Age-related epileptic encephalopathies

Handbook of Clinical Neurology, Vol. 107 (3rd series) Epilepsy, Part I H. Stefan and W.H. Theodore, Editors # 2012 Elsevier B.V. All rights reserved

Chapter 11

Age-related epileptic encephalopathies RENZO GUERRINI 1* AND JOHN M. PELLOCK 2 Department of Neuroscience, Pediatric Neurology Unit and Laboratories, Children’s Hospital A. Meyer, University of Florence, Florence, Italy

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Division of Child Neurology, Department of Neurology, Virginia Commonwealth University, Richmond, VA, USA

INTRODUCTION Epileptic encephalopathies are conditions in which seizures, the epileptiform abnormalities, or both, contribute to the progressive disturbance in cerebral function (Engel, 2001). About 40% of all epilepsies occurring in the first 3 years of life fit this definition (Dalla Bernardina et al., 1983). However, the epileptic encephalopathies represent more a concept and an operational category than a syndrome spectrum. Some syndromes such as infantile spasms, Dravet syndrome (severe myoclonic epilepsy), epilepsy with continuous spike and waves during sleep, and Lennox–Gastaut syndrome always manifest as epileptic encephalopathies, irrespective of the underlying cause and severity of electroencephalographic (EEG) abnormalities. Some syndromes with usually good outcome, such as benign rolandic epilepsy, might have a complicated evolution, including learning and language impairment, when severe spike-and-wave discharges appear on the EEG. Persistent spike–waverelated anatomo-specific cortical dysfunction has been blamed for such an ominous evolution (Piccirilli et al., 1988; Shewmon and Erwin, 1988). Myoclonic–astatic epilepsy might unpredictably evolve as an epileptic encephalopathy or rapidly remit without major consequences on cognitive outcome, irrespective of its initial clinical and EEG characteristics (Guerrini and Aicardi, 2003). In such cases it is often entirely unclear which factors, clinical or EEG, can be blamed for either outcome. Finally, a particular situation is represented by epileptic encephalopathies that appear in children with a highly epileptogenic, usually developmental, brain lesion from which epileptic activity spreading to intact, remote areas interferes with their function and amplifies the clinical consequences of the malformation.

Correct diagnostic recognition and more appropriate treatment choices provide a higher chance of a better seizure outcome and reduced cognitive impairment in most epileptic encephalopathies, although this is difficult to demonstrate unequivocally. Although vigorous early treatment is often advocated in epileptic encephalopathies, for most conditions there are no established endpoints and drug choices are empirically established. Surgical treatment can be successful in selected cases. However, only in some surgically treatable syndromes does early treatment have a definite effect on long-term prognosis (Pulsifer et al., 2004). In many individuals the underlying cause, which often remains unrecognized, probably plays a greater part than is acknowledged in determining cognitive outcome.

INFANTILE SPASMS AND WEST SYNDROME Infantile spasms are typical of the first year of life, are usually resistant to conventional antiepileptic drugs, and are associated with developmental delay, or deterioration. EEG often reveals a hypsarrhythmic pattern, which is characterized by very high-voltage (up to 500 mV) slow waves, irregularly interspersed with spikes and sharp waves that occur randomly in all cortical areas. The abnormal discharges are not synchronous over both hemispheres, so the general appearance is that of a chaotic disorganization of electrogenesis. Hypsarrhythmia is an interictal pattern and is observed mainly while the child is awake. During slow sleep, bursts of more synchronous, polyspikes and waves, often appear. In West syndrome, spasms, hypsarrhythmia, and cognitive deterioration occur together. However, infantile spasms might

*Correspondence to: Renzo Guerrini, M.D., Pediatric Neurology Unit and Laboratories, Children’s Hospital A. Meyer-University of Florence, Viale Pieraccini 24, 50139 Firenze, Italy. Tel: 390555662573, Fax: 390555662329, E-mail: [email protected]

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occur without the typical EEG or developmental features. A cumulative incidence of 2.9 per 10 000 live births and an age-specific prevalence of 2.0 per 10 000 in 10-year-old children were observed in the USA (Trevathan et al., 1999). Epileptic spasms can persist or, rarely, appear in older children. Infantile spasms are manifested as clusters of increasing plateau–decreasing intensity brisk (0.5–2.0 s) flexions or extensions of the neck, with abduction or adduction of the upper limbs. Clusters include a few units to several dozens of spasms and are repeated many times per day. After a series, the child is usually exhausted. Asymmetrical spasms are often associated with a lateralized brain lesion (Kramer et al., 1997), although unilateral lesions might cause symmetrical spasms. Lateralized motor phenomena, including lateral or upward eye deviation and eyebrow contraction, and abduction of one shoulder, may sometimes constitute the entire series of spasms or initiate a series that will eventually develop into bilateral phenomena. Such lateralized manifestations are usually accompanied by unilateral or asymmetric ictal EEG changes. Other seizure types can coexist. The hypsarrhythmic EEG is often absent in severe brain lesions, such as tuberous sclerosis or lissencephaly (Dulac, 1997). Misdiagnosis of colic, startles, Moro response, or shoulder shrugs is still frequent. Duration of spasms is variable, depending both on treatment and on their tendency to remit or evolve into other seizure types. Rapid spontaneous remission is rare. In about 50% of children, spasms disappear before the age of 3 years and in 90% before the age of 5 years (Cowan and Hudson, 1991). Developmental delay predates the onset of spasms in about 70% of children (Guerrini, 2006). Disappearance of social smile, loss of visual attention, or autistic withdrawal are often reported by the parents with the onset of spasms. Although infantile spasms are traditionally divided into cases of symptomatic and cryptogenic origin, the meaning of these terms varies among studies and according to the extent of investigation. The specific nature of the underlying cause also implies a variable prognostic outlook. Most investigators define as symptomatic those cases in which an etiological factor can be clearly identified. Others link symptomaticity to either or both abnormal development prior to the onset of spasms and clinical or imaging evidence of a brain lesion, with brain malformations and perinatal hypoxic–ischemic encephalopathy being the most frequent causes. Cryptogenic spasms are those for which no cause can be identified, or where development was normal before clinical onset. In addition, the term cryptogenic does not necessarily mean that a lesion is not present; therefore, a difference of nature between cryptogenic and symptomatic cases is not clearly established. A few cases that are not included in the

