31. Dan B. Angelman syndrome: Current understanding and research retardation: the role of surgery . In: Sillanp M , Gram L , Johannessen SI , Tomson T ( eds) Epilepsy and Mental Retardation , pp. 105 \200\223 113 . Philadelphia, PA : Biomedica l Publishing Limited , 1999 . prospects . Epilepsia 2009 ; 50 ( 11 ): 2331 \200\223 9 . 32. Fiumara A , Pittal \203 A , Cocuzza M , Sorge G. Epilepsy in patients with Angelman syndrome . Ital J Pediatr 2010 ; 36 : 31 . 53. Deb S . Epilepsy in people with mental retardation . In: Jacobson JW , Mulick JA (eds) Handbook of Mental Retardation and Developmental Disabilities , pp. 81 \200\223 96 . New Y ork : Kluwer Academic Publishers , 2007 . 33. Miles JH , Takahashi TN , Bagby S , Sahota PK , Vaslow DF , Wang CH , et al . Essential versus complex autism: de \201 nition of fundamental prognostic subtypes . Am J Med Genet A 2005 ; 135 ( 2 ): 171 \200\223 80 . This page intentionally left blank CHAPTER 18 Epilepsy in the Elderly Trevor T.-J. Chong and Wendyl D \200\231Souza Introduction Epilepsy has traditionally been thought of as a disease of the young, primaril y affecting infants, children, and adolescents. Increasingly, however, epilepsy is becoming recognized as a common disorder of the elderly ( 1 ). 1 Within that population, it is the third most common neurological disease, after cerebrovascular disease and the dementias. Ep ilepsy today is therefore more a disease of old age, and our aging population will see it e volve into an increasingly important public health issue. Furthermore, although the phe- no menon of population ageing is evident for high-income coun- tries, the changing global econ omic landscape will also see it become an important consideration for low- and middle-incom e countries (LAMICs). In this chapter, we aim to provide a concise and practical reference to guide the treatment of the elderly patient with epilepsy. Epilepsy in the elderly is associated with a signi \201 cant morbidity and mortality. Old age is a signi \201 cant predictor of seizure recur- rence ( 9 , 10 , 13 ), and patients w ith a \201 rst unprovoked seizure have an overall risk of recurrence beyond 2 years of 25 \200\22352 % ( 14 \200\22317 ). Similar to other age groups, this risk is increased in the presence of an abnormal electroencephalogram (EEG) and/or an identi \201 able epileptogen ic substrate ( 15 ). Status epilepticus becomes more common with age, with a 2- to 10-fold increase in incidence in those older than 60 relative to younger adults ( 18 \200\22320 ). This increase is accompanied by a rise in mortality associated with status epilep- ticus, w ith a rate of 38 % in those over 60 to nearly 50 % in those over 80 ( 21 , 22 ). Overall, t he mortality in elderly patients with epi- lepsy is two to three times greater than that of the general popula- tion ( 23 ), which is likely due to their greater susceptibility to sy stemic illnesses, comorbidities, and the underlying etiology of their epilepsy. Together, t hese \201 ndings underline the importance of optimizing the total care of the elderly pat ient with epilepsy. Epidemiology Any cerebral insult can predispose an individual to developing seizures. It is therefore unsurprising that seizures and epilepsy are so common in the elderly, who have a high incidence of stroke and neurodegenerative disorders. The prevalence of unprovoked sei - zures in those aged over 60 is at least 1 % . This rate rises to 1.5 % in those aged over 75, which is approximately twice that of younger adults ( 2 , 3 ). Predictably, the preval ence is even higher (3 \200\2239 % ) in populations such as nursing home residents, who are more likely to suffer from cerebrovascular disease and dementia ( 4 \200\2236 ). 