Immediate, early, and late seizures and epilepsy in relation to TBI Seizures may occur imme diately after, or early (within 7 days) or later (after 7 days) following TBI. Immediate se izures (also known as impact convulsions or concussive convulsions) occur at the time of in jury and consist of few focal or generalized myoclonic jerks or sometimes frank generalized tonic \200\223clonic convulsions. They are generally regarded as non-epileptic as they are probably the result of transient loss of cortical inhibition at the time of injury or due to brainstem activation and do not carry any increased risk of late sei- zures. Early seizu res (within 7 days of TBI) occur in about 2 % of all TBIs. The risk of early seizures in \200\230more severe TBI \200\231 is 10 \200\22330 % . The risk of late unprovoked seizures (beyond 7 days) is about 2 % , though estimates in the literature vary on account of differ ences in criteria for selection of TBI samples and for de \201 nition of late sei- zures. Nearly two-thirds of late post-traumatic seizures evolve in to epilepsy (de \201 ned as tw o or more unprovoked seizures). Some of late seizures after TBI might be provoked and in th is context, etha- nol-withdrawal seizures are signi \201 cant, having accounted for nearly 10 % of all late post-traumatic seizures in one series ( 8 ). An increased incidence of et hanol-withdrawal seizures might simply be a re \202 ection of the association between etha nol use and TBI. Course and outcome of post-traumatic epilepsy The cumulative risk of a second seizure follo wing an unprovoked, late post-traumatic seizure is about 75 % ( 18 ). A follow-up study est imated that roughly 30 % of individuals with a late post- traumatic seizure would experienc e at least 10 seizures over the next 10 years ( 18 ). In the Vietnam Head Injury Study, rou ghly half of the individuals with a late post-traumatic seizure following pen- etrating TBI continued to have seizures 15 years after the injury ( 11 , 12 ). Precisely what proportio n of those with a \201 rst late post- traumatic seizure eventually develops intractable e pilepsy and what proportion goes into long-term remission are not known as only very few lo ng-term follow-up studies of post-traumatic epilepsy are available. Risk strati \201 cation for post-traumatic epilepsy The risk of epilepsy following TBI dep ends on several factors, many of which have been dealed with in considerable detail in avai lable studies ( 8 \200\22313 ). The most important determinant of the incidence of post-tra umatic epilepsy appears to be the severity of TBI. The risk of epilepsy is marginally incre ased following mild TBI for at least 5 years, although in some studies, the risk has been s hown to Early post-traumatic seizures are often of the focal motor or generalized, tonic \200\223cl onic type. However, late post-traumatic epi- lepsy manifests with complex partial seizures in as many as 30 % of cases ( 12 ). Few small series of patients who underwent surgical CHAPTER 20 epilepsy due to tbi, cvd, cns infections, and brain tumors 223 How haemosiderin contributes to epileptogenicity is unclear but peroxidation reactions are likely to be involved in the process ( 23 ). The \201 nding of heterotopic neurons in bra in specimens resected during surgery for medically-refractory post-traumatic epilepsy remai ns controversial as microscopic dysplasia might pre-exist and be detected incidentally. It has been conjectured that these pre-ex- isting heterotopias might contribute to the epilept ogenicity of the post-traumatic lesions in the brain. treatment for intractable epilepsy in relation to TBI are available but nothing conclusive can be gathered from these studies as these are descriptions of highly-selected patients mo stly from tertiary- care centers ( 19 \200\22321 ). Limited data available also suggests th at people with post-traumatic epilepsy experience increased mortal- ity rates in comparison to the general population ( 22 ). Traumatic brain injury: association with mesial temporal sclerosis Data from highly-selecte d series of intractable epilepsy have shown that there is a proportion of patients with rad iologically- and often pathologically-veri \201 ed mesial temporal sclerosis (MTS) in whom there is no identi \201 able initial precipitating illness other than TBI ( 19 \200\22321 ). In one such report, all patients with MTS had sustained head injuries before the age of 5 years, while in other reports, the age at which the TBI was sustained was well beyond 10 years of age ( 19 , 20 , 23 ). It remains a matter of speculation, whether in the individu - als with later-life TBI and MTS, the association is causal or merely coincidental (i.e. T BI was antedated by the MTS and it merely her- alded the seizure disorder). In the Olmsted County community, TBI (in addition to other antecedents such as childhood febrile sei- zure s, viral encephalitis, and