The \201 rst landmark epidemiological study of epilepsy was con- ducted in 1959 by Leonar d T. Kurland and colleagues who reported population-based data from Rochester, Minnesota, U SA, over a 10-year period ( 29 ). Early epidemiological studies that followed from Kurland \200\231s work contributed substantially to our current understanding of epilepsy. Addition al studies exploring the Rochester longitudinal population-based data sets provided an evid ence base of the occurrence and prognosis of epilepsy that CHAPTER 5 definitions and epidemiology of epilepsy 53 100,000 person-years ( 44 ). In Africa, studies reported age-adjusted incidence of epilepsy of 51 per 100,000 in Tanzania ( 12 ) and 43 per 100,000 in Ethiopia ( 45 ). Table 5. 2 presents age-adjusted prevalence of epilepsy in studies that used door-to-door s urvey methodology worldwide. In the North American studies, the prevalence was 5.0 in New Y ork ( 48 ) and 7.1 per 1000 ( 49 ) in Mississippi. In Central and South America, the overal l prevalence ranged from 3.7 per 1000 in Argentina ( 50 ) to 22.2 per 1000 in Ecuador ( 51 ). Real differences in prevalence may be related to the presence of endemic conditions such as neu- rocysticercosis or malaria, the medical infrastructure in place, including availab ility of preventive regional health programs, and accessible local medical care. A region w hich has eradicated the porcine tapeworm, has established effective malaria prevention stra tegies, or has established immunization programs, can reduce or minimize risk factors assoc iated with epilepsy ( 52 ). In Europe, prevalence was low, 2.7 per 1000 and 3.3 per 1000, r espec- tively in each study conducted in Italy ( 53 , 54 ), when compared to a prevalence o f 7.0 per 1000 in the study conducted in the European region of Turkey ( 55 ). In contrast to the majority of studies con- ducted in Asia, the prevalence of 10.2 per 1000 in Asian Tu rkey ( 56 ) Point prevalence is the proportion of individuals in the popula- tion who are affected by a health condition at a single point in time, usually designated as a speci \201 c day. It is useful for indicating the degree of disease burden in a population. With epilepsy, the p oint prevalence of active epilepsy is typically considered of most interest ( 6 ). A pletho ra of studies has been made of the prevalence of epi- lepsy in many different settings and it has usually been found to be 4 \200\22310 per 1000 persons ( 26 ). Most large-scale stud ies of popula- tions in resource-poor countries have reported prevalence rates for active e pilepsy of 6 \200\22310 per 1,000; many of these studies have, how- ever, reported differen t rates for urban and rural areas, usually with higher rates in the latter ( 11 , 30 , 31 , 46 , 47 ). The differences seem unlikely to be artefactual or attributable to differential case ascer- tainment between regions as many of these studies used identical methods, stud y design, and diagnostic con \201 rmation in each area. Table 5.1 Incidence of epilepsy in population based studies of all ages worldwide Region Publication year (reference) Gender Population Number of cases Incidence (per 100,000 population) Crude Age-adjusted to 2000 US standard population North America Rochester, MN 1935 \200\22344 1993 ( 24 ) M > F 245,969 94 38 41 Rochester, MN 1945 \200\22354 1993 ( 24 ) M > F 282,452 142 50 49 Rochester, MN 1955 \200\22364 1993 ( 24 ) M > F 384,881 187 45 44 Rochester, MN 1965 \200\22374 1993 ( 24 ) M > F 516,903 182 35 36 Rochester, MN 1975 \200\22384 1993 ( 24 ) M > F 573,152 275 48 51 Texas 1999 ( 117 ) M > F 601,448 197 33 28 New York 2008 ( 41 ) M > F 279,677 82 15 16 Central and South America Chile 1992 ( 42 ) M > F 90,596 102 113 111 Europe England 1966 ( 118 ) \200\223 497,707 141 29 28 Norway 1974 ( 43 ) M > F 213,116 70 33 26 Italy 1983 ( 119 ) M > F 697,000 230 33 33 Faroes 1986 ( 120 ) M > F 452,584 194 43 37 Iceland 1996 ( 121 ) M > F 90,237 42 47 43 England 2000 ( 33 ) \200\223 100,230 46 46 47 Netherlands 2002 ( 34 ) M > F 316,828 94 30 29 Iceland 2005 ( 122 ) M > F 882,151 290 33 31 Asia India 1998 ( 44 ) M > F 64,963 32 49 35 Africa Tanzania 1992 ( 12 ) \200\223 165,684 122 73 51 Ethiopia 1997 ( 45 ) M > F 215,901 139 64 43 From Banerjee et al. ( 52 ). oxford textbook of epilepsy and epileptic seizures 54 Table 5.2 Age-adjusted prevalence of epilepsy in studies that used door-to-door survey meth