deltoid muscles. b) Waking stage: brain activity

constituted by an association of delta and theta waves and low-voltage beta rhythms, with a diffuse

distribution. Frequent focal paroxysms were observed in the form of spikes and complex spike-waves of

irregular medium and high amplitude, located independently in the frontal and parieto-occipital regions

of both hemispheres.

There is a chance that DS in association with West’s syndrome may evolve to Lennox-Gastaut syndrome

(LGS). LGS has classically been defined by the triad of drug-resistant epilepsy with multiple seizure

types, typically diurnal atonic as well as atypical absences, and mainly nocturnal tonic seizures;

electroencephalography abnormalities, principally diffuse slow spike-wave or polyspike-wave

discharges during wakefulness and bursts of diffuse fast rhythms at 10–20 Hz during sleep; mental

deterioration of variable severity as well as behavioural disturbances may also occur (Gastaut et al.,

1966; Dulac & N’Guyen, 1993). A series of DS patients with late onset LGS has been described, having

a higher frequency of reflex seizures and more cognitive impairment ( Figure 3). (Ferlazzo et al., 2009)

FIGURE 3.

year-old boy. Tonic seizure triggered by a sudden noise (black arrow). Note the marked tonic contraction

recorded over both deltoid muscles. Ictal electroencephalography (EEG) shows a diphasic, mid-voltage

slow wave, followed by recruiting low-voltage fast activity, replaced by spike and polyspike and wave

discharges, predominant over anterior leads, lasting for about 10 s. Electrocardiography shows an

increased heart rate during seizure. Zoom: detail of the ictal discharge recorded over the vertex

derivation, where muscular artifacts are less evident. (Ferlazzo et al. 2009)

Why do some infants with DS develop infantile spasms, whereas others with the same disorder do not?

The cause has never been fully understood. Naming DS as the ‘‘cause’’ of the infantile spasms may,

therefore, be at best inaccurate and at worst totally misleading, suggesting that we understand why the

disorder has arisen in that particular child when DS has merely predisposed the child to infantile spasms.

Only a few infants with Down syndrome develop infantile spasms, yet Down syndrome is accepted

(Eisermann et al., 2003) as a ‘‘cause,’’ and frequently such infants are not given a brain scan. As a

result, other authors have proposed adopting a terminology that distinguishes the underlying etiology

from the cause. According to this scheme, we use the term proven etiology to refer to any identified

underlying neurological disorder, and employ cause as a more specific term that may be a complex and

less well-understood sequence or combination of events. Perhaps because of the many different

diagnoses that can be made in these infants and the developmental outcomes associated with them,

classification into diagnostic groups has been commonly attempted. (Osborne et al., 2010)

The most frequent nomenclature has classified cases as either symptomatic, cryptogenic, or idiopathic,

but unfortunately there is no clear definition of these terms (Lux & Osborne, 2005). “Symptomatic” is

often used to indicate that a prior disorder exists. “Cryptogenic” is often used to mean that there must be

an etiology, but that one has not been found. A recent report of the International League Against

Epilepsy (ILAE) Commission on Classification and Terminology also suggests that the terms idiopathic,

symptomatic, and cryptogenic should be replaced (Berg et al., 2010). It has suggested broad etiologic

categories: genetic, structural–metabolic, and unknown.

4.2. SEIZURE IN ADULTHOOD

The prevalence of epilepsy in DS has increased with longevity, reaching 46% in those older than 50.

Descriptions of late-onset epilepsy in the absence of dementia in DS patients (LOMEDS) are rare, but

since life expectancy of DS patients has markedly increased, LOMEDS may be more frequent than

currently acknowledged and should be considered in the differential diagnosis of adult-onset myoclonic

epilepsies. The electroclinical features are myoclonic jerks on awakening and generalised tonic-clonic

seizures, with generalised spike and wave on EEG, and progressive dementia (Moller et al., 2002).

Familial Alzheimer’s dementia (FAD) and progressive myoclonic epilepsy (Unverricht–Lundborg type)

are both linked to chromosome 21. In an interesting study of 68 DS adults, it was found that among

those with a history of seizures, individuals aged over 45 years were significantly more likely to develop

AD than those under 45, and up to 84% of demented individuals with DS developed seizures. It suggests

that late-onset epilepsy in DS is associated with AD, while early-onset epilepsy is associated with an

absence of dementia (Menéndez, 2005).

Seizures in adults with DS differ from those in adults with Alzheimer’s disease who do not have DS:

myoclonic seizures usually occur late in the course of Alzheimer’s disease whereas partial or tonic–

clonic seizures occur in adults with Down’s syndrome and are often precursors to cognitive decline.

