Advantages : once daily. No titration. Cheap Disadvantages : allergic reactions. Narrow the rapeutic range. Saturation kinetics. Enzyme inducer. Multiple interactions Caution : conduc tion defects Pragmatic dosing : 200 mg/day (cid:146) 230 mg/day (cid:146) 260 mg/day Notable : hyperammonaemic encephalopathy, weight gain, tremor, parkinsonism and cognitive d ecline, bone loss Other : headache, fatigue, dizziness, diplopia, hair loss, reduced platel et function Advantages : gold standard for generalized seizures. Broad spectrum. Rapid titration. Few i nteractions. Lack of sedating and motor slowing effects. No hepatic enzyme induction. Relat ively cheap Disadvantages : side effects. Enzyme inhibition Pragmatic dosing: 200 mg bd (ci d:146) 400 mg bd Valproate (VPA) 9 \200\22315 90 Hepatic glucuronidation (UGT 2B7) and oxidation VPA increases levels of LTG Gabapentin (GBP) 5 \200\2237 <3 Renal Nil Nil Notable : sedation, dizziness, weight gain Other : cognitive, gait/ataxia, affect, tremor Advantages : therapeutic ef \201 cacy at starting dose. No interactions. Studied in elderl y Disadvantages : thrice-daily dosing. Weak effect Caution : dose adjust with renal failure Pragmatic dosing: 400 mg bd (cid:146) 400 mg tds (cid:146) 600 mg tds (cid:146) 800 mg tds \206\221 (LTG) by VPA, sertraline \206\223 (LTG) by inducers of CYP 450 enzymes (CBZ, PHT , PB, hormone replacement therapy) Lamotrigine (LTG) 30 55 Hepatic glucuronidation (UGT 1A4) Minimal Generally well-tolerated. Notable : allergic skin reactions. Insomnia (morning dosing) Advantages : broad spectrum. Well tolerated. Few interactions. Studied in elderly. Single d aily dosing tolerated Disadvantages : needs slow titration due to dose- associated rash Cau tion : interaction with VPA Pragmatic dosing : 25mg/d (cid:146) 50mg/d (cid:146) 75mg/d (ci d:146) 100mg/d (cid:146) 150mg/d (cid:146) 200mg/d (fortnightly, halve dose with concomitan t sodium valproate) Levetiracetam (LEV) 6 \200\2238 < 10 Renal (75 % ), hepatic hydrolysis (hydrolase) Nil Nil Generally well-tolerated. Notable : sedation early, neurobehavioural Advantages : therapeutic ef \201 cacy at starting doses. No interactions Disadvantages : i rritability, sedation at onset, mood disturbance uncommon but can be profound Pragmatic dos ing : 250 mg bd (cid:146) 500 mg bd (monthly increments) First-pass \206\222 MHD (aldoketo- reductase; CYP 3A4); then glucuronidation + renal excre tion \206\223 (MHD) by inducers of CYP 450 enzymes (i.e. CBZ, PHT, PB) Oxcarbazepine (active metabolite MHD) 9 (MHD) 40 (MHD) MHD increases levels of PHT \206\223 drugs metabolized by CYP 3A4 (Table 18.5 ) Notable : neurotoxicity (dizziness, ataxia, diplopia), fatigue, hyponatraemia ( 95 ) Other : tremor, rash Advantages : well tolerated. Disadvantages : can induce CYP3A4 Caution : hyponatraemia espe cially with diuretics although clinically relevant when <124 ( 94 ) Pragmatic dosing: 150 m g bd (cid:146) 300 mg bd (cid:146) 450 mg bd (cid:146) 600mg/d (monthly increments; may nee d reduction if concomitant PHT) Pregabalin 6 <1 Renal ( > 90 % ) Nil Nil Notable : dizziness, weight gain. Constipation Advantages : no interactions. Disadvantages : few data in elderly Pragmatic dosing: 75mg bd (cid:146) 150 mg bd (monthly increments) \206\223 (TPM) by inducing agents Advantages : broad spectrum Disadvantages : slow titration. Nephrolithiasis. Cognitive slow ing. Caution : clearance may decrease with age. Ensure adequate hydration. May need reducti on if concomitant PHT Pragmatic dosing : 12.5 mg bd (cid:146) 25 mg bd (cid:146) 37.5 mg bd (cid:146) 50 mg bd (monthly increments) Topiramate (TPM) 18 \200\22323 15 Hepatic (CYP 2C19) + unchanged renal excretion TPM increases PHT Generally well-tolerated. Notable : cognitive, nephrolithiasis, word- \201 nding dif \201 culties (weak carbonic anhydrase inhibitor) Other : headache, fatigue, dizziness, paraesth esiae, affect, gait/ataxia, weight loss Zonisamide (ZNS) 63 40 Hepatic (CYP 3A4) Nil Nil Generally well-tolerated. Notable : cognitive and behavioral, rash, sedation, nephrolithias is (weak carbonic anhydrase inhibitor). Other : somnolence, dizziness, weight loss Advantages : broad spectrum; once daily; no interactions Disadvantages : slow titration. Ne phrolithiasis Caution: ensure adequate hydration Pragmatic dosing: 50 mg/day (cid:146) 100 mg/day (cid:146) 150 mg/day (monthly increments) C H A P T E R Advantages : no drug levels Disadvantages : slow titration Caution : theoretical caution in comorbid cardiac dysfunction and rhythm disturbances. Warn patient and family that small d ecrement in other AEDs may be required (pharmacodynamics interaction?). Reduce dose in seve re renal impairment (creatinine clearance \211 80 mL/min). Target dose : 25 mg bd (cid:14 6) 50 mg bd (cid:146) 75 mg bd (cid:146) 100 mg bd (monthly to bimonthly increments) Lacosamide (LAC) 13 15 Renal (95 % ) + some