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Murthy , and Ashalatha Radhakrishnan Introduction Together, epilepsy due to traumatic brain injury (TBI), brain tumors, cerebrov ascular disease (CVD), and central nervous system (CNS) infections comprise over one- \201 fth (20 % ) of cases of newly-diagnosed epilepsy ( 1 ). This estimate is based on data fro m a single community of Rochester, Minnesota in the United States. Although, this estimate might be different for other communities across the world, it provides suf \201 cient just i \201 cation to review the characteristics and management of epilepsy associated with eac h of these risk factors. In this chapter, each of the risk factors is dis- cussed with resp ect to the following: classi \201 cation and criteria, epidemiology, measurement and strat i \201 cation of risk of epilepsy, clinical characteristics, outcome, and speci \201 c ma nagement of epilepsy associated with each of the conditions. Classi \201 cation and criteria The term, \200\230traumatic brain injury \200\231 is pref erred to head injury as the latter is somewhat ambiguous and might include other craniofaci al injuries. Generally, TBI occurs in three different scenarios: road traf \201 c accident s, falls, and violence. It is customary to classify TBI according to its severity and the a natomical extent of damage (Table 20. 1 ). Classi \201 cation of severity is traditionally based on the Glasgow Coma Scale and the durations of loss of consciousness and post-trauma tic amnesia. The mildest form of TBI is concus- sion, which is a form of diffuse injury in the absence of contact damage and leads to transient impairment of consciousness only. A mo re serious form of diffuse injury is \200\230diffuse axonal injury \200\231, which represe nts severe angular or rotational injury. Focal injuries Table 20.1 Classi \201 cation of types of traumatic brain injury Traumatic brain injury It has been predicted that TBIs would surpass any other cause for de ath and disability by the year 2020 ( 2 ). In the US, TBI affects about 1.4 million people, and leaves 50,000 dead and 80,000 with long- term disability each year ( 3 ). The \201 g ures might be an underestimate as many cases of mild TBI either do not present to hospital or are discharged from the Emergency Department and as a result, remain undocumented. Moreo ver, de \201 nitions of various categories of TBI vary between studies and hence it is not possible to provide reliable estimates from the available studies. The \201 gures cannot be extrapo- lated to other countries and regions of the world on account of differences in socioeconomic, ethnic, and perhaps genetic composi- tions. If anything, the incidence of T BI appears to be higher in low- and middle-income countries of the world ( 4 , 5 ). In all, 5 million deaths worldwide might perhaps be a result of TBI each year ( 6 ). Classi \201 cation Type of injury 1 Diffuse: A Concussion B Diffuse axonal injury 2 Focal: A Contusion B Intracranial hemorrhage: (i) Epidural haematoma (ii) Subarachnoid hemorrhage (iii) Subdural haematoma (iv) Intracerebral haematoma oxford textbook of epilepsy and epileptic seizures 222 be elevated beyond 5 years also ( 10 ). Following more severe TBI, the risk is elevated con siderably and might remain elevated for a period much beyond 10 years of follow-up. In the Vietnam Head Injury Study, which is a prospective longitudinal follow-up study of over 35 y ears of US war veterans, the risk was highest in the \201 rst year after penetrating TBI and decreased exponentially thereafter, but remained elevated up to 15 years after head inj ury ( 11 , 12 ). The observations led the authors of the study to propose mathematical form ulas to calculate the risk of epilepsy at any given period of time following penetrating TB I ( 13 ). The overall incidence of post- traumatic epilepsy in the Vietnam Head Injury coho rt was 53 % . Thus, a clear distinction in terms of the risk of post-traumatic epi- lepsy c an be drawn in literature between civilian and military inju- ries. The high incidence of e pilepsy following military injuries is probably due to more frequent penetrating injuries a nd haemato- mas, haematoma-products or retained metal fragments in the cer- ebral parenchym a. In civilian injuries, the risk is proportional to the severity of TBI and in follow-up s tudies of severe TBI, the risk over the \201 rst 1 \200\2232 years is 15 \200\22330 % , r egardless of whether antiepilep- tic drug (AED) treatment is prescribed to the patient or n ot ( 14 , 15 ). In most follow-up studies, subjects with cerebral contusions and intracrani al haematomas have been included in the category of severe TBI and this practice differs fr om the ACRM criteria for grading of severity of TBI (see \200\230Classi \201 cation and c riteria \200\231 section). The risk appears to be highest among those with focal neurologic al de \201 cits, demonstrable brain contusions, and intracranial haemor- rhage (including subdural haematoma). The risk of post-traumatic epilepsy following mild TBI was not found t o be related to the occurrence of early post-traumatic seizures in the Olmsted County studi es and none of the subjects with mild TBI who had early sei- zures, went on to have late se izures or epilepsy in this cohort ( 8 , 9 ). In other studies however, those with early sei zures particularly in relation to severe TBI were found to be at increased risk of devel- o ping epilepsy ( 16 , 17 ). These differences might re \202 ect the dispa- rate mechanisms underlying seizures following mild and more severe TBI ( 16 ). Age, gender and family histo ry of epilepsy also appear to in \202 uence the risk of developing late post-traumatic sei - zures and epilepsy ( 10 ). The risk possibly appears to be lesser in children and increas es beyond the age of 65 years ( 8 \200\22310 ). Female gender and a family history of epile psy are risk factors identi \201 ed in some of the population studies of post-traumatic ep ilepsy ( 9 , 10 ). might be classi \201 ed as either contusions (comprised of subpial swelling and collection of blood) or intracranial hemorrhage (including epidural haematoma, subdural haematoma, su barach- noid hemorrhage, and intracerebral hemorrhage). Other injury- related terms include coup injury in which the contusion is located below the site of impact and countre coup , in which the injury is located opposite to the site of impact. Another term, laceration, re fers to a tear in the pia matter. The American Congress of Rehabilitation Medicine (ACRM) de \201 nes mild TBI as any period of transient confusion, disorienta- tion, impairment (or loss) of consciousness, or amnesi a lasting for less than 30 minutes with or without other neurological symptoms and signs su ch as seizures, headache and focal neurological de \201 cits ( 7 ). \200\230More severe T BI \200\231 is de \201 ned as either loss of consciousness for more than 30 minutes or dur ation of amnesia more than 24 hours or penetrating cerebral injury. According to these de \201 nitions, the presence of focal neurological de \201 cit (implying focal brain lesions such as either contusion or hemorrhage) or the demonstration of intracranial lesion/s on n euroimaging studies can occur in mild TBI and does not necessarily qualify for \200\230mor e severe TBI \200\231. However, from the standpoint of risk strati \201 cation with regard to the incidence of post-traumatic epilepsy, the criteria for severity of TBI used in vari ous epidemiological studies of TBI and epilepsy are somewhat different from the ACRM recomm ended de \201 nitions ( 8 \200\22310 ). In these studies, much importance has been accorde d to the presence of cerebral contusions, focal neurological de \201 cits, depressed skull fractures, and intracerebral haematomas as predic- tive factors for post-traumatic epileps y. 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