Epilepsy in dementia Dr. Yotin Chinvarun M..D. Ph.D. CEP, PMK hospital Case 1 M 90 years old Had a history of tonic of both limbs (Lt > Rt) at the age of 88 years old, eye rolled up, no grunting, lasting < minutes, usually had blurred consciousness after that for three minutes, had frequently attack nearly everyday Seen by doctor, had CT brain shows generalized cortical atrophy, then had been Rx PHT 300 mg hs, but patient did not take the medication 1
Case 2 The patient had been treated with Levitiracetam 3ml bid and had a remarkably reduced of the attack Then, became seizure-free, when on Levitiracetam 4 ml bid for two years now 2
Case 2 M 61 years old, university lecturer Hx of cognitive impairment for a few months, witnessed by colleague and students that patient had several episodes of blank staring, poor short term memory, frequently repeated same question, missed the appointment and forgot recent memory, patient had apathy and not active as before Weight loss 10 Kg recently, underwent fully checked up did not found anything abnormal PE: well neat dressing, thinner, good cooperated, memory testing - pending 3
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Case 2 He had been treated with Valproate chrono 500 mg 0.5 tab bid and Rivastigmine Follow up two weeks later, the patient was remarkably improved His blank staring was remarkably decreased Memory particularly, short term memory and recall improved, the repetitive question was also reduced, he had more interactive during conversation Introduction Epilepsy and AD are common neurologic disorders for which increasing age common and well-established risk factor From clinical aspect, patients with AD have an increased risk of developing seizures and epilepsy; thus AD may be an important cause of epilepsy in the elderly AD and other neurodegenerative conditions represent etiology for 10% of new onset epilepsy in patients older than 65 5
Risk of Seizures in AD Diagnosis of seizures in patients with AD not always easy because manifestation of partial seizures might be hard to recognize and distinguish from other behaviors common in these patients Lead to underestimation of the real frequency of seizures in AD. Possibility funny or unusual behaviors of demented patients considered seizures particularly by nonepileptologists, may lead to overestimation of seizure rates Risk of Seizures in AD Patients with sporadic AD have a 6-10 fold increased risk of developing clinical seizures during the course of their illness Prospective and retrospective studies reporting great variability in the lifetime prevalence of seizures in patients with AD, ranging 1.5 to 64 percent However, it is difficult to accurately assess the real prevalence of seizures in AD 6
Risk of Seizures in AD Studies in elderly reporting recurrence risk after the 1 st seizure as high as 80%, probably because epilepsy in elderly mainly associated with underlying structural lesion In terms of seizure types, Generalized convulsive seizures identified in 90% of cases Other data suggest 70% of seizures are complex partial seizures Partial seizures without convulsive character underestimated Risk of Seizures in AD Characterization of clinical manifestations of seizures usually based on information derived from patient or caregiver; Limitations both sources of information. Even in nondemented patients, fewer than 25% (19, 20) are able to report their true seizure frequency for the simple reason that they don t remember the event. In demented patients, percentage could be even lower. it is difficult for caregivers to report seizure frequency accurately, because Unaware of how partial seizures manifest It may be challenging to separate seizures from certain behaviors that demented patients often manifest (e.g., fluctuations in alertness and attention, hallucinations, confusion). 7
Risk of Seizures in AD Seizures in AD should be of focal origin because neurodegenerative pathology is multifocal Beyond complex partial seizures, other seizure subtypes such as transient epileptic amnesia (where the patients experience memory problems reminiscent of dementia for repeated short time periods) may also be underestimated Therefore, it remains doubtful whether convulsive seizures represent majority of seizure types in AD Risk of Seizures in AD In early-onset familial AD (EOFAD), seizures and epilepsy occur more often than in sporadic AD, for example Seizures have been described in 37 to 58 percent of patients with the PSEN1 E280A mutation 30 percent with presenilin 2 mutations 57 percent of patients with amyloid precursor protein (APP) duplications Alzheimer-type neuropathologic abnormalities demonstrated also in patients with Down syndrome (DS), and DS patients develop dementia at young ages Up to 84 percent of demented individuals with DS develop seizures 8
Pathogenesis of Epilepsy in AD Substantial body of evidence spontaneous recurrent seizures occur in a subset of patients with Alzheimer disease (AD), especially familial forms that have an early onset In transgenic mice AD, seizures or reduced seizure threshold reported Mechanisms underlying seizures or reduced seizure threshold in these mice not yet clear, and likely to be complex, because synthesis of amyloid b (Ab) involves many peptides and proteases that infuence excitability Pathogenesis of Epilepsy in AD Based on transgenic mouse models of AD Ab and its precursor elevated suggesting seizures caused by downregulation of the Nav1.1 sodium channel in a subset of GABAergicinterneurons, leading to a reduction in GABAergicinhibition Another mechanism of hyperexcitability appears to involve tau Deletion of tau reduces seizures in some of same transgenic mouse models of AD, Therefore, altered excitability may be as much a characteristic of AD as plaques and tangles 9