hepatic Nil Nil Generally well-tolerated. Notable : sedation, ataxia, nausea Other : potentiates side effec ts of concomitant Na + channel- blocking AEDs. Potential AV block 1 8 e p i l e p s y i n t h e bd, twice a day. See Table 18.3 for drug abbreviations. e l d e r l y 2 0 7 oxford textbook of epilepsy and epileptic seizures 208 Table 18.5 Drugs whose serum concentrations are lowered by enzyme-inducing drugs (phenytoin , carbamazepine, phenobarbital) medications used to treat it can pose a threat to the independence of the elderly patient. There is signi \201 cant potential for social isola- tion caused by falls, confusion, and amnesia, which can be further enhanced by the driving restrictions that are imposed followi ng a seizure. Furthermore, there is a higher prevalence of depression, anxiety, and poor sl eep compared to age-matched controls ( 96 ), which may be worsened by the stigma towards th e disease. Together, these issues have the potential to contribute to a poorer overall qual ity of life, and the physician needs to be vigilant to advocate for independence with spous es, family, and regulating bodies. Antidepressants Amitriptyline, bupropion, citalopram, clomipramine, desipramine, doxepin, imipramine, mians erin, mirtazapine, nefazodone, nortriptyline, paroxetine Antimicrobials Albendazole, doxycycline, griseofulvin, indinavir, itraconazole, metronidazole, praziquante l Antineoplastics Busulfan, cyclophosphamide, etoposide, irinotecan, methotrexate, nitroureas, paclitaxel, pr ocarbazine, tamoxifen, tenoposide, vinca alkaloids Antipsychotics Chlorpromazine, clozapine, haloperidol, olanazapine, quetiapine, risperidone, ziprasidone Conclusions Overall, the care of the elderly patient with epilepsy poses special challenges to the modern neurologist. Similar to other age groups, the cornerstone of management rema ins diagnostic rigor, espe- cially as seizures present commonly, and sometimes atypically, in this population. However, this must always be balanced against the alternative likelihoo d of seizure \200\230mimickers \200\231. Comorbidities, including cerebrovascular risk fac tors and cognitive impairment should be sought, as the impact of treatment should not risk over- all morbidity and mortality. Close attention to anticonvulsant impact on patient \200 \231s physical status, comorbidities, and concomi- tant medications is critical if these id eals are to be realized. It is important for physicians to have an understanding of the pat ient \200\231s social environment and the potential impact of any future seizures on indivi dual safety and independence, which may require a more multidisciplinary perspective. Benzodiazepines Alprazolam, clobazam, clonazepam, diazepam, midazolam Cardiovascular Amiodarone, atorvastatin, warfarin, digoxin, felodipine, metoprolol, mexiletine, nifedipine , nimodipine, propranolol, quinidine, simvastatin, verapamil Immunosuppressants Cyclosporine, sirolimus, tacrolimus Steroids Cortisol, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, oral contracepti ves Miscellaneous Fentanyl, methadone, paracetamol, pethidine, theophylline, thyroxine, vecuronium Other management issues In addition to the epilepsy itself, bone health is an important man agement issue. In the elderly, not only is the incidence of oste- oporosis increased, but l ack of exercise, inadequate nutrition, and poor mobility can contribute to impaired balance . Epilepsy increases the risk for falls and fractures by two- to sixfold. In addi- tion, AE Ds themselves pose two potential problems: \201 rst, neuro- toxic side effects can predis pose patients to falls; and, second, certain AEDs (most notably valproate and phenytoin) ha ve been associated with bone loss which can increase the likelihood of fractures. It is the refore critical to monitor elderly patients for the development of such side effects, and t o reduce the dose to the minimum. Vitamin D supplementation should be considered. References 1. Hauser W , Hesdorffer D. Epilepsy, Frequency, Causes and Consequences. New York : Demos Publications , 1990 . 2. de la Court A , Breteler MM , Meinardi H , Hauser WA , Hofman A. Prevalence of epilepsy in the elderly: the Rotterdam Study . Epilepsia 1996 ; 37 ( 2 ): 141 \200\223 7 . 3. Hauser W , Annegers J , Kurland L. Prevalence of epilepsy in Rochester, Minnesota: 1940 \200\2231980 . Epilepsia 1991 ; 32 ( 4 ): 429 \200\223 45 . 4. Galimberti CA , Magri F , Magnani B , Arbasino C , Cravello L , Marchioni E , et al . Antiepileptic drug use and epileptic seizures in elderly nursing home residents: a survey in the province of Pavia, Northern Italy . Epilepsy Res 2006 ; 68 ( 1 ): 1 \200\223 8 . 