symptomatic group, despite increasingly accurate investigations, may belong to an “idiopathic” group (Dulac et al., 1986; Vigevano et al., 1993). A family history of infantile spasm is found in only about 4% of the cases (Sugai et al., 2001). Familial cases are probably the expression of several genetic disorders, some of which are well characterized, including leukodystrophy (Coleman et al., 1977), tuberous sclerosis (Riikonen, 1984), X-linked lissencephaly and band heterotopia (Guerrini and Carrozzo, 2001), X-linked mental retardation, and infantile spasms due to mutations of the ARX gene (Stromme et al., 2002; Guerrini et al., 2007). Boys with X-linked infantile spasms due to ARX mutations usually have severe developmental delay and may have microcephaly. Onset of spasms is usually early and hypsarrhythmia is frequent (Stromme et al., 2002; Kato et al., 2003), although not constantly reported. Follow-up data on infantile spasms in these patients are not available. A syndrome of early-onset infantile spasms and severe quadriplegic dyskinesia, in which spasms tend to remit but episodes of status dystonicus complicate the course, has been associated with expansions in the first polyalanine tract of the ARX gene (Guerrini et al., 2007). A syndrome with microcephaly and early-onset intractable seizures, including spasms with or without hypsarrhythmia, has been associated with mutations or deletions of the X-linked gene CDKL5 (Archer et al., 2006; Elia et al., 2008; Mei et al., 2010). The syndrome is much more frequent in females. No unique EEG pattern seems to be typical for this etiology. Patients harboring deletions on chromosome 7q11.23, including the MAGI2 gene, involved in regulation of trafficking, distribution, or function of the glutamate receptors, have infantile spasms. MAGI2 might therefore be considered as a new gene for infantile spasms (Marshall et al., 2008). A possibly recessive syndrome of early-onset infantile spasms, often preceded and followed by other types of seizure, associated with hypsarrhythmia, facial dysmorphism, optic atrophy, and peripheral edema, has been reported from Finland as PEHO syndrome (progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy) (Riikonen, 2001). Cases exist outside Finland. Other genetic disorders are more rare and may be of recessive (Fleiszar et al., 1977; Ciardo et al., 2001) or undetermined (Reiter et al., 2000) nature. Infantile spasms and West syndrome have also been associated with various mitochondrial disorders, inherited disorders of metabolism, chromosomal abnormalities, and copy number variations (Table 11.1). Prognosis depends more on the cause than on treatment. Unfavorable prognostic factors include manifest symptomaticity, early onset (before 3 months),

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Table 11.1 Etiologies of West and Lennox–Gastaut syndromes Type of etiology

Specific etiology

Syndrome

Malformations of cortical development

Focal cortical dysplasia Tuberous sclerosis TSC1, TSC2 genes Lissencephaly LIS1, DCX, ARX genes Subcortical band heterotopia DCX, LIS1 genes Bilateral perisylvian polymicrogyria Bilateral frontoparietal polymicrogyria GPR56 gene mutations Diffuse polymicrogyria Hemimegalencephaly Neurocutaneous disorders Aicardi syndrome Schizencephaly Periventricular heterotopia/microcephaly ARFGEF2 gene Holoprosencephaly SIX3, SHH, TGIF, ZIC2, PTCH1, GLI2 genes Hypoxic–ischemic sequelae Hemorrhagic Fetal infections Postnatal infection (encephalitis and meningitis) Trauma Cardiac surgery with hypothermia 15q11.2-q13.1 duplication 4p- (Wolf–Hirschhorn syndrome) invdup15 Angelman syndrome Down syndrome Miller–Dieker syndrome del1p36 del7q11.23-q21.1 (MAGI2) Pallister–Killian syndrome: mosaic 12p(i[12p]) Menkes disease Phenylketonuria Mitochondrial disease (NARP) Complex 1 deficiency Hypoglycemia PEHO syndrome Nonketotic hyperglycinemia Other organic acid disorders Pyridoxine dependency Biotinidase dependency Congenital disorders of glycosylation Sturge–Weber syndrome All brain tumors ARX CDKL5 STPBX1 About 40% positive family history of epilepsy

WS WS, LGS WS, LGS WS, LGS WS WS

Pre-, peri-, or post-natal damage

Chromosomal abnormalities and copy number variations

Inborn errors of metabolism

Vascular malformations Brain tumors Monogenic: nonmalformative, nonmetabolic

No identifiable causes

WS, LGS WS WS IS IS IS WS WS WS WS, LGS WS, LGS WS WS LGS LGS LGS WS WS, LGS WS, LGS WS WS IS WS WS WS IS WS WS WS WS IS WS WS WS, LGS WS IS WS WS WS, LGS

West syndrome, infantile spasms, and epileptic spasms have the same etiology. The column legend indicates the prominent syndrome presentation, for example girls with Aicardi syndrome exhibit infantile spasms, rather than West syndrome; however, this distinction may not always be feasible. IS, infantile spasms; LGS, Lennox–Gastaut syndrome; NARP, neuropathy, ataxia, retinitis pigmentosa, and ptosis; PEHO, progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy; WS, West syndrome.

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pre-existing seizures other than spasms, asymmetrical EEG, and relapse after initial response to treatment (Guerrini, 2006). Adequate resolution requires the cessation of clinical spasms and normalization of the EEG (Pellock et al., 2010). Good prognostic indicators include cryptogenicity, normal findings on brain magnetic resonance imaging (MRI) (Saltik et al., 2002), typical hypsarrhythmia, rapid response to treatment, and no regression after onset of spasms or its short duration (Kivity et al., 2004). About 80% of patients have residual cognitive or behavioral impairment, but only one-third of cryptogenic cases do (Kivity et al., 2004). About 50% of children have other epilepsy types. Mortality rates of 5–31% have been reported, with higher rates arising from cumulative data and long-term follow-up (Riikonen, 1996). Infantile spasms must be differentiated from rarer, earlier-onset conditions with ominous prognosis, such as early infantile epileptic encephalopathy and early myoclonic encephalopathy. Vigabatrin and adrenocorticotropic hormone (ACTH) have proven effective in a few controlled trials, but uncertainties remain regarding the best treatment (Hancock et al., 2002; MacKay et al., 2004). In three comparative studies, vigabatrin was slightly less effective than, or as effective as, ACTH (Vigevano and Cilio, 1997; Cossette et al., 1999; Lux et al., 2004), but possibly better tolerated (Vigevano and Cilio, 1997). Two randomized trials reported a 78% responder rate (Appleton et al., 1999) and greater effectiveness with high doses (100–148 mg per kg per day) (Elterman et al., 2001). Particular efficacy has been shown in children with tuberous sclerosis (Jambaque´ et al., 2000). Response to 100 mg per kg per day occurs within a few days. Many researchers regard vigabatrin as the first-line drug, despite the risk of visual field constriction (Lewis and Wallace, 2001). This sideeffect appears in 30–50% of patients who receive a substantial drug load, but is not ascertainable in small children. According to the Vigabatrin Paediatric Advisory Group (2000), responders should receive vigabatrin for no more than 6 months and non-responders should be switched to ACTH within 3 weeks. Transient MRI hyperintensities of globus pallidi, thalami, dentate nuclei, and cerebral peduncles have recently been described in infants treated with vigabatrin for infantile spasms (Milh et al., 2009; Thelle et al., 2011). However, the meaning of these findings and how their report would affect treatment choices is still unclear. The UK Infantile Spasms Study (UKISS), comparing hormonal treatment with vigabatrin in the management, showed that tetracosactide (synthetic ACTH) or prednisolone controlled spasms better than vigabatrin initially, but not at 12–14 months of age (Lux et al., 2005). At 24-month follow-up, cognitive outcome was superior for the hormonal group. Tetracosactide is used in a daily dose of 20–40 IU. Nondepot ACTH has