0 1 ) 0 0 0 1 r e p ( 8 The high prevalence of seizures in the elderly (Fig. 18.1 ) is com- mensurate with the high er incidence of epilepsy in this population. Indeed, the incidence of epilepsy is greatest in those over the age of 65 (Fig. 18.2 ) ( 8 \200\22310 ). Above that age, the incidence co ntinues to rise, with an annual incidence of 85.9 per 100,000 in those aged 65 \200\22369, to more than 135 per 100 000 in those aged older than 80 ( 11 ). This is compared to an ove rall incidence of 80.8 per 100,000 people across all age groups. 6 e c n e a v e r 4P l 2 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 Age (years) 1 In most high-income countries, the de \201 nition of an \200\230elderly \200\231 person is held to be one who has exceeded a chronological age of 65 years. Of course, the situati on is different in low- and middle-income countries and, although the United Nations does n ot have a standard numerical criterion for the \200\230elderly \200\231, it has accepted a cutoff of 60 + years. Fig. 18.1 The prevalence of treated epilepsy across age groups in Tasmania, Australia ( 7 ) Imputed prevalence reported (middle curve) with smoother and 95 % con \201 dence interval s also shown (top and bottom curve). The smoother and 95 % con \201 dence interval was obt ained from a log binomial regression model with age modeled as 1/ \210\232age. oxford textbook of epilepsy and epileptic seizures 202 Table 18.1 Identi \201 able aetiologies of symptomatic seizures in the elderly 300 Kelsey-Seybold HMO, 1988 \200\22394 Sweden, 1992 \200\22394 Rochester, 1985 \200\22394 250 Etiology Symptomatic seizures Structural causes 60 \200\22380 % 0 0 0 0 0 1 r e p e c n e d c n 200 \227\206 Cerebrovascular disease ( 8 , 25 , 29 \200\22333 ) (40 \200\22350 % ) , \227\206 Head trauma ( 8 , 25 , 29 , 34 , 35 ) (4 \200\22317 % ) 150 \227\206 CNS infections ( 8 , 25 , 29 ) (5 \200\22310 % ) Drugs and metabolic disturbances ( 36 \200\22339 ) 10 \200\22340 % i 100 I \227\206 Drugs a , toxins, alcohol (5 \200\22310 % ) \227\206 Metabolic disturbances b (6 \200\22330 % ) 50 a Drugs including: psychotropic agents, theophylline, narcotics, antimicrobials (high-dose penicillins and cephalosporins, imipenem, isoniazid, antimalarials), chemotherapeutic agent s (methotrexate, chlorambucil, cyclosporin), anesthetic agents (ketamine, toxic doses of li gnocaine, disopyramide, bupivacaine), anti-arrhythmics (overdose of vera- pamil, propranolo l), diphenhydramine, baclofen, chlorpromazine 0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 Age group b Metabolic insults including: hypo-/hypernatraemia, hypomagnesaemia, hypocalcaemia, hypogl ycaemia/non-ketotic hyperglycaemia, uraemia, hypoxia, hyperthyroidism, por- phyria, dialysi s disequilibrium syndrome. Note that the rate of change of the respective metabolites, rath er than their absolute value, predicts seizures. Fig. 18.2 The incidence of epilepsy across age groups. Reproduced from Annegers, J.F., et a l. The incidence of epilepsy and unprovoked seizures in multiethnic, urban health maintenan ce organizations. Epilepsia 1999; 40( 4 ):502 \200\2236. Etiology Symptomatic seizures An \200\230acute \200\231 symptomatic seizure is one that oc curs shortly after a recent epileptogenic insult (e.g. strokes, metabolic disturbances, dru g withdrawal), in contrast to a \200\230remote \200\231 symptomatic seizure which is one t hat occurs in the days to weeks following such an insult. In practice, the distinction betw een acute and remote symp- tomatic seizures is often blurred, particularly in the elderly. This is due to the inherent imprecision of the circumstances surrounding events, and the va rying de \201 nitions for the acute period, from 48 hours to up to 3 months depending on t he underlying etiology ( 24 ). For example, the period for acute symptomatic seizures sec- ondary to alcohol withdrawal is 48 hours, but that secondary to a head injury is up to 14 d ays. Therefore, a more pragmatic approach is to consider symptomatic seizures in the elderl y in relation to their underlying structural or metabolic causes (Table 18.1 ). In high-income countries, the most common identi \201 able anteced- ents include cerebrova scular disease, neurodegenerative disorders, intracerebral tumors, traumatic head injury, a nd CNS infections ( 44 ). However, in 33 \200\22350 % of elderly patients, the etiology rem ains unclear ( 9 , 25 , 34 ). Cerebrovascular disease is the most common cause of epilepsy in the elderly, accounting for 30 \200\22340 % of new cases ( 1 , 26 , 43 ). In fact population-based studies have shown that stroke increases the risk of a seizure by a factor of 23 and the risk of epilepsy in t he \201 rst year after stroke by a factor of 17 ( 45 ). The risk of epilepsy can be fur- ther strati \201 ed depending on the type of stroke, with the risk being greatest in those that are haemorrhagic, cortical, large, multiple, and/or that present with acute symptomat ic seizures ( 46 ). The association between epilepsy and stroke is not always obvi- ous and seizures may be the \201 rst presentation of previously unrec- ognized cerebrovascular disease. In one large study of patients with new-onset seizures over the age of 60, none of whom had any known h istory of cerebrovascular disease, tumor, trauma, demen- tia, or alcohol abuse, the 5-year risk of stroke was 2.89 times higher than that of control subjects without seizures ( 47 ). One may specu- late that this is because such seizures re \202 ect the presence of sub- c linical cortical lesions in patients with predisposing vascular risk factors. Indeed, hyper tension itself has been identi \201 ed as a risk factor for seizures, perhaps because of i ts association with progres- sive arterial changes ( 48 ). In the elderly, symptomatic seizures are most often precipitated by cerebrovascular disease (40 \200\22350 % ), which includes haemorrhagic, ischaemic, and embolic strokes, as well a s subarachnoid haemor- rhages ( 8 , 25 , 26 ). Other structural insults, such as head traum a and central nervous system (CNS) infection, may also precipitate sei- zures and obviously increase the risk for epilepsy (although epilepsy is not an inevitable consequence). Drugs and metabolic insults also account for a significant proportion of symptomatic seizures. H owever, such seizures are eminently treatable by withdrawing the offending agent or correct ing the metabolic abnormality. Finally, it is worth noting that the incidence of non-epilep tic seizures in the elderly is not insigni \201 cant, with an incidence roughly similar to that seen in younger populations ( 27 , 28 ). Table 18.2 Identi \201 able aetiologies of epilepsy in the elderly Etiology Symptomatic seizures Cerebrovascular disease 30 \200\22350 % Epilepsy With regards to epilepsy itself, descriptions of its etiology vary depending on th e population studied, the definition of the elderly, and methodological factors ( 9 , 40 \200\22343 ) (Table 18.2 ). Neurodegenerative 10 \200\22320 % Neoplastic 10 \200\22330 % Trauma 10 \200\22320 % CHAPTER 18 epilepsy in the elderly 203 The second most common antecedent of epilepsy in the elderly is neurodegenerative disease, which is associated with a 5- to 10-fold increase in epilepsy relative to the general popul ation ( 26 , 49 , 50 ). Alzheimer disease, Creutzfeldt \200\223Jakob disease, and the adult form of Huntington disease have all been associated with epilepsy. Interestingly, however, it is rarely seen in dementia with Lewy bodies. Amongst patients with Alzheimer dementia, the incidence of epilepsy is approximately 8 \200\22320 % ( 49 , 51 , 52 ). The risk of a p atient with dementia developing epilepsy can be further strati \201 ed based on the earlie r age of onset of the dementia, the stage of disease, and the presence of epileptiform chan ges on the EEG ( 51 ). Although seizure control does not appear to be more dif \201 cult a s the disease progresses, the long-term effect of epilepsy on cognition and subsequent neur odegeneration is unknown ( 53 ). Box 18.1 Reasons for dif \201 culties in diagnosing epilepsy in the