VIMS Journal: December 2017

Review Article

Management of Epilepsy in The Elderly

Dr. Koushik Pan, Dr. Barun Kumar Sen, Dr. Ansu Sen, Dr. Debasish Roy, Dr. Angshuman Mukherjee, Dr. Amit Halder

Introduction :
Seizures and epilepsy are the third most common neurological disorder affecting older adults, after stroke and dementia

Epidemiology :
The incidence of both acute symptomatic seizures and unprovoked seizures/epilepsy is highest in people over the age of 65yrs among all age groups[1,2,3]. The incidence continues to rise with increasing age, and is greatest in the group older than 75 years of age, in which the incidence is five times that of younger adults.[4]

Etiology in The Older Adult :
- Up to 50% of new-onset seizures and epilepsy in the older adult population are caused by stroke, either hemorrhagic or ischemic.
Development of epilepsy after a stroke is associated with several factors, including type of stroke, localization, and severity.
Hemorrhagic strokes have the greatest propensity to cause seizures, followed by embolic and then thrombotic ischemic strokes.
Strokes that involve the cortex have higher seizure.
- Approximately 7% of ischaemic and 15% of haemorrhagic cortical strokes are complicated by acute or early seizures (within 2 weeks of stroke onset)[5] and approximately one-third of these patients develop late epilepsy. A further 10% of stroke patients without early seizures go on to develop late epilepsy[6] Review Article
- The risk of epilepsy in the first year after a stroke is up to 20 times greater than in individuals who have not experienced a stroke. In addition, individuals with a history of epilepsy are more likely to experience a stroke rates than do subcortical strokes.
- Traumatic brain injuries are the next most common cause of seizures and epilepsy in older adults. Around 20% of older adults with new-onset epilepsy have a temporally related traumatic brain injury. Predictive factors identified for the development of epilepsy caused by a traumatic brain injury in this age group are brain contusion with subdural hematoma, skull fracture, and loss of consciousness.
- Tumors and dementia are also common causes of epilepsy in older adults. Up to one third of seizures in older adults are caused by tumors. The risk seems to be higher with primary and low-grade tumors than in secondary and high-grade tumors. Even relatively small tumors can cause seizures, and the surgical resection of tumors does not appear to greatly alter epileptogenesis.
- Similar to tumors, dementia is associated with disruption and degeneration of neuronal pathways. Several prospective observational studies have explored the relationship between seizures and dementia. The risk of seizures seems to be highest in individuals with more severe dementia and in those who develop dementia at a younger age.
- Underlying toxic, metabolic, and infectious disorders can result in seizures. The main toxic events that result in seizures in older adults are adverse reactions to drugs, abuse of illicit or prescription medications, and alcohol withdrawal. Although not often considered in the assessment of older adults, urine toxicologic screening is especially helpful in detecting potential toxic causes of seizures and should be routinely performed.
- Hyponatremia and hypoglycemia are the most common metabolic disturbances in older adults that can result in seizures. Diuretic use can result in hyponatremia, and serum sodium should be evaluated in patients with seizures. If hyponatremia is detected, sodium replacement should be given before initiating an AED. Hypoglycemia is an issue for patients treated for diabetes and should be corrected before initiating AEDs for seizures.
- Meningitis and encephalitis can also result in seizures, necessitating the use of appropriate antimicrobial treatment.
Seizure type and Epilepsy syndrome :
- There is a different distribution of seizure types and epilepsy syndromes in the elderly compared to younger patients.
- As it is extremely unusual for idiopathic generalized epilepsy syndromes to present in this age group, even apparently generalized tonicñclonic seizures without obvious focal features should be presumed to be partial in onset unless proven otherwise.[7]
- Seizures in elderly patients may manifest with sensory symptoms, visual phenomena or language disturbances, which may be more difficult to recognize as epileptic in nature.
- Although it is generally stated that elderly patients have fewer auras and longer durations of postictal confusion.
- Auras, however, may be very nonspecific, for example simply consisting of dizziness. Complex partial seizures are probably more common than appreciated with and clinical features different to the more typical mesial temporal lobe complex partial seizures seen in younger patients.
- Status epilepticus, both convulsive and nonconvulsive, is relatively common in the aged, with stroke being the most commonly identified cause.