Adults with DS aged over 45 years who have seizures are substantially more likely to develop signs of

Alzheimer’s disease (Puri et al; 2001). Once seizures occur in the course of dementia in patients with

DS, functional decline is often rapid, to the point where floor effects preclude further cognitive testing.

Seizures are common in people with early-onset Alzheimer’s disease associated with genetic defects,

including mutations that result in overexpression of amyloid-β, such as those involving presenilin 1

genes.

Animals with overexpression of the APP gene have a lower threshold to induced seizures. High

concentrations of amyloid-β caused by APP overexpression result in epileptiform activity in vivo, even

in the absence of neurodegeneration, suggesting these high concentrations directly as a cause of aberrant

neuronal network synchronisation. Slowing of the dominant occipital rhythm seems to be associated

with dementia in individuals with DS, and the frequency of dominant occipital activity decreases as

cognition deteriorates.

4.3. SEIZURE IN ALZHEIMER´S AND DS

Despite the apparent clinical heterogeneity in aged individuals with DS, age-associated AD-like

neuropathology is a consistent feature. This is due to the fact that trisomy 21 leads to a dose-dependent

increase in the production of the APP and subsequently the production of the amyloidogenic fragments

leading to early and predominant senile plaque formation.

Ten percent of patients with AD have seizures, and another 10% have myoclonus. The incidence of

seizures is about 10 times higher than expected in a reference population. Both seizures and myoclonus,

individually or together, are manifestations of AD and may be seen at any time in the course of the

illness, but myoclonus is often a late manifestation. (Volicer et al., 1995)

4.4. ELECTROENCEPHALOGRAPHY (EEG) FEATURES

Individuals with DS have increased absolute power in all the EEG bands, independent of cognition

functions. In the power spectrum of the resting EEG, there is a cognition-related increase in power at

theta- and alpha-slowing. Furthermore, in the stimulated EEG, there are several cognition-related

abnormalities, such as decreased responses to 12-Hz stimulation and decreased integral of beta- and

gamma-band responses, indicative of decreased responsiveness to photic stimulation. Other reports note

an increase in power at theta and delta in children with DS during sleep. (S’migielska-Kuzia et al.,

2009). There is a significant increase in theta, delta, and beta power and a decrease in alpha compared

with non-DS with epilepsy. (Figure 4)

FIGURE 4.

Spectral power of alpha, theta, delta, and beta bands of DS, n = 12, DS Non-Epilepsy (Non-Epi) n=10

versus Non-DS (epileptic children) n = 28. Alpha Non-DS versus alpha DS P <.001; alpha Non-DS

versus alpha DS Non-Epi P =.001; alpha DS versus alpha DS Non-Epi P <.001; theta Non-DS versus

theta DS P =.767; theta Non-DS versus theta DS Non-Epi P <.001; theta DS versus theta DS Non-Epi P

<.001; delta Non-DS versus delta DS P <.001; delta Non-DS versus delta DS Non-Epi P <.001; delta DS

versus delta DS Non-Epi P <.001;beta Non-DS versus beta DS P <.001; beta Non-DS versus beta DS

Non-Epi P <.001; beta DS versus beta DS Non-Epi P <.001. (S’migielska-Kuzia et al., 2009)

5. Treatment of epilepsy in DS

The pharmacological treatment of epilepsy in DS is no different from that of other patients diagnosed

with epilepsy; the key is proper clinical and electrical classification to guide epilepsy treatment and

thereby obtain good therapeutic results.

Although the cognitive profiles of newer antiepileptic drugs (AEDs) are in general better than those of

older antiepileptic drugs, neurological adverse events do occur, including somnolence, distractibility,

dizziness, and an altered pattern of sleep architecture. Individuals with DS have an unusually high

number of side-effects from phenytoin (Tsiouris et al., 2002).

Over time, with the advent of advances in molecular biology, many AEDs have been uncovered, so they

have come to be classified as first-, second- and third-generation drugs. (see table 2)

1a.Generation 2a.Generation 3a.Generation

Valproat

Phenobarbital

Carbamazepine

Ethosuximide

Benzodiacepine

Phenytoin

Felbamate

Gabapentine

Oxcarbamazepine

Topiramate

Lamotrigine

Zonisamide

Levetiracetam

Pregabalin

Vigabatrin

Rufinamide

Safinamide

Eslicarbamazepine

Licarbamazepine

Estirepentol

Bribaracetam, etc.

TABLE 2.

Antipileptica drugs by generation

Figures 5 a & b and table 3 describe the different mechanisms of action demonstrated for antiepileptic

drugs (AEDs).

http://www.intechopen.com/source/html/18448/media/image6.jpeg

FIGURE 5.