a lower risk of causing persistent hypertension. An individualized regimen allows dose-related side-effects such as hypertension, brain shrinking, adrenal hyporesponsiveness, and cardiac hypertrophy to be kept to a minimum (Heiskala et al., 1996). Infections are an ominous complication of ACTH treatment and are responsible for most deaths (Wong and Trevathan, 2001). A 4–6-week course of ACTH is advisable. Spasms may respond within days, but behavioral improvement needs several weeks. The relapse rate is 30%. A second cycle of ACTH is recommended in cases of relapse after an initial good response. ACTH proved superior to prednisone in a controlled trial (Baram et al., 1996). However, oral high-dose prednisolone has been suggested as an alternative to ACTH, providing equivalent efficacy with fewer sideeffects and at considerably lower cost (Kossoff et al., 2009). Nevertheless, a recent complete review of the literature led the US Consensus report (Pellock et al., 2010) to suggest that a short course of high-dose ACTH (150 units per m2 per day in two divided doses for 2 weeks, followed by a 2-week taper) and vigabatrin (100–150 mg per kg per day) demonstrated the best evidence for efficacy. The report stressed that a short course with higher dose led to an overall better tolerated and safer adverse event profile (Table 11.2). Pulsed intravenous methylprednisolone (Mytinger et al., 2010), valproate, topiramate, and benzodiazepines, especially nitrazepam, might represent interesting treatment alternatives. Pyridoxine is a preferred agent in Japan but its use is not supported by controlled studies (Mackay et al., 2004). Video-EEG monitoring is necessary to show that the spasms have truly disappeared (Gaily et al., 2001; Pellock et al., 2010). Surgical treatment should be considered early when drug resistance is faced and focal epileptogenesis is shown. About 60% of children operated on become seizure-free; the best results are obtained when operating on small lesions (Asano et al., 2001). However, most children have large multilobar cortical dysplasia needing Table 11.2 Infantile spasms: US consensus (Pellock et al., 2010) 1 Early recognition and prompt treatment are mandatory 2 Broad clinical evaluation, including detailed neurophysiology 3 ACTH and vigabatrin demonstrate efficacy to suppress spasms and abolish hypsarrhythmic EEG 4 Timely efficacy assessment recommended; longer trials (>2 weeks ACTH; >3 months vigabatrin) less successful and may lead to serious adverse effects 5 Effective treatment: cessation of spasm and resolution of EEG hypsarrhythmia – “all or none” response ACTH, adrenocorticotropic hormone; EEG, electroencephalography.

AGE-RELATED EPILEPTIC ENCEPHALOPATHIES extensive resection, with limited cognitive improvement (Pulsifer et al., 2004). There is some evidence for use of the ketogenic diet in patients with resistant spasms (Kossoff et al., 2002; Kossoff, 2010).

LENNOX^GASTAUT SYNDROME Lennox–Gastaut syndrome is characterized by intractable brief tonic and atonic seizures, atypical absences, and a generalized interictal EEG pattern of spike and slow-wave discharges. It accounts for 2.9% of all childhood epilepsy (Berg et al., 2000). Incidence peaks between 3 and 5 years of age. Cognitive and psychiatric impairment are frequent. About 30% of cases occur in previously healthy children; multiple etiologies are possible but most cases result from neuronal migration disorders and hypoxic brain damage. About 40% of children have previous infantile spasms (Guerrini, 2006). Persistence of seizures in adulthood is frequent. The term Lennox–Gastaut syndrome, which was accepted by the International League Against Epilepsy in 1989, has often been used loosely to designate epilepsy syndromes of childhood featuring multiple types of intractable seizure, including falls. Epilepsy with myoclonic–astatic seizures and Dravet syndrome have likely been designated as Lennox–Gastaut syndrome in the past (Guerrini and Aicardi, 2003). Cognitive impairment is present in most patients and is often associated with behavioral disturbances and psychiatric disorders. Many patients (20–60%) are already delayed at the onset of the syndrome, but the proportion of mentally retarded patients increases to 75–95% at 5 years from onset (Arzimanoglou et al., 2009). In primary cases (30%), the child’s development seems normal before the appearance of the first seizures, but slowing of mental processing seems to be an almost constant element of the syndrome. About 80% of patients continue to have seizures later in life, with those with symptomatic origin and early onset having the poorest outcome. Long-term follow-up studies report mortality rates of up to 17% (Guerrini, 2006). The core seizure types of the syndrome, including tonic, atonic seizures, atypical absences, and episodes of nonconvulsive status, are not always present at onset, nor is the interictal EEG pattern of slow spike–wave. Some authors consider the presence of fast (10 Hz) rhythms associated with tonic seizures or occurring with minimal manifestations, especially during non-rapideye-movement (NREM) sleep, to be an essential diagnostic criterion (Beaumanoir, 1985; Genton et al., 2000). Tonic seizures, with a “sustained increase in muscle contraction lasting a few seconds to minutes,” are the

