Epilepsy Times
Newer Anticonvulsants in Patients with Dementia
Dementia is a clinical syndrome that causes 'a global deterioration of mental functioning in its cognitive, emotional and conative aspects'. It is a common problem in the aging population. In the coming years, with increasing life expectancy, the number of such patients are expected to rise exponentially. Alzheimer's disease alone now affects several million people, while millions more are affected by vascular dementia, Lewy bodies disease and fronto-temporal dementia. Behavioural disturbances in Alzheimer's disease and other dementias are common therapeutic challenges for clinicians. Non-pharmacological therapy, though most often recommended, is often inadequate. A large proportion of patients with Alzheimer's disease and other dementias require medication for treating moderate-to-severe behavioural disturbances.
Current pharmacological options have a relatively poor balance of efficacy and safety. Antipsychotics are considered viable agents for the treatment of moderate-to-severe psychosis and agitation in patients with dementia; however, many published studies have not shown significant benefit when these drugs were compared with placebo. Also, these medications carry with them a substantial risk of adverse effects. The clinical significance of cholinesterase inhibitors and memantine in terms of their ability to substantially improve behavioural disturbances in dementia patients is questionable. Benzodiazepines are associated with cognitive adverse effects and falls in the elderly. Antidepressants may provide some benefit in the treatment of agitated patients with dementia, but the supporting data is limited. Anticonvulsants, especially valproate and carbamazepine, have been popular alternatives to antipsychotics in these cases, but their efficacy and safety are again debatable.
When discussing the use of anticonvulsants for behavioural disturbances in dementia, treatment guidelines use terms such as 'minimal', 'limited', 'generally not recommended' and 'significant adverse effects' as descriptors. These guidelines also support an anticonvulsant trial in patients for whom other medications have failed.
The recommendations made for anticonvulsants in dementia are largely based on data from studies involving valproate and carbamazepine. Several recent reviews inspect the use of newer anticonvulsants in patients with dementia, with authors highlighting the small number of trials and hinting at a possible place in therapy for gabapentin, oxcarbazepine and topiramate. Many such varying reports create uncertainty among clinicians about how to best use these agents in dementia, if at all.1
Dementia occurs across all populations and ethnic groups. Due to increasing life expectancy, the number of people suffering from dementia is increasing rapidly all over the world. More than 25 million people suffered from dementia in 2000. By 2030, that number is expected to rise to 63 million, 65% of whom will be in less developed countries. Most dementias are found in people over the age of 65 years, and about 4 - 15% of the population over the age of 65 years have some form of at least mild dementing illness. There is a doubling of prevalence rates for dementia approximately every 5 years after the age of 60 or 65 years. The prevalence is < 1% for people aged 60 - 65 years, 2 - 25% for those aged 65 - 74 years, and ≥ 34.5% for those aged 85 years and older. Alzheimer's is the most common form of dementia. Among those with dementing diseases, 55 - 70% has pure Alzheimer's disease or a mixture of Alzheimer's disease and cerebrovascular disease, about 25% have cerebrovascular changes, and about 15% have dementia with Lewy bodies. Cerebrovascular disease, as confirmed by advanced neuroimaging, seems to be responsible for 10 - 30% of all dementing diseases.
The prevalence of other dementias is less clear. Other dementing diseases are movement disorders such as Huntington's disease and Parkinson's disease, infections such as Creutzfeldt-Jakob disease and toxic-metabolic disorders such as alcoholism and chronic metabolic disorders.2
In the elderly, unprovoked and acute symptomatic seizures are common. The incidence of any type of first seizure is 52 - 59 per 1,00,000 population in persons aged 40 - 59 years, but rises to 127 per 1,00,000 in those aged 60 years. The use of anti-epileptic drugs (AEDs) is common in patients residing in nursing homes. About 10 - 11% of residents in long-term care facilities use anti-epileptic medication. Phenytoin is the most common drug, used in two-third of these patients, followed by carbamazepine in nearly one-third
Dementing illnesses are major risk factors for the development of epilepsy in the elderly. Alzheimer's disease and other dementias are associated with a 5 - to 10 - fold increase in the risk of epilepsy compared with a control population; 10 - 22% of patients with Alzheimer's disease have at least one unprovoked seizure. The specific risk of epilepsy in other dementing diseases is less clear, but tends to be high in vascular dementia and Creutzfeldt-Jakob disease. Almost all seizures in the elderly are of partial onset; however, Alzheimer's disease and other dementias increase the risk of generalized tonic-clonic seizures too. Unlike the non-demented elderly, patients with Alzheimer's disease have a prevalence (79 - 100%) of generalized seizures. Presumably, these are secondarily generalized from a partial seizure focus, suggesting that many partial seizures are missed in dementia patients. The often subtle and subjective nature of partial complex and partial simple seizures may make them difficult to detect among cognitively impaired dementia patients.2 Dementing illnesses predispose patients to seizures because of the development of epileptogenic lesions. A selective loss of inhibitory neurons may be encouraging the occurrence of seizures. In Alzheimer's disease, there may be epileptogenic alterations of neurons and glia in the hippocampal and neocortical areas. One study suggests that epileptogenesis in Alzheimer's disease correlates with lower counts of pyramidal cells in cortical layers III - IV of the parietal cortex (area 7) and, to a lesser extent, in the parahippocampal gyri (area 28).