odology worldwide Region Publication year (reference number) Gender Population Number of cases Prevalence (per 1000 population) Crude Age-adjusted to 2000 US standard population North America Mississippi 1986 ( 49 ) M > F 23,597 160 6.8 7.1 2007 ( 48 ) a M < F 208,301 42 5.2 5.0 New York Central and South America Ecuador 1985 ( 51 ) M < F 1113 19 17.1 22.2 Ecuador 1992 ( 46 ) M < F 72,121 575 8.0 9.1 5 b 22.6 11.4 Ecuador 1997 ( 123 ) M > F 221 Bolivia 1999 ( 124 ) M < F 10,124 112 11.1 14.0 Honduras 2005 ( 125 ) M < F 6473 100 15.4 16.0 Argentina 2007 ( 50 ) M < F 17,049 64 3.8 3.7 Europe Italy 1996 ( 53 ) M < F 9956 27 2.7 2.7 Italy 2001 ( 54 ) M > F 24,496 81 3.3 3.3 Turkey 2002 ( 55 ) M > F 2817 17 6.0 7.0 Asia China 1985 ( 61 ) M > F 63,195 289 4.6 4.4 India 1988 1988 ( 58 ) M > F 63,645 157 2.5 2.2 India 1988 ( 59 ) M > F 14,010 50 3.6 3.6 Pakistan 1997 ( 57 ) M < F 24,130 241 9.9 9.8 Turkey c 1997 ( 57 ) M > F 11,497 81 7.0 6.6 Turkey c 1999 ( 56 ) M > F 4803 49 10.2 10.2 India 2000 2000 ( 60 ) M > F 238,102 1,175 4.9 4.4 Saudi Arabia 2001 ( 126 ) M > F 23,700 155 6.5 5.1 Africa Nigeria 1982 ( 127 ) M < F 903 33 37 41.0 Nigeria 1987 ( 128 ) M < F 18,954 101 5.3 4.9 Nigeria 1989 ( 8 ) M < F 2925 18 6.2 4.7 Ethiopia 1990 ( 129 ) M > F 60,820 316 5.2 5.4 Tanzania 1992 ( 12 ) M < F 18,183 185 10.2 12.5 Tunisia 1993 ( 130 ) M > F 35,370 141 4.0 3.9 Kenya 1994 ( 131 ) M > F 7450 (5 + ) 30 4.0 3.7 Uganda 1996 ( 132 ) M < F 4743 61 12.9 9.2 Zambia 2004 ( 10 ) M > F 55,000 799 14.5 13.2 Tanzania 2005 ( 133 ) M > F 4905 42 8.6 6.8 Paci \201 c Islands Guam 1968 ( 134 ) \200\223 6967 16 2.3 2.7 a This study was done using random-digit dial methodology in the Northern Manhattan communi ty. A follow-up interview was administered to those who screened positive for epilepsy over the telephone. Epileptologists reviewed all information from interviews to determine whether each potentia l case was actually a case. b All 5 cases were between 7 \200\22314 years of age. c These s tudies were conducted in a region of Turkey that is geographically part of Asia. However, t he population may be more comparable to the western region of Turkey, which is part of Europe. From Banerjee et al. ( 52 ). CHAPTER 5 definitions and epidemiology of epilepsy 55 Death in people with epilepsy can be classi \201 ed into three groups: epilepsy-related de aths, deaths related to the underlying cause of the epilepsy, and deaths that are unrelated to the epilepsy or its underlying etiology (Table 5. 3 ) ( 84 ). The PMRs for epilepsy- re lated conditions range from 1 \200\22345 % ( 63 , 76 , 78 , 80 , 82 , 84 ). was higher than that reported in studies conducted in Pakistan, India, and China, where pre valence ranged from 2.2 \200\2234.4 per 1000 ( 57 \200\22361 ). Lifetime prevalence is the risk of having a non-febrile epileptic seizure at some point in an average lifetime. In both industrialized and resource-poor countries, up to 5 % of a pop ulation will experi- ence non-febrile seizures at some point in life ( 30 , 31 ). From the difference between lifetime prevalence and the point prevalence of active epilepsy it is ap parent that most patients developing epilepsy will either cease to have seizures or die ( 6 2 ). It is likely that in most patients the condition remits. Epilepsy, however, is associa ted with increased mortality particularly, but not exclusively, in sympto- matic cases ( 63 \200\22365 ). Patients with chronic epilepsy are most at risk but the impact of mortality on the prevalence of epilepsy and the extent to which the difference in lifetime and point prevalence rates is due to mortality has not yet been fully appraised. SUDEP is de \201 ned as a sudden, unexpected, witnessed or unwit- nessed, non-traumatic, a nd non-drowning death in patients with epilepsy, with or without evidence of seizure and ex cluding docu- mented SE, in which postmortem examination does not reveal a toxicological or anatomical cause of death ( 85 ). The reported inci- dence of SUDEP has ranged from 0.35 \200\2239.3 per 1000 person-years depending on the different study population and methodolo gies employed ( 86 ). The incidence of death for young adults with intractable epilepsy is many times that of the general population, with a peak between the ages of 20 \200\22340 ye ars ( 87 ). SE accounts for between 0.5 \200\22310 % of all deaths in epilepsy, with a SMR of 2.8 (95 % con \201 