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most characteristic type (Blume et al., 2001). When the patient is standing, tonic seizures may forcefully throw the patient to the ground, causing sudden drop attacks. During sleep, tonic seizures may have a subtle expression with only opening of the eyes, or a short lasting apnea can be manifested as full-blown stiffening of the whole body with abduction and elevation of the limbs. Atypical absences can be difficult to identify due to their gradual onset and termination, especially in patients with cognitive impairment. Myoclonic seizures occur in a minority of patients. They are distinctly shorter (< 100 ms) than tonic events but may also lead to falls (Blume et al., 2001). Between 50% and 75% of patients also exhibit episodes of nonconvulsive status, manifested as subcontinuous atypical absences with fluctuating responsiveness that may sometimes be interspersed with recurring brief tonic seizures (Arzimanoglou et al., 2009). Episodes of nonconvulsive status seem definitely to worsen cognitive deterioration (Hoffmann-Riem et al., 2000). In addition to the main types of attack, generalized tonic–clonic seizures or focal seizures may be present in a minority of patients. The classical EEG feature of Lennox–Gastaut syndrome is the slow spike-and-wave pattern, often repeated in bilaterally synchronous complexes at 1–2 Hz. Although slow spike-and-wave discharges are often associated with staring, confusion, or, at times, with an atonic fall, they can be interictal in many cases. Generalized bursts of “polyspikes” or fast rhythms (> 10 Hz), also called generalized paroxysmal fast activity, are recorded during slow sleep. They last from a few seconds to 15 seconds and tend to recur at relatively brief intervals (Blume et al., 1973). They occur as an interictal manifestation or are accompanied by a graded range of clinical manifestations, ranging from opening and upward deviation of the eyes, brief apnea or a mild electromyographic (EMG) axial contraction, to a typical tonic seizure. Sleep EEG recordings may be necessary to elicit their presence (Arzimanoglou et al., 2009). The typical clinical and EEG manifestations of Lennox–Gastaut syndrome may not all be present at onset, which makes diagnosis difficult especially in cases whose onset is de novo (not resulting as transition from a previous different type of epilepsy). In about 20% of patients, Lennox–Gastaut syndrome evolves gradually after infantile spasms and hypsarrhythmia. Distinction between a prolonged spasm and a short tonic seizure may be arbitrary, although spasms usually appear in cluster whereas tonic seizures do so only rarely. Drop attacks are also observed in other epilepsy syndromes typical of childhood. In particular, children with myoclonic astatic epilepsy, aged 2–5 years, have prominently myoclonic or myoclonic–astatic seizures, causing drop attacks, and episodes of nonconvulsive status epilepticus

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(also defined as spike-and-wave stupor), interictal spike– wave, and slow spike-and-wave EEG complexes. Some also develop tonic seizures during sleep, which, however, tend to be isolated (Guerrini and Aicardi, 2003). Although myoclonic–astatic epilepsy is usually less severe than Lennox–Gastaut syndrome, it fulfils its major diagnostic criteria, making differential diagnosis difficult (Kaminska et al., 1999). Difficult problems of differential diagnosis are sometimes posed by epilepsy with continuous spike and waves during sleep (Guerrini et al., 1998b) and the atypical benign rolandic epilepsy (Aicardi and Chevrie, 1982). Children with this syndrome spectrum present with atypical and atonic absences that may cause repeated falls. Recording of continuous spike–waves during slow sleep and absence of tonic seizures usually permits differential diagnosis. Lennox–Gastaut syndrome can appear in the absence of any obvious or suspected etiology (cryptogenic) in otherwise healthy children, or be symptomatic. As observed in West syndrome, the etiology of Lennox– Gastaut syndrome is extremely heterogeneous (see Table 11.1). The multiple causes that can be related to the syndrome can play a role in prognosis or sometimes for therapeutic strategies. A family history of epilepsy is observed in 2.5–28% of cases (Genton and Dravet, 2008), but genetic factors, overall, appear to play a minor role. Perinatal hypoxic ischemic brain damage, intrauterine or postnatal infection, malformations of cortical development, chromosomal abnormality syndromes, head trauma, radiotherapy, acute disseminated encephalomyelitis, and brain tumors have been reported (Genton et al., 2000). Familial cases of Lennox–Gastaut syndrome have been associated with familial bilateral frontoparietal polymicrogyria due to GPR56 gene mutations (Parrini et al., 2009) and with familial pachygyria associated with DCX gene mutations (Lawrence et al., 2010). In many cases, in spite of normal brain imaging, there is no obvious etiology. The neurophysiological bases leading to the interictal and ictal EEG manifestations of Lennox–Gastaut syndrome are poorly understood. The process of secondary bilateral synchrony likely plays a major role in the generation of the seemingly generalized discharges. There is no obvious explanation for this abnormal tendency to secondary bilateral synchrony in Lennox–Gastaut syndrome. Blume (2004) hypothesized that overwhelming diffuse ictal and interictal discharges at a crucial age play a major role in diverting the brain from physiological developmental processes towards seizure control mechanisms. The optimal treatment for Lennox–Gastaut syndrome remains uncertain, and only limited clinical trial data are available. Broad-spectrum drugs should be preferred (French et al., 2004). Only a few controlled

studies are available, usually designed to evaluate the efficacy of one drug on one or two types of seizure, and no study is available investigating early overall effect of a given drug on the syndrome evolution. Randomized clinical trials in Lennox–Gastaut syndrome have been performed for lamotrigine, topiramate, felbamate, rufinamide, thyrotropin-releasing hormone (TRH) analog, and cinromide (reviewed in Arzimanoglou et al., 2009). A recent Cochrane review (Hancock and Cross, 2009) concluded that, although the optimal treatment for Lennox–Gastaut syndrome remains uncertain and no study to date has shown any one drug to be highly efficacious, rufinamide, lamotrigine, topiramate, and felbamate may be helpful as add-on therapy. A decrease in the frequency of all seizures was found for lamotrigine (Motte et al., 1997), felbamate (Felbamate Study Group, 1993), and rufinamide (Glauser et al., 2008), whereas for topiramate the decrease in total seizure frequency failed to reach statistical significance (Sachdeo et al., 1999). However, there is no guidance on how to combine these drugs and many researchers combine them with valproate, ethosuximide, or benzodiazepines, especially clobazam where available. Antiepileptic drug treatment approaches are complicated by the potential of polytherapies for adverse events and seizure aggravation (Guerrini et al., 1998a). Corticosteroids and ACTH have been used for short-term exacerbations with anecdotal reports of good results (Arzimanoglou et al., 2009). However, their role is limited by loss of efficacy and side-effects with prolonged treatment. It has been suggested that vagus nerve stimulation and the ketogenic diet can be useful in some cases, but formal trials have not been performed (Neal et al., 2008). Corpus callosotomy might reduce seizures with drop attacks (Oguni et al., 1991), and a recent report suggests that results are superior and better tolerated when performed at a younger age (Asadi-Pooya et al., 2008). In the treatment of refractory encephalopathic epilepsy syndrome, treatment strategies need to be re-evaluated throughout the lifespan. The total quality of life may dictate therapeutic success rather than seizure freedom (Table 11.3).