Seizures are observed to occur in later stages of Alzheimer's disease or ≥ 6 years after the onset of dementia. The cumulative risk of epilepsy increases by 11% and 26% at 10 and 15 years, respectively following a diagnosis of Alzheimer's disease. Alzheimer's disease patients with seizures are twice as likely to have an age of onset of dementia of < 65 years compared with Alzheimer's disease patients without seizure. Dementia patients with seizures are more cognitively impaired than those with dementia only. Seizures are particularly associated with early-onset familial Alzheimer's disease. Compared with Alzheimer's patients without seizures, the Alzheimer's patients with seizures do not differ with respect to psychotropic or other medication use, hypertension or other underlying medical conditions, history of stroke-like events, alcohol use, medical illnesses and degree of focal neuropathology. Advanced dementia related neuropathology seems to the main reason of seizures in Alzheimer's disease.2
In its early stage, diagnosis of dementia can be difficult. This is because many of the symptoms of dementia can be caused by other conditions. Similarly, diagnosing the presence and type of epilepsy in dementia patients is difficult. This is because the history given by the elderly patient with dementia is often unreliable or unavailable. Alzheimer's disease itself can cause certain signs and symptoms suggesting partial seizures. Seizure-like spells such as syncope, transient ischaemic attacks, rapid eye movement-sleep behaviour disorder, acute labyrinthitis and amnestic episodes can cause difficulty in making the correct diagnosis. Conversely, partial complex seizures may be interpreted as worsening dementia, amnesia or recurrent episodes of confusion. Also, complex partial seizures that occur with subtle clinical signs or loss of awareness, or that occur during sleep may not be easily identified.2
The evaluation of suspected seizures in dementia patients should include a clinical neurological examination, routine blood tests, an electroencephalogram (EEG) and neuroimaging. Magnetic resonance imaging (MRI) is preferred because it gives a better resolution. In case of a seizure, acute symptomatic seizures should be first ruled out by an evaluation for acute brain and metabolic illnesses. The most frequent EEG findings in Alzheimer's disease and other dementias is a generalized slowing of the background rhythm, which may rarely show epileptiform discharges.2
The process of aging is associated with decreased albumin and serum protein, altered drug absorption and distribution, changes in hepatic metabolism, and decreased renal elimination. These changes in metabolism can affect the efficacy and adverse effects of AEDs. The most significant is the degree of drug protein binding. Low albumin levels of many elderly individuals (aged > 65 years) particularly affect the pharmacokinetics of drugs such as phenytoin and valproic acid, which are highly protein-bound. The unbound drug concentrations of phenytoin and valproic acid reflect the therapeutically active fraction of the ingested drug. Measurement of these unbound drug concentrations is indicated when the drug protein binding is altered.2
The second most significant pharmacokinetic change that occurs with aging is a reduction in hepatic mass and blood flow, with a decrease in hepatic drug metabolism of about 10% per decade from the age of 40 to 70 years.Most AEDs are degraded through the cytochrome P450 system of the liver. Oxidative metabolism mediated by this system is reduced more in the elderly. However, conjugation reactions such as glucuronidation involved in lamotrigine metabolism are not equally affected. A third pharmacokinetic change is the reduction in renal glomerular filtration rate by about 10% with each decade after the age of 40 years. Active tubular re-absorption also plays a part in the renal excretion of drugs. AEDs such as gabapentin and levetiracetam are primarily excreted unmetabolized through the kidneys. Other potential pharmacokinetic factors to consider in the elderly include changes in absorption because of decreased gastric motility and gastric mucosal atrophy and an increase in the ratio of fat to lean mass, resulting in the wider distribution of fat-soluble drugs. These pharmacokinetic changes indicate the need for smaller doses and longer dosing intervals of antiepileptics in elderly patients with dementia.2
AEDs can suppress neuronal excitability or enhance inhibitory neurotransmission adversely affecting cognitive function. The severity of these effects is mild-to-moderate for most AEDs; however, patients with dementia appear to be more susceptible to them. Elderly patients with dementia are observed to be vulnerable to delirium from medications. Most hospitalized patients with delirium have an underlying dementia or baseline cognitive impairment.
