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Drowning in people with epilepsy: how great is the risk? Neurology 2008 ; 71 : 578 \200\223 82 . epilepsy . Epilepsia 1980 ; 21 : 399 \200\223 412 . 79 . Cockerell OC , Johnson AL , Sander JW, Hart YM, Goodridge DM, 103 . Barraclough BM . The suicide rate of epilepsy . Acta Psychiatr Scand Shorvon SD. Mortality from epilepsy: results from a prospective population-based study . La ncet 1994 ; 344 : 918 \200\223 21 . 1987 ; 76 : 339 \200\223 45 . 104 . Nilsson L , Ahlbom A , Farahmand BY , Asberg M , Tomson T . Risk factors for suicide in epilepsy: a case control study . Epilepsia 2002 ; 43 : 644 \200\223 51 . 80 . Loiseau J , Picot MC , Loiseau P . Short-term mortality after a \201 rst epileptic seizure: a population-based study . Epilepsia 1999 ; 40 : 1388 \200\223 92 . 81 . Ding D , Wang W , Wu J , Ma G , Dai X , Yang B , et al . Premature 105 . Christensen J , Vestergaard M , Mortensen PB , Sidenius P, Agerbo E. Epilepsy and ris k of suicide: a population-based case-control study . Lancet Neurol 2007 ; 6 : 693 \200 \223 8 . mortality in people with epilepsy in rural China: a prospective study . Lancet Neurol 2006 : 823 \200\223 7 . 82 . Zielinski JJ . Epilepsy and mortality rate and cause of death . Epilepsia 106 . Singh G , Fletcher O , Bell GS , McLean AE , Sander JW . Cancer 1974 ; 15 : 191 \200\223 201 . mortality amongst people with epilepsy: a study of two cohorts with severe and presumed mil der epilepsy . Epilepsy Res 2009 ; 83 : 190 \200\223 7 . 83 . Annegers JF , Hauser WA , Shirts SB . Heart disease mortality and morbidity in patient s with epilepsy . Epilepsia 1984 ; 25 : 699 \200\223 704 . 84 . Nashef L , Shorvon SD . Mo rtality in epilepsy . Epilepsia 1997 ; 38 : 1059 \200\223 61 . 85 . Nashef L . Sudden unex plained death in epilepsy: terminology and 107 . Shafer SQ , Hauser WA , Annegers JF , Klass DW . EEG and other early predictors of ep ilepsy remission: a community study . Epilepsia 1988 ; 29 : 590 \200\223 60 . de \201 nitions . Epilepsia 1997 ; 38 : S6 \200\223 8 . 108 . Cockerell OC , Johnson AL , Sander JW , Hart YM , Shorvon SD . 86 . Jehi L , Najm IM . Sudden unexpected death in epilepsy: impact, Remission of epilepsy: results from the National General Practice Study of Epilepsy . Lance t 1995 ; 346 : 140 \200\223 4 . mechanisms, and prevention . Cleve Clin Med 2008 ; 75 (S 2 ): 66 \200\223 70 . CHAPTER 5 definitions and epidemiology of epilepsy 59 epilepsy in Iceland and assessment of the epilepsy syndrome classi \201 cation: a prospect ive study . Lancet Neurol 2005 ; 4 ( 10 ): 627 \200\223 34 . 109 . Cockerell OC , Johnson AL , Sander JW , Shorvon SD . Prognosis of epilepsy: a review and further analysis of the \201 rst nine years of the British National General Practice Study of Epilepsy, a prospective population-based study . Epilepsia 1997 ; 38 : 31 \200 \223 46 . 110 . Kwan P , Sander JW . The natural history of epilepsy: an 123 . Basch EM , Cruz ME , Tapia D , Cruz A . Prevalence of epilepsy in a migrant population near Quito, Ecuador . Neuroepidemiology 1997 ; 16 ( 2 ): 94 \200\223 8 . epidemiological view . J Neurol Neurosurg Psychiatry 2004 ; 75 : 1376 \200\223 81 . 124 . Nicoletti A , Reggio A , Bartoloni A , Failla G , So \201 a V , Bartalesi F , et al . Prevalence of epilepsy in rural Bolivia: a door-to-door survey . Neurology 1999 ; 53 ( 9 ): 2064 \200\223 9 . 111 . Kwan P , Brodie MJ . Early identi \201 cation of refractory epilepsy . N Engl J Med 2000 ; 342 : 314 \200\223 19 . 125 . Medina MT , Duron RM , Martinez L , Osorio JR , Estrada AL , Zuniga C , et al . Prevalence, incidence, and etiology of epilepsies in rural Honduras: the Salama Study . Epilepsia 2005 ; 46 ( 1 ): 124 \200\223 31 . 112 . Placencia M , Sander JW , Roman M , Madera A , Crespo F , Cascante S , et al . The ch aracteristics of epilepsy in a largely untreated population in rural Ecuador . J Neurol Neu rosurg Psychiatry 1994 ; 57 : 320 \200\223 5 . 113 . Nicoletti A , So \201 a V , Vitale G , Bonelli SI , Bejarano V , Bartalesi F , et al . Natural history and mortality of chronic epilepsy in an untreated population of rural Bolivia: a follow-up after 10 years . Epileps ia 2009 ; 50 : 2199 \200\223 206 . 126 . Al Rajeh S , Awada A , Bademosi O , Ogunniyi A . The prevalence of epilepsy and other seizure disorders in an Arab population: a community-based study . Seizure 2001 ; 10 ( 6 ) : 410 \200\223 14 . 