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 ). febrile seizure 1 per 19,496 pertussis vaccinations; risk of an afe- brile seizure 1 per 76 ,133 vaccinations; risk of encephalopathy 0 \200\2233 cases per million vaccinations. Some cases of apparent vaccination injury in fact carry an inherited genetic defect of the SCNIA gene which is the root cause of the epilepsy. Post-traumatic epilepsy Head trauma is an important cause of epilepsy. Identi \201 ed head injury accounts for about 6 % of all cases of epilepsy. It is custom- ary to draw distinct ions between open head injury, where the dura is breached, and closed head injury, where th ere is no dural breach, and also between civilian and military head injury, the latter due to blast and high-velocity injuries. The epilepsies in acute cerebral conditions \200\224 for example, stroke, head injury, or infections \200\224 share a number of general features. The epilepsies are often divided i nto \200\230early \200\231 (i.e. seizures occurring within a week of the insult) and \200 \230late \200\231 (i.e. chronic epilepsy devel- oping later). There is often a \200\230sil ent period \200\231 between the injury and the onset of late epilepsy. Presumably, epilepto genic processes are developing during this period, and this raises the possibility of neuro protective interventions to inhibit these processes and pre- vent later epilepsy. Antiepile ptic drug therapy will prevent early epilepsy but does not reduce the frequency of late sei zures. Early seizures are often not followed by late epilepsy \200\224 a fact that is impo rtant to emphasize to patients. Post-traumatic seizures are traditionally subdivided into imme- diate, early, and late cate gories. Immediate seizures are de \201 ned as those that occur within the \201 rst 24 ho urs after injury (these sei- zures are sometimes excluded from the early post-traumatic est i- mates), early seizures are those that occur within the \201 rst week, and late seizure s those that occur after 1 week. About 5 % of all those admitted to hospital with head inju ry experience early sei- zures, and they are more common in children than adults. About 25 % of those with early seizures develop late seizures. Commonly, late seizures deve lop in the months after a head injury and 57 % of late seizures occur within a year, but th e risk of develop- ing seizures remains elevated for the \201 rst 5 \200\22310 years afte r the injury. Closed head injuries are usually caused by road traf \201 c accidents, falls , assault, or sporting injuries. In mild head injury, de \201 ned as head injury without s kull fracture and with less than 30 minutes of post-traumatic amnesia, the risk of epilepsy is very small. Moderate head injury, de \201 ned as a head injury complicated by skull fr acture and/or post-traumatic amnesia for more than 30 minutes, is fol- lowed by epilepsy in about 1 \200\2234 % of cases. Severe closed head injury, de \201 ned as a head injury wit h post-traumatic amnesia of more than 24 hours, intracranial haematoma, and/or depressed sk ull fracture has been found in most studies to be followed by epi- lepsy in about 10 \200 \22315 % of patients. In a recent, very large popula- tion-based study of children and youn g adults, the relative risk for epilepsy was 2.22 (95 % con \201 dence interval (CI) 2.07 \200\2232.38) in the presence of mild brain injury and 7.40 (95 % CI 6.16 \200\2238.89) in the presence of severe brain injury ( 25 ). Open head injury is a more potent cause of epil epsy. Between 30 \200\22350 % of patients in penetrat- ing wartime injuries suffer subseque nt epilepsy. In Jennet \200\231s study from Glasgow of patients admitted to hospital, after head injury, the risk of late epilepsy was: 25 % if early epilepsy was present and 3 % if not; 35 % if there is an intracranial haematoma and about 5 % if not; 17 % if there is a de pressed skull facture and 4 % if not. If there is neither haematoma nor depressed skull fra cture, the risk of epilepsy is 1 % if there were no early seizures and 26 % if there were e arly seizures ( 26 ). Hippocampal sclerosis Hippocampal sclerosis is the most common cause of temporal lobe epile psy, and has a rather typical clinical form ( 21 \200\22323 ). The princi- pal pathological abnormality is atrophy and neuronal cell loss and gliosis in the CA1 and CA3 regions and i n the hilar region of den- tate gyrus, and relative sparing of the CA2 region. There is ext ensive synaptic rearrangement, including re-current innervation of den- tate granule cells by their own neurons ( \200\230mossy \201 bre \200\231 innervation). Hippocampal sclerosi s can be caused in a variety of ways includ- ing cerebral