The most common cognitive effect of AEDs is a mild slowing of mental speed. It is believed that in Alzheimer's disease and related disorders, this slowing can greatly magnify memory and other traits of dementia. Studies show that the traditional AEDs have greater cognitive effects than the newer AEDs. However, few studies have evaluated the cognitive adverse effects of the newer AEDs. Gabapentin has fewer cognitive effects than carbamazepine. Of the newer drugs, topiramate can result in significant cognitive impairments.2
Results from placebo-controlled clinical trials and community-based practice have demonstrated that levetiracetam has a broad spectrum of activity in suppressing seizures as add-on treatment and monotherapy and that it is safe and well tolerated. Levetiracetam also has a favourable pharmacokinetic profile characterized by rapid and nearly complete absorption, very low potential for drug interactions and a prolonged pharmacodynamics effect that permits twice-daily dosing.
Lippa CF et al., conducted a prospective, uncontrolled, phase 4, open-label, 12-week study of levetiracetam to better profile its efficacy, safety and impact on cognitive/behavioural status in 24 cognitively impaired, elderly individuals. In total, 69% were seizure-free for the duration of the study; the remaining participants had satisfactory seizure control. Fatigue was the most common side effect (5 participants). Significant overall improvements were observed for the Folstein's Mini- Mental State Examination and the Alzheimer's disease Assessment Scale-Cognitive.3
This study concluded that levetiracetam is a well- tolerated and effective AED in elderly individuals with cognitive impairments. Reduced doses, however, are needed in this population due to decreased renal clearance. Initiation of levetiracetam therapy resulted in improved seizure control. Except for the group with early intolerability due to fatigue, improved cognition with no significant incidence of serious adverse effects or increased risk of neuropsychiatric disturbances were seen.3
At present, there are no published trials regarding the choice of AEDs in elderly patients with dementia. Much of this discussion is extrapolated from what is known in the elderly in general. The newer AEDs are comparatively less likely to interfere with hepatic metabolism and may have a larger role in this patient population.
The pertinent AEDs are reviewed here. Phenobarbital, primidone and the benzodiazepines are not recommended in dementia patients because of their cognitive effects. Felbamate is not discussed because it can cause aplastic anaemia and liver failure, and vigabatrin is not discussed because of the high incidence of irreversible visual field constriction. Finally, there is minimal information on the use of some of the other, newer AEDs (tiagabine, levetiracetam and zonisamide) in elderly patients, although early studies suggest that they are not associated with significant cognitive impairment.
Valproic acid is useful for treating generalized epilepsies and localization-related epilepsies. It acts on sodium currents and T-calcium channel currents and also inhibits Gamma Amino Butyric Acid (GABA) metabolism. Although valproic acid is well absorbed, food can delay its absorption. In the elderly, its protein binding and unbound clearance is reduced. Thus, a lower dose than that for young adults can bring about the desired clinical response. Measurement of unbound drug concentrations should be considered if the albumin level is low or if the patient's response to the drug does not correlate with total drug concentration. Valproic acid has drug interactions with enzyme-inducing and -inhibiting drugs. It is a weak enzyme inducer and can slow clearance of other AED. Its efficacy is comparable to phenytoin and carbamazepine, but it is less effective for partial seizures. Intravenous valproic acid does not produce significant changes in blood pressure or pulse and is well tolerated in elderly patients.2
Carbamazepine is effective in partial and generalized tonic-clonic seizures. It acts on the sodium channels to stabilize the neural membranes. It is 65 - 85% bound to albumin.