LANDAU^KLEFFNER AND CONTINUOUS SPIKE AND WAVES DURING SLOW-WAVE SLEEP SYNDROMES In Landau–Kleffner and continuous spike and waves during slow-wave sleep syndromes, frequent or persistent discharges, with or without accompanying seizures, cause impairment of cortical functions. These two syndromes, which may on occasion partially overlap, epitomize the essence of nonconvulsive age-related epileptic encephalopathies.

AGE-RELATED EPILEPTIC ENCEPHALOPATHIES Table 11.3 Lennox–Gastaut syndrome Intractable brief tonic and atonic seizures, atypical absences Generalized interictal EEG pattern of spike and slow-wave discharges Peak incidence between 3 and 5 years of age Frequent neuropsychiatric comorbidities Sleep EEG may be valuable to confirm diagnosis by showing specific features such as generalized paroxysmal fast activity Clinical experience and studies suggest that broad spectrum AEDs (sodium valproate, benzodiazepines, and/or lamotrigine) be used early, when drop attacks predominate. They may also be effective against atypical absence seizures Long-term treatment can be disappointing, but excessive therapy should be avoided due to risks for cognitive and behavioral toxicity Some AEDs in combination may facilitate episodes of nonconvulsive/tonic status epilepticus Benzodiazepines have only transitory efficacy with rapid tolerance and side-effects Corticosteroids/ACTH may be helpful temporarily during periods of electroclinical aggravation Carbamazepine may control tonic seizures but may aggravate atypical absences, myoclonic, nonconvulsive status Management of Lennox–Gastaut syndrome requires a multidisciplinary medical and psychosocial team Modified from Arzimanoglou et al., 2009. ACTH, adrenocorticotropic hormone; AED, antiepileptic drug; EEG, electroencephalography.

Landau–Kleffner syndrome is a rare, severely disabling disorder, with an insidious, or sudden, loss of language understanding (auditory agnosia), followed by progressive or fluctuating loss of verbal expression (Deonna, 2004). Age at onset is between 3 and 7 years. Focal seizures represent the initial symptom in 60% of children, but are absent altogether in 25%. They have variable severity but remit before adulthood. EEG abnormalities predominate in the temporoparietal regions, bilaterally, or on either side (Deonna, 2004). Interference by EEG discharges with auditory-evoked responses (Seri et al., 1998) suggests epilepsy-induced dysfunction of auditory processing. The prognosis of aphasia is unpredictable but recovery without consequences is exceptional (Duran et al., 2009). However, onset before age 5 years and persistent EEG anomalies over the language areas forecast a severe evolution. Patients might be left with normal language or mildto-severe persistent defects. No cause has been identified, although rare lesional cases have been reported. Treatment efficacy has been investigated empirically. Large doses of ACTH or steroids for prolonged periods (> 3 months) have a definite effect on EEG

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and language (Marescaux et al., 1990; Buzatu et al., 2009). Repeated injections several days apart might prevent major side-effects. Benzodiazepines, valproate, ethosuximide, and immunoglobulins have obtained some success (Guerrini, 2006). Surgical treatment with multiple subpial transections has produced longlasting improvement in selected cases (Grote et al., 1999), but the merit of this approach is difficult to assess and remains highly uncertain. Language therapy is indicated, and alternatives to oral language should be offered to the most severely impaired children. In epilepsy with continuous spike-and-wave discharges during slow sleep (or electrical status epilepticus during slow sleep), continuous sleep-related EEG discharges, persisting for months to years, are associated with cognitive decline. The syndrome appears in previously healthy or in delayed children. Brain lesions, especially polymicrogyria (Guerrini et al., 1998b) and porencephaly (Tassinari et al., 2002), are found in 30–50% of patients. Onset is insidious. Seizures start at 3–5 years as nocturnal and focal attacks, and share similarities to those seen in rolandic epilepsy. After a few months, continuous spike and waves during slow-wave sleep and atypical or atonic absences appear. There is a marked decrease in intelligence quotient scores with attention deficit and hyperactivity, sometimes with language disturbances and autistic features. The long-term course of epilepsy is favorable, but cognitive impairment persists in most children. Earlier onset and long duration of continuous spike and waves during slow-wave sleep are major factors for a poor prognosis (Smith and Hoeppner, 2003). The benign atypical partial epilepsy syndrome (Aicardi and Chevrie, 1982) has a close relationship with continuous spike and waves during slow-wave sleep. Drug treatment is the same as in Landau–Kleffner syndrome, as many aspects of these syndromes truly overlap (Hughes, 2011).

DRAVET SYNDROME (SEVERE MYOCLONIC EPILEPSY IN INFANCY) Dravet syndrome, otherwise known as severe myoclonic epilepsy of infancy (SMEI), is an increasingly recognized epileptic encephalopathy where the clinical diagnosis can be genetically confirmed in around 80% of patients. Dravet syndrome includes a spectrum of conditions with variable severity, all appearing in otherwise normal infants (Dravet et al., 2005), spanning from the classical phenotype to “borderline SMEI” (SMEB) in which patients share most but not all of the characteristic clinical features (Oguni et al., 2001). Since its first descriptions, Dravet syndrome has been recognized increasingly worldwide, yet it remains a rare disorder with an incidence probably lower than 1 per

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40 000 (Hurst, 1990). The prevalence of Dravet syndrome in children with seizure onset in the first year of life varies between 3% and 8% (Yakoub et al., 1992; Dravet et al., 2005). The initial manifestations start before 12 months of age, with repeated generalized or unilateral clonic (hemiclonic with alternating side) seizures, typically triggered by fever. Seizures are often prolonged, tend to recur in clusters in the same day, and may evolve into status epilepticus. Factors that increase body temperature, such as vaccinations or hot water immersion, can precipitate seizures. Between the ages of 1 and 4 years, other seizure types appear, including myoclonic, absences, focal, and, exceptionally, tonic seizures. Most patients also exhibit myoclonic seizures, which appear between the ages of 1 and 5 years. Myoclonic jerks can be massive and involve the whole body, leading to falling, or be mild and barely visible, exhibiting a multifocal distribution. They are often precipitated by photic stimulation. Polygraphic EEG recordings show that generalized jerks are accompanied by high-voltage discharges of generalized spike and wave, or polyspike and wave discharges. However, not all myoclonic jerks are accompanied by time-locked paroxysmal EEG activity. Absence seizures are present in 40–90% of patients (Dravet et al., 2005) and appear between ages 1 and 3 years. Absences are classified as atypical and can be associated with a prominent myoclonic component. Ictal EEG shows 2.5–3 Hz generalized spike-and-wave discharges. About 40% of patients experience nonconvulsive status epilepticus or obtundation status, characterized by unresponsiveness of variable intensity, with erratic myoclonic jerks, involving the limbs or the face. These episodes may be very prolonged, lasting for days, and fluctuate in intensity, which makes them particularly insidious. Ictal EEG shows diffuse slow waves intermingled with focal or diffuse spikes, sharp waves, or spike and waves. More than 50% of patients have focal seizures, occurring from 4 months of age on. Focal seizures can have a main motor component – versive or clonic jerking limited to one limb or one hemiface – or be complex partial with prominent autonomic symptoms. Convulsive seizures tend to be present throughout as generalized clonic or tonic–clonic seizures, unilateral seizures, or “unstable seizures” (Dravet et al., 2005). Tonic seizures are exceptional in this syndrome. Interictal EEG, normal at onset, subsequently shows generalized or multifocal paroxysmal activity. About 25% of children are photosensitive and may indulge in self-stimulation. Early developmental skills and behavior are usually reported as normal. However, following seizure onset,