Diagnosis :
- The diagnosis of epilepsy in the elderly is often a challenging process that may be significantly prolonged in many cases. Delay in diagnosis of epileptic seizures in the elderly is not uncommon.[8]
- In the elderly where dementia is common, and memory function is declining, obtaining a clear history of the seizure-like event from the patient can be very difficult. This increases the need for an accurate eyewitness account.
- Partial seizures may be misdiagnosed as nonspecific confusional states.
- Non-convulsive status epilepticus may simply be interpreted as acute behavioural changes, dementia or delirium.
- Of patients with generalized tonicñclonic (GTC) seizures, only two-thirds were diagnosed immediately, and of patients with complex partial seizures, only one-quarter were diagnosed immediately.
- Other patient factors further complicate the identification of seizures. From a social perspective, many in this age group live alone, so no other individuals are available to regularly observe brief events such as seizures.
- Symptoms of common diseases in this age group can also mimic seizures. Cardiac arrhythmias, panic attacks, falls, global transient amnesia, myoclonus, orthostatic hypotension, REM (rapid eye movement) sleep behavior disorder, cataplexy, migraine, restless leg syndrome, syncope, transient ischemic attack, and tremor all have features that may be confused with seizures.
- For example, brief cardiac arrhythmias may cause episodes of acute loss of consciousness, with motor activity that appears similar to seizures; transient ischemic attacks often produce neurologic symptoms such as numbness, tingling, and altered consciousness, all of which can be features of seizures. Even simple falls can be mistaken for seizures.

Diagnostic Criteria
The findings from an extensive literature were able to identify three major and four minor diagnostic criteria.
The major criteria were confusional state with sudden onset, rhythmic muscular contractions in a focal territory, and paroxysmal behavioural disorder associated with a focal neurologic sign. Minor criteria were impairment of consciousness, isolated paroxysmal behavioral disorder, history of epilepsy, and focal slow waves on electroencephalography (EEG).
A diagnosis of epilepsy in the older adult can be made if at least one major criterion is present or two or more minor criteria are present.

Seizure vs. Psychogenic Nonepileptic Seizures
Psychogenic nonepileptic seizures can be easily mistaken for epilepsy because they are repeated, stereotypical spells that clinically appear to be seizures. Depression or anxiety disorders were identified in more than 50% of these individuals, and 90% had somatoform disorders identified.
During video monitoring, the most common clinical symptoms of psychogenic nonepileptic seizures were waxing and waning tremors or shaking of the extremities, rocking of the body, bicycling movement of the legs, pelvic thrusts, thrashing movements, cheek biting, and unusual dystonic postures. The definitive diagnosis of psychogenic nonepileptic seizures is accomplished through 24-hour video EEG Treatment of these spells typically involves psychiatric and psychological interventions, including the potential use of antidepressants, antipsychotics, and/ or cognitive behavior therapy. The use of AEDs, except for psychiatric indications, is not effective for the treatment of nonepileptic events and should be avoided. If the patient is receiving an AED, it should be gradually tapered and discontinued unless needed for psychiatric indications or for epileptic seizures.

Isolated seizure vs. Epilepsy
It is important to determine whether a seizure is an isolated event or one that will recur and become epilepsy. This is a key decision point in determining the need for pharmacotherapy. Recurrence rates of a seizure are much higher in the older adult than in the younger adult, with a 70% to 80% chance of a seizure recurring after the first event. Because of this high recurrence rate, most recommendations for treating seizures in older adults encourage the use of an appropriate AED, even after a single seizure.

Seizure vs Syncope :
Syncopal attacks, as the latter may have multiple causes in older patients, most notably cardiac arrhythmias, carotid sinus syncope and postural hypotension, often due to drugs[9]. Of all the discriminating features, the rapidity of recovery after syncope compared with a seizure is often thought to be the most useful. However, a seizure may be brief (or be reported as brief) whereas syncope associated with an arrhythmia or with prolonged vertical posture may be prolonged. Post-event confusional states are typically prolonged in epileptic seizures and brief with syncope, but may also be prolonged in cerebral anoxia due to syncope associated with a serious cardiac arrhythmia. Cardiogenic or neurocardiogenic (vasovagal) syncope is often accompanied by brief myoclonic jerks, posturing, head turning, automatisms (lip smacking, chewing) or upward deviation of the eyes, and vocalizations may occur. It should be noted that incontinence is not uncommon in syncope, and does not help differentiate syncope from seizures. Postictal hemiparesis (Todds paresis) is a common occurrence. This may lead to misdiagnosis of stroke.