elderly \227\206 Lack of medical awareness: \226 Lack of awareness of the high incidence of seizures in the elderly. \226 Nuances of seizure semiology, especially the presence of automatisms, not appreciate d or systematically sought. \226 Inappropriate diagnostic expectation and interpretation of interictal EEG. \226 Failure to involve a specialist with expertise early in the diagnostic process. In some studies, head trauma, usually secondary to falls, can account for up to 20 % of epi lepsy in the elderly ( 54 ). The severity of the injury can predict the risk of subsequent epilepsy, with a loss of consciousness increasing the risk of subsequent epilepsy threefold ( 26 ). Similar to other age-groups, other risk factors include sustaining a brain contusi on with subdural haematoma, skull fracture, and loss of consciousness or amnesia for more t han 1 day ( 55 ). \227\206 Limited, vague, or incomplete history: \226 Under-reporting of events ( 68 ). \226 Absence of a witness \200\224 imprecise semiology. \226 Cognitive impairment affecting patient and/or witness. \227\206 Clinical features of complex partial seizures are more subtle: \226 Lack of auras and recognized automatisms ( 69 ). Of the remaining causes of epilepsy in the elderly, tumors account for between 10 \200\2233 0 % of seizures, and are typically menin- giomas, gliomas, or brain metastases ( 41 , 56 ). Epilepsy is more common with primary relative to secondary tumors, and with low-grade tumo rs rather than high grade ( 57 ). Finally, CNS infec- tions carry a threefold increase in r isk of developing epilepsy ( 56 ). \226 Seizures may manifest as confusion and staring rather than convulsive events. \227\206 Non-epileptic paroxysmal phenomena ( \200\230seizure mimickers \200\231) may be m isattributed to, or be misdiagnosed as, epilepsy (see Box 18.2 ). Presentation and diagnostic evaluation The preceding considerations imply that epilepsy in the elderly is almost always focal, and indeed complex partial seizures are the most common seizure type ( 34 , 43 , 58 ). In fact, it is highly unusual for idiopathic generalized ep ilepsy to present in this demographic and, therefore, even apparently generalized tonic \200\223clonic seizures rarely have a truly generalized onset. witness. In fact, in the authors \200\231 experience, the diagnosis of epi- lepsy in an eld erly patient is most dif \201 cult when such witnesses are unavailable or unreliable and r emains accurate when present ( 60 ). Taking a corroborative history often takes time and pa tience, and sometimes requires a number of consultations if a precise record of the events cannot be gleaned. Making the diagnosis of epilepsy in the elderly can be dif \201 cult. In fact, in the Vete rans \200\231 Administration cooperative study of new- onset epilepsy in a community-dwelli ng cohort, 27 % of patients with epilepsy had been initially misdiagnosed ( 43 ). Some elde rly patients with epilepsy may remain undiagnosed altogether ( 59 ), and several factors co ntribute to making the diagnosis dif \201 cult (Box 18.1 ). A principal problem relates to the fact that epilep- togenic lesions in the elderly appear to produce symptoms that may b e atypical to those found in younger patients, and may be as non-speci \201 c as confusion or simply a sensation of feeling or appear- ing vague. Conversely, more typical epileptic phenomena that are seen in younger patients (e.g. auras, automatisms) may be less common in the elderly. Given the atypical nature of epileptiform symptoms in the elderly, such sympt oms are often misattributed to non-epileptic paroxysmal phenomena, or \200\230seizure mimi ckers \200\231 (Box 18.2 ). The dif \201 culty in making a diagnosis of epilepsy in the el derly is further compounded by the issues of cognitive impair- ment and social isolation. After performing a neurological examination, with particular emphasis on establishing the p resence of any cortical de \201 