5. Garrard J , Cloyd J , Gross C , Hardie N , Thomas L , Lackner T , et al . It is also worth recalling the association between seizures and stroke as described earlier . Because late-onset seizures are a predic- tor of subsequent stroke ( 91 ), those who have their \201 rst unpro- voked seizure above age 60 should have their vascular risk evaluat ed, and their risk factors managed appropriately. Factors associated with antiepileptic drug use among elderly nursing home residents . J Ger ontol A Biol Sci Med Sci 2000 ; 55 ( 7 ): M384 \200\223 92 . 6. Schachter SC , Cramer GW , Thompson GD , Chaponis RJ , Mendelson MA , Lawhorne L. An evaluation of antiepileptic drug therapy in nursing facilities . J Am G eriatr Soc 1998 ; 46 ( 9 ): 1137 \200\223 41 . In the two-thirds in whom no etiology is found, it is prudent to remain vigilant and monito r for the possibility of seizures as the sentinel event of an emerging neurodegenerative di sorder. 7. D \200\231Souza WJ , Quinn SJ , Fryer JL , Taylor BV , Ficker DM , O \200\231Brien TJ , et al . The prevalence and demographic distribution of treated epilepsy: A community-based study in Tasmania, Australia . Acta Neurol Scand 2012; 125 ( 2 ): 96 \200\223 104 . Finally, for those patients who have had a severe traumatic brain injury ( 92 ) or cerebral neoplasm ( 93 ), there is no evidence for long-term seizure prophylaxis with anticonvulsan t therapy. 8. Annegers JF , Hauser WA , Lee JR , Rocca WA. Incidence of acute symptomatic seizures in Rochester, Minnesota, 1935 \200\2231984 . Epilepsia 1995 ; 36 ( 4 ) : 327 \200\223 33 . 9. Hauser W , Annegers J , Kurland L. Incidence of epilepsy and Lifestyle factors Against the background of having to manage the epilepsy itself is the pat ient \200\231s own complex psychosocial milieu. Few studies have been conducted on the impa ct of epilepsy on the morbidity of eld- erly patients. However, it is clear that the effect of epilepsy and the unprovoked seizures in Rochester, Minnesota: 1935 \200\2231984 . Epilepsia 1993 ; 34 ( 3 ): 453 \200\223 68 . 10. Olafsson E , Ludvigsson P , Gudmundsson G , Hesdorffer D , Kjartansson O , Hauser WA. Incidence of unprovoked seizures and epilepsy in Iceland and ass essment of the epilepsy syndrome classi \201 cation: a prospective study . Lancet Neurol 2 005 ; 4 ( 10 ): 627 \200\223 34 . CHAPTER 18 epilepsy in the elderly 209 33. Lancman ME , Golimstok A , Norscini J , Granillo R. Risk factors for developing seizure s after a stroke . Epilepsia 1993 ; 34 ( 1 ): 141 \200\223 3 . 34. Hauser W. Seizure disor ders: the changes with age . Epilepsia 1992 ; 11. Wallace H , Shorvon S , Tallis R. Age-speci \201 c incidence and prevalence rates of t reated epilepsy in an unselected population of 2,052,922 and age-speci \201 c fertility ra tes of women with epilepsy . Lancet 1998 ; 352 : 1970 \200\223 3 . 33 (Suppl 4 ): S6 \200\223 S14 . 12. Annegers JF , Dubinsky S , Coan SP , Newmark ME , Roht L. The 35. Bruns JJ , Hauser W. The epidemiology of traumatic brain injury: a incidence of epilepsy and unprovoked seizures in multiethnic, urban health maintenance orga nizations . Epilepsia 1999 ; 40 ( 4 ): 502 \200\223 6 . 13. Musicco M , Beghi E , Solari A , for the First Seizure Trial Group . review . Epilepsia 2003 ; 44 (Suppl 10 ): 2 \200\223 10 . 36. Messing R , Closson R , Simon R. Drug-induced seizures: a 10-year experience . Neurology 1984 ; 34 : 1582 . Treatment of \201 rst tonic-clonic seizure does not improve the prognosis of epilepsy . N eurology 1997 ; 49 : 991 \200\223 8 . 37. Kearney TE , Dyer JE , Benowitz NL , Blanc PD. Seizures associated with poisoning and drug overdose . Am J Emerg Med 1994 ; 12 : 392 . 14. First Seizure Trial Group (FIR.S.T. Group). Randomized clinical trial on the ef \201 c acy of antiepileptic drugs in reducing the risk of relapse after a \201 rst unprovoked to nic-clonic seizure . Neurology 1993 ; 43 ( 3 (Part 1) ): 478 \200\223 83 . 38. Shorvon S , Tallis R , Wallace H. Antiepileptic drugs: coprescription of proconvulsant drugs and oral contraceptives: a national study of antiepileptic drug prescribing practice . J Neurol Neurosurg Psychiatry 2002 ; 72 : 114 . 15. Berg A , Shinnar S. The risk of seizure recurrence following a \201 rst unprovoked se izure: a quantitative review . Neurology , 1991 ; 41 ( 7 ): 965 \200\223 72 . 39. Gilmore R. Seizures associated with non-neurological medical conditions . In: Wyllie E (ed) The treatment of epilepsy: principles and practice , pp. 657 \200\223 69 . Baltimore, MA : Williams and Wilkins , 2001 . 40. Luhdorf K , Jensen L , Pl esner A. Etiology of seizures in the elderly . 16. Hart YM , Sander JW , Johnson AL , Shorvon SD. National General Practice Study of Epilepsy: recurrence after a \201 rst seizure . Lancet 1990 ; 336 ( 872 6 ): 1271 \200\223 4 . Epilepsia 1986 ; 27 : 458 \200\223 63 . 41. Roberts M , Godfrey J , Caird F. Epileptic seizures in the elderly: I . 17. Hauser W , Rich SS , Annegers JF , Anderson VE. Seizure recurrence Etiology and type of seizure . Age Ageing 1982 ; 11 : 24 \200\223 8 . after a 1st unprovoked seizure: an extended follow-up . Neurology 1990 ; 40 ( 8 ): 1163 \200\223 70 . 