Subclinical epileptiform activity accelerates the progression of Alzheimer's disease: A long-term EEG study.

OBJECTIVE: While many studies suggest that patients with Alzheimer's disease have a higher chance for developing epileptic seizures, only a few studies are available examining independent epileptic discharges. The major aims of our study was to determine the prevalence of subclinical epileptiform activity (SEA) in AD compared to healthy elderly controls with the hypothesis that SEA is more frequent in AD than in cognitively normal individuals. Another aim was to analyze the effect of baseline SEA captured with electroencephalography on the progression of the disease with longitudinal cognitive testing. METHODS: We investigated 52 Alzheimer patients with no history of epileptic seizures and 20 healthy individuals. All participants underwent a 24-hour electroencephalography, neurology, neuroimaging and neuropsychology examination. Two independent raters analyzed visually the electroencephalograms and both raters were blind to the diagnoses. Thirty-eight Alzheimer patients were enrolled in a 3-year long prospective follow-up study with yearly repeated cognitive evaluation. RESULTS: Subclinical epileptiform discharges were recorded significantly (p:0.018) more frequently in Alzheimer patients (54%) than in healthy elderly (25%). Epileptiform discharges were associated with lower performance scores in memory. Alzheimer patients with spikes showed 1.5-times faster decline in global cognitive scores than patients without (p < 0.001). The decline in cognitive performance scores showed a significant positive correlation with spike frequency (r:+0.664; p < 0.001). CONCLUSIONS: Subclinical epileptiform activity occurs in half of Alzheimer patients who have never suffered epileptic seizures. Alzheimer patients with subclinical epileptiform activity showed accelerated cognitive decline with a strong relation to the frequency and spatial distribution (left temporal) of spikes. SIGNIFICANCE: Our findings suggest the prominent role of epileptiform discharges in the pathomechanism of Alzheimer's disease which might serve as potential therapeutic target.

Prevalence, Semiology, and Risk Factors of Epilepsy in Alzheimer's Disease: An Ambulatory EEG Study.

BACKGROUND: Alzheimer's disease (AD) is the primary cause of cognitive decline. A growing body of evidence suggests that AD patients have a higher risk to develop epileptic seizures; however, results are contradictory due to different methodological approaches of previous studies. OBJECTIVE: We aimed to identify the prevalence, semiology, and risk factors of epilepsy in AD using long-term EEG. METHODS: We selected forty-two AD patients and examined them using 24-hour ambulatory EEG. Neurological and epileptological data were collected with retro- and prospective methods. We analyzed the semiology of the identified seizures and the possible risk factors using logistic regression analysis. RESULTS: We identified seizures confirmed by EEG in 24%. The majority of the seizures were aware focal (72%) without any motor activity (55%). We found epileptiform discharges without seizures in 28%. Patients with seizures and only with epileptic EEG activity showed similar clinical and demographical features. Higher education (OR:1.8) and lower Addenbrooke Examination Score (OR: 0.9) were identified as risk factors of epilepsy. Increase of 0.1 point in the Verbal-Language/Orientation-Memory ratio (VLOM) was associated with higher epilepsy risk as well (OR:2.9). CONCLUSION: Epilepsy is a frequent comorbidity of AD. Since most of the seizures are aware non-motor focal seizures, sensitive EEG techniques are required for precise diagnosis of epilepsy. Long-term ambulatory EEG is a safe and well-tolerated option. Epileptiform EEG in AD signals the presence of concomitant epilepsy. Clinicians have to pay attention to comorbid epilepsy in dementia patients with high education, with high VLOM ratio and severe stage.

Sleep EEG Detects Epileptiform Activity in Alzheimer's Disease with High Sensitivity.

BACKGROUND: The reported prevalence of epilepsy in Alzheimer's disease (AD) is variable, probably due to the different methodological approaches. OBJECTIVE: We aimed to define the optimal electroencephalogram (EEG) settings for reliable detection of epileptiform discharges in AD patients. METHODS: We analyzed 24-h EEGs of 5 patients living with AD and epilepsy. The sensitivity of various length EEGs in detecting epileptiform discharges in different periods of the day, the diurnal distribution of the discharges, and their relation to sleep-stages were calculated. RESULTS: Significant high correlation was identified between the sensitivity of EEG and the length of recordings (r = 0.972, p = 0.005). The sensitivity of a 30-min EEG-epoch recorded between 8:00 and 16:00 was 0.0375 compared to 0.7 between 0:00 and 8:00 (p = 0.005). The average sensitivity of an 8-h EEG-epoch was≥0.8. 82% of epileptiform discharges occurred during sleep, mainly related to non-REM sleep (p < 0.001). CONCLUSION: 8-h awake-, or 1-h sleep-EEG provide sufficient sensitivity in detecting epileptiform activity in AD. This needs to be considered in studies on AD-related epilepsy. Recognizing epilepsy in AD patients is essential because it might compromise cognitive functions and accelerate the progression of the disease.