cits, dedi- cated magnetic resonance imaging (MRI) is the critical investiga- tion in establishing the presence of any structural lesions that may pr edispose to epilepsy. Computed tomography is useful only as an initial screening study (or when MRI is unavailable) for intracere- bral hemorrhage, tumors and encephalomalacia, and s hould be followed by a MRI if any obvious pathology is not detected in a patient with de \201 nite epilepsy ( 61 ). Generally, EEG has an important role in providing information pertinent to the activity and localization of the epilepsy. There is also data to suggest that the EEG may aid prognosti cation \200\224 for example, patients who experience focal spikes or periodic lateral- ize d epileptiform discharges (PLEDs) after a stroke are at greater risk for developing seizure s in the future ( 62 ). Furthermore, EEG is useful in patients who present with prolonged c onfusional states or unexplained coma due to non-convulsive status epilepticus ( 63 \200 \22366 ). As an extension of routine EEG monitoring, video telemetry, is useful in uncertai n cases, in which patients present with recurrent and frequent atypical events ( 28 , 67 ), and to distinguish epileptic seizures from sleep disorders. In spite of its utility, howev er, one should also be aware that the interictal EEG is of relatively less When epilepsy is suspected a detailed seizure history should be acquired, with the broad ai m of distinguishing seizures arising from brain pathology from seizure mimickers. The key s tep in reaching an accurate diagnosis is taking a detailed history from a oxford textbook of epilepsy and epileptic seizures 204 Box 18.2 Seizure mimickers in the elderly Box 18.3 Key principles in the treatment of the elderly patient with epilepsy \227\206 Syncope. \227\206 Document previous drug reactions \200\224 idiosyncratic skin reac- \227\206 Psychogenic non-epileptic attacks. tions and cross-reactivity is common ( 70 ). \227\206 Falls \200\224 multifactorial aetiologies. \227\206 Attempt to use single, non-enzyme inducing, anticonvulsant \227\206 Confusional states (especially in cognitively vulnerable patients) secondary to s ystemic causes (e.g. electrolyte imbal- ance, infection, medications). drugs ( 71 ). \227\206 Titrate AEDs cautiously with lower dose at onset, increment, and target. \227\206 Transient ischaemic attacks. \227\206 Screen for and manage the underlying aetiological disorder (e.g. cerebrovascular risk factors, neurodegenerative disorders). \227\206 Simple forgetfulness. \227\206 Sleep disorders \200\224 periodic limb movements in sleep; REM \227\206 Consider surgical work-up and intervention if seizures remain refractory and the underlying pathological substrate is known ( 72 ). sleep behavior disorder. \227\206 Stereotyped repetitive behaviors associated with dementia and other cognitive problems. \227\206 Movement disorders (tremors, paroxysmal dyskinesias). \227\206 Transient global amnesia. may be more susceptible to drugs which lower the seizure thresh- old (e.g. antidepressants, antipsychotics, certain antibiotics ( 77 )). However, these medications may be required fo r improved mor- bidity, mortality, and quality of life, thus necessitating their contin- ue d use. From a practical perspective, the impaired regulatory mechanisms imply that side eff ects can be seen at lower drug doses and, in the elderly, these adverse effects (e.g. falls ) can be more devastating than in a younger adult. Thus, any anticonvulsant medication shou ld be started at a lower dose and titrated cautiously to a lower target level. The patient, spouse, and family should be counseled regarding common and important side effects. \227\206 Hallucinations. \227\206 Vertigo. utility in the elderly due to the high occurrence of non-speci \201 c abnormalities. In on e study, for example, video-EEG monitoring detected interictal epileptiform discharges in 2 6 % of those with non-epileptic