a family history of epilepsy) was identi- \201 ed as an import ant risk factor for complex partial seizures, although the strength of association was not as strong as childhood febrile seizures ( 24 ). In this community, 12 % of complex partial seizures were attributable to TBI and 20 % to childhood febrile seizures. In clinical pract ice, there is a proportion of cases with MTS that have no other identi \201 able anteceden t risk factor other than TBI, suggest- ing a cause \200\223effect relationship between TBI and MTS. Non-epileptic seizures and TBI Antecedent TBI has been reported in one-third of cases of no n- epileptic seizures (NES) ( 30 ). The injury is most often mild as opposed to the relatio nship between TBI and epileptic seizures, for which the strength of the association increas es with severity of TBI. Another characteristic feature is that individuals reporting NES f ol- lowing head injury are mostly males as opposed to NES in relation to physical and sexua l abuse, which are commonly encountered among women. In individuals with prior TBI, NES rep resent a means of obtaining enduring disability bene \201 ts or \201 nancial compensatio n for the injury at workplace or otherwise. The mechanisms underlying the occurrence of NES following TBI are unclear but might include susceptibility of the injured brain to behavio ral disorders. Post-traumatic epilepsy: treatment considerations The practice of administering anticonvuls ants to patients with head injury regardless of whether they have seizures or not at any st age is widespread. The Quality Standards Subcommittee of the American Academy of Neurology and others have reviewed avail- able studies of AED administration following TBI ( 31 , 32 ). Pooled evidence from four trials of AED prophylaxis in severe TBI (two class I studies o f phenytoin, one class II study of carbamazepine and one class III study of phenytoin) show ed a signi \201 cantly reduced rate of early (<7 days) seizures in the treated group versu s the control group (relative risk: 0.37; 95 % con \201 dence interval (CI) 0.18 \200\2230 .74) ( 32 ). There was no difference in the incidence of adverse effects in the treatment a nd control groups. In the same meta-analysis, pooled data from eight trials of AED treatmen t for the prevention of late post-traumatic seizures (including two class I studies of phen ytoin, three class II studies \200\224 one each of pheny- toin, carbamazepine, and valproa te, and three class III studies \200\224 of phenytoin and phenobarbital), showed no differ ence in the inci- dence of late post-traumatic seizures between the treated and con- trol g roups ( 32 ). It is recommended that for adults with severe TBI, prophylactic treatment sho uld begin with a loading dose of pheny- toin as soon as possible after injury in order to d ecrease the risk of early seizures (in the \201 rst 7 days). Further treatment beyond 7 d ays does not reduce the incidence of late post-traumatic seizures and is not recommended. T hese recommendations do not apply for mild TBI in which case, AED prophylaxis might be cons idered on a case- by-case basis, largely determined by the occurrence of early post- trauma tic seizures. Since the risk of seizure recurrence following a late unprovoked post-traumat ic seizure is higher than 75 % , AED treatment is generally indicated after a single late u nprovoked post- traumatic seizure ( 18 ). The choice of AED largely depends upon the patien t characteristics and side-effect pro \201 le of the AED used. These recommendations are b ased on studies performed with the conventional AEDs (including phenytoin, phenobarbital, c ar- bamazepine, and valproate). The role of the newer AEDs (particu- larly levetiracetam) i n preventing unprovoked late post-traumatic The pathophysiological events that might lead to development of MTS after TBI are unclear. It is unlikely that the hippocampus gets involved directly during TBI episodes because it i s located deeply and is hence well protected. Hippocampal involvement is more likely to be due to secondary damage during or after TBI, e.g. the effect of early seizures and status e pilepticus, hypoxia, intracra- nial hypertension, cerebral circulatory impairment, and exci totoxic damage. Indeed, autopsy studies of fatal TBI, corroborated by experimental studies in animals have documented bilateral hip- pocampal pathology in the form of selective necro sis and loss of neurons in the CA1 sub \201 eld of the hippocampus in majority of the case s ( 25 \200\22328 ). In the rat \202 uid percussion model, which is used to study TBI-rel ated epileptogenesis, the electrical disinhibition is preferentially located in the hilar r egion of the dentate gyrus in comparison to the CA1 sub \201 eld ( 29 ). Pathological stud ies have also shown preferential loss of neurons in the hilar region in the rat \202 uid percussion model. Likewise, an