dence interval (CI) 2.1 \200\2233.5) ( 88 ). The CFR from SE was reported as 7.6 \200\22322 % for short-term mortality (within 30 days of SE) ( 89 \200\22393 ) and 43 % fo r long-term mortality (30 days after SE to 10 years) ( 88 ). Mortality Different measures are used to estimate mortality, depending upon the study desig n and available information on deaths. The meas- ures include mortality rate, case fatality , standardized mortality ratio, and proportionate mortality. People with epilepsy may sustain a fatal accident either during a seizure or as a consequen ce of a seizure. Accidental deaths related to epilepsy are commonly due to drowning, traf \201 c accidents, trauma, falls, burns, or aspiration. Based on attendance records of 4 acc ident and emergency departments, the risk of injury as a result of a seizure was estimated to be 29.5 per 100,000 per year ( 94 ). Mortality rate is the number of deaths that occur in the de \201 ned population divided by the person-years at risk in that population, and can be an indirect estimator of severity ( 66 ). People with epi- lepsy have a mortality rate 2 \200\2233 times higher than that of the general population ( 67 ). Mortality rate from epilepsy shows a small peak in early lif e, which possibly re \202 ects the mortality of those children with severe hypoxic-ischaem ic encephalopathy, brain malforma- tions, and inherited metabolic disorders. The risk then falls to a minimum around the age of 10 years. It rises again in late adoles- cence and ear ly adulthood before leveling off throughout most of adult life. There is a late peak of epi lepsy-related mortality in old age, presumably secondary to CVD ( 68 ). Table 5.3 Causes of death in epilepsy Unrelated deaths Neoplasms outside the central nervous system Ischaemic heart disease Pneumonia Mortality is best expressed as the standardized mortality ratio (SMR), the ratio of the obs erved number of deaths in an epilepsy population to that expected based on the age- and sex -speci \201 c mortality rates in a reference population, in a given time. The pro- portion al mortality ratio (PMR), the proportion of deaths due to a particular cause in a cohort of patients in a given period, can be used to compare the relative contribution of various ca uses to the overall mortality in the population. Case fatality rate (CFR), the number of de aths caused by a disease divided by the number of diagnosed cases of the disease, can also be used to describe the severity of mortality ( 5 , 69 ). Others Related to underlying disease Brain tumors Cerebrovascular disease Cerebral infection \200\224 abscesses and encephalitis Inherited disorders, e.g. Batten disease Epilepsy-related deaths Suicides Treatment-related deaths In large cohort studies of patients over 15 years, SMRs ranging from 2.1 \200\2235.1 were r eported ( 63 , 70 \200\22373 ). The majority of deaths in people whose seizures start in ch ildhood occur in adulthood. Prospective studies in which children with large sample size we re followed for 15 to more than 30 years reported higher SMRs of 8.8 \200\22313.2 ( 74 \200 \22377 ). For patients with epilepsy, population-based studies demonstrate PMRs of 12 \200 \22339 % for CVD, 12 \200\22337 % for ischaemic heart disease (IHD), 18 \200\22340 % for ne oplasia (including brain tumors), 9 \200\22315 % for brain tumors, 8 \200\22318 % for pneum onia, 0 \200\2237 % for suicides, 0 \200\22312 % for accidents, 0 \200\2234 % for sudden un ex- pected death in epilepsy (SUDEP), 0 \200\22310 % for seizure-related causes (including SE), and 5 \200\22330 % for other causes ( 63 , 78 \200\22383 ). Idiosyncratic drug reactions Medication adverse effects Seizure-related deaths Status epilepticus Trauma, burns, drowning Asphyxiation, aspiration Aspiration pneumonia after a seizure Sudden unexpected death in epilepsy From Nashef and Shorvon ( 84 ). oxford textbook of epilepsy and epileptic seizures 56 northern Ecuador and who had never received AED treatment were seizure free for at least 12 months ( 112 ). A recent study from rural Bolivia reported 43.7 % of untreated epilepsy ca ses were seizure free for more than 5 years when the cohort was revisited after 10 years ( 113 ). Besides developing countries, spontaneous remission of epi- lepsy has also been obse rved in developed countries. In a Finnish study, it was found that 42 % of 33 untreated epi lepsy patients entered a 