42. Sander JW , Hart YM , Johnson AL , Shorvon SD. National General Practice Study of Epile psy: newly diagnosed epileptic seizures in a general population . Lancet 1990 ; 336 ( 8726 ): 1267 \200\223 71 . 18. DeLorenzo RJ , Hauser WA , Towne AR , Boggs JG , Pellock JM , Penberthy L , et al . A prospective population-based epidemiologic study of status epilepti cus in Richmond Virginia . Neurology 1996 ; 46 : 1029 \200\223 35 . 43. Ramsay RE , Rowan A , Pryor F. Special considerations in treating the elderly patient with epilepsy . Neurology 2004 ; 62 : S24 \200\223 9 . 44. Pugh MJ , Knoefel JE , Mortensen EM , Amuan ME , Berlowitz DR , 19. Knake S , Rosenow F , Vescovi M , Oertel WH , Mueller HH , Wirbatz A , Van Cott AC. New-onset epilepsy risk factors in older veterans . J Am Geriatr Soc 2009 ; 57 : 237 \200\223 42 . et al . Incidence of status epilepticus in adults in Germany: a prospective, population-bas ed study . Epilepsia 2001 ; 42 ( 6 ): 714 \200\223 18 . 45. So EL , Annegers JF , Hauser WA , O \200\231Brien PC , Whisnant JP. 20. Vignatelli L , Tonon C , D \200\231Alessandro R. Incidence and short-term prognosis of status epilepticus in adults in Bologna, Italy . Epilepsia 2003 ; 44 ( 7 ): 964 \200\223 8 . Population-based study of seizure disorders after cerebral infarction . Neurology 1996 ; 46 ( 2 ): 350 \200\223 5 . 46. Lancman ME , Golimstok A , Norscini J , Granillo R. Risk factors for developing seizure s after a stroke . Epilepsia 1993 ; 34 : 141 \200\223 43 . 47. Cleary P , Shorvon S , Tall is R. Late-onset seizures as a predictor of 21. DeLorenzo RJ , Pellock JM , Towne AR , Boggs JG. Epidemiology of status epilepticus . J Clin Neurophysiol 1995 ; 12 ( 4 ): 316 \200\223 25 . 22. Delorenzo R. Clinical and epidemiologic study of status epilepticus in the elderly . In: Rowan A , Ra msay R (eds) Seizures and Epilepsy in the Elderly , pp. 191 \200\223 205 . Boston, MA : Bu tterworth-Heineman, 1997. subsequent stroke . Lancet 2004 ; 363 : 1184 \200\223 6 . 48. Ng SK , Hauser WA , Brust JC , Susser M. Hypertension and the risk of new-onset unprovo ked seizures . Neurology 1993 ; 43 ( 2 ): 425 \200\223 8 . 49. Hesdorffer DC , Hauser WA , Annegers JF , Kokmen E , Rocca WA . Dementia and adult-onset unprovoked seizures . Neurolo gy 1996 ; 46 ( 3 ): 727 \200\223 30 . 23. Lhatoo SD , Johnson AL , Goodridge DM , MacDonald BK , Sander JW , Shorvon SD. Mortalit y in epilepsy in the \201 rst 11 to 14 years after diagnosis: multivariate analysis of a long-term, prospective, population-based cohort . Ann Neurol 2001 ; 49 : 336 \200\223 44 . 50. McAreavey M , Ballinger B , Fenton G. Epileptic seizures in elderly patients with dementia . Epilepsia 1992 ; 33 : 657 \200\223 60 . 24. Hauser WA , Annegers JF , Kurland LT. Prevalence of epilepsy in Rochester Minnesota: 19 40 \200\2231980 . Epilepsia 1991 ; 42 ( 4 ): 429 \200\223 45 . 25. Loiseau J , Loiseau P , Duch B , Guyot M , Dartigues JF , Aublet B. 51. Amatniek JC , Hauser WA , DelCastillo-Castaneda C , Jacobs DM , Marder K , Bell K , Albert M , et al . Incidence and predictors of seizures in patients wit h Alzheimer \200\231s disease . Epilepsia 2006 ; 47 : 867 \200\223 72 . A survey of epileptic disorders in southwest France: seizures in elderly patients . Ann Neu rol 1990 ; 27 ( 3 ): 232 \200\223 7 . 52. Hommet C , Mondon K , Camus V , De Toffol B , Constans T. Epilepsy and dementia in the elderly . Dement Geriatr Cogn Disord 2008 ; 25 : 293 \200\223 300 . 26. Hauser W. Epidemiology of seizures and epilepsy in the elderly . In: Rowan A , Ramsay R (eds) Seizures and Epilepsy in the Elderly , pp. 7 \200\223 20 . Boston , MA : Butterworth-Heineman, 1997. 53. Rao SC , Dove G , Cascino GD , Petersen RC. Recurrent seizures in patients with dementia: frequency, seizure types, and treatment outcome . Epilepsy Behav 20 09 ; 14 : 118 \200\223 20 . 27. Kellinghaus C , Loddenkemper T , Dinner DS , Lachhwani D , L ders HO. Non-epileptic se izures of the elderly . J Neurol 2004 ; 251 : 704 \200\223 9 . 28. McBride A , Shih T , Hi rsch I. Video-EEG monitoring in the elderly: a 54. Hiyoshi T , Yagi K. Epilepsy in the elderly . Epilepsia 2004 ; 41 (Suppl 9 ): 31 \200\223 5 . review of 93 patients . Epilepsia 2002 ; 43 ( 2 ): 165 \200\223 9 . 55. Annegers JF , Hauser WA , Coan SP , Rocca WA. A population-based 29. Stephen L , Brodie M. Epilepsy in elderly people . Lancet 2000 ; study of seizures after traumatic brain injuries . N Engl J Med 1998 ; 338 : 20 \200\223 4 . 355 ( 9213 ): 1441 \200\223 6 . 30. Giroud M , Gras P , Fayolle H , Andr N , Soichot P , Dumas R. Early seizures after ac ute stroke: a study of 1,640 cases . Epilepsia 1994 ; 35 ( 5 ): 959 \200\223 64 . 56. Annegers JF , Hauser WA , Beghi E , Nicolosi A , Kurland LT. The risk of unprovoked sei zures after encephalitis and meningitis . Neurology 1988 ; 38 ( 9 ): 1407 \200\223 10 . 