A & b Proposed mechanisms of action of currently available AEDs at excitatory and inhibitory

synapses.

a | Currently available antiepileptic drugs (AEDs) are thought to target several molecules at the

excitatory synapse. These include voltage-gated Na+ channels, synaptic vesicle glycoprotein 2A (SV2A),

the α2δ subunit of the voltage-gated Ca2+ channel, AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole

propionic acid) receptors, and NMDA (N-methyl-D-aspartate) receptors. Many of the AEDs can

modulate voltage-gated Na+ channels. This would be expected to decrease depolarization-induced

Ca+ influx and vesicular release of neurotransmitters. In addition, lacosamide is thought to enhance slow

inactivation of voltage-gated Na+ channels. This effect is different from that of other listed AEDs, which

are thought to enhance fast inactivation. Levetiracetam is the only available drug that binds to SV2A,

which might have a role in neurotransmitter release. Gabapentin and pregabalin bind to the a2δ subunit

of voltage-gated Ca2+ channels, which is thought to be associated with a decrease in neurotransmitter

release. Excitatory neurotransmission at the postsynaptic membrane can be limited by topiramate (acting

on AMPA and kainate receptors) and felbamate (acting on NMDA receptors).

b | AED targets at inhibitory synapses have also been proposed. These include the g-aminobutyric acid

(GABA) transporter GAT1 (also known as SLC6A1), which is inhibited by tiagabine, leading to a

decrease in GABA uptake into presynaptic terminals and surrounding glia; and GABA transaminase

(GABA-T), which is irreversibly inhibited by vigabatrin. This decreases the metabolism of GABA in

presynaptic terminals and glial cells. The benzodiazepines, barbiturates, topiramate and felbamate have

been found to enhance inhibitory neurotransmission by allosterically modulating GABAA receptor-

mediated Cl− currents. However, the action of each of these drugs is different and is dependent on the

subunit conformation of the GABAA receptor complex. GAD, glutamic acid decarboxylase.

(Bailer & White 2010).

Blockade

of

voltage-

dependen

t sodium

channels

Increas

e in

brain

or

synapti

c GABA

Selective

potentiatio

n of

GABAA-

mediated

responses

Direct

facilitatio

n or

chloride-

ion influx

Blockad

e of

calcium

channel

s

Other

action

s

levels

First generation

AEDs.

Benzodiazepines - - ++ - - -

Carbamazepine ++ ? - - + +

Ethosuximide - - - - ++ -

Phenobarbital - ++ + ++ ? +

Phenytoin ++ - - - ? +

Valproic acid ? + ? - + ++

Second generation AEDs.

Felbamate ++ + + - + +

Gabapentin ? ? - - ++ ?

Lamotrigine ++ + - - ++ +

Levetiracetam - ? + - + ++

Oxcarbamacepine

++ ? - - + +

Pregabalin - - - - ++ -

Tiagabaline - ++ - - - -

Topiramate ++ + + - + +

Vigabatrin - ++ - - - -

Zonisamide + ? - - ++ +

TABLE 3.

+ primary action; + secundari action; -, no action described; ?, controversial evidence. Main Mechanism

of action of AEDs.

Table 4 describes the different AEDs and the main indication for the type of epilepsy diagnosed. Table

5 describes the AEDs, dose in children and adults and side effects.

FIRST GENERATION

AEDsMAIN INDICATION

Benzodiazepines Status epilpeticus. Partial an generalizated seizures

CarbamazepinePartial seizures (with and whithout secondary generalization) and primarily

generalized tonic-clonic seizures.

Ethosuximide Absence seizures, continuous spike – waves during slow sleep.

PhenytoinPartial seizures (with and whithout secondary generalization) and primarily

generalized tonic-clonic seizures. Status epilepticus.

Valproic acid Generalized and partial seizures. Status epilepticus.

SECOND GENERATION

AEDsMAIN INDICATION

FelbamateSevere epilepsies, particulary Lennox-Gastaut syndrome, refractory to all

other AEDs.

Gabapentin Partial seizures (with and whithout secondary generalization)

LamotriginePartial and generalized seizures (may aggravate severe myoclonic epilepsy of

infancy)

Levetiracetam Partial and probably generalized seizures.

OxcarbamacepinePartial seizures (with and whithout secondary generalization) and primarily

generalized tonic-clonic seizures.

Pregabalin Partial seizures (with and whithout secondary generalization).

Tiagabaline Partial seizures (with and whithout secondary generalization).