events, and in 75 % of those with epilepsy ( 28 ). Treatment The overarching goals in treating any patient with epilepsy are to improve overal l quality of life, with good seizure control, while minimizing adverse pharmacological side effects. In the elderly, however, this can be challenging, as treatment is complicated by three main issues: ( 1 ) their comorbid medical conditions; ( 2 ) poly- drugstore and drug \200\223drug interactions; and ( 3 ) altered homeostatic mechanisms, which may render patie nts more susceptible to drug side effects. Key principles in treating the elderly patient w ith epi- lepsy are summarized in Box 18.3 . However, no published guide- lines, systematic reviews, or meta-analyzes are currently available to formally guide management. Choice of antiepileptic drug Because old age is a signi \201 cant predictor for seizure re currence ( 13 ), patients should be carefully counseled about the risks and bene \201 ts o f delaying treatment. In general, the older-generation antiepileptic drugs (AEDs), which in clude phenytoin, phenobarbi- tal, carbamazepine, and valproate, have been effective in the treat- ment of focal epilepsies (Table 18.4 ). However, most of these drugs are subject to multiple interactions, and are poorly tolerated in the elderly (in particular carbamazepine ). Of the older-generation drugs, valproate is notable in that it lacks the side effects of seda- tion and motor slowing, and does not induce hepatic enzymes \200\224 and can be a u seful \201 rst treatment option when used in low dose (400 \200\223800 mg/day) in the eld erly. Pharmacology in the elderly Pharmacokinetic changes For otherwise healthy elderly patients who are not frail or mal- nourished, the main pharmacokinetic issue is that of a progressiv e decline in renal function. Thus, care must be given to those drugs that are excreted unch anged by the kidneys, and such drugs should be administered at lower doses in patients with moderate-to-severe renal impairment. Table 18.3 lists the other changes that occur during ageing and precautions one should take in prescribing the corresponding drugs. Overall, there has been a trend away from the use of older drugs, as the newer-generation A EDs are less sedating and offer more favorable side effect pro \201 les particularly drug \200\223drug interactions (Table 18.4 ). However, when used in lower doses the older drugs still have a role in this group. The reader is also referred to the 2004 AAN Guidelines on the ef \201 cacy and tolerability of the newer gen- eration drugs ( 78 ). Unfortunately, d ue to the dif \201 culty in conduct- ing well-controlled trials in this population, there is limited evidence to guide treatment decisions. The only class I or II evidence for the treatment of epilepsy in the elderly comes from thr ee randomized, double-blind comparative clinical trials, which suggest lamotrigine to be th e best tolerated AED. Brodie et al. ( 79 ) showed that lamotrigine is as effective as carba mazepine, but better tolerated, with a lower incidence of rash (3 % vs. 19 % ) and somnolen ce (12 % vs. 29 % ), resulting in an Pharmacodynamic changes Ageing is accompanied by a progressive decline in homeostatic mecha nisms, which leads to a rise in the rate and severity of adverse drug reactions. Due to the se impaired mechanisms, elderly patients CHAPTER 18 epilepsy in the elderly 205 Table 18.3 Pharmacokinetic changes in the elderly and the antiepileptic drugs (AEDs) most a ffected Pharmacokinetic parameter Change in the elderly AEDs affected Absorption Variable and unpredictable, but overall reduction in bioavailability: \227\206 Reduced gas tric acid secretion \227\206 Slowed gastric emptying \227\206 Increased intestinal transi t time \227\206 Decreased mesenteric blood \202 ow \227\206 Decreased intestinal absorp tive area ( 73 , 74 ) \227\206 PHT \227\206 GBP ( 75 ) Protein binding Minimally reduced, unless frail or malnourished: \227\206 