at around the second year of life, developmental slowing or stagnation becomes obvious in most patients (Wolff et al., 2006; Ragona et al., 2011). Behavioral disturbances with hyperactivity and autistic traits are frequent. The frequency of convulsive seizures seems to correlate with the severity of developmental delay, suggesting that Dravet syndrome might be considered as a paradigmatic example of epileptic encephalopathy (Wolff et al., 2006). Early onset of absence and myoclonic seizures appears to carry a higher risk of severe cognitive impairment (Ragona et al., 2011). A family history of epilepsy is often found. Affected relatives most often exhibit epilepsy phenotypes consistent with the generalized epilepsy with febrile seizure plus (GEFS þ) spectrum (Singh et al., 1999). The initial finding that mutations of the gene coding for the a1 subunit of the sodium channel (SCN1A) were present in patients with GEFS þ (Escayg et al., 2000) led to the subsequent discovery that an overwhelming number of SCN1A mutations are associated with Dravet syndrome (Claes et al., 2001; Mulley et al., 2005), including the borderline forms. The frequency of detectable mutations is around 70–80%; truncating mutations account for nearly 50% of the abnormalities with the remaining comprising splice-site and missense mutations. Intragenic deletions and whole gene deletions including only SCN1A and contiguous genes account for 2–3% of all cases and for about 12.5% of those exhibiting no point mutations (Marini et al., 2009). Duplications and amplifications involving SCN1A are additional, rare, molecular mechanisms (Marini et al., 2009). Most mutations are de novo, but familial SCN1A mutations also occur (Claes et al., 2001; Sugawara et al., 2002; Nabbout et al., 2003; Wallace et al., 2003). Somatic mosaic mutations have been reported in some patients and should be considered when estimating the recurrence (Depienne et al., 2006; Marini et al., 2006). Although mosaic SCN1A mutations might explain the phenotypic variability, including age of seizure onset, seizure types, and severity seen even within the same family (Guerrini et al., 2010), there certainly exist additional factors such as modifier genes, the genetic background, or environmental factors that can influence variability. Some general genotype–phenotype correlations have been suggested: truncating, nonsense, frame-shift mutations, and partial or whole gene deletions are correlated with a classical Dravet syndrome phenotype and appear to have a significant correlation with an earlier age of seizure onset (Marini et al., 2007). The severity of the phenotypes is also correlated with SCN1A missense mutations falling in the pore-forming region of the sodium channel, whereas missense changes associated to the GEFS þ spectrum are nearly always localized outside the pore-forming region (Meisler and Kearney, 2005).

AGE-RELATED EPILEPTIC ENCEPHALOPATHIES Mutations are randomly distributed across the SCN1A protein in both Dravet syndrome and GEFS þ epilepsies. Depienne et al. (2009) reported PCDH19 mutations and one deletion in 12 of 74 patients (16%) with early-onset epileptic encephalopathy mimicking Dravet syndrome. PCDH19 encodes protocadherin 19, a transmembrane protein of the cadherin family of calcium-dependent cell–cell adhesion molecules, which is strongly expressed in the central nervous system. PCDH19 should be tested in patients with Dravet syndrome in whom no SCN1A abnormalities can be found. Despite intensive investigation, the etiology of about 15% of patients sharing features with Dravet syndrome remains unknown. The definition “intractable childhood epilepsy with generalized tonic–clonic seizures (ICEGTC)” has been used to designate infants with frequent and intractable generalized tonic–clonic seizures often induced by fever and beginning before 1 year of age (Fujiwara et al., 2003). The major feature that differentiates Dravet syndrome and ICEGTC is the presence or absence of myoclonic seizures. Neuroradiological studies are unrevealing in most patients, but structural abnormalities such as cerebral or cerebellar atrophy of various degree and focal arachnoid cysts have been reported anecdotally (Fujiwara et al., 2003; Dravet et al., 2005; Striano et al., 2007). At onset, children are often regarded as having febrile seizures; only their frequent repetition, often as prolonged episodes with unilateral features, makes one suspect Dravet syndrome or GEFSþ. Children may manifest myoclonic seizures at onset and be misdiagnosed as having benign myoclonic epilepsy of infancy. Myoclonic–astatic epilepsy should also be considered in the differential diagnosis because some children with this type of epilepsy manifest febrile seizures before the second year of life, whereas the classical myoclonic–astatic seizures occur only later on during the course. Data on long-term evolution are sparse. Seizures persist into adulthood but are less frequent, rarely prolonged, and usually confined to sleep (Jansen et al., 2006). In the course of the disease, cognitive and motor functions may slightly improve but remain at a low level. Mortality rates are around 16% (Dravet et al., 2005), resulting mainly from sudden death or seizure-related accidents. Valproic acid, benzodiazepines, topiramate, and levetiracetam have shown some efficacy (Dravet et al., 2005). Stiripentol, an inhibitor of the P450 cytochrome, was effective in combination with clobazam in a class I trial (Chiron et al., 2000). Stiripentol acts by increasing the concentration of norclobazam, an active metabolite of clobazam. Phenytoin, carbamazepine, and lamotrigine can worsen seizures and must be avoided (Guerrini et al., 1998a; Dravet et al., 2005).