Pathogenesis of Epilepsy in AD Increasing evidence that mechanisms of AD and epilepsy overlap AD and epilepsy are related beneficial to both fields, because potential therapeutic advances in one may help translational efforts in other Complexities of clinical disorders and the limitations of mouse models need to be carefully considered It is opportunity i.e. remarkable anticonvulsant effects of tau suggest that it could be a new target for AED development Factors Modifying Risk for Seizures in AD Seizure prevalence seems to increase with AD duration Most of the studies support onset of seizures at later stages, ~6.8 years after onset This might be because of the increasing accuracy of AD diagnosis, increasing age or increasing severity of neurodegenerative process According to diagnostic criteria for AD, seizures in advanced stage consistent with a diagnosis of probable AD, while seizures earlier in the course or at onset of dementia suggest uncertain or unlikely diagnosis No reports suggesting increased rates of seizures in mild cognitive impairment 10
Factors Modifying Risk for Seizures in AD Report patients with a younger age of AD onset more susceptible to seizures compared with age-matched populations. Seizure incidence increases 3-fold around the age of 70 and nearly 87-fold around the age of 50 Could be explained by higher prevalence of familial AD in younger patients, associated with higher seizure rates, or more aggressive AD course in younger AD patients. However, there contrasts with other studies Reporting neither disease duration nor age of onset were significant risks for seizures in AD patients Factors Modifying Risk for Seizures in AD AD severity seems to constitute another risk factor for seizures In prospective studies of patients with probable AD of mild severity, seizures occurred in 1.5 to 16 percent over 1 to 8.5 years of follow-up Whereas studies of institutionalized AD patients, most had more severe dementia, seizure frequencies ranging 9-64 percent 11
Factors Modifying Risk for Seizures in AD Dementia severity or worse performance on tests of orientation and information reported associated with an increased risk of seizures in AD patients. African-American ethnicity suggested as a risk factor for developing seizures in AD Infrequent, inconsistent reports of other possible risk factors i.e. diabetes, hypertension, and antipsychotic-cholinesterase inhibitor drugs Potential risk factors for developing seizures in AD A number of risk factors have been identified, including Antipsychotic drug use African-American race Epileptiform findings on EEG Greater cognitive impairment at baseline However, most robust association has been with young age at dementia onset While seizures can appear at any stage of the disease, the odds of developing epilepsy in AD highest in Young patients with AD and early in the disease course 12
Role of EEG If seizures in AD related to hyperexcitability in the hippocampus, a higher frequency of epileptiform activity in scalp EEG should be seen similar in human mesial temporal lobe epilepsy Some observational studies reporting epileptiform discharges in minority of AD patients with seizures, but also in some AD patients without seizures In a study of 1,674 patients with dementia, routine EEGs showed epileptiform discharges 3% Focal and mainly located in the temporal lobe Sixty percent did not have clinical seizures at or before the time of EEG 10% of these AD patients, with epileptiform discharges and no clinical seizures at or before the time of EEG, developed seizures later on However, EEGs performed in only a subset of patients with AD, limiting our ability to adequately derive safe conclusions Role of EEG Even if a larger number of AD patients to be studied with scalp EEG Significant limitations still remain as detection of epileptiform activity is low even in patients with temporal lobe epilepsy The yield would probably increase if video-eeg monitoring performed Also, video- EEG monitoring may be limited by poor cooperation of AD patients and confusional episodes associated with hospitalization and changes of environment 13
Seizure Treatment in AD No randomized controlled trials exploring usefulness and efficacy of specific antiepileptic drugs (AEDs) for seizure treatment in AD patients Some observational studies suggest small differences in the efficacy of AEDs in elderly Efficacy of AEDs in elderly people seems to be either comparable or even better than in younger individuals, with seizure freedom rates as high as 62% Seizure Treatment in AD Adverse drug reactions of AEDs, could be either from Dose-dependent (i.e., dizziness, unsteadiness, lethargy) Specific drug- related (i.e., tremor, hyponatremia, osteopenia) Although, it less frequent at lower doses. To use of AEDs in AD patients should be based on their pharmacokinetic and side effects profile Using AED with the fewest possible interactions with other medications commonly taken by older patients, and titrating AEDs slowly, employing lowest possible doses 14
Seizure Treatment in AD In studies of the general population, newer AEDs seem to be better tolerated than the 1 st generation AEDs in elderly Avoid to use AEDs with deleterious cognitive sequelae such as Valproic acid (VPA) and benzodiazepines (BZDs) Long term use of BZDs associated with increased risk for cognitive deterioration and falls Seizures and AD Course The higher rates of seizures in more advanced dementia could suggest either Seizures lead to higher rates of cognitive decline Seizures are an epiphenomenon or a marker of more severe dementia stages Some small series reported cognitive deterioration after seizure onset, limited in terms of sample size Overall, relatively limited studies on question of impact of seizures in further AD course and severity 15
In conclusion AD is a clear risk factor for seizures Risk of seizures and epilepsy in AD seems to increase 3 to 87 times compared with the age-matched general population Increased risk is age dependent, with higher risk at younger ages Increasing dementia severity is other reliable risk factor for seizures in AD. Variability reports regarding seizure frequency in patients with AD; overall incidence of newonset nonprovoked seizures in AD ~ 1 per 200 person-years In conclusion Role of EEG and its prognostic value in predicting seizures has not been adequately explored, video-eeg monitoring might be useful but difficult to do When seizures in AD occur, they seem to be infrequent In the absence of specific studies, choice of AEDs of treatment is mostly empirical and based primarily on side effect profiles 16