31. Sung C , Chu N. Epileptic seizures in thrombotic stroke . J Neurol 1990 ; 57. Lote K , Stenwig AE , Skullerud K , Hirschberg H. Prevalence and prognostic signi \201 cance of epilepsy in patients with gliomas . Eur J Cancer 1998 ; 34 : 98 \200\223 102 . 237 ( 3 ): 166 \200\223 70 . 32. Bladin CF , Alexandrov AV , Bellavance A , Bornstein N , Chambers B , Cot R , et al . Seizures after stroke: a prospective multicenter study . Arch Neurol 2000 ; 57 ( 11 ): 1617 \200\223 22 . 58. Dam AM , Fuglsang-Frederiksen A , Svarre-Olsen U , Dam M. Late-onset epilepsy: etiologies, types of seizure, and value of clinical oxford textbook of epilepsy and epileptic seizures 210 79. Brodie MJ , Overstall PW , Giorgi L. Multicentre, double-blind, investigation, EEG, and computerized tomography scan . Epilepsia 1985 ; 26 ( 3 ): 227 \200 \223 31 . randomized comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy . Epilepsy Res 1999 ; 37 : 81 \200\223 7 . 59. Chadwick D , Smith D. The misdiagnosis of epilepsy . Br Med J 2002 ; 324 : 495 \200\2236 . 80. Saetre E , Perucca E , Isoj rvi J , Gjerstad L ; LAM 40089 Study Group . An 60. D \200\231Souza WJ , Stankovich J , O \200\231Brien TJ , Bower S , Pearce N , Cook MJ. The use of computer-assisted-telephone-interviewing to diagnose seizures, epilepsy and idio pathic generalized epilepsy . Epilepsy Res 2010 ; 91 ( 1 ): 20 \200\223 7 . international multicenter randomized double-blind controlled trial of lamotrigine and susta ined-release carbamazepine in the treatment of newly diagnosed epilepsy . Epilepsia 2007 ; 48 : 1292 \200\223 302 . 81. Rowan AJ , Ramsay RE , Collins JF , Pryor F , Boardman KD , Uthman BM , et al . New ons et geriatric epilepsy: a randomized study of gabapentin, lamotrigine and carbamazepine . Ne urology 2005 ; 64 : 1868 \200\223 73 . 61. Duncan JS , Sander JW , Sisodiya SM , Walker MC. Adult epilepsy . Lance t 2006 ; 367 : 1087 \200\223 100 . 62. Holmes G. The electroencephalogram as a predictor of seizures following cerebral infarction . Clin Electroencephalogr 1980 ; 11 ( 2 ): 83 \200\223 86 . 82. Alsaadi TM , Koopmans S , Apperson M , Farias S. Levetiracetam monotherapy for elderly patients with epilepsy . Seizure 2004 ; 13 : 58 \200\223 60 . 63. Towne AR , Waterhouse EJ , Boggs JG , Garnett LK , Brown AJ , Smith JR Jr , et al . Pre valence of nonconvulsive status epilepticus in comatose patients . Neurology 2000 ; 54 : 34 0 \200\223 5 . 83. Morrell MJ , Leppik I , French J , Ferrendelli J , Han J , Magnus L. The KEEPER(TM) trial: levetiracetam adjunctive treatment of partial-onset seizures in an open-l abel community-based study . Epilepsy Res 2003 ; 43 : 153 \200\223 61 . 64. Sheth RD , Drazkowski JF , Sirven JI , Gidal BE , Hermann BP. Protracted ictal confusion in elderly patients . Arch Neurol 2006 ; 60 : 529 \200\223 32 . 65. Beyenb urg S , Elger C , Rueber M. Acute confusion or altered mental 84. Ferrendelli JA , French J , Leppik I , Morrell MJ , Herbeuval A , Han J , et al . Use o f levetiracetam in a population of patients aged 65 years and older: a subset analysis of t he KEEPER trial . Epilepsy Behav 2003 ; 4 : 702 \200\223 9 . state: consider nonconvulsive status epilepticus . Gerontology 2007 ; 53 : 388 \200\223 96 . 66. Bottaro FJ , Martinez OA , Pardal MM , Bruetman JE , Reisin RC. Nonconvulsive status epilepticus in the elderly: a case-control study . Epilepsia 2007 ; 48 : 966 \200\223 72 . 85. Garcia-Escriva A , Lopez-Hernandez N. The use of levetiracetam in monotherapy in post s troke seizures in the elderly population . Rev Neurol 2007 ; 45 : 523 \200\223 5 . 67. Drury I , Selwa LM , Schuh LA , Kapur J , Varma N , Beydoun A , et al . Value of inpati ent diagnostic CCTV-EEG monitoring in the elderly . Epilepsia 1999 ; 40 : 1100 \200\223 2 . 86. Kutluay E , McCague K , D \200\231Souza J , Beydoun A. Safety and tolerability of oxcarbazepine in elderly patients with epilepsy . Epilepsy Behav 2003 ; 4 : 175 \200 \223 80 . 68. Detoledo J. Changing presentation of seizures with ageing: clinical and aetiological factors . Gerontology 1999 ; 45 : 329 \200\223 35 . 87. Ramsay RE , Uthman B , Pryor FM , Rowan AJ , Bainbridge J , Spitz M , et al . Topiramat e in older patients with partial-onset seizures: a pilot double-blind, dose-comparison stud y . Epilepsia 2008 ; 49 : 1180 \200\223 5 . 69. Ramsay RE , Pryor F. Epilepsy in the elderly . Neurology 2000 ; 55 (Suppl 1 ): S9 \200\223 14 . 70. Hirsch LJ , Arif H , Nahm EA , Buchsbaum R , Resor SR Jr , Bazil CW. 88. Read CL , Stephen LJ , Stolarek IH , Paul A , Sills GJ , Brodie MJ. Cross-sensitivity of skin rashes with antiepileptic drug use . Neurology 2008 ; 71 : 1527 \200\223 34 . Cognitive effects of anticonvulsant monotherapy in elderly patients: a placebo-controlled s tudy . Seizure 1998 ; 7 : 159 \200\223 62 . 71. Vecht CJ. Optimizing therapy of seizures in patients with brain tumors . 