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MYOCLONIC^ASTATIC EPILEPSY Myoclonic–astatic epilepsy is a generalized epilepsy syndrome with multiple seizure types, including myoclonic– astatic, absences, tonic–clonic, and eventually tonic seizures, appearing in a previously normal child between the ages of 18 and 60 months, with a peak around 3 years of age (Guerrini and Aicardi, 2003). The nosological limits of the disorder are difficult to determine and the course has variable severity, manifesting as an epileptic encephalopathy only in some patients. To understand the difficulties that have surrounded the recognition of this type of epilepsy, some historical notes may be useful. Under the term “centrencephalic myoclonic–astatic petit mal,” Herman Doose reported in 1970 a series of patients who shared with Lennox– Gastaut syndrome the same age of onset, generalized seizures often causing the patient to fall, cognitive delay, and generalized spike-and-wave discharges (Doose et al., 1970). These patients exhibited different combinations of generalized seizures and evolutive patterns, lacked any evidence of brain lesion, had a high incidence of familial antecedents, and thus a suspected genetic etiology. A main point raised by Doose was that of a genetic predisposition as opposed to the Lennox– Gastaut syndrome. This view, based mainly on the concept of etiology, contrasts with the syndromic approach, in which it is the combination of particular symptoms and the rather uniform prognostic outlook that determines the group, whatever the etiology. For this reason, with the purpose of assigning a prognostic outlook, in the past children with myoclonic–astatic epilepsy were often classified within the framework of syndromes with somewhat overlapping electroclinical manifestations, such as Lennox–Gastaut or Dravet syndrome. The incidence of myoclonic–astatic epilepsy was defined by Doose and Sitepu (1983) as 1–2% of all childhood epilepsies up to age 9 years. In a hospital population of children presenting their first seizure between 1 and 10 years of age, it was estimated that myoclonic–astatic epilepsy represented 2.2% (Kaminska et al., 1999). The sex ratio has been defined as 2.7–3 : 1 in favor of males (Doose, 1992; Kaminska et al., 1999). Genetic factors seem to play a major role. A family history of epilepsy was present in 32% of children described by Doose (1992) and in 15% in the series from Kaminska et al. (1999). Ten patients of 88 belonging to families with the GEFS þ complex had myoclonic– astatic epilepsy (Scheffer and Berkovic, 1997; Singh et al., 1999, 2001). Myoclonic and myoclonic–astatic seizures are present in all affected children and are prominent in most. Clinically, myoclonic seizures present as brief, generalized jerks, isolated or replicated in short series of two–three

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events. Proximal muscles are more involved, producing a sudden flexion of the head and trunk with possible collapse to the ground (Oguni et al., 1992). A wide range of severity is observed, ranging from head nodding to falls with possible injury. The duration of these episodes is brief (0.3–1 s according to video-EEG analysis) (Oguni et al., 1992). Falls can either be the direct consequence of massive myoclonic jerks or result from the postmyoclonic silent period that may sometimes be prominent (Oguni et al., 1992). In some children, myoclonic seizures are also triggered by photic stimulation (Doose, 1992). Tonic– clonic seizures are the second most frequent seizure type, present in 75–95% of children (Doose, 1992; Kaminska et al., 1999). They are usually the first manifestation to appear. According to Doose (1992), they appear initially during daytime and later in the course of the disorder during night-time sleep. Absence seizures are present in 62–89% of patients (Doose, 1992; Kaminska et al., 1999). Most often, they present as atypical absences associated with a reduction of muscle tone (Doose, 1992). Some 14–95% of children suffer from nonconvulsive status, presenting as stupor and apathy associated with multifocal, arrhythmic twitching of the face and extremities. Episodes of status can last for several days and seem to be longer in children with an unfavorable evolution (Kaminska et al., 1999). They appear spontaneously or can be triggered by inappropriate treatment, especially with carbamazepine (Guerrini et al., 2002) or vigabatrin (Lortie et al., 1993). Tonic seizures have been described in 30–95% of patients (Doose, 1992; Kaminska et al., 1999). They can manifest as typical axial, tonic attacks during sleep or as tonic–vibratory seizures, especially at the end of night-time sleep, particularly between 4 and 6 a.m. (Doose, 1992). Only about one-third of children with a favorable course have tonic seizures (Kaminska et al., 1999). Febrile seizures, usually simple in type, are reported to precede nonfebrile seizures in 11–28% of children (Doose, 1992; Kaminska et al., 1999). The initial febrile seizure can appear as early as 6 weeks of age (Singh et al., 1999), but in most children it presents between 17 and 40 months (Kaminska et al., 1999). Background EEG activity may be normal at seizure onset, although a characteristic 4–7-Hz, monomorphic theta activity with diffuse distribution, but prominent on centroparietal areas, is often observed. Interictal abnormalities consist of bursts of 2–3-Hz generalized (poly)spike-and-wave discharges, sometimes asymmetrical (Doose, 1992). Sleep is accompanied by an increase in generalized discharges. Myoclonic seizures are characterized electrographically by a generalized (poly) spike-and-wave complex, which may be isolated or repeated rhythmically at 3–4 Hz, lasting for 2–6 s (Oguni et al., 1992). Myoclonic jerks, involving mostly

the proximal upper limbs, are time-locked to a spikeand-wave complex. The EMG correlate of each jerk is a burst lasting for around 100 ms, followed by a longer (200–500 ms) postmyoclonic silent period. A single jerk or a series of 2–3 jerks is observed most commonly. Neurophysiological analysis of myoclonic seizures (Bonanni et al., 2002; Guerrini et al., 2002) showed that: spike-and-wave discharges and myoclonic jerks are bilateral and synchronous, supporting a thalamocortical origin of myoclonic jerks. The atonic component of seizures is characterized on polygraphic studies by a rhythmic discharge of (poly) spike-and-slow wave complexes at 3–4 Hz, accompanied by EMG inhibition, lasting 60–400 ms, synchronous in the recorded muscles, and time-locked to the onset of the slow wave (Oguni et al., 1992, 1997). Tonic seizures are accompanied by 10–15-Hz polyspike discharges lasting as long as the tonic contraction on EMG. Myoclonic status is associated to a very irregular and chaotic EEG with independent spike-and-wave discharges, sometimes resembling hypsarrhythmia (Doose, 1992). Focal, erratic, myoclonic jerks are recorded on distal and facial muscles. They are brief (30–100 ms) and are not time-locked to individual spikes on visual inspection of EEG (Guerrini et al., 2002). The evolution of myoclonic–astatic epilepsy can be either favorable with seizure control within 3 years from onset and normal cognitive development, or unfavorable with drug-resistant seizures and cognitive impairment (Dulac et al., 1990; Kaminska et al., 1999; Guerrini and Aicardi, 2003). There is no distinguishable cluster of clinical or EEG characteristics at epilepsy onset that can help predict the outcome (Kaminska et al., 1999). Myoclonic–astatic epilepsy must be differentiated from cryptogenic Lennox–Gastaut syndrome and atypical benign rolandic epilepsy (Aicardi and Chevrie, 1982), and from epilepsy with continuous spike–wave activity during slow sleep (Patry et al., 1971). The so-called myoclonic variant of Lennox–Gastaut syndrome shares many similarities with unfavorable myoclonic–astatic epilepsy (Kaminska et al., 1999). Atypical benign rolandic epilepsy (Aicardi and Chevrie, 1982) is observed in children with normal development who, after experiencing some sleep-related “sylvian” seizures, develop multiple seizure types including atypical absences and atonic drop attacks accompanied by very abnormal EEG showing continuous spike-and-wave activity during sleep. Differential diagnosis is sometimes necessary with the late infantile variant of ceroid-lipofuscinosis at its clinical onset. Valproate is the first choice drug, because of its wide spectrum of action. If valproate fails, a combination of valproate with lamotrigine should be the next step. Ethosuximide can be effective, particularly when myoclonus