elegant study of human tem- poral lobectomy specimens obtain ed from surgery for intractable epilepsy in relation to TBI showed preferential loss of neu rons in the hilar region as opposed to the CA1 sub \201 eld, which is typically found to b e involved in pathological studies of hippocampal scle- rosis in relation to childhood febr ile seizures ( 23 ). The histological \201 ndings in TBI are thus more or less similar to end folium sclero- sis. Elsewhere, however, preferential loss of neurons in the CA1 sub \201 eld in has been reported in TBI-related MTS ( 21 ). Post-traumatic epilepsy: other pathological substrates Other than MTS, pathological examina tion of resected specimens of the brain obtained after surgery for medically-refractory pos t- traumatic epilepsy have mostly shown gliosis and haemosiderin deposition either in the m esial temporal or neocortical location. oxford textbook of epilepsy and epileptic seizures 224 As alluded to earlier, estimates of the incidence of early seizures following stroke vary. In the Oxfordshire Community project, the incidence of onset seizures (within 24 hours) was 2 % ( 37 ). The incidence was higher in other studies as the time criteria for early seizu res was up to 1 \200\2232 weeks and many of the other studies were hospital-based and hence had a bias towards more severe stroke ( 42 \200\22344 ). One report stated an incidence of 43 % but this was per- haps due to the highly-selected nature of the patient population ( 45 ). Over 90 % of early seizures and 40 % of all stroke-related sei- zures occur within th e \201 rst 24 hours ( 43 , 44 ). seizures is worth considering especially in light of its demonstrated antiepileptogenic eff ects in animal experiments. Two small, pre- liminary controlled trials demonstrated that it s administration in TBI is safe and of equivalent ef \201 cacy in comparison to phenytoin for the prevention of early seizures ( 33 , 34 ). An undetermined proportion of individuals with post-traumatic epilepsy continue to experien ce seizures that might be refractory to medical treatment. Presurgical evaluation and surgi cal treatment should be considered in such individuals. When imaging studies in such indivi duals unequivocally demonstrate unilateral MTS, the chances of seizure remission following surgery are excellent, though some authors have described slightly less favorable surgical out- come in MTS with TBI as an antecedent ( 19 \200\22321 , 35 ). When MTS is not demonstr ated, the surgical outcome is less favorable; it is comparatively better with focal, discre te lesions amenable to resec- tion in comparison to extensive or multifocal lesions ( 20 ). The 5-year cumulative probability of a late stroke-related seizure varies from 7 \200\22312 % ( 37 , 43 ). Half of the late seizures can be expected to occur within the \201 rst ye ar after stroke. The incidence of epilepsy following stroke is about 2 \200\2234 % ( 37 , 4 3 , 46 , 47 ). Risk factors for stroke-related epilepsy include the type, loca- tion and size of the brain lesion/s. Although stroke-related epi- lepsy occurs mostly in the elderly, within this eld erly group age appears to have no effect on the incidence of epilepsy ( 37 , 43 ). In one s tudy, however, younger age was identi \201 ed as a signi \201 cant risk factor for epilep sy ( 47 ). The risk of stroke-related epilepsy appears to be higher following intracerebral hemorrhage and subarachnoid hemorrhage ( 37 , 43 , 48 ). Epilepsy after subarach- noid hem orrhage appears to be more frequent among individu- als with subdural haematoma and/or foca l cerebral infarcts ( 49 ). Regardless of the type of stroke, i.e. whether intracerebral ha em- orrhage or ischaemic stroke, the risk of stroke-related epilepsy is elevated mainly in those with cortically-located lesions. The size of the lesion also determines the propensit y to epilepsy; in the Oxfordshire Community Stroke project, the risk was highest in total a nterior circulation occlusions, followed by partial anterior circulation occlusions, lacuna r occlusions, and posterior circula- tion occlusions in that order ( 37 ). It has not been determined whether among all posterior circulation strokes, the risk is differ- ent for cer ebral cortical infarcts and brainstem/cerebellar infarcts. In most studies, stroke survivor s who were independent at dis- charge from hospital or at 1 or 6 months did not appear to h ave an increased risk of late seizures or epilepsy ( 37 , 44 ). Lacunar infarcts and basal ganglionic hemorrhages do not appear to increase the risk of epilepsy; however there have b een documented cases of late seizures in both conditions; these are probably due to concomi - tant cortical vascular lesions ( 37 ). In most studies, early stroke- related seizures or onset seizures were found to increase the risk of late seizures or epilepsy ( 43 ). A stud y examined the effect of treat- ment setting, between