TopiramatePartial and generalized seizures (efficacy against absence seizures not

proven)

VigabatrinInfantile spasms and West Sindrome. Partial seizure (with and whithout

secondary generalization) refractory to all other AEDs.

Zonisamide Partial and, probably, generalized seizures.

TABLE 4.

AEDs and the main indication for the type of epilepsy diagnosed

AEDs

Childrens

Dose

mg/kg/d

Adults

Dose mg/day.Side Effects.

Carbamacepine 15-30

600 – 2000 mg

divided into up to 4

doses a day.

Skin rash, if allergic to

carbamazepine. Diplopia (double

vision), ataxia (unsteadiness) and

nausea may occur initially or if the

dose is too high.

Clobazam 0,1-0,2

20 - 50 mg divided

into 1 or 2 doses a

day.

Drowsiness may occur but this drug

is less sedating than clonazepam or

diazepam. Tolerance may develop.

Clonazepam 0,5-0,81 – 4 mg divided into

2 doses a day.

Drowsiness and sedation are quite

common but these may wear off.

Ethosuximide 20-35

750 – 1500 mg

divided into 2 or 3

doses a day.

Nausea and drowsiness may occur

initially or if the dose is too high.

Anorexia (weight loss).

Gabapentine 30

1800 – 3600 mg

divided into 3 doses

a day.

Drowsiness, dizziness, and

headache

Levetiracetam 20-60 1000 – 3000 mg

divided into 2 doses

a day.

Dizziness, drowsiness, irritability,

behavioural problems, insomnia,

ataxia (unsteadiness), tremor,

headache, nausea may occur in

high dosages or when doses are

increased, but will usually

disappear after a few days.

Lamotrigine

5-15

1-5 +

VPA

100 - 200mg if taken

alone or if also

taking sodium

valproate. 200 – 400

mg if also taking

phenytoin ,

phenobarbitone or

carbamazepine.

Skin rash if allergic to lamotrigine.

Drowsiness, diplopia (double

vision), dizziness, headache,

insomnia, tremor and flu-like

symptoms.

Oxcarbamazepine 15-30

1200 - 2400mg

divided into 2 or 3

doses a day.

Skin rash, if allergic to

oxcarbazepine. Diplopia (double

vision), ataxia (unsteadiness),

headache, nausea, confusion and

vomiting.

Phenobarbital 3-530 – 180 mg divided

into 2 doses a day.

Drowsiness may occur initially.

Lethargy, sedation and slowing of

mental performance may be long-

lasting.

Phenytoin 5-10 150 – 600 mg

divided into 1 or 2

doses a day.

Skin rash if allergic to phenytoin.

Drowsiness, ataxia (unsteadiness)

and slurred speech may occur if the

dose is too high. Coarsening of

facial features, overgrowth of

gums, excess hair growth and acne

may occur with prolonged therapy

(over many years), as can some

anaemias.

Topiramate 5-9

Up to 400 mg daily if

taken alone. Usually

200 – 400 mg daily if

taken with other

anti-epileptic drugs,

up to 800 mg.

Headache, drowsiness, dizziness,

paraesthesia (pins and needles in

hands and feet), loss of weight, and

kidney stones. Speech disorder,

impaired memory and

concentration may occur when

dose is increased but will usually

disappear after a few days.

Sodium valproate 20-50

400 – 2000 mg

divided into 1 or 2

doses a day.

Drowsiness and tremor are

infrequent side effects. Hair loss

occurs in some people but is not

usually severe and is usually

reversible if the dose is reduced.

Weight gain may occur. Liver.

damage is rare. Sodium valproate

has been associated with increased

incidence of Polycystic Ovary

Syndrome and menstrual

irregularitiesthan other AEDs, if

taken in pregnancy.

Vigabatrine 50-200 1000 – 4000 mg

divided into 1 or 2

doses a day.

Drowsiness, behaviour and mood

changes. Psychotic reactions have

been reported. Visual field defects

have been reported in one in three

people taking vigabatrin in the long

term.

Zonizamide 4-8

300 - 500mg divided

into 1 or 2 doses a

day.

Skin rash if allergic to zonisamide.

Drowsiness, dizziness, weight loss,

kidney stones, confusion, cognitive

slowing, agitation,

irritability,depression,

TABLE 5.

AEDs, dose in children and adults. Side effects.

6. Conclusions

The findings of the last decade regarding the significant percentage of children with DS and epilepsy

(approximately 1 in 10) highlight the importance of the awareness that physicians should start

developing about this association so that they can intervene as early as possible when seizures are

suspected, to maximize the patient’s development and improve quality of life as much as possible.

The diagnosis, classification and treatment of epilepsy in DS must follow the guidelines applied to the

general population.