AGE-RELATED EPILEPTIC ENCEPHALOPATHIES 189 ● biotinidase deficiency (biotin) and absence seizures are prominent in the clinical picture. ● Menkes disease (copper histidinate). Alternatively, small doses of a benzodiazepine in combination with valproate can sometimes prove effective. As one can appreciate, the number of metabolic disorAlthough the use of lamotrigine in epilepsies with ders presenting with encephalopathy and seizures conmyoclonus should be cautious, particularly in Dravet tinues to grow. As noted, the semiology of the events syndrome and juvenile myoclonic epilepsy (Guerrini will depend upon the age of seizure onset and may et al., 1998a; Biraben et al., 2000), this drug seems to change over time. The degree of encephalopathy may be of use in myoclonic–astatic epilepsy (Dulac and be progressive, or seem more static, depending upon Kaminska, 1997). Carbamazepine and vigabatrin should be avoided in the degree of metabolic dysfunction. Similarly, when myoclonic–astatic epilepsy, because they can increase children have relatively few seizures but then have an inseizure frequency and trigger episodes of myoclonic stacrease in both seizures and motor or cognitive symptus (Lortie et al., 1993; Kaminska et al., 1999; Guerrini toms, re-evaluation should be considered. One of the important aspects of diagnosis is not only to correct et al., 2002). or treat existing metabolic defects but also to realize which treatments may worsen the condition. Conditions that may worsen with certain antiepileptic medications ENCEPHALOPATHIC CHILDHOOD include pyruvate carboxylase deficiency worsened by EPILEPSIES ASSOCIATED WITH ketogenic diet or ACTH, some organic acidurias worsINHERITED METABOLIC DISORDERS ened by the ketogenic diet, GLUT1 deficiency worsened More than 50 genetically determined metabolic diseases by phenobarbital, caffeine, and other substances interhave been described as associated with seizures or epifering with glucose transport across the blood–brain lepsy. Most, when they present in childhood, are associbarrier, conditions with lactic acidosis worsened by carated with encephalopathy. Thus, these disorders overlap bonic anhydrase inhibitors, which could worsen the with descriptions of the more classical epilepsy synacidosis, and some mitochondrial disorders that may dromes discussed above. However, they often present be worsened by valproate, even to the degree of lifeearly in life with few, if any, specific findings (Nordli threatening hepatotoxicity. and DeVivo, 2008; Pellock et al., 2008). Systemic findAbnormalities demonstrated on EEG recording may ings or dysmorphisms may be helpful for orienting diagbe helpful. Suppression burst pattern is noted in nonnosis, but they are not always present. A variety of ketotic hyperglycemia, phenylketonuria, maple syrup seizure types has been noted and in young infants they urine disease, molybdenum cofactor deficiency, and may be multifocal, myoclonic, or tonic in nature. Later, disorders of biotin metabolism. A comb-like rhythm they may manifest as infantile spasms. As children bewith 7–9-Hz central activity may be demonstrated in come older, both partial and generalized mixed seizures those with maple syrup urine disease, vertex-positive may continue. The degree of encephalopathy depends spikes in sialidosis type 1, and bioccipital polymorupon the severity of the metabolic defect. This section phic delta activity in X-linked adrenal leukodystrostresses the importance of considering these possible etiphia, and 14–22-Hz persistent rhythm is frequently ologies with attention to possible specific treatments. noted with infantile neuroaxonal dystrophy. However, The reader is referred to a more comprehensive review these neurophysiological findings, along with imaging (Nordli and DeVivo, 2008). Metabolic disorder should abnormalities, may vary. be suspected when specific etiology or a well-recognized Numerous mitochondrial diseases may be characteridiopathic syndrome is not established, or the history of ized by encephalopathy and seizures. Mitochondrial the patient is more malignant than expected. encephalomyopathies are in fact heterogeneous, but alExamples of metabolic disorders with specific treatmost all that present with seizures have significant enments include the following (with their treatment listed cephalopathic features. Two best known of these in parentheses): mitochondrial disorders are myoclonus epilepsy with ● pyridoxine-responsive epilepsies (pyridoxine, pyriragged red fibers (MERRF) and mitochondrial encephdoxal phosphate) alopathy, lactic acidosis, and stroke-like episodes ● central creatinine deficiency (creatinine) (MELAS). Maternal inheritance is the rule, but symp● phenylketonuria (dietary restriction) toms may be quite variable within families. Seizures ● glucose transporter deficiency syndrome – GLUT1 in these patients may be focal or generalized and varied DS (ketogenic diet) depending upon the degree of mitochondrial abnormal● pyruvate dehydrogenase deficiency (ketogenic diet) ity affecting the brain. Other mitochondrial encephalop● disorders of lactic acidosis (thiamine, leukovorin) athies that are associated with nuclear mutations rather

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than mitochondrial DNA mutations include Leigh syndrome, Alpers syndrome, and coenzyme Q10 deficiency. These encephalopathic diseases have variable presentation with multisystemic involvement and epilepsy. A recent review discusses these disorders more comprehensively (Hirano et al., 2008). Mitochondrial disorders are treated by metabolic therapy, typically comprising cocktails containing coenzyme Q10, L-carnitine, dichloroacetate, and multivitamins, although the effects of such a treatment approach to seizure severity have not been assessed.

CONCLUSION Nonconvulsive and convulsive age-related epileptic encephalopathies may present as a characteristic epilepsy syndrome of childhood. Alternatively, seizures may be a manifestation of underlying systemic disorders, including genetically determined metabolic defects. The clinical manifestations are of the underlying etiology, including systemic disorders, sometimes genetically determined metabolic defects. The epilepsies are typically therapyresistant, but others are responsive to specific treatments, aggravated occasionally by classical anticonvulsants and especially polytherapy. Careful attention to the history and evolution of the clinical course of seizures and encephalopathy along with neurophysiological and imaging findings allow proper diagnosis and optimal management.

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