a specialized stroke unit and a gener al med- ical ward and found no effect of this variable on the incidence of epilepsy ( 47 ). Another study found that the cumulative risk of late seizures in subjects with recurrent s trokes was higher after but not before 10 years when compared to those with a single stroke epi- sode suggesting that recurrent stroke increases the risk of epilepsy over the long te rm ( 43 ). A post-stroke epilepsy risk scale has been proposed but needs further validation ( 50 ). Perhaps the effects of more variables such as haemorrhagic conversion of cerebral inf- arcts and magnetic resonance imaging (MRI) characteristics of the vascular lesion and the effect of interventions such as throm- bolysis need to be examined in the evaluation of the risk of epi- lepsy. Finally, the occurrence of venous infarcts due to cerebral venous thrombosis also appears to increase the risk of epilepsy but the magnitude of risk cannot b e determined due to the small number of reported cases ( 51 ). Cerebrovascular disease The occurrence of epileptic seizures in the aftermath of stroke has a devastating impact on patient outcome and might lead to hospi- talization, an increased cost of treatment, falls, and fractures, and very rarely even death. Besides the occurrence of epileptic seizures impacts the quality of life in general, which compounds upon the alr eady compromised quality of life due to stroke. Classi \201 cation As in the case of seizures in relation to TBI, post-stroke seizures are classi \201 ed as \200\230early \200\231 and \200\230late \200\231. However, unlike TBI , the time criteria for distinction between early and late epilepsy are not uniform. In dif ferent published studies, seizures occurring within 24 hours, 1 week, 2 weeks, or even 30 d ays of stroke have all been labeled as early seizures. As a result, the estimates of the in cidence of early versus late seizures following stroke vary. Epidemiology The causal association between CVD and epileptic seizures is well known. Five per cent of all new-onset epilepsies and 30 % of all epi- lepsies in the elderly ( > 60 yea rs) can be attributed to stroke ( 1 , 36 ). In the Olmsted County study, most of the epilep sies related to stroke occurred after the age of 70 years and none before the age of 50 yea rs ( 1 ). The incidence of seizures and epilepsy appears to be increased both in the period preceding and that following stroke. In the Oxfordshire Community project, 1 % of the subjects with stroke had a seizure in the preceding 1 year ( 37 ). The occurrence of sei- zures preceding stroke can be explained if one considers seizures to be a manifestation of occult CVD, i.e . silent or asymptomatic cere- bral infarcts or hemorrhages. Indeed, seizures and epilepsy have been documented to be presenting features of otherwise asympto- matic CVD ( 38 ). A sm all case \200\223control study found signi \201 cantly higher frequency of preceding seizu res among stroke patients in comparison to controls ( 39 ). Another study concluded that el derly people ( > 60 years) with newly-diagnosed epilepsy were nearly three times more likel y to have a stroke in comparison to the general population ( 40 ). These \201 ndings have led some authors to conclude that seizures might presage the usual manifestations of strok e in the elderly and that elderly people with newly-diagnosed epilepsy should be investigat ed for vascular risk factors for stroke ( 40 , 41 ). CHAPTER 20 epilepsy due to tbi, cvd, cns infections, and brain tumors 225 Course and outcome of stroke-related epilepsy One-half to two-thirds of those with a late u nprovoked stroke- related seizure would have another unprovoked seizure, but this risk is p robably less than the risk following an unprovoked late post-traumatic seizure ( 37 , 43 ). Frequent seizures amounting to intractability appears to be uncommon; in the Oxfordshire C ommunity Stroke project, 17 % of those with stroke-related epi- lepsy had seizures more fre quently than once a month ( 37 ). From the standpoint of semiology, both early and late str oke-related sei- zures are either simple partial or secondary-generalized seizures; complex partial seizures appear to be uncommon. Interesting but yet unanswered questions include w hether the occurrence of late unprovoked stroke-related seizures independently alter the ri sk of subsequent stroke or long-term mortality. A Norwegian study found increased mortality due to stroke in those with stroke- related epilepsy but the size of this cohort was small ( 46 ). There has been concern that the administration of some of the conventional AEDs, particular ly phenobarbital, benzodiazepines, and phenytoin might negatively in \202 uence motor and perhaps cog- nitive recovery following stroke ( 61 ). Indeed, small studies of pat- ents wi th intracerebral and sub-arachnoid hemorrhage have shown that administration of a short cou