trauma, infection (encephalitis o r meningitis), vascu- lar damage, or toxins (e.g. domoic acid). Familial genetic forms also exist. However, there is a clear association with a history of childhood febrile convulsio ns, and it is widely believed that the most common cause of hippocampal sclerosis is a prol onged or complex childhood febrile convulsion which causes excitotoxic damage acutely to th e hippocampus and results in later hippocam- pal sclerosis and then temporal lobe epilepsy. Prenatal or perinatal injury In the past, epilepsy has often been attributed to perinatal i njury, although it is now recognized that this is a misattribution, and many such cases hav e had in fact other genetic or developmental causes. In controlled studies, only severe per inatal insults have been found to increase the risk of subsequent epilepsy (e.g. perina- ta l hemorrhage, ischaemic \200\223hypoxic encephalopathy). Less severe injuries such as toxem ia, eclampsia, forceps delivery, being born with the \200\230cord round the neck \200\231, low birth weight, or prematurity have only a very modest association, if any, with subsequ ent epilepsy. Epilepsy due to brain tumors Brain tumors are responsible for about 5 \200\22310 % of all n ewly diag- nosed cases of epilepsy ( 27 ). The rate is greatest in adults, and about one-fo urth of adults presenting with newly developing focal epilepsy have an underlying tumor, co mpared to less than 5 % in children. The frequency of seizures is high in tumors in the fro ntal, central, and temporal regions, lower in posterior cortically placed tumors and very l ow in subcortical tumors. Epilepsy occurs in Post-vaccination encephalitic encephalomyelitis There has been controversy about a possible role of vaccination (particularly pertussis vaccination) in the causation of childhood enc ephalopathy and subsequent epilepsy ( 24 ). There is now a gen- eral consensus that the ris k of vaccine-induced encephalopathy and/or epilepsy is extremely low. Risk estimates includ e: risk of a CHAPTER 6 the causes of epilepsy 67 95 % CI 1.3 \200\2238.5). Status epilepticus occurs in the acute phase of about 1 % of all strokes, and 20 % of status epilepticus is due to stroke. In cerebral hemorrhage, epilepsy is more common after large hemorrhages and hemorrhages which involve the cerebral cortex, a nd less common in deep haematomas and rare after sub- tentorial hemorrhage ( 30 ). The epil epsy almost always develops within 2 years of the hemorrhage and the risk of epilepsy is ab out 1 % . Twenty to 34 % of patients develop seizures after subarachnoid hemorrhage. Epilep sy occurs in about 6 % of patients within 12 months and 11 % within 5 years of a stroke due to cerebral inf- arction. The risk of epilepsy is about 17 \200\22320 times greater than i n non-stroke controls. Factors associated with a greater risk of epi- lepsy have been the s ubject of several studies, and are: severity, size of infarct, haemorrhagic transformation, a cortical (as opposed to subcortical) site of the stroke, and, in some studies, embolism as a cause of the stroke. 92 % of those with oligodendrogliomas, 70 % of those with astrocy- tomas, and 37 % of those with glioblastomas. Epilepsy is the \201 rst symptom of meningioma in 20 \200\22350 % of cases. In slow-growing tumors, the history of epilepsy will often have extended for dec- a des, sometimes even into infancy. In hospital-based studies of chronic epilepsy due to cerebral tumors, oligodendrogliomas ac count for between 10 \200\22340 % of cases, dysembryoplastic neuroepithelial tumors (DNETs) for 10 \200\22330 % , astrocytomas for 10 \200\22330 % , and gangliogliomas or hamar- toma s each for between 10 \200\22320 % . Hypothalamic hamartomas are a rare tumor, but one with a characteristic phenotype. They usually present in young children with gelastic seizures, learning disability, behavioral disturbance, and later with precocious puberty. Epilepsy following cerebral infection Encephalitis is a potent cause of epilepsy ( 28 ). Th e risk of develop- ing chronic epilepsy following encephalitis is estimated to be 16-fold g reater than that in the general population and 4.2 times greater after bacterial meningitis , and 2.3 times greater after aseptic meningitis. The increased risk is highest during the \201 rst 5 years after infection, but remains elevated for up to 15 years. The com- mones t serious viral encephalitis is due to herpes simplex virus type-1 (HSV-1) and this frequen tly results in severe and intractable epilepsy. The incidence of severe HSV-1 encephalitis is about 1 per million persons per year. Pyogenic brain abscess is a now uncom- mon but ser ious cause of infective epilepsy. Commonly