Reduced serum albumin results in higher free fraction of protein-bound drugs. Causes Highly protein-bound AEDs ( 76 ): \227\206 PHT \227\206 CBZ \227\206 VPA \227\206 Benzo diazepines more prominent side effects despite little change in the total serum level Hepatic clearance Hepatically metabolized drugs: \227\206 Primarily CYP450: PHT, PB, CBZ, OXC \227\206 Part ially CYP450: TPM, VPA, ZNS, LAC \227\206 Glucuronidation: LTG, VPA, ZNS Variable and unpredictable, but overall reduction in clearance: \227\206 Reduction in hepa tic mass and blood \202 ow \227\206 Reduced function of CYP 450 \227\206 Glucuronidatio n is less affected Renal clearance Most consistent age-related change Renally excreted drugs \227\206 Primarily GBP, LEV, LAC AED, antiepileptic drug; CBZ, carbamazepine; GBP, gabapentin; LAC, lacosamide; LEV, levetir acetam; LTG, lamotrigine; OXC, oxcarbazepine; PB, phenobarbitone; PHT, phenytoin; TPM, topi ramate; VPA, valproate; ZNS, zonisamide. their anticonvulsant effect. One study on elderly patients showed that both good seizure co ntrol and minimal side effects could be achieved with serum concentrations of valproate or carbamazepine that were at, or well below, the \200\230therapeutic range \200\231 ( 89 ). In general, therefore, we suggest halving the target dose of most AEDs, and titrating these drugs at dosage increments half that for younger adults, and over intervals twice as long ( 90 ). For example, car- bamazepine may be started at a dose of 100 mg twice a day, and in creased in 1 month \200\231s time to a maximum of 200 mg twice a day if the drug is tolerat ed and the patient continues to experience seizures (Table 18.4 ). overall lower dropout rate (18 % vs. 42 % ). The \202 exible dosing design used a low dai ly maintenance dose of 400 mg of car- bamazepine and 100 mg of lamotrigine. A second study with an identical design actually showed no difference between lamotrigine and carbamazepin e if a controlled-release formulation of car- bamazepine was used, with a target dose of 40 0 mg daily ( 80 ). Finally, the Veterans \200\231 Administration Study compared lamotrigine , gabapentin, and carbamazepine (standard release) in a randomized double-blind design ( 81 ). The authors found that seizure control was similar across all groups, but that carbamaz epine was signi \201 - cantly less well tolerated (discontinuation rates: lamotrigine 12 % , gabapentin 22 % , carbamazepine 31 % ). A further issue that arises in managing the elderly is that of poly- drugstore. In one stud y, 25 % of older patients with epilepsy were taking 15 or more drugs (mean of seven) ( 43 ) . Such \201 ndings have two important implications. First, they raise the obvious issue o f drug interactions, which one must consider prior to commencing patients on anticonvulsant therapy. Second, the need to administer multiple medications on a daily basis can very eas ily result in the omission of medications, uncertainty regarding their necessity, and confu sion regarding the dosing regimes. Such potential problems with adherence are further ampli \201 ed by the cognitive decline and visual impairment that are more prevalent amongst th is cohort. Overall, therefore, we advocate starting patients on single agents with as simpl i \201 ed a regimen as possible. Other than lamotrigine, levetiracetam has been suggested as an alternative \201 rst-line agent for several reasons ( 82 ). First, it is not metabolized by the liver, implying that it is free of non-linear elim- ination kinetics, auto-induction kinetics, and drug interact ions. Second, it is not protein-bound, and therefore does not displace protein-bound drugs. Finally, it is largely well tolerated, and has favorable ef \201 cacy as indicated by one prospective Phase IV study ( 83 ). Furthermore, several open studies have supported its us e ( 82 , 84 , 85 ), although a randomized controlled trial is yet to be con- ducted in the elderly. In addition to