rse of phenytoin was asso- ciated with poor motor and cognitive recovery during or after ho s- pitalization ( 62 , 63 ). The newer anticonvulsants, some of which are neuroprotective ( e.g. levetiracetam) might be theoretically advan- tageous but little is known about their e f \201 cacy, safety, and their effect on long-term motor and cognitive outcomes. Choice of AEDs following late unprovoked stroke-related seizures There are no large randomi zed-controlled trials of AEDs in stroke- related epilepsy. A limited number of small, uncon trolled, and open-labeled studies (of levetiracetam and gabapentin) have shown that seizure s are well-controlled over follow-up periods of 12 \200\22330 months in stroke-related epil epsy ( 64 , 65 ). Randomized-controlled trials of AEDs in stroke-related epilepsy are not a vailable. Since stroke is an important risk factor for epilepsy in the elderly, it is perti nent to review randomized trials of AEDs in elderly people with epilepsy. A randomized, par allel trial comparing monotherapy with gabapentin (1500 mg/day), lamotrigine (150 mg/day), and carbamazepine (600 mg/day) in which cerebral infarction was the most common etiology of seizures found signi \201 cantly higher retention rates in the lamotrigine and gabapentin groups in com- parison to the carbamazepine group at 1 year ( 66 ). Ef \201 cacy (seizure control) was similar in all three groups, implying that both lamot- rigine and gabapentin had superior tolerability pro \201 les. The UK Lamotrigine Elderly Study compared lamotrig ine (100 mg/day) with carbamazepine (400 mg/day) and reported greater drop-out rates due to adverse effects with carbamazepine (42 % ) in compari- son to lamotrigine (18 % ) ( 67 ). Another small, open-labeled trial compared lamotrigine with sustained-release carbamazepine in patients with a \201 rst post-stroke seizure (excluding the \201 rst 24 hours) and found better seizure control rates and lesser adverse effects with lamotrigine ( 68 ). Fina lly, a fourth randomized trial compared lamotrigine (target dose: 100 mg/day) with sustaine d- release carbamazepine (target dose: 400 mg/day) and found no sig- ni \201 cant differen ce in ef \201 cacy and tolerability of the two AEDs ( 69 ). From the available controlled and uncontrolled trials of various AEDs in elderly people with epilepsy, it appears that go od seizure control is achieved with the usual AEDs in approximately 80 % of stroke-related epilepsies; however, since seizure control is not very dif \201 cult, tolerability becomes an important issue. With regard to tolerability, lamotrigine (100 \200\223150 mg/day), gab apentin (up to 1500 mg/day) and sustained-release (400 mg/day) (but not immediate- release) carbamazepine appear to be well-tolerated in the elderly. Stroke-related epilepsy: treatment considerations Early seizures The European Stroke Initia tive and the American Stroke Association/American Heart Association recommend that routine primary prophylaxis with AEDs is generally not indicated in intrac- erebral hemorrhage but might be considered in selected patients with lobar hemorrhage ( 52 , 53 ). If instituted, the AED treatment should be given for 1 week. Otherwise, AED treatment is indicated only if early seizures occur and in such instances, the AEDs might be given for 4 weeks ( 53 ). Th ere is no role for primary prophylaxis with AEDs in ischaemic stroke. When AEDs are indicat ed, intrave- nously administered AEDs including benzodiazepines and pheny- toin or fos-phen ytoin should be preferred. Some of the newer AEDs (e.g. levetiracetam) might have neuroprot ective effects by counteracting excitatory neurotransmitters that are highly active during acute stroke ( 54 ). There is preliminary evidence of the use- fulness of levetiracetam in preventing stroke-related seizures but clearly, this is an area for future research ( 55 ). Effect of seizures and AEDs on stroke outcome and functional status It is unclear whether t he occurrence of early seizures independently in \202 uences functional status following s troke as measured by the modi \201 ed Rankin \200\231s Scale upon discharge from hospital or later. Some hospital-based studies of selected patients have shown that early seizures i ncrease mortality or the likelihood of poor func- tional outcome but have not adjusted outc ome measures for stroke severity ( 39 , 44 ). Hence, it is possible that the higher mortali ty rates or the poorer functional outcome in stroke patients with early sei- zures might be a re \202 ection of stroke severity as more severe strokes are associated with an increas ed likelihood of occurrence of sei- zures. Likewise, it remains unclear whether status epil epticus has an independent effect on mortality and outcome of stroke as small studies of se lected patients have shown contrasting effects on short- term mortality ( 56 \200\22358 ). While expectedly, late unprovoked stroke- related