The clearance of this drug in the elderly is 40% lower than that of younger patients. This is similar to that seen with phenytoin and valproic acid in these patients. Hence, the elderly may need lower and less frequent doses. Carbamazepine has similar efficacy to that of valproic acid or phenytoin and a better efficacy than vigabatrin. It has similar efficacy but poor tolerability as compared to oxcarbazepine and lamotrigine. In addition to potential hematological and dermatological effects, carbamazepine can also affect cardiac rhythms and should probably not be used in patients with rhythm disturbances.2
Apart from being recommended for partial seizures, gabapentin is found to show good anxiolytic and anti-panic effects too. Its analgesic properties have made it more useful in treating post-herpetic neuralgia, diabetic neuropathy and migraine headache prophylaxis, than to the epilepsy patients to whom they were originally prescribed. These pain syndromes can be said to be over-represented in elderly people. Neuropathic pain is often co-morbid with diabetes mellitus and has a high prevalence rate. Elderly individuals may suffer disproportionately from diabetes mellitus and post-herpetic neuralgia.
Gabapentin has been rarely studied in controlled trials for bipolar disorder. One open-label study of several elderly patients with acute mania found no adverse effects and improvement in all subjects. Another open-label trial in 5 geriatric patients (mean age of 73 years) showed gabapentin to be well tolerated, but ineffective when patients were assessed over a 6-month period. Although gabapentin is structurally similar to GABA, it neither binds to GABA receptors nor effects GABA uptake or catabolism. It's subtle GABAergic effects may increase glial GABA release, acting on GABA transporters and increasing GABA concentrations in the brain.4
Lamotrigine has been found to be an acceptable choice as firstline treatment for partial and generalized seizures in the elderly. Lamotrigine is equally efficacious to carbamazepine and the dropout rate is less, with fewer rashes and less frequent occurrences of somnolence. Lamotrigine acts via presynaptic blockage of sodium-dependent channels and the inhibition of glutamate release. It is useful in partial and generalized seizures, has good absorption and is metabolized in the liver and eliminated by glucuronide conjugation, which is largely unaffected by age. Dosage adjustment in the elderly may not be necessary, since conjugation reactions are only slightly decreased in the elderly. Lamotrigine has an efficacy similar to phenytoin and carbamazepine, but appears to be better tolerated with a lower incidence of central nervous system (CNS) adverse effects.
Although, the adverse effects of lamotrigine are relatively mild in terms of cognitive function, rashes can be a significant problem.2
Oxcarbazepine rapidly reduced to 10, 11-dihydro-10-hydroxy-carbamazepine (monohydroxy derivative [MHD]). This is the clinically relevant metabolite of oxcarbazepine. It has been thought that the lack of an epoxide moiety in oxcarbazepine or its metabolites makes it better tolerated than carbamazepine and some epilepsy clinical trials have indeed found that withdrawal rates from adverse effects are lower for oxcarbazepine than for phenytoin and similar to valproate. Oxcarbazepine exerts effects ranging from the inhibition of sodium-dependent action potentials and enhancement of potassium channels to the inhibition of glutamatergic excitatory post- synaptic potentials. These effects suggest presynaptic mechanisms of action. Like phenytoin, both carbamazepine and oxcarbazepine are effective in blocking seizures resulting from amygdala kindling, a model of partial seizures. Neither oxcarbazepine nor MHD binds to multiple receptor sites, and although MHD does have weak reactivity with adenosine receptors, this is not thought to be clinically significant. Oxcarbazepine seems to have fewer drug interactions than carbamazepine.4
Topiramate first became available as an adjunctive treatment for epilepsy and then was also approved for migraine prophylaxis. Later, clinical experience suggested efficacy in other neurologic and psychiatric conditions, including essential tremors and bipolar disorder. Some studies suggest that topiramate may be effective in elderly patients with the aggressive behaviour seen in dementia. For example, Fhager et al., retrospectively reviewed the treatment of 15 patients with dementia and severe aggression. They found that in 8 patients receiving topiramate monotherapy (median 75 mg/ day) for a mean of 17.6 days, the Cohen-Mansfield Agitation Inventory (CMAI) scores decreased from 32.0 to 16.5 (p = 0.008). In 7 patients (mean age of 80 years) receiving topiramate (median 50 mg/day) added to risperidone (median 1 mg/day) or, as in 1 patient, zuclopenthixol (12 mg/day for a mean of 16 days), CMAI scores decreased from 39.0 to 20.0 (p = 0.016). The improvements with topiramate alone and topiramate added to antipsychotic medication were statistically similar. Controlled trials are needed to determine whether topiramate is effective in older patients with aggressive behaviour in dementia. Topiramate has been observed to induce weight loss as opposed to weight gain caused by other psychotropic medications. Topiramate also has fewer drug interactions compared to anticonvulsants like carbamazepine.4/p>
A number of newer anticonvulsants are being considered for the treatment of patients with dementia. However, clear evidence of their efficacy and safety, derived from controlled trials with well-accepted outcome measures in patients with dementia, are scarce. Nonetheless, the absence of any other ideal agents for the treatment of behavioural disturbances in dementia warrants further examination of these new drugs.
