2. Commission on Classi \201 cation and Terminology of the International League Against Epilepsy . Proposal for revised classi \201 cation of epilepsies and epilep tic syndromes . Epilepsia 1989 ; 30 ( 4 ): 389 \200\223 99 . 3. Shorvon SD . The etiologic classi \201 cation of epilepsy . Epilepsia 2011 ; 52 ( 6 ): 1052 \200\223 7 . 4. Bleck TP , Smith MC , Pierre-Louis SJ , Jares JJ , Murray J , Hansen CA . Neurologic com plications of critical medical illnesses . Crit Care Med 1993 ; 21 ( 1 ): 98 \200\223 103 . 5. Neligan A , Shorvon SD . Frequency and prognosis of status epilepticus of different causes: a systematic review . Arch Neurol 2010 ; 67 ( 8 ): 931 \200\223 40 . 6. Menon B , Shorvon SD . Electrolyte and sugar disturbances . In: Shorvon SD , Andermann F , Guerrini R (eds) The Causes of Epilepsy , pp. 655 \200\223 63 . Cambridge : Cambridge U niversity Press , 2011 . 7. Delanty N , Vaughan CJ , French JA . Medical causes of seizures . Lancet 1998 ; 352 ( 9125 ): 383 \200\223 90 . 8. Brouns R , De Deyn PP . Neurological complications in renal review: a review . Clin Neurol Neurosurg 2004 ; 107 ( 1 ): 1 \200\223 16 . 9. Palmer CA . Neurologic manifestations of renal disease . Neurol Clin 2002 ; 20 ( 1 ): 23 \200\223 34 . 10. Danlami ZT , Obeid T , Awada A , Huraib S , Iqbal A . Absence status; an overlooked cau se of acute confusion in haemodialysis patients . J Nephrol 1998 ; 11 ( 3 ): 146 \200\223 7 . 11. Canavese C , Morellini V , Lazzarich E , Brustia M , Quaglia M , Stratta P . Seizures a nd renal failure: is there a link? Nephrol Dial Transplant 2005 ; 20 ( 12 ): 2855 \200\223 7 . Autoimmune encephalitis Seizures are a common feature of the newly described CNS autoim- mu ne diseases presenting with limbic or more diffuse encephalitis or encephalopathy ( 45 ). S eizures occur in almost all cases of limbic encephalitis and three-quarters of cases of ant i-NMDA receptor encephalitis ( 45 , 46 ). Voltage-gated potassium channel (VGKC)- complex/L gi1 antibodies can present with a distinctive seizure semi- ology typically involving the f ace and ipsilateral arm (faciobrachial dystonic seizures). These seizures may occur prior t o the onset of the typical limbic encephalitis ( 47 ). In a study of the causes of encepha- litis in 203 patients in England, seizures were much more common with antibody associated causes compared to other causes of encephalitis ((14/16 (88 % ); 95 % CI 62 \200\22398) ver sus (24/38 (63 % ); 95 % CI 46 \200\22378, p <0.001) for herpes simplex virus encephalitis) ( 48 ). Seizures are often refractory to standard antiepileptic medication and often progr ess to status epilepticus. Effective management of the seizures involves immunotherapy (cor ticosteroids, intravenous immunoglobulin, or plasma exchange), tumor removal (in cases of c on \201 rmed paraneoplastic immune mediated encephalitis), and antiepileptic medication. O verall more than three-quarters of people with anti-NMDAR encephalitis will respond to trea tment although many are left with signi \201 cant cognitive dysfunction and a long-term po tential for seizures persists ( 45 , 46 ). 12. Glenn CM , Astley SJ , Watkins SL . Dialysis-associated seizures in children and adoles cents . Pediatr Nephrol 1992 ; 6 ( 2 ): 182 \200\223 6 . 13. Arieff AI . Dialysis disequil ibrium syndrome: Current concepts on pathogenesis and prevention . Kidney Int 1944 ; 45 ( 3 ): 629 \200\223 45 . 14. Eschbach JW , Abdulhadi MH , Browne JK, Delano BG , Downing MR , Egrie JC , et al . Rec ombinant human erythropoietin in anemic patients with end-stage renal disease . Ann Intern Med 1989 ; 111 ( 12 ): 992 \200\223 1000 . 15. Strippoli GFM , Craig JC , Manno C , Schena FP . Hemoglobin targets for the anemia of chronic kidney disease: A meta-analysis of randomized, controlled trials . J Am Soc Nephrol 2004 ; 15 ( 12 ): 3154 \200\223 65 . 16. Delanty N , Vaughan C , Frucht S , Stubgen P . Erythropoietin-associated hypertensive posterior leukoencephalopathy . Neurology 1997 ; 49 ( 3 ): 686 \200\223 9 . 17. Seliger SL , Gillen DL , Longstreth WT , Kestenbaum B , Stehman-Breen CO . Elevated ris k of stroke among patients with end-stage renal disease . Kidney Int 2003 ; 64 ( 2 ): 603 \200\223 9 . 18. Abramson JL , Jurkovitz CT , Vaccarino V , Weinstraub WS , McClellan W . Chronic kidney disease, anemia, and incident stroke in a middle-aged, communi ty-based population: The ARIC Study . Kidney Int 2003 ; 64 ( 2 ): 610 \200\223 5 . 19. McEnery PT , Nathan J , Bates SR , Daniels SR . Convulsions in children undergoing transplantation . J Pediatr 1989 ; 115 ( 4 ): 532 \200\223 6 . 20. Awan AQ , Lewis MA , Postlethwaite RJ , Webb NA . Seizures following renal transplantation in childhood . Pediatr Nephrol 1999 ; 13 ( 4 ): 275 \200\223 7 . 