seizures might adversely impact quality o f life in general as well the rehabilitation process following stroke by leading to poten- tial hospitalization and falls and fractures as well as a temporary decline in functional s tatus postictally, at least one follow-up study demonstrated that the occurrence of late se izures did not have any impact on the long-term functional outcome ( 59 , 60 ). Among the newer AEDs, topiramate is best avoided in view of its propensity to cause cogniti ve impairments, worsening of speech disorder in aphasic subjects and sometimes also motor d e \201 cit in hemiplegics ( 70 , 71 ). There is no data available regarding the use of oth er newer AEDs, including levetiracetam and lacosamide in stroke-related epilepsy. Theoretic ally, these drugs do not have any known pharmacokinetic interactions with other medications . This might represent a signi \201 cant advantage for many people with stroke-related epi lepsy, who are often on multiple drugs with potential for drug interactions with AEDs. oxford textbook of epilepsy and epileptic seizures 226 Central nervous system infections Seizures and status epilepticus can occur during the acti ve phase of infectious disorders of the CNS and recurrent unprovoked seizures (or epilepsy) can be a long-term consequence of CNS infections. The interpretation of the association be tween CNS infections and epilepsy is complicated by the variety of known acute and chronic infectious disorders. In the Swedish nationwide retrospective study of HSE, the most fre- quent diagnosis upon re admission following an episode of HSE was epilepsy. A diagnosis of epilepsy on follow-up wa s documented in 21 % of the entire cohort and 24 % of survivors, with a median onset of 9 m onths after the diagnosis of HSE ( 85 ). Factors associated with a high risk of epilepsy in clude early seizures, anatomical involve- ment of hippocampal regions and associated change s in hippocam- pal excitability, and chronic, persistent herpes simplex virus infection or immunoreactivity in the CNS during HSE ( 86 \200\22388 ). Epidemiology The risk of an unprovoked seizures increases 11-fold after an episode of CNS i nfection ( 72 ). In population-based cohorts of sur- vivors of all CNS infections, the repo rted risk of developing an unprovoked seizure is 6.8 \200\2238.3 % , corresponding to an ob served:expected ratio of 6.9 ( 72 , 73 ). The increased incidence of unprovoked seizures is highest during the initial 5 years after the infection episode but remains elevated over t he next 15 years ( 72 ). In the general population of high-income countries, about 1 \200 \2235 % of incident cases of epilepsy might be presumed to be related to prior CNS infectio n ( 74 \200\22376 ). CNS infections have been cited as one of the reasons for the higher in cidence of epilepsy observed in low- and middle-income countries of the world ( 77 \200\223 80 ). In an Ecuadorian study, CNS infections were the antecedent events in 4.5 % of cases o f epilepsy ( 81 ); in sub-Saharan Africa, they accounted for 26 % of putative risk factors for epilepsy ( 78 ); and \201 nally, in a hospital-based study from south India, these ac counted for 24.5 % of established remote symptomatic aetiologies of focal epilepsies ( 82 ) . Malaria Malaria is the most common parasitic disease and is a major public health problem i n much of the sub-Saharan Africa and parts of South and Southeast Asia and South America. T he estimated number of cases across the world each is 225 million with approxi- mately 800, 000 deaths thereof every year. Cerebral malaria, the neurological form of malaria, is a pot ential cause of epilepsy in the countries endemic to malaria. In sub-Saharan Africa, cerebr al malaria is estimated to affect 600,000 children (<5 years of age) each year ( 89 ). Stud ies that have examined the association between cerebral malaria and epilepsy suggest a mode stly-strong associa- tion between the two ( 90 ). Neurocysticercosis (including calci \201 c neurocysticercosis) Cerebral infestation with t he larval form of the pork tapeworm, Taenia solium , is endemic in many regions of the worl d including South and Central America and South and Southeast Asia and Africa. Cerebral cal ci \201 cations, essentially constituting presumptive evidence of brain parenchymal involv ement by cysticerci, are common \201 ndings on imaging studies in people with epilepsy in T. solium -endemic populations in these regions (Fig. 20. 