Children with DS have a greater predisposition to epilepsy (specifically to West Syndrome and infantile

spasms) attributed to structural and molecular abnormalities. In contrast, in adults with DS, epilepsy is

associated with the accumulation of amyloid-β, due to the expression of APP that is observed in DS

patients with early-onset Alzheimer-like dementia.

The prognosis of patients with DS and epilepsy will depend on several factors: type of epilepsy, age of

initiation, etiology, early diagnosis and treatment’s response. Epilepsy in patients with DS, as well as in

the general population, in most cases represents an alteration of brain function that can be detrimental to

neurological development; this produces a great amount of anxiety and concern in their parents and

relatives. For this reason, all of the prognostic factors must be carefully taken into account when

considering each individual case. The disease, its control and its management should be discussed in a

clear and simple way with the family.

Acknowledgements

We would like to express our gratitude to all the patients with DS and their families; to the Library’s

department of the Fundació Catalana Sindrome de Down whom have made a good work in the

translation of this chapter; to the members of the Epilepsy Unit from the Neurolgy Service of Sant Joan

de Dèu’s Hospital and to our families for their support and time.

 

 

Seizure Disorders In Childhood

Timothy F. Hoban, MDAssistant Professor of Neurology & PediatricsLoyola University Medical Center

http://www.meddean.luc.edu/lumen/MedEd/pedneuro/epilepsy.htm

Case Studies:o Staring and guttural vocalizations in an 8 year old o Generalized seizures and sudden arm jerks in a 14

year old

o Recurrent seizures during fever in an 24 month old

o Spells of inattention and staring in a 6 year old

o "Startle spells" affecting an 8 month old

Video de Lennox-Gastaut Syndrome con caso de una mujer de 34 años y encefalogramahttp://www.youtube.com/watch?v=Ek7EO6U5enE

IMAGEN LENNOX EEG

Electroencephalograms (EEGs) from a patient with Lennox-Gastaut syndrome. A, EEG showing slow spike-wave complexes typical of the Lennox-Gastaut syndrome. Although the EEG is severely abnormal in these patients they are fully conscious and able to talk. B, The same patient with a seizure has the first 2 seconds of nonepileptiform EEG followed by bursts of generalized spike wave complexes that evolve to low-voltage fast activity and a tonic seizure. This is one of the seizure types that is typical of the Lennox-Gastaut syndrome, which often includes generalized tonic-clonic seizures, atypical absences, and even partial seizures.

Electroencephalograms (EEGs) from a patient with Lennox‐Gastaut syndrome. A, EEG showing slow spike‐wave complexes typical of the Lennox‐Gastaut syndrome. While the EEG is severely abnormal in these patients they are fully conscious and able to talk. B, The same patient with a seizure has the first 2 seconds of nonepileptiform EEG followed by bursts of generalized spike and wave complexes that evolve to low voltage fast activity and a tonic seizure. This is one of the seizure types that is typical of the Lennox‐Gastaut syndrome, which often includes generalized tonic‐clonic seizures, atypical absences, and even partial seizures.

http://www.springerimages.com/Images/MedicineAndPublicHealth/2-ACNEU02-10-016A

Electroencephalograms (EEGs) from a patient with Lennox-Gastaut syndrome. A, EEG showing slow spike-wave complexes typical of the Lennox-Gastaut syndrome. Although the EEG is severely abnormal in these patients they are fully conscious and able to talk. B, The same patient with a seizure has the first 2 seconds of nonepileptiform EEG followed by bursts of generalized spike wave complexes that evolve to low-voltage fast activity and a tonic seizure. This is one of the seizure types that is typical of the Lennox-Gastaut syndrome, which often includes generalized tonic-clonic seizures, atypical absences, and even partial seizures.

http://www.springerimages.com/Images/MedicineAndPublicHealth/2-ACN0103-10-016A

Electroencephalograms (EEGs) from a patient with Lennox-Gastaut syndrome. A, EEG showing slow spike-wave complexes typical of the Lennox-Gastaut syndrome. Although the EEG is severely abnormal in these patients they are fully conscious and able to talk. B, The same patient with a seizure has the first 2 seconds of nonepileptiform EEG followed by bursts of generalized spike wave complexes that evolve to low-voltage fast activity and a tonic seizure. This is one of the seizure types that is typical of the Lennox-Gastaut syndrome, which often includes generalized tonic-clonic seizures, atypical absences, and even partial seizures.

http://www.springerimages.com/Images/MedicineAndPublicHealth/2-ACN0103-10-016A

Dr. Alexander Sumich "EEG studies of Down's syndrome"http://www.youtube.com/watch?v=d9PgXOj8E7w