21. Gerber A , Karch H , Allerberger F , Verweyen HM , Zimmerhackl LB . Clinical course and role of shiga toxin-producing Escherichia coli infection in the haemolytic-uraemic syndrom e in pediatric patients, In summary, seizures can occur in the context of many systemic conditions particularly rena l and hepatic dysfunction. In the oxford textbook of epilepsy and epileptic seizures 244 36. Gaida-Hommernick B , Rieck K , Runge U . Oxcarbazepine in focal epilepsy and hepatic po rphyria: A case report . Epilepsia 2001 ; 42 ( 6 ): 793 \200\223 5 . 1997-2000, in Germany and Austria: a prospective study . J Infect Dis 2002 ; 186 ( 4 ): 493 \200\223 500 . 22. Bale JF Jr , Brasher C , Siegler RL . CNS manifestations of the 37. Mikdashi J , Krumholz A , Handwerger H . Factors at diagnosis predict haemolytic-uraemic syndrome. Relationship to metabolic alterations and prognosis . Am J Dis Child 1980 ; 134 ( 9 ): 869 \200\223 72 . subsequent occurrence of seizures in systemic lupus erythematosus . Neurology 2005 ; 64 ( 1 2 ): 2102 \200\223 7 . 23. Garg AX , Suri RS , Barrowman N , Rehman F , Matsell D , Rosas- 38. Appenzeller S , Cendes F , Costallat LTL . Epileptic seizures in systemic Arellano MP , et al . Long-term renal prognosis of diarrhea-associated haemolytic uraemic s yndrome: A systematic review, meta-analysis, and meta-regression . JAMA 2003 ; 290 ( 10 ): 1360 \200\223 70 . lupus erythematosus . Neurology 2004 ; 63 ( 10 ): 1808 \200\223 12 . 39. Andrade RM , Alarc n GS , Gonz lez LA , Fern ndez M , Apte M , Vil LM , et al . Seizures in patients with systemic lupus erythematosus: data from LUMINA, a mu ltiethnic cohort (LUMINA LIV) . Ann Rheum Dis 2008 ; 67 ( 6 ): 829 \200\223 34 . 24. Dhuna A , Pascual-Leone A , Talwar D , Torres F . EEG and seizures in children with haemolytic \200\223uraemic syndrome . Epilepsia 1992 ; 33 ( 3 ): 482 \200 \223 6 . 40. Malik S , Bruner GR , Williams-Weese C , Feo L , Sco \201 eld RH , Reichlin M , et al . Presence of anti-La autoantibody is associated with a lower risk of nephritis and seizure s in lupus patients . Lupus 2007 ; 16 ( 11 ): 863 \200\223 6 . 25. Lacerda G , Krummel T , Sabourdy C , Ryvlin P , Hirsch E . Optimizing therapy of seizur es in patients with renal or hepatic dysfunction . Neurology 2006 ; 67 ( 12, Suppl 4 ): S28 \200\223 33 . 26. Israni RK , Kasbekar N , Haynes K , Berns JS . Use of antiepileptic drugs in patients w ith kidney disease . Semin Dial 2006 ; 19 ( 5 ): 408 \200\223 16 . 27. De Schoenmakere G , De Waele J , Terryn W , Deweweire M , Verstraete A , Hoste E , et al . Phenytoin intoxicat ion in critically ill patients . Am J Kid Dis 2005 ; 45 ( 1 ): 189 \200\223 92 . 41. Hinchey J , Chaves C , Appignani B , Breen J , Pao L , Wang A , et al . A reversible posterior leukoencephalopathy syndrome . New Eng J Med 1996 ; 334 ( 8 ): 494 \200\223 500 . 42. Lee VH , Wijdicks EF , Manno EM , Rabinstein AA . Clinical spectrum of reversible poste rior leukoencephalopathy syndrome . Arch Neurol 2007 ; 65 ( 2 ): 205 \200\223 10 . 28. Zhang C , Glenn DG , Bell WL , O \200\231Donovan CA . Gabapentin-induced myoclonus in end-stage renal disease . Epilepsia 2005 ; 46 ( 1 ): 156 \200\223 8 . 43. Kozak OS , Wijdicks EF , Manno EM , Miley JT , Rabinstein AA . Status 29. Eleftheriadis N , Fourla E , Eleftheriadis D , Karlovasitou A . Status epilepticus as initial manifestation of posterior reversible encephalopathy syndrome . Neur ology 2007 ; 69 ( 9 ): 894 \200\223 7 . epilepticus as a manifestation of hepatic encephalopathy . Acta Neurol Scand 2003 ; 107 ( 2 ): 142 \200\223 4 . 44. Roth C , Ferbert A . Posterior reversible encephalopathy syndrome: 30. Bhatia V , Batra Y , Acharya SK . Prophylactic phenytoin does not improve cerebral oede ma or survival in acute liver failure \200\224 a controlled clinical trail . J Hepatol 200 4 ; 41 ( 1 ): 89 \200\223 96 . long-term follow-up . J Neurol Neurosurg Psychiatry 2010 ; 81 ( 7 ): 773 \200\223 7 . 45. Lunn MPT . In \202 ammatory and immunological diseases of the nervous system . In: Sho rvon SD , Andermann F , Guerrini R (eds) The Causes of Epilepsy , pp. 585 \200\223 92 . Ca mbridge : Cambridge University Press , 2011 46. Dalmau J , Lancaster E , Martinez-Hernandez E , Rosenfeld MR , Balice- 31. Dening TR , Berrios GE , Walshe M . Wilson \200\231s disease and epilepsy . Brain 1988 ; 111 ( 5 ): 1139 \200\223 55 . 32. Prashanth LK , Sinha S , Tally AB , Mahadevan A , Shankar SK . Spectrum of epilepsy in Wilson \200\231s disease with electroencephalographic, MR imaging and pathological correlat es . J Neurol Sci 2010 ; 291 ( 1 \200\2232 ): 44 \200\223 51 . 33. Wijdicks EFM , Plevak D J , Wiesner RH , Steers JL . Causes and outcome of seizures in liver transplant recipients . Neurology 1996 ; 47 ( 6 ): 1523 \200\223 5 . Gordon R . Clinical experience and laboratory investigations in patients with anti-NMDAR en cephalitis . Lancet Neurol 2011 ; 10 ( 1 ): 63 \200\223 74 . 47. Irani SR , Mitchell A , L ang B , Pettingill P , Waters P , Johnson MR , et al . Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis . Ann Neurol 2011 ; 69 ( 5 ): 892 \200\223 900 . 34. Menegaux F , Keeffe EB , Andrews BT , Egawa H , Monge H , Concepcion W , et al . Neurological complications of liver transplantation in adult versus pediatric patients . Transplantation 1994 ; 58 ( 4 ): 447 \200\223 50 . 48. Granerod J , Ambrose HE , Davies NW , Clewley JP , Walsh AL , Morgan D , et al . Causes of encephalitis and differences in their clinical presentations i n England: a multicentre, population-based prospective study . Lancet Infect Dis 2010 ; 10 ( 12 ), 835 \200\223 44 . 35. Anderson GD . Pharmacogenetics and enzyme induction/inhibition properties of antiepileptic drugs . Neurology 2004 ; 63 ( 10, Suppl 4 ): S3 \200\223 8 . CHAPTER 22 Management of Patients with First Seizure and Early Epilepsy Zachary Grinspan and Shlomo Sh innar Introduction Clinical and epidemiological research over the past 30 years has established a rational approach to the evaluation and treatment for an individual presenting with seizur es. For patients with single sei- zures and early epilepsy (excluding epileptic encephalopa thy), antiepileptic drug (AED) therapy reduces seizure recurrence risk, but it does not alt er the underlying disease process, overturning Gower \200\231s idea that in epilepsy \200 \230the tendency of the disease is to self- perpetuation \200\231 ( 1 ), i.e. seizures bege t seizures. In most cases, treat- ment with AEDs can be safely deferred after a single unpr ovoked seizure. For patients with early epilepsy (i.e. those with two or more unprovoked se izures), treatment is usually indicated, given the morbidity of recurrent seizures. This ch apter will review the ration- ale for withholding treatment in children and adults with a s ingle unprovoked seizure as well as the approach to treating an individ- ual with early epi lepsy. Treatment of epileptic encephalopathy (which requires aggressive management from ons et) and medically refractory epilepsy are covered elsewhere in this volume. etiology, abnormal electroencephalogram (EEG), and seizure while asleep. The data are less consistent on the effect of other fac- tors, such as age of onset, number of seizures in 24 hours, duration of seizure, type of seizure, family history, and prior history of febrile seizures. These should not be considered to confer additional risk ( 16 , 20 , 21 ). The etiology of unprovoked seizures is classi \201 ed as remote symptomatic (i.e. due to a n underlying structural or metabolic abnormality), idiopathic (i.e. probably genetic), or c ryptogenic (i.e. unknown cause) ( 22 , 23 ). Unsurprisingly, most studies \201 nd patient s with a remote symptomatic etiology have increased risk for recurrence. A meta-analysis of studies prior to 1991 found a relative risk of 1.8 (95 % con \201 dence interval (CI) 1.5 \200\2232.1) suggest- ing a 57 % recurrence risk for patients with a remote symptomatic et iology and 32 % for those without ( 5 ). Except for the FIR.S.T. (First Seizure Trial Group ) trial ( 7 ), subsequent multivariable analyzes have repeatedly con \201 rmed the increas ed risk in this group ( 13 , 14 , 17 , 24 ). Most studies report that an abnormal EEG predicts increased risk for recurrence ( 5 , 8 , 9 , 11 , 14 , 24 ). The effect is uniformly found in children and is more pronounced in pati ents with idio- pathic or cryptogenic etiology ( 5 , 11 , 12 , 14 \200\22317 , 21 ). Epilep tiform abnormalities are probably more important than slow wave abnor- malities ( 8 , 17 , 19 , 25 ), but any EEG abnormality predicts increased risk ( 5 , 14 , 21 , 24 ). Single seizure Overview and natural history Patients with a single unprovoked seizure make up one-third to one-half of initial of \201 ce visits for seizure ( 2 ). They form a disti nct group with a lower risk of recurrence than those who initially present with multiple se izures, i.e. with new onset epilepsy. The de \201 nition of one seizure in this case inclu des a single seizure or a \202 urry of seizures in 24 hours in patients older than 1 mont h with- out prior unprovoked seizures ( 3 , 4 ). Studies investigating sleep state \201 nd that individuals who have a \201 rst seizure while asleep are more likely to have recurrences ( 12 , 14 ). This \201 nding appears ind ependent of the association of certain epilepsy syndromes with seizures in sleep. For examp le, even chil- dren with centrotemporal spikes meeting criteria for benign rolan- dic epile psy ( 26 ) have a higher risk of recurrence if their \201 rst seizure occurred in sleep ( 14 ). However, seizures that occur during sleep tend to recur in sleep ( 14 ) and are thus less likely to cause injury. Review of the natural history after one unprovoked seizure guides both evaluation and treat ment ( 5 \200\22319 ). Carefully excluding patients with prior seizures from studies before 1991 ( 5 ) and inte- grating recent studies ( 7 , 13 , 17 ) suggest