2 ). Accumulating evidence impli cates calci \201 c neurocysticercosis in the development and maintenance of seizures and e pilepsy ( 91 ). In rural Guatemalan communities, calci \201 cations alone were more freque nt in those with epileptic seizures compared to matched controls without history of seizure s (35 \200\22336 % versus 9 \200\22315 % ) ( 92 ). Epilepsy was etiologically related to ca lci \201 c neurocysticercosis in 8 % of cases in a hospital-based study in south India, an d in 9.6 % of new-onset epilepsy cases in Ecuador ( 82 , 93 ). The prevalence of epilepsy a ssociated with calci \201 c neurocysticercosis was 0.9 \200\2231.0 per 1000 in a populatio n-based survey in south India ( 94 , 95 ). There is evidence to suggest that calci \201 c neurocysticercosis can be the focus of seizure activity. Electroclinical activity correlate s with the loca- tion of brain calci \201 cations in 26 \200\22355 % of the cases ( 96-98 ). The other evidence implicating calci \201 cations as foci of seizure activity is the ep isodic appearance of perilesional oedema often associated with seizures ( 91 , 99 ). Speci \201 c CNS infections The nature of epileptic complication depends on the type of th e infectious illness, its duration, characteristics, and extent of CNS damage. Bacterial meningitis Epilepsy can be a long-term consequence of bacterial meningitis ( 83 ) . In the Olmsted County cohort of survivors of bacterial men- ingitis, the 20-year risk of developing unprovoked seizures was 13 % in those with early seizures and 2 % in those witho ut an early seizure ( 72 ). A meta-analysis of the 19 prospective cohorts of bac- terial me ningitis in children aged between 2 months and 19 years from developed countries found that the mean probability of developing an unprovoked seizure was 4.2 % . In cohorts that were either retrospectively assembled or from developing countries, the mean probability was 5 % ( 84 ). The likelihood of developing unprovoked seizures probably varies according to the aetiologi cal agent responsible for meningi- tis; it appears to be highest for meningitis caused by S treptococcus pneumoniae (14.8 % ) and is comparatively lower following Haemophilus in \202 uenzae (6.1 % ) and Neisseria meningitides menin- gitis (1.4 % ) ( 84 ). The risk factors for late epilepsy include early sei- zures during acute phase and persistent neurological d e \201 cits other than sensorineural hearing loss ( 83 ). Three possible scenarios exist with regard to the relationship between calci \201 c neuroc ysticercosis and epilepsy: ( 1 ) a non-causal relationship, i.e. simple coincidence of two unrelated diseases in the same individual; ( 2 ) a causal relationship; and ( 3 ) dual path ol- ogy. However, calci \201 c neurocysticercosis does not appear to be a risk factor for medically-intractable epilepsy. In a cross-sectional study of the 512 patients with intract able epilepsy, calci \201 c neuro- cysticercosis was found in eight (1.6 % ) patients, but a clear rela- tionship between calci \201 ed cysticercotic lesions and intractable epilep sy was con \201 rmed in only two (0.4 % ) patients ( 100 ). In one small series, perilesio nal gliosis in relation to a calci \201 c neurocyst- icercus lesion was associated with me dically-intractable epilepsy (K. Radhakrishnan, personal communication). Encephalitis For patients with viral encephalitis, the risk of epilepsy is increased 16-fol d and the increased risk persists for at least 15 years after the episode. In the Olmsted C ounty study, the 20-year risk of unpro- voked seizures was 22 % in those with early seizure s and 10 % in those without early seizures ( 72 ). Epilepsy is one of the common consequenc es of herpes simplex encephalitis (HSE) (Fig. 20. 1 A \200\223D). CHAPTER 20 epilepsy due to tbi, cvd, cns infections, and brain tumors 227 A B C D Fig. 20.1 A \200\223D) Serial MRIs in an individual with presumed herpes simplex encephalit is showing (A) bilateral mesial temporal hyperintensities (more on the right side) on a cor onal T2-weighted image during the acute encephalitic illness and follow-up \202 uid atten uated inversion recovery (FLAIR) (B) and T2-weighted (C) images obtained 3 years later demo nstrating right-sided hippocampal atrophy and sclerosis. Following the encephalitic episode , this individual developed medically-refractory complex partial seizures that were demonst rated to be of right anterior temporal origin on EEG telemetry (D). She remains seizure fre e after standard right antero-mesial temporal lobe resection. Courtesy: Epilepsia with perm ission. Seizure type and semiology Epileptic seizures following CNS infections can be both focal-on set and generalized ( 72 , 101 , 102 ). In the Olmsted County study, the risk of focal-onse t seizures after any CNS infection was increased by 12-fold, while that of generalized-onse t seizures was increased by 3-fold ( 72 ). Myoclonic seizures might also occur ( 101 ). The sei- zure semiology includes automotor seizures, complex motor/ hypermotor seizures, diale ptic seizures, tonic seizures and bilateral asymmetric tonic-clonic seizures. In patients w ith MTS in relation to CNS infection, the seizure semiology is similar to mesial tempo- ral lobe epilepsy associated with other antecedents ( 103 ). action and the side-effect and interaction pro \201 les of the