levetiracetam, there are also data from open studies in support of oxcarbazepine ( 86 ) and topiramate ( 87 ). To summarize, valproate, lamotrigine, levetiracetam, or pregab- alin are useful as initial anticonvulsant therapy, as these drugs have the least potential for interaction with common ly used medica- tions and are largely well tolerated. Lamotrigine has the strongest evidenc e in support of its use in the elderly, and should be titrated slowly to a target dose of 1 00 mg/day. An alternative is lower-dose oxcarbazepine if cerebrovascular risk management wi th warfarin is not anticipated. Zonisamide and topiramate also have relatively few drug \200\223drug interactions, but are more likely to produce cogni- tive side effects and incr ease the risk of nephrolithiasis. The elderly are more sensitive to the central and systemic side effects of AEDs ( 88 ). Alm ost all AEDs are associated with neuro- toxicity, resulting in ataxia, dizziness, tremor, a nd cognitive side effects. Such toxicity may be even more problematic in the pres- ence of comorbid conditions affecting balance, coexistent demen- tia, or previous cerebrovascular d isease. In addition, unpleasant sedation is another side effect, which may be exacerbated i n patients already on psychoactive drugs (e.g. benzodiazepines, antidepres- sants, antipsyc hotics). Lowering the dose of AED may reduce the number of side effects experienced by the patient while preserving 2 0 6 Table 18.4 The pharmacokinetics, pharmacodynamics, adverse effects, and recommended practic al dosing regimens of commonly prescribed antiepileptic drugs (AEDs) in the elderly o x f o r d AED T 1/2 (hr) Protein- binding ( % ) Main route of elimination (enzyme) Effect of other drugs on (AED) Effect of AED on (other drugs) Common side effects Comments t e x t b o o k \206\221 (CBZ) by drugs that inhibit CYP 3A4 (SSRIs, erythromycin, azoles, ritonavir, cime tidine, Ca 2 + channel blockers, grapefruit juice) \206\223 (CBZ) by drugs that induce CYP 3A4 (St John \200\231s wort) \206\223 levels of VPA, LTG, TPM, ZNS, LEV, BZD and drugs metabolized by CYP 3A4 (Table 18 .5 ) Carbamazepine (CBZ) 5 \200\22326 75 \200\22385 Hepatic oxidation and glucuronidation (CYP 3A4/5) Notable : hyponatraemia, sedation, neurotoxicity (gait/ataxia, dizziness, tremor, nystagmus ), arrhythmias, bone loss Other : cognitive and behavioral, headache, gastrointestinal Advantages : gold standard for partial seizures. Studied in elderly. Cheap. As effective as , and better tolerated than, PHT, PB, VPA Disadvantages : allergic reactions. Side effects. Multiple interactions as protein bound and enzyme inducer. Multiple interactions. As effec tive as LTG, but more side effects Caution : salt-restriction/diuretics ( 94 ), conduction defects, dose adjust with renal failure Pragmatic dosing : 100 mg bd (cid:146) 200 mg bd o f e p i l e p s y a n d \206\221 (PB) by chloramphenicol, dextropropoxyphene \206\223 levels of VPA, LTG, TPM, ZNS, LEV, BZD and drugs metabolized by CYP 3A4 (Table 18 .5 ) \206\223 levels of VPA, LTG, TPM, ZNS, LEV, BZD, and drugs metabolized by CYP 3A4 (Ta ble 18.5 ) Phenobarbital (PB) 77 \200\223128 55 Hepatic oxidation and glucuronidation (CYP 2C9) Notable : sedation, cognitive, depression, bone loss Advantages : broad spectrum. Once daily. Cheap Disadvantages : side effects. Enzyme inducer . Poorly tolerated relative to CBZ or PHT Pragmatic dosing : 15 mg bd (cid:146) 30 mg bd e p i l e p t i c s e i z u r e s \206\221 (PHT) by VPA, OXC, TPM; and drugs that inhibit CYP 3A4 (SSRIs, chloramphenicol, a zoles, tamoxifen, allopurinol, omeprazole) \206\223 (PHT) by CBZ \206\221 (VPA) by sertra line, isoniazid, cimetiidine \206\223 (VPA) by CBZ, PHT Phenytoin (PHT) 7 \200\22342 90 Hepatic glucuronidation and oxidation (CYP 2C9, CYP 2C19) Notable : sedation, cognition, imbalance/ataxia (even at modest doses), arrhythmias, bone l oss 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