a recurrence risk of 2 7 \200\22354 % . If seizures recur, most recur early, with approximately 50 % within 6 mont hs of the initial seizure, and 80 % within 2 years of the initial seizure ( 5 , 13 , 14 ). Later recurrences are unusual, but may occur up to 10 years after the initial event ( 14 , 16 ). Risks and bene \201 ts of treatment The decision to treat after a single seizure rests on weighing the risk of further seizures, estimated by the epidemiological and trial data, aga inst the risks of treatment, and typically favors watchful wait- ing as an initial strategy (Table 22.1 ). Risk factors for recurrence Only three factors consistently predict increased risk for seiz ure recurrence after a single unprovoked seizure: remote symptomatic Starting treatment after a \201 rst seizure reduces the risk of recur- rence, as demonstr ated in several trials comparing treatment with oxford textbook of epilepsy and epileptic seizures 246 Table 22.1 Balancing the risks of antiepileptic therapy versus seizures In the MESS trial, more patients complained of at least one adverse effect in the immediate treatment group than the delayed treatment group (39 % versus 31 % ). Furthermore, at 5 ye ars, 60 % in the immediate treatment group were still taking AEDs versus 41 % in delayed gr oup, suggesting patients who begin treatment early are more likely to remain on treatment, and are therefore at greater risk for chronic medication toxicities ( 13 ). Risk of antiepileptic drug therapy Risk of seizures Toxicity/injury Dose-related toxicity (i.e. ataxia) Falls Chronic toxicity (i.e. osteoporosis) Burns (bathing or cooking) The economic impact of AED therapy should also be considered, including both the cost of th e medication and time lost to doctor \200\231s visits and diagnostic testing. Idiosyncratic toxicity (i.e. drug rash) Drowning Teratogenicity Driving accidents Finally, there is the hidden side effect of being labeled. People who had a single seizure but do not take medication are considered healthy by themselves and society, whereas those taking a daily medication are considered to have a chronic disease, even if they have not h ad a seizure for many years. This concern is particularly important in children and adolesc ents, as the perception of chronic illness may negatively affect psychosocial development ( 39 , 40 ). Reduced fertility Fractures (especially in the elderly) SUDEP Higher cortical functioning Cognitive impairment Postictal confusion Behavioral dyscontrol (including aggression) Postictal aggression/psychosis Suicidality (especially with premorbid depression) Risks and bene \201 ts of deferring treatment The major risk of deferring medication after a \201 rst seizure or in early epilepsy is seizure recurrence. However, for patients wit h a single seizure, several observations temper the potential harm from a second seizure. Psychosocial Need for daily medication Fear of more seizures Stigma of chronic illness Stigma of seizures Of key importance, delaying treatment after a \201 rst seizure does not lead to chronic e pilepsy ( 13 , 18 , 28 , 29 , 41 \200\22346 ). In the MESS trial, for example, among the pa tients who presented with a single seizure, the percent seizure free between years 1 \200 \2233 was not statisti- cally different between the immediate and deferred treatment groups (74 % vs. 71 % ), and the percentage seizure free for 2 years by year 5 was identical at 9 2 % ( 13 ). In other words, delayed treatment did not affect remission. Additional evidence comes from the developing world, where limited availability of medications and poor access to care leads to treatment delays. Patients who receive medication after prolonged untreat ed epilepsy have the same response rates as patients treated shortly after the seizures beg in ( 44 , 45 ). Restrictions on school/social activities Loss of driving privileges Dif \201 culty providing childcare Economic/time Cost of medications Time lost from seizure and recovery Cost/time of medical testing Discrimination in employment Cost/time of physician visits Adapted from Shinnar and O \200\231Dell, 2008 ( 59 ). There is no convincing evidence that brief seizures cause brain damage ( 29 , 43 , 47 , 48 ). While there is substantial risk of injury in patients having many seizures, the risk fro m a single seizure is low ( 49 , 50 ). Interestingly, scalds and injuries were more common in the early treatment group of the MESS trial than in the deferred treatment group ( 13 ). In the elderly, increased risk for fractures with seizures should be considered in treatme nt decisions ( 51 ). watchful waiting ( 6 , 7 , 13 , 27 ). In the most recent and largest study from the UK, the MESS trial (Multicenter Trial for Early Epilepsy and Single Seizures), immediate treatment reduced seizure recur- rence from 26 % to 18 % at 6 months and from 39 % to 32 % at 2 year s ( 13 ). An older Italian