2-year remission within 10 years after onset ( 114 ). Accident-related deaths in people with epilepsy comprise 1.2 \200\2236.5 % of all deaths in community-based studies ( 63 , 74 , 82 ) and 7.3 \200\22342 % in selected population studi es with SMRs ranging from 2.4 \200\2235.6 ( 67 , 71 , 95 \200\223101 ). People with epileps y have an increased risk of drowning with SMR of 5.4 \200\22396.9 that varied depending on the study population ( 102 ). Studies performed during the 1970s and 1980s demonstrated tha t the suicide PMRs range from 0 \200\22320 % and the SMRs from 1 \200\2235.8 ( 103 \200\223 105 ). Common non-epileptic causes of death cited in mortality studies include neoplasia, CVD, IHD , and pneumonia. Reports have noted increased SMR for malignant neoplasia of the lung, panc reas, hepa- tobiliary system, breast, and lymphoid and haematopoietic tissue ( 89 ). Cancer accounts for 16 \200\22329 % of deaths with reported SMRs ranging from 3.4 \200\2235.4 ( 7 0 , 96 , 98 ); although in one study, hospital- ized patients with epilepsy appeared to be at much higher risk, with a reported SMR of 29.9 ( 71 ). The SMR for neoplasia remains at 1 .4 \200\2232.5 even when CNS tumors are excluded ( 63 , 71 , 72 , 78 , 96 ). The SMR for al l cancers in an institutional cohort with more severe epilepsy (SMR 1.42; 95 % CI 1.18 \200 \2231.69) was higher than that for the milder cases in a community-based population (SMR 0. 93; 95 % CI 0.84 \200\2231.03). The SMR for brain and CNS neoplasms was signi \201 - cantl y elevated in the group with milder epilepsy ( 106 ). Prognosis of intractable epilepsy Only 5 \200\22310 % of all incidence cases of epilepsy ul timately result in truly intractable disease. These cases probably account for half the pre valence cases of epilepsy. Approximately 60 % of patients with intractable epilepsy can be expected to suffer from partial seizures. Studies suggest that failure to control seizures with the \201 rst or second AED implies that the probability of subsequent seizure contro l with further AEDs is only about 4 % ( 110 ). Recent studies reported that approximately 5 % per year of patients with intracta- ble epilepsy were seizure free for 12 months followi ng medication changes. This \201 nding highlights the fact that, irrespective of the numb er of previous AEDs, there is still a small possibility of induc- ing meaningful seizure re mission in the population ( 115 , 116 ). Prognosis of epilepsy Remission of treated epilepsy Given that in developed countries antie pileptic medication is usu- ally commenced after two unprovoked seizures, prognostic studie s from Western countries are essentially those of treated epilepsy. A landmark study of the natural history of treated epilepsy was a community-based project carried out in Rochester , Minnesota, USA. The probability of being in remission for 5 years at 20 years after diagn osis (terminal remission) was 75 % ( 107 ). The National General Practice Study of Epilepsy (NGPSE) conducted in the UK reported that, when patients with acute symptomatic seizures a nd those who had only one seizure were excluded, 60 % had achieved a 5-year remission by 9 years of follow up ( 108 , 109 ). Other modern large-scale studies that include only newly diagnosed patients fol- lowed for long periods also tend to suggest a remission rate of 60 \200\22390 % ( 110 ). At a conservative estimate, at least 60 % of newly diagnosed patients will enter long-term remission on treatment initiation, and approximately 50 % of these pa tients will remain in remission after antiepileptic medication withdrawal. A long-term stud y of newly diagnosed patients in Glasgow, Scotland demon- strated that, among the 470 patie nts who had never previously received antiepileptic drug (AED) treatment, 64 % entered term i- nal remission of at least 1 year, including 47 % of patients who became and remained sei zure-free on the \201 rst drug, 13 % on the second drug, but only 4 % on the third drug o r a combination of two drugs. Thus, response to the \201 rst AED was the most powerful pr edictor of prognosis ( 111 ). References 1 . Shorvon SD , Farmer PJ . Epilepsy in developing countries: a review of epidemiological, sociocultural, and treatment aspects . Epilepsia 1988 : 29 (Suppl. 1 ): 36 \200\223 54 . 2 . Leonardi M , Ustun B . The global burden of epilepsy . 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