89. Cameron H , Macphee G. Anticonvulsant therapy in the elderly \200\224 a need for place bo controlled trials . Epilepsy Res 1995 ; 21 : 149 \200\223 57 . 90. Leppik IE , Birnbaum AK. Epilepsy in the elderly . Semin Neurol 2002 ; Neurology 2006 ; 67 ( 12, Suppl 4 ): S10 \200\223 13 . 72. Grivas A , Schramm J , Kral T. Surgical treatment for refractory temporal lobe epilepsy in the elderly: seizure outcome and neuropsychological sequels compared with a younger coh ort . Epilepsia ; 2006; 47 : 1364 \200\223 72 . 22 : 309 \200\223 20 . 91. Cleary P , Shorvon S , Tallis R. Late onset seizures as a predictor of subsequent stroke . Lancet 2004 ; 363 : 1184 \200\223 6 . 73. Schmucker D. Aging and drug disposition: an update . Pharmacol Rev 92. Chang B , Lowenstein D. Practice parameter: antiepileptic drug 1985 ; 37 ( 2 ): 133 \200\223 48 . prophylaxis in severe traumatic brain injury: report of the Quality Standards Subcommittee of the American Academy of Neurology . Neurolog y 2003 ; 60 : 10 \200\223 16 . 74. Schwartz J. The current state of knowledge on age, sex, and their interactions on clini cal pharmacology . Clin Pharmacol Ther 2007 ; 82 ( 1 ): 87 \200\223 96 . 93. Glantz MJ , Cole BF , Forsyth PA , Recht LD , Wen PY , Chamberlain MC , et al . Practic e parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors: repo rt of the Quality Standards Subcommittee of the American Academy of Neurology . Neurology 2 000 ; 54 : 1886 \200\223 93 . 75. Goa K , Sorkin E. Gabapentin . A review of its pharmacological properties and clinical potential in epilepsy . Drugs 1993 ; 46 ( 3 ): 409 \200\223 27 . 76. Perucca E. Pharmacokinetics . In: Engel J Jr , Pedley T (eds) Epilepsy: A Comprehensive Textbook , pp. 1131 \200\223 44 . Philadelphia, PA : Lippincott-Raven Publ ishers , 1997 . 94. Ranta A , Wooten G. Hyponatraemia due to an additive effect of carbamazepine and thiazi de diuretics . Epilepsia 2004 ; 45 : 879 . 77. Granger A. Ginkgo biloba precipitating epileptic seizures . Age Ageing 2001 ; 30 : 523 \200\223 5 . 95. Dong X , Leppik IE , White J , Rarick J. Hyponatraemia from 78. French JA , Kanner AM , Bautista J , Abou-Khalil B , Browne T , Harden CL , et al . Ef \201 cacy and tolerability of the new antiepileptic drugs. II: treatment of refractory epi lepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standa rds Subcommittee of the American Academy of Neurology and the American Epilepsy Society . N eurology 2004 ; 62 ( 8 ): 1261 \200\223 73 . oxcarbazepine and carbamazepine . Neurology 2005 ; 65 : 1976 \200\223 8 . 96. Haut SR , Katz M , Masur J , Lipton RB. Seizures in the elderly: impact on mental status, mood and sleep . Epilepsy Behav 2009 ; 14 : 540 \200\223 4 . CHAPTE R 19 Psychiatric Comorbidity in Epilepsy Marco Mula Introduction Prevalence rates of psychiatric disorders are higher in people with seizures a s compared with the general population, predominantly in patients with refractory epilepsy. Depression occurs in about 30 % , anxiety disorders in 10 \200\22325 % , and psychosis in 2 \200\2237 % ( 1 ). However, such comorbidity frequently goes unrecognized and untreated w hile it should represent a major concern in the assess- ment of patients with epilepsy, as there are important reciprocal interactions between the disorders, not only in their clinic al mani- festations, but also in the effects of their treatments. In fact, antie- pileptic drugs (AEDs), as well as other treatments for epilepsy, may exert various psychotropic effe cts, which can be negative as well as positive ( 2 , 3 ). Conversely, psychotropic drugs ma y in \202 uence the propensity to have seizures. neurochemical principles such as the involvement of the temporal lobes ( 9 ) and the psycho tropic effects of AEDs ( 10 ). Mood disor- ders are one of the most important predictors of quality of life ( 11 ), and people with epilepsy and depression are more likely to experi- ence side effects of AEDs ( 12 ), are more often drug-refractory ( 13 ), and have a poorer outcome after epilepsy surgery ( 14 ). Peri-ictal mood and anxiety symptoms Around one-third of patients with partial seizures rep ort premoni- tory symptoms, usually before secondary generalized tonic \200\223clonic seizu res ( 1 ). Prodromal moods of depression or irritability may occur hours to days before a s eizure and are often relieved by the convulsion ( 15 ). Among pre-ictal symptoms, behaviora l changes are those most frequently reported ( 16 ). In our case series, around 13 % of pat ients experience irritability, dysphoria, or depressed mood preceding seizures ( 17 ). Such feelings are almost indistin- guishable from interictal ones, apart from duration and clos e rela- tion with seizure occurrence. It seems, therefore, important for clinicians to enqu ire about these phenomena, because they cannot be detected by rating scales or questionnair es ( 18 ). The \201 rst step in the management of these patients should be an attempt to analyze and identify the various elements that may con- tribute to psychiatric symptoms, such as psych osocial issues, adverse treatment effects, or neurobiological factors directly related to t he seizures or the epileptic disorder. Patients with epilepsy may experience a number of ps ychiatric manifestations around the ictus that have to be clearly differentiated from true psychiatric comor- bidities. The practicality of classifying such symptoms according to the ir temporal relation to seizure occurrence (peri-ictal/paraictal symptoms vs. interictal sy mptoms) is well established (Table 19. 