127 . Osuntokun BO , Schoenberg BS , Nottidge VA . Research protocol for measuring the prev alence of neurologic disorders in developing countries: results of a pilot study in Nigeria . Neuroepidemiology 1982 ; 1 : 143 \200\223 53 . 114 . Keranen T , Riekkinen PJ . Remission of seizures in untreated epilepsy . BMJ 1993 ; 307 : 483 . 115 . Luciano AL , Shorvon SD . Results of treatment changes in patients with apparently dr ug-resistant chronic epilepsy . Ann Neurol 2007 ; 62 : 375 \200\223 81 . 128 . Osuntokun BO , Adeuja AO , Nottidge VA , Bademosi O , Olumide A , Ige O , et al . Pre valence of the epilepsies in Nigerian Africans: a community-based study . Epilepsia 1987 ; 28 ( 3 ): 272 \200\223 9 . 116 . Callaghan BC , Anand K , Hesdorffer D , Hauser WA , French JA . 129 . Tekle-Haimanot R , Forsgren L , Abebe M , Gebre-Mariam A , Heijbel J , Likelihood of seizure remission in an adult population with refractory epilepsy . Ann Neuro l 2007 ; 62 : 382 \200\223 9 . Holmgren G , et al . Clinical and electroencephalographic characteristics of epilepsy in ru ral Ethiopia: a community-based study . Epilepsy Res 1990 ; 7 ( 3 ): 230 \200\223 9 . 117 . Annegers JF , Dubinsky S , Coan SP , Newmark ME , Roht L . The incidence of epilepsy and unprovoked seizures in multiethnic, urban health maintenance orga nizations . Epilepsia 1999 ; 40 ( 4 ): 502 \200\223 6 . 118 . Brewis , M . Neurological di sease in an English city . Copenhagen : 130 . Attia-Romdhane N , Mrabet A , Ben Hamida M . Prevalence of epilepsy in Kelibia, Tunisia . Epilepsia 1993 ; 34 ( 6 ): 1028 \200\223 32 . 131 . Snow RW , Williams RE , Rogers JE , Mung \200\231ala VO , Peshu N . The prevalence of epilepsy among a rural Kenyan population. Its association with premature mortality . Trop Geogr Med 1994 ; 46 ( 3 ): 175 \200\223 9 . Munksgaard , 1966 . 119 . Granieri E , Rosati G , Tola R , Pavoni M , Paolino E , Pinna L , Mon et al . A descr iptive study of epilepsy in the district of Copparo, Italy, 1964 \200\2231978 . Epilepsia 1 983 ; 24 ( 4 ): 502 \200\223 14 . 132 . Kaiser C , Kipp W , Asaba G , Mugisa C , Kabagambe G , Rating D, et al . The prevalence of epilepsy follows the distribution of onchocerciasis in a west Ugandan foc us . Bull World Health Organ 1996 ; 74 ( 4 ): 361 \200\223 7 . 133 . Dent W , Helbok R , M atuja WB , Scheunemann S , Schmutzhard E . 120 . Joensen P . Prevalence, incidence, and classi \201 cation of epilepsy in the Faroes . Acta Neurol Scand 1986 ; 74 ( 2 ): 150 \200\223 5 . 121 . Olafsson E , Hauser WA , Ludvigsson P , Gudmundsson G . Incidence of epilepsy in rura l Iceland: a population-based study . Epilepsia 1996 ; 37 ( 10 ): 951 \200\223 5 . Prevalence of active epilepsy in a rural area in South Tanzania: a door-to-door survey . Ep ilepsia 2005 ; 46 ( 12 ): 1963 \200\223 9 . 134 . Mathai KV , Dunn DP , Kurland LT , Reeder FA . Convulsive disorders 122 . Olafsson E , Ludvigsson P , Gudmundsson G , Hesdorffer D , in the Mariana Islands . Epilepsia 1968 ; 9 ( 2 ): 77 \200\223 85 . Kjartansson O , Hauser WA . Incidence of unprovoked seizures and This page intentionally left blank CHAPTER 6 The Causes of Epilepsy Simon Shorvon In any individual, the occurrence of seizures is often the result of both genetic and acqui red influences and provoking factors. Despite this multifactorial nature of causation, case s can be classi- \201 ed according to the predominant cause (or presumed cause) into four categories ( 1 ): It is important to note that these categories do not map easily to focal/generalized groupi ngs, and some symptomatic epilepsies are generalized and some idiopathic epilepsies are foc al. Furthermore, both generalized and focal seizures may be \200\230provoked \200\231, and pro- voked seizures can be either genetic or acquired. It is also notewor- thy that the me aning of \200\230etiology \200\231 now refers to the \200\230underlying cause \200\231 wh ere in the past it referred often to the mechanisms of epi- leptogenesis (1). Both approach es would be valid, and it is likely that many downstream causes converge on a \201 nal co mmon path- way of epileptogenesis. This is a poorly researched area. It is also clear that the mechanisms underpinning idiopathic, symptomatic, and provoked epilepsy are quite distin ct. Bearing these issues in mind, a list of aetiologies divided into the four categories is pre- sented in Table 6.1 . 