study, the FIR.S.T. trial, focused only on generalized tonic \200\223clonic seizures and reported a 50 % reduction of recurrence risk associated with tr eatment ( 7 ). Of critical impor- tance, early treatment did not change long-term outcome ( i.e. remission rate) in either of these studies ( 13 , 28 ). Although 10 \200\22312 % of initial seizures present as status epilepticus ( 4 , 14 , 52 ) (de \201 ned as seizures lasting longer than 30 minutes, or recurrent seizures over more t han 30 minutes without return to neurological baseline between seizures), these patients do not have a higher risk of recurrence ( 53 ). However, should their seizures recur, these i ndividuals are at increased risk for a prolonged seizure ( 53 ). Therefore, while the autho rs recommend abortive therapy rather than chronic AED therapy in most cases, it is legitima te to consider that these patients require a somewhat different risk:bene \201 t assessmen t ( 29 ). Starting AED therapy entails several potential risks, primarily from medication side effect s. Like all medications, AEDs have dose related, idiosyncratic, and chronic side effects. T he chronic toxici- ties are particularly important to consider given the tendency for patie nts to stay on AEDs for several years. Many AEDs have adverse cognitive and behavioral side effects, which may affect school performance, speech \202 uency, and memory ( 29 \200 \22331 ). Women of childbearing age face issues of teratogenicity and negative repro- ducti ve and endocrine consequences from AED therapy. Long- term use of AEDs may decrease bone de nsity, particularly in women and in the elderly ( 32 \200\22336 ). Patients with comorbid d epres- sion may be at increased risk of self-harm and suicidal behavior, in particular with some of the newer AEDs ( 37 , 38 ). The risk of status epilepticus is often cited as a reason to treat individuals with a singl e seizure. However, for patients whose \201 rst seizure was self-limited, the risk of sta tus epilepticus is low. For exam- ple, in a prospective study of 407 children with a \201 rst unprovoked seizure, a subgroup of 137 children had a brief initial seizure and then re curred. Of these 137 second seizures, only 2 were status epilepticus CHAPTER 22 management of patients with first seizure and early epilepsy 247 The majority of patients with early epilepsy who are starting their \201 rst drug will ac hieve seizure freedom. Given that these patients may need years of treatment, medication se lection should prioritize safety and tolerability from within the spectrum of appropriate A EDs for the seizure type. For example, although phe- nobarbital and topiramate are both eff ective agents in a variety of circumstances, neither is widely used as \201 rst line ther apy because of adverse cognitive effects ( 31 , 64 ). ( 29 ). Similarly, in the MESS trial, only 2 of the 721 patients in the deferred treatment group experienced an episode of status epilepti- cus after enrolment ( 13 ). Furthermore, t he morbidity of status epi- lepticus is largely a function of etiology, and is usually low in patients with only a single unprovoked seizure ( 47 , 54 \200\22356 ). The effect of treatment on quality of life is mixed. In adults, loss of driving privileges is the most salient disadvantage of deferred treatment ( 57 ). In the MESS trial, more pati ents in the delayed treatment group did not hold a driver \200\231s license because of seiz ures (17 % vs. 10 % ) ( 58 ). However, other quality of life indicators, including general health, anxiety, depression, social restriction, feeling stigmatized, and paid work were no t statistically different between the two groups ( 58 ). In selecting the proper AED, seizure type is the most important factor to consider. The epi lepsy syndrome is next in importance, in that it predicts the expected length of therapy, a s well as the expected seizure types. Age, gender, comorbidities, and genetic background ea ch merit additional consideration, as they will in \202 u- ence the tolerability and safet y of the medication chosen. Cost also needs thought, as many people with epilepsy need year s of therapy, which may \201 nancially burden those who are uninsured or under-insured. For children and adolescents, we generally do not treat individu- als with a single unprovo ked seizure, even for patients with remote symptomatic etiology and an abnormal routine EEG . For some patients with a single seizure presenting as status epilepticus, an acceptable s trategy is to provide an abortive medication, such as rectal diazepam, and defer daily AED therapy. In all cases, the risks and bene \201 ts of early treatment versus deferred treat ment must be considered and tailored to the speci \201 c patient. In select patients the r isk bene \201 t assessment may favor treatment after even a single seizure, e.g. to reduce the risk of fractures in the elderly. Many