isolated organisms are streptococci, including a erobic, anaerobic, and microaerophilic types. Streptococcus pneumoniae is a rarer cause of brain abscesses, which are often the sequel to occult cerebrospinal \202 uid rhinorrhoea and also to pneumococcal pneumonia in elderly patients. Enteric bacteria and Bacteroides ar e isolated in 20 \200\22340 % of cases and often in mixed culture. Staphylococcal abscesses account for 10 \200\22315 % of cases and are usually caused by penetrating head injury or bacteraemia secondary to endocarditis. Clostridial infec- tions are most often post-traumat ic. Very rarely, brain abscess can be caused by fungi such as Actinomyces or Nocardia . Late-onset epilepsy can be the \201 rst manifestation of occult cere- brovascular disease . Between 5 \200\22310 % of patients presenting with stroke have a history of prior epilept ic seizures in the recent past, and in the absence of other causes, new-onset seizures shou ld prompt an emergency screen for vascular risk factors with the aim of preventing a stroke . Between 17 \200\22336 % of supratentorial arteriovenous malformations (AVMs) present with s eizures, with or without associated neuro- logical de \201 cits, and 40 \200\22350 % with hemorrhage. Smaller arterial AVMs (<3 cm diameter) are more likely to present with haemor- rhage than large ones. Conversely, large and/or super \201 cial malfor- mations are more e pileptogenic, as are AVMs in the temporal lobe. About 40 % of patients with large anterior venous malformations have epilepsy, and epilepsy is the presenting symptom in about 20 % . Small venous malformations do not usually result in any symptoms. The risk of hemorrhage fr om a venous angioma is lower than from an arterial angioma. Cavernous haemangioma (cavernoma) account for 5 \200\22313 % of vascular malformations of t he CNS and are present in 0.02 \200\2230.13 % of autopsy series. Patients present with seiz ures (40 \200\22370 % ), focal neurological de \201 cits (35 \200\22350 % ), non-speci \201 c headaches (10 \200\22330 % ), and cerebral hemorrhage. Familial clustering can be fo und in 10 \200\22330 % of cavernous haemangiomas, and familial cases have been found to be linked to genes at three different loci, the CCM1 , CCM2 , and CCM3 genes. Forty per cent o f familial cases are due to CCM1 , with higher rates amongst Hispanic cases. Genetic testin g is available. Appearances on magnetic resonance imaging are characteristic. The frequency of post-infective epilepsy also varies according to geographic region. In Afr ica, for instance, malaria is a particularly common cause with seizures and typically statu s epilepticus in the acute phase of cerebral malaria, and there is a 9 \200\22311-fold (CI 2 \200\22318) increase in risk of chronic epilepsy in children with a history of malaria. N eurocysticercosis is the most common parasitic disease of the central nervous system (CNS) and a major cause of epilepsy in endemic areas such as Mexico, India, and China. The brain cysts can be single or multiple. Epilepsy is the commonest clinical mani- festation and usu al presenting feature. Diagnosis is made by imag- ing and by serological tests. Epilepsy is also frequently the presenting symptom of tuberculoma. Tuberculoma account for about 3 % o f all cerebral mass lesions in India, for instance, and 13 % of all cerebral lesions in HIV -infected patients. Diagnosis depends on the clinical context, imaging, serology, and histo logical examina- tion of biopsy material. Epilepsy can also be a symptom of cortical venous infarcts, rheu- matic heart disease, endo carditis, mitral valve prolapse, cardiac tumors and cardiac arrhythmia, or after carotid en darterectomy. Infarction is also an important cause for seizures in neonatal epi- lepsy. Ep ilepsy is also common in eclampsia, hypertensive encepha- lopathy, malignant hypertension, and in the anoxic encephalopathy which follows cardiac arrest or cardiopulmonary surgery. U nruptured aneurysms occasionally present as epilepsy, especially if large and if embedded i n the temporal lobe \200\224 for instance, a giant middle cerebral or anterior communicati ng aneurysm. Epilepsy, with a vascular basis, also occurs in antiphospholipid syndrome, CAD ASIL (cerebral autosomal dominant arteriopathy with subcor- tical infarcts and leucoencepha lopathy), Moya Moya disease, colla- gen disease (e.g. Ehlers \200\223Danlos syndrome, Marfa n syndrome), vasculitis, Beh et \200\231s disease, and amyloid angiography. Other rare Epilepsy due to cerebrovascular disease Stroke is the most commonly identi \201 ed cause o f epilepsy in the elderly, and occult stroke also explains the occurrence of many cases of apparently