1. Idiopathic epilepsy. Defined as: epilepsy of predominately genetic origin and in which t here is no gross neuroanatomical or neuropathological abnormality. There are a small number of rare epilepsies which are caused by a single gene. More common are epilepsies with pres umed polygenic or complex inheritance but the nature of the genetic mechanisms has remained elusive. Most \200\230idiopathic generalized epilepsies \200\231 and most \200\230benign epilepsies of childhood \200\231 fall into this category. The term idiopathic is preferred as the production of the epilepsy is a complex mix of likely genetic and non-genetic mecha nisms, and includes epigenetic and epistatic mechanisms, with chance and environmental in \202 uences operating over time as the brain develops. It must be emphasized that there are obviously cases where categorization is, to a signi \201 cant extent, arbitrary, especially where the genetic or symptomatic in \202 uences ar e \200\230presumed \200\231 rather than identi \201 ed. 2. Symptomatic epilepsy. De \201 ned as: epilepsy, of an acquired or genetic cause, associ ated with neuroanatomical or neuropatho- logical abnormalities indicative of an underlying disease or con- dition. This category includes both (a) acquired conditions and also (b) de velopmental and congenital disorders where these are associated with cerebral pathological changes, whether genetic or acquired (or indeed cryptogenic) in origin. Idiopathic epilepsy As Hippocrates realized, 2000 years ago, inheritance is very impor- tan t as a cause of epilepsy. In the 19th century too, epilepsy was considered a largely inheri ted disorder, often as one symptom of the \200\230neurological trait \200\231. With the re cent discoveries of molecular genetics and the unraveling of the human genome, genetics is again the focus of much interest ( 2 ). 3. Provoked epilepsy. De \201 ned as: epilepsy in which a speci \201 c sys- temic or envi ronmental factor is the predominant cause of the seizures and in which there are no gross c ausative neuroana- tomical or neuropathological changes. Pure epilepsies as a result of single-gene disorders \200\230Pure epilepsy \200\231 (i.e. a condition with seizures as the only predomi- nant symptom) resulting from a single-gene d efect is very rare, and some have been described in single families only. Fifteen genes so far have been identi \201 ed. Interestingly, almost all of the genes iden- ti \201 ed are genes that code for ion channels (see Chapter 11, Table 11.9). It is notable that mutation s in the same gene can cause dif- ferent epilepsy syndromes (phenotypic heterogeneity) and the same syndrome can be caused by mutations in different genes (genotypic heterogeneity) a nd clearly even in these single-gene dis- orders, there are more complex polygenic or envir onmental in \202 u- ences ( 3 , 4 ). Some \200\230provoked epilepsies \200\231 will have a genetic basis and some an acquired b asis. The re \202 ex epilepsies are included in this cat- egory (which are usually genetic ) as well as the epilepsies with a marked seizure precipitant. 4. Cryptogenic epilepsy. De \201 ned as: epilepsy of presumed sympto- matic nature in whic h the cause has not been identi \201 ed. The number of such cases is diminishing, but curr ently this is still an important category, accounting for at least 40 % of adult-onset case s of epilepsy. oxford textbook of epilepsy and epileptic seizures 62 Table 6. 1 A n aetiological classi \201 cation of epilepsy Examples a Main category Subcategory Subcategory Idiopathic epilepsy Pure epilepsies due to single gene disorders Benign familial neonatal convulsions; autosomal dominant nocturnal frontal lobe epilepsy; g eneralized epilepsy with febrile seizures plus; severe myoclonic epilepsy of childhood (and others) Pure epilepsies with complex inheritance Idiopathic generalized epilepsy (and its subtypes); benign partial epilepsies of childhood (various subtypes) Symptomatic epilepsy Predominately genetic or developmental causation Childhood epilepsy syndromes West syndrome; Lennox \200\223Gastaut syndrome Progressive myoclonic epilepsies Unverricht \200\223Lundborg disease; dentato-rubro-pallido-luysian atrophy; Lafora body dis ease; mitochondrial cytopathy; neuronal ceroid lipofuscinosis; myoclonus renal failure synd rome Neurocutaneous syndromes Tuberose sclerosis, neuro \201 bromatosis, Sturge \200\223Weber syndrome Other single-gene disorders Angelman syndrome; lysosomal disorders; neuroacanthocytosis; organic acidurias; porphyria; pyridoxine-dependent epilepsy; Rett syndrome; urea cycle disorders; Wilson disease Disorders of chromosome function Down syndrome; fragile X syndrome; 4p-syndrome; ring chromosome 20 Developmental anomalies of cerebral structure Hemimegalencephaly; focal cortical dysplasia; agyria-pachygyria-band spectrum; agenesis of corpus callosum; polymicrogyria; schizencephaly; periventricular nodular heterotopia; micro cephaly Predominately acquired causation Hippocampal sclerosis Perinatal and infantile causes Neonatal seizures (various causes); cerebral palsy; post-vaccination Cerebral trauma Open head injury; closed head injury; neurosurgery; non-accidental head injury in infants Cerebral tumor Glioma; ganglioglioma and hamatoma; DNET; hypothalamic hamartoma; meningioma; secondary tum ors Cerebral infection Viral meningitis and encephalitis; bacterial meningitis and abscess; malaria; neurocysticer cosis, tuberculosis; HIV Cerebrovascular disorders Cerebral hemorrhage; cerebral infarction; arteriovenous malformation; cavernous haemangioma Cerebral immunological disorders Rasmussen encephalitis; SLE and collagen vascular disorders; in \202 ammatory disorders Degenerative diseases, and other neurological conditions Alzheimer disease and other dementing disorders; multiple sclerosis and demyelinating disor ders; hydrocephalus; arachnoid cyst and porencephaly Provoked epilepsy Provoking factors Fever; menstrual cycle and catamenial epilepsy sleep \200\223wake cycle; metabolic and endo crine-induced seizures; drug-induced seizures; alcohol- and toxin- induced seizures Re \202 ex epilepsies Photosensitive epilepsies; startle-induced epilepsies; reading epilepsy; auditory-induced e pilepsy; eating epilepsy; hot-water epilepsy Cryptogenic epilepsies b a These examples are not comprehensive, and in every category there are other causes (usual ly lumped together in a \201 nal section chapter). b By de \201 nition, the causes of th e cryptogenic epilepsies are \200\230unknown \200\231. However, these are an important cat egory, accounting for at least 40 % of epilepsies encountered in adult practice and a lesse r proportion in pediatric practice. (Derived from reference 1.) genetic study, but to date no common susceptibility genes have been identi \201 ed and the genetic mechanisms are obscure ( 5 ). Pure epilepsies with complex (presumed polygenic) inheritance Pure epilepsies with complex inheritance are much more frequent than the single-gene epilepsies. These conditions are di vided into the idiopathic generalized epilepsies (IGEs) and the benign partial epilepsies o f childhood. Both have been the subject of intensive Idiopathic generalized epilepsy IGE (also known as primary generalized epilepsy) is a very common condition, accounting for up to 20 % of all cases of epilepsy, which probably has a genetic basis, although the genetic mechanisms and CHAPTER 6 the causes of epilepsy 63 Table 6. 3 Benign epilepsy with centrotemporal spikes causes have not been elucidated. The condition is often subdivided into subgroups (Table 6. 2 ), although the basis for this is arguable and certainly overlap between syndromes occur s ( 6 ). The com- monest variant is juvenile myoclonic epilepsy (JME) which may account for 10 % of all epilepsies. The core clinical features are shared to a greater or lesser exten t by these syndromes (at least those with onset in later childhood or early adult life) and are shown in Table 6. 2 . \227\206 15 % of all childhood epilepsy \227\206 Age of onset 5 \200\22310 years \227 \206 Simple partial seizures with frequent secondary generalization \227\206 Partial seizu res involve the face, oropharynx, and upper limb. \227\206 Typically, spasm or clonic jerk ing of one side of the face, speech arrest, gutteral sounds \227\206 Seizures infrequent \200\224 50 % of cases have 5 seizures or less \227\206 Sei zures typically during sleep \227\206 No other neurological features; normal intelligence \227\206 Some cases have a positive family history \227\206 EEG shows typical centrotempo ral spikes \227\206 Excellent response to antiepileptic drugs \227\206 Excellent prognosi s with remission by mid-teenage years Benign partial epilepsy The most common condition in this category, accounting for up to 15 % of all epilepsies, is benign partial epilepsy with centrotemporal spikes (BECTS; also kn own as rolandic epilepsy or benign epilepsy with rolandic spikes) ( 7 , 8 ). The core clini cal features are shown in Table 6. 