Dementia vs Seizure :
Dementia is a frequent cause of memory loss in the ageing patient. In elderly patients, memory dysfunction may be caused by complex partial seizures and may present either as an insidious fluctuating course of memory loss and confusion that simulates dementia or as discrete episodes of amnesia. The occurrence of such serial complex partial seizures masquerading as dementia is also known as "epileptic pseudodementia" and represents a potentially treatable cause of memory dysfunction. When interictal epileptiform discharges (IEDs) are present in patients with epileptic pseudodementia, they have most often been suggestive of a left temporal seizure focus.

Antiepileptic Drug Therapy
Decision to commence treatment :

The decision to commence antiepileptic drug (AED) treatment should be based on a number of factors, including risk of seizure recurrence, consequences for the individual of further seizures, potential adverse effects of AEDs and ultimately, the patients views. The effects of seizures and epilepsy in the elderly are potentially more debilitating than in younger age groups. As with all patients experiencing a seizure, patients may sustain spinal or head injury, burns from various sources, or a motor vehicle accident. Fall is more likely to be associated with a fracture.

Choice of Antiepileptic Drug :
Of the commonly used AEDs, carbamazepine and phenytoin are drugs of choice for partial epilepsy. Valproate is used in primary generalised epilepsy, although it has a broad spectrum of activity and may be used to prevent partial seizures. Some believe it is as effective as carbamazepine in this patient group.
Phenobarbitone, although not usually recommended for elderly patients, may be useful in preventing partial or generalised seizures. Of the newer agents, both lamotrigine and topiramate have a broad spectrum of activity and are used as add-on therapies to prevent both partial and generalised seizures. Gabapentin, tiagabine and oxcarbazepine are used in the management of partial epilepsies. Vigabatrin is rarely used due to unacceptable adverse effects.

Pharmacokinetics :
- Age-related physiological changes need to be considered when choosing therapy. These changes result in alterations in pharmacokinetics and pharmacodynamics of AEDs, which in turn alter drug absorption, distribution, biotransformation and elimination[10]. Alterations in protein binding are common in the elderly and have a significant impact on highly protein bound AEDs such as phenytoin and valproate. Reduced protein binding in the elderly may be due to an age-related reduction in albumin synthesis[11], liver or renal disease, malnutrition or interaction with other highly protein bound drugs.
- Impaired renal and hepatic function is common in the elderly and influences hepatic metabolism of drugs and renal excretion of parent drug and their metabolites. The hepatic glucuronidation conjugation process is believed to decline much less with age. AEDs primarily undergoing conjugation include lamotrigine, valproate and the active metabolite of oxcarbazepine. Several newer AEDs (e.g., gabapentin, pregabalin, topiramate, zonisamide, lacosamide, levetiracetam) are completely or predominantly cleared by renal elimination. Kidney function should be monitored before initiating therapy with one of these AEDs and during ongoing treatment. The exponential increase in serum concentration of phenytoin with increasing dose occurs earlier in the elderly compared with younger individuals.[12]
- There is an increase in the ratio of fat :lean body mass in the elderly with a decline in total body water resulting in an increased distribution volume for lipid soluble drugs such as carbamazepine, phenytoin and phenobarbitone. The half-life and action of these drugs can increase in elderly patients, as they accumulate in adipose tissue, elevating the risk of adverse effects.[13]
- Many AEDs, especially the older agents such as phenobarbital, phenytoin, carbamazepine, and valproate, have several drug interactions.
This poses a problem in older adult patients, who are likely to be taking several drugs for chronic diseases. The most common clinically important interactions were with cardiovascular drugs, agents for hyperlipidemia, analgesics, and anticoagulants. These interactions were found to potentially result in seri-ous clinical adverse events for the patient. Other classes of commonly used drugs that interact with AEDs include antidepressants (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors), antifungals, antiretrovirals, antineoplastics, antipsychotics, benzodiazepines, immunosuppressants, and steroids. The primary mechanism for most of these interactions involves cytochrome P450 (CYP) isoenzymes. Keys to managing or preventing AED drug interactions include the use of a single AED whenever possible for the control of seizures. Another strategy is to select a drug with a lower propensity for drug interactions. In general, newer AEDs (e.g., gabapentin, lamotrigine, levetiracetam, oxcarbazepine, topiramate, zonisamide, pregabalin, lacosamide) have fewer drug interactions and tend to be easier to manage in older adult patients . Many of these AEDs are at least partially eliminated renally, reducing the possibility of drug interactions. Given the potential changes in pharmacokinetics, plasma levels of AEDs should be monitored more closely.
- The prevalence of reduced gastric acidity increases with age, as does the potential for decreased absorption of weakly basic drugs and increased absorption of weakly acidic drugs. In addition, gastric emptying and gastroin-testinal transit time are slowed and more variable in older patients. This variability in gastrointestinal physiology can result in unreliable absorption of sustained-release AED formulations and poor management of the patients response. This explains the large variations in phenytoin trough concentrations.
- The ideal therapy in the elderly would meet the following criteria:

Ideal therapy :
- No interactions with other medications
- No interactions with other AEDs
- Can be introduced at therapeutic doses
- No metabolism
- No protein binding
- Once- or twice-daily dosing
- Laboratory monitoring not necessary
- Excellent safety record
- Good side-effect profile
- High therapeutic index
- Little effect on cognitive function
- Linear pharmaco-kinetics

Appropriate Dosing
- Typically, AEDs are initiated at low doses and gradually titrated to response. This approach minimizes the impact of doserelated adverse effects and allows more careful dosing, which balances efficacy and toxicity. Older adults typically respond at lower doses.
- Target doses for AEDs in older adults are often 50% to 75% of those in younger adults. Titration typically involves incremental increases on a weekly basis. The rate of increase depends on the drug involved. For example, lamotrigine has a strict protocol for therapy initiation because of the risk of serious rash, whereas other AEDs have more flexible titration options. Determining a rea-sonable target dose is based on several factors including kidney function for drugs with renal elimination, nutri-tional and albumin status for drugs with high protein binding, and liver function for drugs that are hepatically eliminated.

Efficacy Monitoring
The only way to determine the efficacy of AED pharmacotherapy is to keep seizure calendars and counts of seizures. Electroencephalography and AED serum concentrations are unreliable markers of efficacy. Serum concentrations of AEDs can be useful in benchmarking an optimal response, evaluating dose-related adverse effects, or checking adherence.

Adverse Effect Monitoring
- Dose-related adverse effects common to all AEDs in older adults include mental status changes, confusion, and sedation. Adjusting or reducing the dose will usually minimize or eliminate dose-related adverse effects.
- Chronic and idiosyncratic adverse effects also occur with AEDs. Chronic adverse effects occur months to years after therapy initiation. Idiosyncratic effects tend to be hypersensitivity reactions. Patients should be monitored at each clinic visit for these events. Idiosyncratic reactions are more common with AEDs than with other classes of drugs. Typically, these reactions occur during the first 6-12 months of therapy and are more common with the older AEDs. The most common idiosyncratic reactions are dermatologic, hepatic, and hematopoietic. Rashes are of great concern because they can progress to Stevens-Johnson syndrome or toxic epidermal necrolysis. It is not possible to predict which rash will become severe; therefore, it is recommended that a patient discontinue the AED immediately on the first appearance of a rash.
- Recent studies have shown an association between AEDs and the development of osteopenia and osteo-porosis. Contrary to previous impressions, essentially all AEDs have been shown to decrease bone mineral density as early as 6 months after treatment initiation. The precise mechanism for this effect is unclear, but for enzyme-inducing AEDs (i.e., phenobarbital, phenytoin, carbamazepine, and oxcarbazepine), it may be related to the induction of vitamin D metabolism. The risk of developing osteopenia and osteoporosis with AEDs is similar to that with corticosteroids. Current recommendations for individuals taking these drugs are to have vitamin D serum concentrations checked at least annu-ally and bone mineral density checked at baseline and every 2-3 years thereafter. In addition, regular vitamin D and calcium supplementation are recommended. Cal-cium doses are usually 1200-2000 mg/day. Vitamin D doses are typically 800-2000 international units/day.
- All AEDs are associated with an increased risk of depression. Patients taking AEDs should be routinely monitored for depressive symptoms using one of the various tools for assessing mood. Should depression arise, the typical treatment is addition of an antidepressant, such as a selective serotonin reuptake inhibitor. Changing to an AED with less risk of depression (e.g., lamotrigine, gabapentin) is an option, but this could result in the return or worsening of seizures.
- Ataxia is an adverse effect of a number of AEDs, which takes on greater significance in the elderly. Ataxia is particularly common with phenytoin toxicity, but may be associated with all of the AEDs, even at therapeutic concentrations.
- Weight should be measured at each clinic visit, especially for AEDs known to alter body weight (e.g., valpro-ate, gabapentin, pregabalin, topiramate, zonisamide). Serum sodium should be measured regularly in the older adult taking carbamazepine and oxcarbazepine because of increased risk of hyponatremia. Treatment of hyponatremia includes altering the AED dose, changing to another AED, increasing sodium intake, or imple-menting fluid restriction.
- Carbamazepine, also widely prescribed, has a less than favourable pharmacokinetic profile. As an inducer of hepatic enzymes, numerous drug interactions can occur. Hyponatraemia occurs mpore commonly in elderly patients taking carbamazepine[14]. Carbamazepine has been shown to be less well tolerated than many of the newer AEDs.