cryptogenic epilepsies in aged individuals ( 29 ). A history of stroke has been found to be associated with an increased lifetime occurrence of epilepsy (odds ration (OR) 3.3; oxford textbook of epilepsy and epileptic seizures 68 unequivocal EEG evidence of photosensitivity, and differentiated from other, usually more c omplex, cases in which seizures can be apparently precipitated by visual stimuli but in who m EEG evi- dence of photosensitivity can not be demonstrated. Photosensitivity (strictly de \201 ned) is present in a population with a frequency of about 1.1 per 100,000 persons, a nd 5.7 per 100,000 in the 7 \200\22319 years age range, and is strongly associated with epi lepsy. About 3 % of persons with epilepsy are photosensitive and have seizures induced by p hotic stimuli. Most patients with photosensitivity have the syndrome of IGE, although photo sensitivity is also occurs in patients with focal epilepsy arising in the occipital region and occasionally in other conditions. causes of epilepsy include: temporal arteritis, polyarteritis nodosum, Takayasu disease, Fa bry disease, and the hyperviscosity syndrome. Epilepsy in in \202 ammatory and immunological diseases of the nervous system Epilepsy is common in in \202 ammatory disease ( 31 ). The frequency of epilepsy in patients with mult iple sclerosis is about three times that in the general population. In one study, the cumul ative risk of epilepsy in patients with multiple sclerosis was found to be 1.1 % at 5 years , 1.8 % by 10 years, and 3.1 % by 15 years. ADEM (acute dis- seminated encephalomyelitis) i s an acute in \202 ammatory demyeli- nating disorder which can follow systemic infections, and which is immunologically-mediated. Epilepsy is a feature of the acute attack, and occu rs much more commonly than in an acute attack of multiple sclerosis. Many types of metabolic disturbances can cause epilepsy ( 35 ). The degree and rate of fall are important variables in determining whether seizures will occur. The more abnormal the level and the faster the rate of change of metabolic parameters, the higher the chance of a seizure. Seizures occur most commonly in hypoglycae- mia, hyponatraemia, hypocalcaemia, hy percalcaemia, hypomagne- saemia, hypokalaemia, and hyperkalaemia. Ten per cent of patients with severe renal failure have seizures, caused either by the meta- bolic disturbance, rena l encephalopathy, dialysis encephalopathy, or dialysis disequilibrium syndrome. Seizures ar e also a common occurrence in hepatic failure. Hepatic encephalopathy may be overlooked and routine liver function tests can be relatively normal. Hyperammonaemia is sometimes diagno stically helpful in detect- ing liver disease and can be a cause of seizures. Reye syndrome should be considered in children with liver failure where it is associ- ated with aspirin intake. Hypoglycaemia is a potent cause of seizures \200\224 which can occur if the blood sugar levels fall below 2.2 mmol/L. This is commonly due to insulin or other hypo glycaemic s but can also be due to insulinoma. Non-ketotic hyperglycaemia fre- quently causes seizure s. Levels of blood sugar as low as 15 \200\22320 mmol/L can cause seizures if there is asso ciated hyperosmolarity. Epilepsy can occur in all other forms of large-, medium-, or small-vessel vasculitis, somet imes on the basis of infarction. Seizures occur in about 25 % of cases of systemic lupus er ythema- tosus (SLE). Seizures can be the presenting symptom, and are par- ticularly common in severe or chronic cases and in lupus-induced encephalopathy. Epilepsy occurs less often in other vasculitides such as Beh et \200\231s disease and in other \200\230connective ti ssue disorders \200\231 such as Sj gren syndrome and mixed connective tissue disease and H enoch \200\223Sch nlein purpura. Seizures are the commonest neuro- logical complication of the in \202 ammatory bowel diseases (ulcera- tive colitis and Crohn \200\231s disease) oc curring in one series in 6 % of cases. Epilepsy is also a prominent feature of Hashimoto \200\231s thyroidi- tis, a relapsing encephalopathy associated with high titres of thy- roi d antibody. There has been recent interest in the occurrence of epilepsy in the syndrome of limbic encephalitis, associated with high titres of antibodies against voltage-gated potas sium channels and the acute encephalopathy associated with anti-NMDA recep- tor antibodies. In these immunologically mediated disease, epilepsy usually presents as a subacute illness , associated also with psycho- sis, neurological signs (e.g. ataxia), memory loss, and beha vioral change. Other cases of limbic encephalitis have no detectable anti- body present alt hough in such cases