drug. Tolerability is as im portant as ef \201 cacy in determining overall effec- tiveness of the AED. Broad-spectrum AEDs with least cognitive side-effects should be the initial choice; such an approach will be very useful in situations where the seizure type or the epilepsy syn- drome is uncertain . Initial treatment should be with monotherapy and treatment with two or three but not more A EDs may be a useful therapeutic option for patients not responding to monotherapy. Patients who do not attain long-term seizure freedom with the \201 rst three treat- ment schedule s are likely to have refractory epilepsy and such patients are potential candidates for epi lepsy surgery ( 104 , 105 ). There are virtually no data on the long-term prognosis of epi- lepsy related to CNS infecti ons. Remission rates following AED therapy are perhaps similar to other symptomatic epileps ies. The remission rate in patients with epilepsy related to bacterial menin- gitis is abou t 50 % ( 101 ). Remission rates for epilepsy associated Medical treatment The choice of antiepileptic drugs (AEDs) for people with epilepsy related to CNS infections depends on the seizure type and epilepsy syndrome and also takes into co nsideration the mechanism of oxford textbook of epilepsy and epileptic seizures 228 the onset of epilepsy, and seizure-onset localized to one temporal lobe ( 103 , 107 \200 \223111 ). Conversely, postoperative seizure outcome is not favorable in those without a de monstrable focal lesion on MRI, having a short latency period to epilepsy, later age ( > 5 years) at the time of CNS infection, history of encephalitis, or a neocorti- cal origin of seizures ( 72 , 107 \200\223111 ). An association of calci \201 c neurocysticercosis with MTS has been reported by several au thors ( 100 , 113 ). When compared to patients with isolated MTS, those with calci \201 c neurocysticercosis and ipsi- lateral MTS have a lower incidence of febrile seizures, older age at initial precipitating injury or \201 rst seizure, older age at onset of complex pa rtial seizures, higher rates of seizure clustering, and extratemporal/bitemporal interictal discharges. Although prelimi- nary, these observations suggest that MTS associated with ca lci \201 c neurocysticercosis might have a different pathophysiological basis than isolate d MTS. The hypothesis needs to be proven with longi- tudinal follow-up studies. The surgica l approach to a patient with MTS and calcific neurocysticercosis is unclear. In one study, patients underwent anteromesial temporal lobectomy, without resection of the cysticercotic lesion and were rendered seizure free ( 113 ). Others, however, have reported better outcom es following anteromesial temporal lobe resections combined with resection of the calci \201 c lesion (K. Radhakrishnan, personal communication). Fig. 20.2 Computed tomography image showing multiple calci \201 cations as well as cystic lesions in a patient with neurocysticercosis. Brain tumors Epilepsy is one of the most characteristic manifestations of brain tumors and it can signi \201 cantly affect the quality of life of patients with brain tumors. Tumoura l epilepsy is considered to be symp- tomatic, localization-related and manifests as focal o r partial sei- zures with or without alteration of consciousness and/or secondary generaliz ation. with calci \201 c neurocysticercosis is about 72 % (95 % CI 53.7 \200\22385.4) at 3 years and 66 % at 5 years (95 % CI 32.4 \200\22388.2) ( 96 ). As with other symptomatic epilepsie s, prior CNS infection reduces the chance of successful AED withdrawal following a period o f remission in people with epilepsy ( 106 ). High seizure relapse rates in patients with ep ilepsy related to calci \201 ed neurocysticercosis have been reported ( 96 ). Epidemiology of tumoural epilepsy The incidence of epilepsy in patients with brain tumors i s about 30 % ( 114 ). This incidence depends largely on the tumor type (see \200\230Tumor type \200\231 section) (Table 20. 2 ). Epilepsy is often the sole pre- senting manifestatio n of low-grade benign tumors. In contrast, high-grade malignant tumors present with a mixtu re of symptoms and signs including focal neurological de \201 cits, raised intracranial pr essure, and seizures. In population-based samples, brain tumors are the cause of about 4 % of all new-onset epilepsies ( 115 , 116 ). From a different perspective, seizures are the p resenting manifesta- tion in about one-third of the cases of brain tumors ( 117 , 118 ). Epilepsy surgery Surgery is a good option in selected patients with medically-refrac- tory epilepsy related to prior CNS infections, especially in those with discrete, resectable les ions. Common surgical substrates in epilepsy related to CNS infections include hippocampal sclerosis, calci \201 c neurocysticercosis and neocortical gliosis ( 72 , 107 \200\223113 ) (K. Radhakrishnan, personal communication).