1 ). Peri-ictal phenomena have been well described b y Gowers ( 4 ) and Jackson ( 5 ) but also by Kraepelin ( 6 ) and Bleuler ( 7 ). The differe n- tiation between peri-ictal and interictal psychiatric symptoms has relevant implications in terms of prognosis and treatment. Ictal fear or ictal panic is the most frequently reported ictal psy- chiatric manifestation and it usually represents a partial seizure originating in right mesial temporal lobe stru ctures ( 19 ). It seems to be reported by 10 \200\22315 % patients with partial seizures ( 1 ), is more common in women than men ( 20 , 21 ), and seems to have a poor prognostic valu e for surgery ( 22 ). Ictal depression is the second most frequently reported ictal psy- chiatric manifestation. Such mood changes include anhedonia, feelings of guilt and intense suicidal ideation. It is reported in 1 % of patients with temporal lobe epilepsy ( 1 ). In this chapter, major psychiatric syndromes are discussed in the context of the management of epilepsy. Mood and anxiety disorders Mood and anxiety disorders represent the most frequent psychiat- ric comorbidity in patients with epilepsy and reasons for such a close link are both biolo gical and psychosocial ( 8 ). On the one hand, epilepsy is a chronic disorder that brings a bout a number of social limitations (e.g. driving license, job opportunities, etc,) and soc ial discriminations leading to demoralization, poor self-esteem, and phobic avoidance. On t he other hand, the biological contri bution to this association is given by neuroanatomical and Table 19.1 Classi \201 cation of psychiatric symptoms according to their temporal relation with seizures Peri-ictal Preictal Ictal Postictal Paraictal Alternative Interictal No relation oxford textbook of epilepsy and epileptic seizures 212 epilepsy. However, it is equally reasonable to assume that the underlying brain pathology c an in \202 uence the expression of mood disorder symptoms making less evident some aspects or emphasiz- ing others. A number of variables may account for such atypical features such as peri-ictal symptoms, the high comorbidity between mood and anxiety disorders (up to 73 % ), the underlying neuro- logical condition, and the psychotropic effect of AEDs. Postictal mood changes are less recognized in clinical practice. However, they are frequent ly reported by patients and relatives. A case series in a monitoring unit reported 18 % of patients having at least \201 ve symptoms of depression lasting more than 24 hours ( 23 ) . A comparison of seizure-related variables between these sub- jects and patients without a ny postictal psychiatric symptom failed to reveal any differences, although patients with p ostictal depres- sion seem to be more likely to have a previous history of psychiat- ric di sorders ( 24 ). Pre-modern psychiatrists, such as Kraepelin and Bleuler, observed that patients with epilep sy may develop a pleomorphic pattern of depressive symptoms intermixed with euphoric moods, irritability, fear, and anxiety as well as anergia, pain and insomnia ( 42 , 43 ). This co ncept has been revitalized during the 20th century by Blumer who coined the term interictal dysphoric disorder (IDD) to refer to this type of somatoform-depressive disorder claimed a s typical of patients with epilepsy ( 44 ). Studies of our group pointed out that such a co ndition is a mood disorder probably not speci \201 c of epilepsy, being diagnosed also in patients with migraine, which is usually diagnosed during the depressive phase with a signi \201 cant comorbid anxiety (social phobia and/or generalized anxiety disor- der) and a re levant component of mood instability ( 45 ). Moreover, further studies demonstrated that a number of atypical and pheo- morphic features of the so-called IDD are related to peri-icta l symptoms ( 17 ). These issues have relevant implications in terms of prognosis and treatm ent. On one hand, it emphasizes the need to dissect out peri-ictal manifestations from inte rictal ones being the former related to the prognosis and treatment of the epileptic syn- d rome. On the other hand, the presence of mood instability as an essential element of IDD su ggest the need