early epilepsy patients will respond to AEDs at a relatively low dose ( 65 ). Therefor e, one should choose a reasonable target dose and increase it only if ineffective. A slow t itration schedule may delay achieving complete seizure freedom, but will minimize toxicity and often result in better outcomes. Several formal literature reviews, consensus guidelines, and surveys of expert opinion have been published with speci \201 c medi- cation recommendations for patients with new onset seizures ( 66 \200\223 71 ). As clinical experience grows with recently approved medicatio ns, and as new medications and formulations become available, these recommendations will ev olve. Second seizure After a second unprovoked seizure, the balance of risks and bene \201 ts sh ifts towards treatment. In both adults and children, the recurrence risk jumps to approxima tely 70 % ( 10 , 13 , 16 ). Remote symptomatic etiology confers additional risk after two s eizures and is also associated with an increased risk of developing intractable epilepsy ( 16 ). Interestingly, after two unprovoked seizures, abnor- mal EEG and sleep state no longe r affect the rate of recurrence ( 16 ). Although most patients should be treated after two unprovoked Seizure type and epilepsy syndrome Both seizure type and epilepsy syndrome are important in choos- ing an AED, but the primary consideration should be seizure type. There are no stro ng data indicating that a given seizure type will be more responsive to a particular drug i n one syndrome than another. For example, focal seizures in rolandic epilepsy are more like ly to respond to treatment than those in cortical dysplasia, but there are no compelling da ta to choose a different medication as \201 rst line in these two syndromes. Knowledge of the epilepsy syndrome pro- vides insight into the expected course of the disorder, includi ng the length of treatment, and the range of seizure types. For example, a patient with ben ign rolandic epilepsy may need medication only for a few years, whereas a patient with juve nile myoclonic epilepsy may need decades. A 10-year-old with juvenile absence epilepsy is m ore likely to have a tonic clonic convulsion than a 7-year-old with childhood absence epile psy. seizures, at least two potential exceptions deserve mention. It is common to defer treatment in school-aged children with idiopathic epilepsy syndromes who have infrequent and brief seizures, especially if at night (e.g. benign rolandic epilep sy). The morbidity of AED treatment in this group may outweigh the ben- e \201 ts. Further more, the recurrence risk is often age dependent and fades in adolescence ( 42 , 48 , 59 ). Although these children may have signi \201 cant psychosocial dif \201 culties ( 60 , 61 ), there are insuf \201 cient data to support the concept that treatment with conventiona l AEDs alters these comorbidities. Women of childbearing age who wish to conceive in the near future and who have only brief n on-convulsive events need to con- sider potential teratogenicity to the fetus from AEDs. Ho wever, seizures are more dangerous for the fetus and the mother than the AEDs ( 62 ), and t reatment is generally offered in this setting. Many of the new AEDs have fewer teratogenic effects ( 63 ), easing the decision to start treatment. For focal seizures, carbamazepine and oxcarbazepine are the most widely used \201 rst-lin e medications in both children and adults with newly diagnosed epilepsy, followed by lamotr igine, because of their ef \201 cacy and tolerability, based on clinical experience and we ll designed clinical trials ( 72 \200\22374 ). For generalized seizures, the choices depend on the seizure type and the syndrome. Valproat e remains the choice for the sympto- matic generalized epilepsies due to its ef \201 cacy ( 84 ), but is a prob- lematic drug in women of childbearing age. For these women, lamotrig ine is an attractive alternative, as is levetiracetam, which has been shown effective for j uvenile myoclonic epilepsy ( 75 \200\22377 ). In childhood absence epilepsy, ethosuximide h as superior ef \201 cacy and tolerability compared with lamotrigine and valproic acid in a Principles of antiepileptic drug therapy in early epilepsy Once the decision to treat has b een made, several factors guide the appropriate medication choice from among the many curre ntly available AEDs. oxford textbook of epilepsy and epileptic seizures 248 epilepsy tends to occur in young people and persist through the childbearing years. Treatme nt with AEDs, particularly with valp- roic acid, increases risk of birth defects and poor c ognitive out- comes in children exposed in utero ( 88 , 95 ). However, seizures during preg nancy, particularly convulsive seizures, are also associ- ated with adverse pregnancy outco mes ( 62 ). The American Academy of Neurology recommends folate supplementation for all wom en with