the cause is likely to be an as yet unidenti \201 ed antibody, and som e are para-neoplastic ( 32 ). Alcohol abuse is a potent cause of epilepsy ( 36 ). Binge drinking can result in acute cere bral toxicity and seizures. Alcohol with- drawal in an alcohol-dependent person carries an even greater risk of seizures. Seizures can also be caused by the metabolic distur- bances associated with binge drinking, the cerebral damage due to trauma, cerebral infection, subd ural haematoma, the chronic neu- rotoxic effects of chronic alcohol exposure, or to acute W ernicke \200\231s encephalopathy due to thiamine de \201 ciency. Provoked epilepsy In the 19th century, all epilepsies were considered to be in part caused by provoking (exciting factors) ( 33 ) and it has been only recently that the importance of provoking factors has been again recognized ( 34 ). Seizures can also be provoked by exposure to many different toxins, notably heavy metal or carbon monoxide poisoning. A wide range of drugs, toxins, and illicit compounds can cause a cute symptomatic seizures and epilepsy although seizures accounted for less than 1 % of 32, 812 consecutive patients prospectively monitored for drug toxicity ( 37 ). The term re \202 ex epilepsy is used to describe cases in which sei- zures are evoked cons istently by a speci \201 c environmental trigger. Simple re \202 ex seizures are de \201 ned as those precipitated by elemen- tary sensory stimuli (e.g. \202 ashes of light, sta rtle), and complex re \202 ex seizures are those precipitated by more elaborate stimuli (e .g. speci \201 c pieces of music). The complex forms are much more het- erogeneous and les s well de \201 ned than the simple re \202 ex epilepsies. The stimuli most reported to ca use seizures include \202 ashing lights and other visual stimuli, startle, eating, hot wa ter, music, reading, and movement. The commonest re \202 ex epilepsies are those induced b y visual stimuli, such as \202 ashing lights, bright lights, moving visual patterns (e.g. escalators), eye closure, moving from dark into bright light, and viewing speci \201 c ob jects or colors. The term photosensi- tive epilepsy should be con \201 ned to those indivi duals who show Acknowledgements The text of this chapter is based partly on the following: Shorvon SD. Epi lepsy (Oxford Neurology Library Series). Oxford: Oxford University Press, 2009; Shorvon SD. Handbook of the Treatment of Epilepsy . Oxford: Wiley-Blackwell, 2010; Shorvon SD, Anderma nn F, Guerrini R (eds). The Causes of Epilepsy: Common and Uncommon Causes in Adults and Ch ildren . Cambridge: Cambridge University Press, 2011. This work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health \200\231s NIHR Biomedica l Research Centers funding scheme. CHAPTER 6 the causes of epilepsy 69 References 21 . Shorvon SD . Introduction to the concept of symptomatic epilepsy . In: Shorvon SD , Andermann F , Guerrini R (eds) The Causes of Epilepsy. Common and Uncommon Cau ses in Adults and Children , pp. 113 \200\22330. Cambridge: Cambridge University Press , 20 11 . 1 . Shorvon SD , Andermann F , Guerrini R (eds) The Causes of Epilepsy. Common and Uncommon Causes in Adults and Children . Cambridge : Cambridge University Press , 2011 . [ The most comprehensive reference work on the topic of causation of epilepsy. Therein are detailed r eferences to most causes of epilepsy. Details in this chapter are taken from various contri butions and from the historical introduction of this reference work. 22 . Sloviter RS . 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Seizures were de \201 ned as partial if the \201 rst clinical and electroencephalographic (EEG) signs indi- cated that initial activation was limited to part of one cerebral hemisphere. Partial seizures were classi \201 ed in simple or complex on the basis of whether or not awareness was impaired during the attack. Seizures were conside red as generalized if the \201 rst clini- cal and EEG changes indicated the initial invol vement of both hemispheres. Since 1989, various attempts of revision of the 1989 classi \201 cation system have been m ade. In 1998 L ders and colleagues called for a seizure classi \201 cation based exclusiv ely on ictal clinical semiology, either as reported by the patients or observers or as docu mented directly during video monitoring ( 3 ). The classi \201 cation proposal was based o n the assumption that ictal symptoms were produced Table 7.1 International classi \201 cation of epileptic seizures Partial (focal, local) seizures I) Simple partial seizures (without impairment of consciousness): With motor signs With sensory symptoms With autonomic symptoms or signs With psychic sympto ms