Treatment of Status Epilepticus in Older People :
- Status epilepticus is treated in a manner similar to younger patients. Initial control with intravenous benzodiazepines is appropriate followed by intravenous phenytoin.
Fosphenytoin has been advocated, as it can be given at a much faster rate than intravenous phenytoin and is associated with fewer local cutaneous reactions.[15]

Decision to stop treatment :
- If the patient has been seizure free for at least three years, particularly if epileptiform activity has disappeared from the EEG, the possibility of ceasing antiepileptic drug therapy could be considered. The criteria for discontinuing an AED include 2-5 years without documented seizures, a normal EEG, and the absence of any underlying pathology such as a tumor. If these criteria are met, the AED can be tapered over a 1-to 2-month period.
Abrupt discontinuation may result in withdrawal seizures, confounding the attempt to dis-continue the AED. If the patient has had mul-tiple seizures prior to commencing treatment, or the epi-lepsy has been difficult to control, a more conservative approach is recommended, and medication should be continued longer term.

Seizure Prophylaxis :

Head injuries are relatively common events in older adults and, as in younger individuals, can precipitate epilepsy. Several studies have considered various drugs and regimens for the prevention of seizures after a mod-erate to severe head injury. The only effective preven-tive intervention in this instance is the use of phenytoin during the first week after the head injury. Other AEDs including valproate, carbamazepine, levetiracetam, and lamotrigine have been studied but have not been shown to be efficacious.
Seizures caused by primary brain tumors are quite common and should be treated when they occur. It has been thought that enzyme-inducing AEDs (e.g., phenytoin, carbamazepine, phenobarbital) would result in poorer chemotherapy outcomes. However, a study of AEDs in patients with glioblastoma shows that patients taking these drugs actually have bet-ter outcomes.
Seizures occur in about 50% of adults experiencing a stroke. Often, patients with severe strokes will present with status epilepticus, which is treated using the same protocols as in younger adults. The risk of seizures other than status epilepticus increases with factors such as cortical involvement, several lesions on neuroimaging, supratentorial lesions, old lesions on neuroimaging, family history of seizures, use of drugs known to cause seizures, large lesions, hemorrhagic lesions, and concurrent presence of cortical atrophy. At the first indication of seizure activity in a patient who has experienced a stroke, treatment with an AED should be initiated. Based on the previously described studies, Lamotrigine or Gabapentin is the preferred initial drug.

Conclusions :
Epilepsy in the elderly is a significant health problem. The spectrum of seizure, epilepsy types and the aetiologies of the seizure disorder is different in the younger population as compared to the older age group. Age-related physiological changes potentially alter drug pharmacokinetics and these need to be taken into consideration when treating elderly patients with AEDs. As the seizure types and the drug pharmacokinetics is different in the older population there is a need for drug trials in this specific population for better guidelines.

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