to prescribe mood stabi- lizing AED as preferred treatment and the utility o f antipsychotic drugs in selective cases. Manic/hypomanic symptoms are reported postictally in 22 % of patients, often with associate d psychotic phenomenology ( 23 ). It seems that postictal mania has a distinct position amo ng psychiat- ric manifestations observed in the postictal period. Such manic episodes last for a longer period and have a higher frequency of recurrence than postictal psychoses, bei ng associated with an older age at onset, electroencephalographic (EEG) frontal discharges, and non-dominant hemisphere involvement ( 25 ). Postictal anxiety is reported by 45 % patients ( 23 ). The median duration of symptoms rang es from 6 \200\22324 hours. In one-third of cases, postictal anxiety may last 24 hours or l onger. In about 33 % of cases postictal anxiety is reported by patients with a previous his tory of an anxiety disorder. Interictal depressive and anxiety disorders Data from community-based studies report preval ence rates for depressive disorders in the order of 20 \200\22322 % ( 26 , 27 ). In selecte d populations, such as tertiary referral centers or surgery pro- grammes, the prevalence is even higher and ranges between 30 \200\22350 % ( 28 , 29 ). Such differences partially re \202 ect the severity of the seizure disorder; in fact depression seems to occur in only 4 % of seizure-free patients ( 30 ). Data on anxiety disorders are limited mainly because th ey are commonly comorbid with mood disorders but they are believed to have prevalence rates comparable to those of depression. Psychoses Psychoses and thought disorders are relatively rare in patients with epilepsy but represent serious complications affecting prognosis, morbidity, and mortality. Epidemiolog ical evidence pointed out that the incidence of non-organic, non-affective psychoses, inclu d- ing schizophrenia and related disorders, is generally overrepre- sented (around 4 \200 \2235 % ) in epilepsy as compared to the general population or other chronic medical condit ions ( 46 , 47 ). Higher prevalence rates have been found in selected samples such as hos- pital case series ( 48 , 49 ). Interestingly, a family history of psychoses and a family hi story of epilepsy seem to be signi \201 cant risk factors for psychosis suggesting strong neurobiological underpinnings between the two disorders ( 47 ). An interesting point, coming from epidemiological data, relates to the observation that the relationship between epilepsy and depression is not necessarily unidirectional, namely tha t some patients may present a mood disorder before the emergence of the seizure disorder ( 31 ). Although it is tempting to speculate that common pathogenetic mechanisms may be opera nt in both condi- tions, it has to be stated that such a bidirectional relationship has bee n noted in a number of chronic conditions such as Parkinson \200\231s disease ( 32 ), strok e ( 33 ), dementia ( 34 ), diabetes ( 35 ), cardiovas- cular disease ( 36 ), suggesting tha t depression is probably inter- linked with a number of chronic conditions. The issue of phenomenology of depression has been matter of debate having a number of impli cations in terms of diagnosis, treatment and prognosis. A number of authors have pointed ou t that depression in epilepsy is more often than not characterized by atypical features tha t are poorly re \202 ected by conventional classi \201 - catory systems such as DSM (Diag nostic and Statistical Manual of Mental Disorders)-IV and ICD (International Statistical Cl assification of Diseases and Related Health Problems)-10 ( 37 \200\22339 ). However, other studies clearly suggest that it is possible to apply standardized criteria of DSM in a not negligible proportion of patients ( 40 , 41 ). In general terms, the psychopathological spe c- trum of depression in epilepsy is likely to be large. On one hand, it is reasonable to h ypothesize that patients with epilepsy can experi- ence forms of mood disorders identical t o those of patients without Peri-ictal psychotic symptoms The so-called ictal psychosis usually represents a complex pa rtial status of temporal lobe origin and less frequently an extratemporal partial status (i .e. the frontal lobe) ( 50 ). Very rarely it has been reported as the manifestation of an a bsence status but studies are lacking. Simple focal status or aura continua may determine c om- plex hallucinations resembling a thought disorder but insight is usually maintained mak ing the differential diagnosis quite straight- forward. Among peri-ictal psychoses, postictal ones represent the most common type, accounting for a pproximately 25 % of psychoses of epilepsy. They are usually precipitated by a series of se condary gen- eralized tonic \200\223clonic seizures ( 51 , 52 ). Kanemoto and co-authors CHAPTER 19 psychiatric comorbidity in epilepsy 213