3 . Other benign partial syndromes include childhood epi - lepsy with occipital paroxysms (benign occipital epilepsy; Gastaut type \200\224 idiopat hic childhood occipital epilepsy) and early-onset benign occipital epilepsy (synonym: Panay iotopoulos syndrome). NB There are transitional cases which show some features of the benign and more severe chil dhood syndromes. Some cases of BECTS show features of the Landau \200\223Kleffner syndrome and electrical status epilepticus during sleep (ESES). Some also consider febrile seizures, Panayiotopoulos syndrome and BECTS to be manifestations of a continuum (the benign childho od seizure susceptibility syndrome). Symptomatic epilepsy of predominantly genetic or congenital causation Childhood epilepsy sy ndromes These have multiple causes and are included in this section for convenience as, alt hough some causes are acquired, the majority are genetic or developmental in origin. Lennox \200\223Gastaut syndrome Lennox \200\223Gastaut syndrome is a term used to describe the severe epilepsies of childhood in which multiple types of epileptic seizure occur and a re associated with slow (2 \200\2233 Hz) spike-wave discharges on the EEG ( 10 ). The most characteristic seizure type in this syndrome is the tonic seizure, and this is usually asso ciated with atypical absence, myoclonic, tonic \200\223clonic seizures, and later com- plex partial seizures. Learning disability is always present and is often severe. The syndrome accounts for up to 5 % of all childhood epilepsies. The age of onset is usually 1 \200\2237 years. Whether this is a speci \201 c syndrome, or simply a re \202 ection of severe epi lepsy in child- hood associated with learning disability is unclear. There are also overlap cases with other epilepsy syndromes, and Lennox \200\223Gastaut syndrome can evolve from W est syndrome or neonatal convul- sions. There are a number of identi \201 ed causes underl ying this encephalopathy (Table 6. 5 ). West syndrome West syndrome is a severe epileptic encephalopathy, with an inci- dence of 1 \200\2232 per 4000 live births ( 9 ). It is de \201 ned by the occurrence of infantile spa sms with an electroencephalographic (EEG) pattern of hypsarrhythmia. Ninety per cent of cas es develop in the \201 rst years of life and the peak age of onset is 4 \200\2236 months. A wide variety of conditions have been reported to cause this encephalopathy (Table 6. 4 ) . Progressive myoclonic epilepsies This term is used to describe a speci \201 c phenotype wh ich can be caused by a variety of genetically determined neurological disor- ders. The pred ominant clinical feature is the presence of severe myoclonic seizures which evolve progress ively and which are asso- ciated with other features depending on the underlying cause. In most parts of the world there are six common underlying condi- tions: mitochondrial disorde rs, Unverricht \200\223Lundborg disease, Table 6. 2 Subgroups and core clinical features of i diopathic g eneral ize d e pilepsy Subgroups \227\206 Epilepsy with myoclonic absences \227\206 Childhood absence epilepsy (petit mal; pyknolepsy) \227\206 Juvenile absence epilepsy \227\206 Juvenile myoclonic epilepsy (imp ulsive petit mal) \227\206 Epilepsy with grand mal seizures on awakening \227\206 Absence epilepsy with peri-oral myoclonia Core clinical features Table 6. 4 Causes of West s yndrome \227\206 Onset in childhood or early adult life \227\206 Positive family history in some cases \227\206 Generalized seizure types \200\224 myoclonus, generalized absence (petit m al), and \227\206 Neurocutaneous syndromes (especially tuberous sclerosis, Sturge \200\223Weber syndrome: 7 \200\22325 % of all cases) \227\206 Cortical dysplasia (many types: 10 % of all cases) \227\206 Congenital chromosom al disorders (many types) \227\206 Inherited metabolic disorders (many types) \227\206 Mi tochondrial disease \227\206 Neonatal and infantile infections (15 % of all cases) \227 \206 Hypoxic \200\223ischaemic encephalopathy \227\206 Tumors and vascular disorders \227 \206 Trauma \227\206 Degenerative disorders generalized tonic \200\223clonic seizures \227\206 A diurnal pattern of seizure recurrence, with seizures especially on waking and during sleep \227\206 Normal intellect and low comorbidity \227\206 Absence of identi \201 able under lying structural etiology \227\206 Normal EEG background \227\206 Paroxysms of generalize d EEG discharges, either 3 Hz spike and wave or polyspike bursts, often exacerbated by over-breathing and photosensitivity \227\206 Excellent response to therapy with sodium valproate oxford textbook of epilepsy and epileptic seizures 64 Table 6. 