epilepsy ( 88 , 89 ), though folate does not guarantee favorable pregnancy outcomes . As young women are likely to remain on AEDs for many years, it is important to consider t hese issues in all women of childbearing age, including adolescents, even if there are no i mmediate plans for having children. Most of the serious teratogenic effects occur early in pregnancy and so it is pru- dent to utilize medications that, if effective, will be appropr iate to continue during pregnancy. Fortunately, the majority of women with epilepsy are abl e to have successful pregnancies with good outcomes ( 62 ). double blind randomized head-to-head trial, and should be the \201 rst line therapy for t hese children ( 78 ). For other syndromes, the data are less clear. As more experience is gained with the newer drugs, some have moved from add-on therapy to \201 rst-line treatment. Levetiracetam, for example, is increasingly used as a \201 rst- line medication in focal and generalized epilepsies. Several medications may worsen seizures in patients with generalized epilepsy. Carbamazepin e, oxcarbazepine, tiagabine, vigabatrin, and gabapentin may exacerbate generalized seizures , occasionally causing absence or myoclonic status epilepticus ( 79 \200\22381 ), and shoul d be avoided as \201 rst line for generalized epi- lepsy. Lamotrigine, while effective in generalized seizures, may worsen myoclonic jerks ( 82 , 83 ). Age Children, adolescents, and the elderly each require special consid- eration in choosing a medication. Contraception is also an important issue for women with epi- lepsy. For women on oral contr aception, enzyme-inducing drugs may reduce ef \201 cacy of oral contraception pills; highe r doses or a change in birth control method may be required ( 36 , 96 ). Pregnancy decrease s the concentration of several AEDs, including lamotrig- ine, carbamazepine, phenytoin, and possibly levetiracetam and oxcarbazepine ( 89 ). Children often have age-related syndromes, and may require medication only for a few years. Therefore, bone health and tera- togenicity are less of a concern in this population. Beha vioral and cognitive abnormalities in children with epilepsy may be caused either as a como rbidity of the underlying epilepsy syndrome or as a side effect of an AED ( 60 , 61 , 84 ); clinically disentangling these can be challenging. Therefore, there is particular attentio n to choose drugs that have as few adverse effects on cognition and behavior as possible ( 31 , 85 ). Choosing a medication available in liquid, sprinkle, or chewable formulations ma y also help with compliance. Adolescents, as they progress towards independence, may fail t o take medication, experiment with drugs and alcohol, or become sleep deprived when sociali zing or studying ( 86 , 87 ). There is a need to enable adolescents to be compliant without overly disrupt- ing their lives. Long acting formulations or an AED with a long half-life may help in this regard. Adolescents may have a low toler- ance for any adverse effects of a newly started medication, which can be partly mitigated with slow titration schedules and lower goal doses. Since sexual activity often begins in adolescence, ado- lescent females should be considered as women of childbearing age. Valproic acid should be avoided as \201 rst-line therapy in women with epilepsy when less potentially teratogenic options are availa- ble, and folic acid supplementation should accompany any AED choice ( 62 , 88 , 89 ). Comorbidities and concurrent medical problems A signi \201 cant proportion of individuals with epilepsy have comor- bid conditions, particularly the elderly and those with symptomat ic epilepsy. In these individuals, initial choice of medication must take into account pote ntial interactions with other medications as well as potential effects on the comorbidities themselves. Hepatic and renal impairment may affect clearance of medications, leading to h igher than expected blood levels. Many of the older AEDs are hepatic enzyme inducers (pheny toin, carbamazepine, phenobarbi- tal, oxcarbazepine) and may impact the ef \201 cacy of ot her medica- tions. Others, such as valproic acid, are strongly protein bound and may displa ce other medications, potentially causing acute toxicity. In addition, valproic acid inhibi ts the metabolism of other drugs, which may also cause toxicity. Zonisamide and topiramate increase the risk of renal calculi and should be used with cautio n in individuals predisposed to kidney stones. Carbamazepine and oxcarbazepine each may cau se hyponatraemia and should be used cautiously in patients with hyponatraemia from other ca uses. Weight gain (mild with car- bamazepine and gabapentin, moderate with valproic acid an d pre- gabalin) and loss (topiramate, zonisamide, felbamate) should be considered in overwe ight and underweight patients ( 97 , 98 ). The elderly may have more susceptibility