Pharmacological and pharmacokinetic properties of levetiracetam make it attractive for use in patients with dementia over other agents. It has a lower likelihood of drug interactions than older anticonvulsants, it does not affect the cytochrome P450 family, and it does not appear to have substantial effects on sleep or cognition. Levetiracetam has also been found to be efficacious in controlling seizures in older adults, even in patients with Alzheimer's disease.
Topiramate acts similar to carbamazepine and valproic acid and, hence, is being considered as a treatment for behavioural disturbances in dementia. Topiramate has also been shown to have some utility in the treatment of mania in patients with bipolar disorder.1
- The first priority before initiating treatment for seizures in the elderly with dementia is to assess the need to treat seizures, since seizures in Alzheimer's disease are not associated with increased mortality but may result in some worsening of cognition, particularly if they persist. Recurrent seizures predispose these patients to a greater risk of injury as well as a further reduction in independence.
- Single symptomatic seizures with an obvious precipitating cause do not need AED therapy. But seizures without an identifiable cause might require AED therapy after assessing the clinical history and conducting the required examinations. AED therapy is needed if the first seizure is associated with risk factors for further seizures.
- A major goal of treating epilepsy in the elderly with dementia is to avoid significant cognitive or sedative adverse effects. Patients must be screened for hepatic and renal impairment before the administration of AEDs.
- AED therapy should be started at lower doses and titrated slowly to allow for tolerance to CNS adverse effects. Monotherapy should be preferred. The regimen should be simple and drug levels, particularly unbound levels, should be measured where indicated.Two monotherapy options should be tried before adding a second drug.
- When using traditional AEDs, the total daily doses should be in the lower limits of the therapeutic range. The response to AEDs tends to be good, with relatively simple regimens for seizure control even though firm evidence is inadequate.
Since there are no medications approved for the treatment of agitation associated with dementia, the clinician is left with the dilemma of treating the elderly patient with diminished ability to tolerate medications because of pharmacokinetics and pharmacodynamics changes associated with the process of aging. There is a genuine risk of the delirious patient assaulting family or staff members, as any other behaviourally disturbed psychiatric patient. Due to safety considerations, entire classes of medications (such as atypical antipsychotic drugs) must only be prescribed with caution. More drug options, with better efficacy and safety profiles, are needed in the treatment of cognitive and behavioural disturbances in dementia. Specific information about new drugs is lacking due to lack of proper research.
Nevertheless, several management strategies can be recommended. Since the risk of seizures in this population is high, clinicians may begin treatment with AEDs after a single seizure if there is focal neurological involvement or if there is any concern that seizures may recur. AED therapy may be considered particularly if the cause is not identified after a thorough clinical history is taken and a detailed neurological examination is performed.
When choosing an AED for the elderly population, drugs with the least cognitive or sedative adverse effects should be preferred. The therapy should be initiated with a low dose and titrated slowly to the lowest effective dose, monitoring the AED plasma levels where possible.
The process of aging alters processes such as protein binding, hepatic function, renal clearance and the elderly often are malnourished and have vitamin deficiencies. These factors must be taken into account before prescribing AEDs.
1. Dolder CR, Nealy KL. The efficacy and safety of newer anticonvulsants in patients with dementia. Drugs Aging. 2012 Aug 1; 29(8): 627-37.
2. Mendez M, Lim G. Seizures in elderly patients with dementia: Epidemiology and management. Drugs Aging. 2003; 20(11): 791-803.
3. Lippa CF, Rosso A, Hepler M, Jenssen S, Pillai J, Irwin D. Levetiracetam: A practical option for seizure management in elderly patients with cognitive impairment. Am J Alzheimers Dis Other Demen. 2010 Mar; 25(2): 149-54.
4. Sommer BR, Fenn HH, Ketter TA. Safety and efficacy of anticonvulsants in elderly patients with psychiatric disorders: Oxcarbazepine, topiramate and gabapentin. Expert Opin Drug Saf. 2007 Mar; 6(2): 133-45.
5. Ben-Menachem E. Levetiracetam: Treatment in epilepsy. Expert Opin Pharmacother. 2003 Nov; 4(11): 2079-88.