5 Causes of Lennox \200\223 Gastaut s yndrome Table 6. 6 Diagnostic criteria of tuberous sclerosis complex \227\206 Cortical dysplasia (many types) \227\206 Neurocutaneous syndromes (tuberous scle rosis, Sturge \200\223Weber, other forms) \227\206 Cerebral tumor (including hypothalamic hamartoma) \227\206 Inherited metabolic disorders (various types) \227\206 Ischaemic \200 \223hypoxic and perinatal injury \227\206 Congenital chromosomal disorders (many types) \227\206 Trauma \227\206 Cerebral infection \227\206 Major features \227\206 Facial angio \201 bromas or forehead plaque \227\206 N on-traumatic ungual or periungual \201 bromas \227\206 Hypomelanotic macules (3 or more) \227\206 Shagreen patch (connective tissue naevus) \227\206 Multiple retinal nodular ham artomas \227\206 Cortical tuber \227\206 Subependymal nodule \227\206 Subependymal giant cell astrocytoma \227\206 Cardiac rhabdomyoma, single or multiple \227\206 Lymphangiomyo matosis \227\206 Renal angiomyolipoma \227\206 Minor features \227\206 Multiple randomly distributed pits in dental enamel \227\206 Hamartomatous rectal polyps \227\206 Bone cys ts \227\206 Cerebral white matter radial migration lines \227\206 Gingival \201 bromas \227\206 Non-renal hamartoma \227\206 Retinal achromic patch \227\206 \200\230Confetti \200\231 skin lesions \227\206 Multiple renal cysts \227\206 De \201 nite TSC: 2 major f eatures or 1 major feature, plus 2 minor features \227\206 Probable TSC: 1 major feature p lus 1 minor feature \227\206 Possible TSC: 1 major feature or 2 or more minor features dentato-rubro-pallido-luysian atrophy (DRPLA), Lafora body dis- ease, neuronal ceroid lipof uscinosis, and sialidosis. These condi- tions are rare, and progressive myoclonic epilepsie s account for less than 1 % of all referrals to tertiary epilepsy services. The inves- tiga tions to elucidate their underlying causes are outlined in Chapter 11 (Table 11.11). Neurocutaneous disorders Epilepsy is a prominent feature of most of the neurocutaneous cond itions. Tuberous sclerosis complex, Sturge \200\223Weber syndrome, and neuro \201 bromatos is (type 1) are the most commonly encoun- tered. Rarer conditions include hypo-melanosis of Ito, epidermal naevus syndrome, hereditary haemorrhagic telangiectasia, Parry \200\223 Rom berg syndrome, midline linear naevus syndrome, incontinen- tia pigmenti, and Klippel \200 \223Tr naunay \200\223Weber syndrome ( 11 ). Tuberous sclerosis Tuberous sclerosis or tuberous sclerosis complex (TSC) is a common and i mportant cause of epilepsy ( 12 ). The incidence may be as high as 1 in 5800 live births an d there is a high spontaneous mutation rate (1 in 25,000). It is inherited in an autosomal domi- nant fashion, and is usually caused by mutations of the TSC1 or TSC2 genes, both tumo r suppressor genes. To date, about 300 unique TSC1 or TSC2 mutations have been identi \201 ed in nearly 400 separate patients/families and there is also a signi \201 cant degree of mosaicism which complicates genetic assessment. The manifesta- tions of the condition are very variable, but epilepsy is present in 80 % . It can take the form of neonatal seizures, West syndrome, Lennox \200\223Gastaut syndrome, or as adult-onset partial or generalized s eizures. About two-thirds of patients present with seizures before the age of 2 years. Abou t 25 % of all cases of West syndrome are due to TSC. The diagnostic criteria are shown in T able 6. 