to side effects, more medical comorbidities, polyp harmacy, and altered pharmacoki- netics and central nervous system pharmacodynamics ( 90 \200\22392 ). New-onset epilepsy in the elderly is almost always focal and often occurs in individuals with prior stroke or dementia ( 92 ). Preferred medications will have few drug \200\223drug interactions, little protein binding, minimal induction or inhibition of liver enzymes, and minimal cognitive side effects. Slow titration to lower goal doses may help r educe side effects. At present, trial data indicate that lamotrigine ( 90 , 93 ), gabapenti n ( 90 ), and an extended release for- mulation of carbamazepine ( 94 ) are effective and w ell tolerated in the elderly. Long-term AED therapy is associated with decreased bone health and fractures. Enzyme induci ng agents such as phenytoin, pheno- barbital, and primidone are most consistently implicate d, whereas the data are mixed on carbamazepine, oxcarbazepine, and valproic acid. Topiramat e and acetazolamide may lead to increased bone turnover via acidosis. Data on newer, non-en zyme-inducing drugs are limited but not exculpatory ( 99 ). Genetics Advances in epilepsy genetics have increased our understanding of the underlying p athophysiology and may eventually lead to tar- geted treatments. However, at present, speci \201 c genetic mutations Gender and implications for pregnancy Women with epilepsy require special attention to repr oductive and endocrine function. Unlike some other neurological disorders such as stroke or Parkinson \200\231s, which occur after the childbearing years, CHAPTER 22 management of patients with first seizure and early epilepsy 249 notify the Department for Transportation of their status ( 107 ). In the US and Canada, the length of driving prohibition and report- ing requirements vary by state or province. do not alter \201 rst-line therapy for newly diagnosed epilepsy. Instead, clinical phenot ype guides treatment. Even in the rare circumstances where a genetic diagnosis will lead to a speci \201 c AED, such as viga- batrin for infantile spasms in tuberous sclerosis ( 100 ), it is the clin- ical diagnosis (i.e. tuberous sclerosis) rather than the speci \201 c mutation that informs treatment. Prognosis Several factors help predict the prognosis for seizure control, including initial presentation (one seizure versus multiple sei- zures), etiology, number of seizures at ons et and in the \201 rst 6 months after diagnosis, response to initial AED, and epilepsy sy ndrome. Individuals who initially present with a single unpro- voked seizure have a greater than 90 % chance of remission at 5 years, irrespective of drug therapy ( 13 , 16 ). For ne wly diagnosed epilepsy, about half will respond to the \201 rst trial of monotherapy, and another 15 % will respond to a second trial of monotherapy or a two-drug combination ( 65 ). More than 80 % of patients with focal and generalized epilepsies may expect a 1-year rem ission within 5 years of diagnosis ( 74 , 108 ). Remote symptomatic etiology ( 61 , 109 \200\223111 ), failure to respond to the initial AED ( 61 , 109 \200\223111 ), and many sei zures at onset ( 65 ) or in the \201 rst 6 months after treat- ment ( 112 ) each suggest a poorer prognosis for remission. The \201 eld of pharmacogenomics, however, is rapidly assuming clinical importance by ide ntifying individuals at increased risk for dangerous side effects of AEDs ( 101 ). For exam ple, the HLA- B * 1502 allele places some East Asians, particularly Han Chinese, at higher risk for Stevens \200\223Johnson syndrome or toxic epidermal necrolysis when taking carbama zepine ( 102 ), and screening may reduce the risk ( 103 ). Similarly, the HLA-B * 3101 alle le may increase the risk in people of Northern European descent, though the risks are lower and the cost bene \201 t of this screening remains somewhat controversial ( 104 ). It is expected that within a decade, screening tools will identify additional genetic susceptibil ities to adverse events, and help guide clinicians on which medications to avoid in individ ual patients. This susceptibility information may eventually guide medication choice in new ly diagnosed epilepsy. Affordability All of the potential \201 rst-line medications discussed in this chapter ar e available generically, and are thus increasingly affordable to uninsured or underinsured patients. In patients with newly diag- nosed epilepsy, the controversial issue of brand ver sus generic is less important than in refractory patients or in those with prior adverse ev ents. In regions with limited resources for medical care, the older AEDs, such as phenobarb ital or phenytoin, are often sig- ni \201 cantly cheaper than newer medications. These dru gs provide similar ef \201 cacy, though a higher rate of adverse side effects, and may be considered when cost is an over-riding concern ( 105 , 106 ).