6 . Sturge \200\223Weber syndrome This is the third neurocutaneous syndrome in which epilepsy i s a prominent feature. The clinical features are a unilateral or bilateral port wine naevus , epilepsy, hemiparesis, mental impairment, and ocular signs ( 14 ). Seventy per cent of pa tients with Sturge \200\223Weber syndrome develop seizures within the \201 rst year of li fe and almost all have developed epilepsy before the age of 4 years. Other single-gene disorders In addition to the conditions already mentioned, there are many other single-gene and chromosomal disorders in which epilepsy is part of the phenotype. Mo st are rare or very rare, manifest initially in childhood, and present for diagnosis to ped iatric neurological services rather than to an epilepsy specialist, and in only a few of th ese conditions does the epilepsy have distinctive features or is a predominant or consisten t feature. Almost all are associated with learning disabilities and other neurological feat ures (the features of which vary with the speci \201 c condition) and epilepsy is only one symptom of a much broader clinical picture. Conditions in which epilepsy is a prominent fe ature include Angelman syndrome, Rett syndrome, lysosomal storage or transportation disorde rs, peroxisomal, pyridoxine-dependent disorders, inherited disorders of cobalamin and folat e metabolism, amino acid and organic acid disorders, neuroacanthocytosis, porphyrias, urea cycle disorders, and Wilson disease (see also Chapter 11). Neuro \201 bromatosis Neuro \201 bromatosis type 1 (NF1) is a common, dominantly inherite d genetic disorder, occurring in about 1 in 3000 live births ( 13 ). Almost half of all cas es are new mutations and the new mutation rate for the NF1 gene is about 1 in 10,000, among st the highest known for any human gene. Many different mutations have been reported in thi s large gene, and although the penetrance is essentially complete, the clinical manifestati ons are extremely variable. The incidence of epi- lepsy is about 5 \200\22310 % . The clini cal features include: six or more caf au lait macules over 5 mm in greatest diameter in p repubertal individu- als and over 15 mm in greatest diameter in postpubertal individual, tw o or more neuro \201 bromas of any type or one plexiform neuro \201 - broma, freckling in the axillary or inguinal regions, optic glioma, Lisch nodules (iris hamartomas), and bone lesion such as sphenoid dyspla- sia or thinning of the long bone cortex, and pseudarthrosis . Epilepsy occurs but is less common in neuro \201 bromatosis type 2. Angelman syndrome This condition, with a frequency of about 1 in every 10,000 \200\22320,00 0 births, accounts for about 6 % of all those with mental retardation and epilepsy. There i s a rather characteristic phenotype with CHAPTER 6 the causes of epilepsy 65 various forms. Repeat numbers vary, and mosaicism is common, and these may account for the variable clinical features. dysmorphic features, learning disability, severe epilepsy, a charac- teristic motor disturb ance with \200\230puppet-like \200\231 movements due to truncal ataxia and titubation, a h appy demeanor, and speech dis- turbance. Epilepsy is present in 85 \200\22390 % of cases. I n about 80 % of cases defects are present in the chromosome 15q11 \200\223q13 region, and i nvolve a deletion, maternal disomy, imprinting defect, or, rarely, translocation. This regi on contains a cluster of GABA recep- tor subunit genes. Iatrogenic mutations in the UBE3A g ene are found in about 10 % of cases. Ring chromosome 20 This is a rare condition, but one in which epilepsy is the predomi- nant feature and it has a highly characteristic phenotype. Seizures typically take the form of long episodes of non-convulsive status epilepticus characterized by confusion, staring, per ioral and eyelid myoclonus, and with a highly characteristic EEG. The locus of fusion betwe en the deleted short and long arms of the chromosome is at p13q13, p13q13.3.3, or p13q13.33 . Mosaicism is common and the condition can develop at any age and varies considerable in s everity. Rett syndrome This is an X-linked dominant disorder, almost always presenting in females. T he defect is in the MECP2 gene, which controls RNA production. Birth and development in the \201 rst 6 months are normal. In the classic phenotype, the children then decline with s evere mental regression with autistic features, motor disturbances with highly characterist ic manual stereotypies, and eventually total quadraparesis, apnoeic attacks, and a complex disturbance of breathing and a tendency for gastric regurgitation. Short stature, wasting, and microcephaly are typical. Language is severely affected and speech may cease altogether . Epilepsy occurs in over 50 % of identi \201 ed cases, and tends to develop when the dise ase has stabi- lized. It has recently become clear that the phenotype is much wider than in the classic descriptions, and it is recognized that some adult women with only mild intell ectual disability have the same genetic defect. Occasional male cases survive who have eith er a 47,XXY karyotype or somatic mosaicism (those with 47,XY and MECP2 mutations die in the \201 rst years of life). Cortical dysplasia Cortical dysplasia (synonyms: cortical dysgenesis, malformations of cort ical development) is a term that is applied to developmental disorders of the cortex produc ing structural change (Table 6. 7 ) ( 18 , 19 ). A minority of these conditions are caused by identi \201 able genetic abnormalities, others by environmental in \202 uences such as infec- tion, trauma, hypoxia, or exposure to drugs or toxins, but in most instances the ca use is unclear. Cortical malformations can be due to abnormal neuronal and glial proliferat ion, abnormal neuronal migration, or abnormal synaptogenesis, cortical organization, or pro grammed cell death. Epilepsy is a predominant symptom, and occasionally the only symptoms ( particularly in adult-onset epi- lepsy due to cortical dysplasia). Usually, though, there i s also learn- ing disability which can be severe and focal neurological signs. Disorders of chromosome structure Epilepsy is also a feature of two common chromosomal abno rmal- ities: Down syndrome and fragile X syndrome ( 15 , 16 ). It also takes a highly chara cteristic form in the rare ring chromosome 20. Other uncommon chromosomal abnormalities in which epilepsy is found include trisomy 12p, 8, 13; ring chromosome 14; partial mono- somy 4p (Wolf \200\223Hirschhorn syndrome); inverted duplication of pericentromeric chromosome 1 5; and Klinefelter syndrome (where epilepsy occurs in about 10 % of cases). In all these co nditions, there are additional behavioral and intellectual disabilities and characteristic dysmorphic features. The seizures often take multi- ple forms, including myoclonus, and are of variable severity. Genetic testing is available for most conditions. Table 6. 7 Types of cortical dysplasia Abnormalities of gyration \227\206 Agyria (lissencephaly), macrogyria, pachygyria spectrum (focal or diffuse) ( LIS1 , RELN , ARX , and DCX genes) \227\206 Polymicrogyria \227\206 Cobblestone complex ( FCMD gene) \227\206 Schizencephal y ( EMX2 gene) \227\206 Minor gyral abnormalities Heterotopias \227\206 Periventricular nodular heterotopia ( FLNA gene) \227\206 Subcortical nodular he terotopia \227\206 Subcortical band heterotopia ( DCX and LIS1 genes) Down syndrome The Down phenotype occurs in about 1 in every 650 live births. It is usually caused by trisomy of chromosome 21, and triplication of 21q22.3 results in the typical phen otype. In 95 % of cases the cause is a non-disjunction, and in about 4 % an unbalanced tran sloca- tion. About 1 % of cases are due to mosaicism. The risk of trisomy increases with ma ternal age. Epilepsy is present in up to 12 % of cases and EEG abnormalities in more than 2 0 % . Other gross malformations \227\206 Megalencephaly and hemimegalencephaly \227\206 Agenesis of corpus callosum \227 \206 Anencephaly and holoprosencephaly \227\206 Microcephaly Cortical dysgenesis associated with neoplasia \227\206 DNET \227\206 Ganglioglioma \227\206 Gangliocytoma Fragile X syndrome Fragile X syndrome is a condition due to an increased number of CGG repe ats (typically more than 200) in the FMR1 gene (at Xq27.3) accompanied by aberrant methylat ion of the gene ( 17 ). It is an X-linked condition in which males have more severe symp- t oms. It is diagnosed in about 1 in 4000 male births, and carrier rates in females (CAG repe ats of approx 50 \200\223200) may be as high as 1 in 250. Seizures are present in one-fourt h of cases and can take Other cortical dysplasias \227\206 Hypothalamic hamartoma \227\206 Focal cortical dysplasia \227\206 Tuberous scle rosis ( TSC1 and TSC2 genes) Microdysgenesis (From reference 38.) oxford textbook of epilepsy and epileptic seizures 66 Symptomatic epilepsy due to acquired causes Almost any condition affecting the cerebral gra y matter can result in epilepsy. The seizures in symptomatic and acquired epilepsy usually but not always take a partial or secondarily generalized form, and there are often no parti cularly distinctive features associ- ated with any particular cause. The seizures also may have a strongly \200\230provoked \200\231 element, as may those in idiopathic epilepsy ( 2 0 ).