Interictal Epileptiform Activity in the Foramen Ovale Electrodes of a Frontotemporal Dementia Patient.

Frontotemporal dementia (FTD) is a frequent cause of cognitive decline. While epilepsy is an important comorbidity of Alzheimer's disease, we lack studies on its presence in FTD. We report on an FTD patient with transient, short-term changes of behavior and cognitive performance suggesting non-convulsive epilepsy. Video-EEG recording with foramen ovale (FO) electrodes revealed mesio-temporal epileptiform potentials, undetectable by scalp leads. We also found beta spindles in the FO electrodes, not described in the literature. We conclude that video-EEG monitoring with FO electrodes might usefully complement the assessment of dementia-associated epilepsy opening new perspectives in dementia-research.

Epileptic Seizures in Alzheimer Disease: A Review.

Alzheimer disease (AD) is the most frequent cause of major neurocognitive disorders with a huge economical and medical burden. Several studies pointed out that AD is associated with a high risk for developing epileptic seizures. The aims of our review were to evaluate and to summarize the current literature (ending in September 2015) of animal and human studies in the relation of AD and epileptic seizures. It seems likely that epileptic hyperexcitation could be partially responsible for the progression of AD due to the increased rate of amyloid deposition. Pathologic changes in animal models of AD are similar to those seen in human temporal lobe epilepsy. Antiepileptic treatment had a positive effect on cognitive function in animal and human studies. Because the detection of seizures in patients with cognitive decline is extremely difficult because of methodological problems, the true prevalence of seizures has remained unclear. Nonconvulsive seizures with no overt clinical symptoms may be frequent seizure types in AD. These are difficult to detect by clinical observation and with standard scalp electroencephalogram (EEG) methods. We propose that long-term EEG recording and video-EEG monitoring is necessary to prove the presence of epileptiform activity in demented patients.

Anti glutamate-decarboxylase antibodies: a liaison between localisation related epilepsy, stiff-person syndrome and type-1 diabetes mellitus.

We present two patients with partial epilepsy, type-1 diabetes and stiff person syndrome associated with high serum auto-antibody levels to glutamate-decarboxylase (anti-GAD). Both patients were or have suffered from additional autoimmune conditions. The presence of stiff person syndrome and elevated anti-GAD levels have to make clinicians look for additional autoimmune conditions including type-1 diabetes. On the other hand, the co-morbidity of partial epilepsy with autoimmune conditions in patients with elevated serum anti-GAD suggests an autoimmune mechanism of partial epilepsy in these cases.

LADA type diabetes, celiac diasease, cerebellar ataxia and stiff person syndrome. A rare association of autoimmune disorders.

Celiac disease--in its typical form--is a chronic immune-mediated enteropathy with typical clinical symptoms that develops against gliadin content of cereal grains, and is often associated with other autoimmune diseases. In cases of atypical manifestation classic symptoms may be absent or mild, and extra-intestinal symptoms or associated syndromes dominate clinical picture. The authors present a longitudinal follow-up of such a case. A 63-years old woman was diagnosed with epilepsy at the age of 19, and with progressive limb ataxia at the age of 36, which was initially thought to be caused by cerebellar atrophy, later probably by stiff person syndrome. At the age 59, her diabetes mellitus manifested with type 2 diabetic phenotype, but based on GAD positivity later was reclassified as type 1 diabetes. Only the last check-up discovered the celiac disease, retrospectively explaining the entire disease course and neurological symptoms. By presenting this case, the authors would like to draw attention to the fact that one should think of the possibility of celiac disease when cerebellar ataxia, progressive neurological symptoms and diabetes are present at the same time. An early diagnosis may help to delay the progression of disease and help better treatment.

Violent somnambulism: a parasomnia of young men with stereotyped dream-like experiences.

OBJECTIVE: To characterize a subgroup of arousal parasomnias associated with violent behavior in adults. DESIGN: A pilot study on clinical and polysomnographic data of 13 adult patients seen in a tertiary sleep center for the suspicion of arousal parasomnia associated with violence. RESULTS: Nine young patients (8 males 1 female) had a common pattern of abnormalities: similar 'claustrophobic' dream-like experiences and complex, vehement dream enactments; no REM sleep without atonia on polysomnography. We call this syndrome 'violent somnambulism'. The rest of the patients had alcoholic delirium, partial epilepsy, possible REM sleep behavior disorder and a single sleep walking episode provoked by a sleeping pill. CONCLUSIONS AND HYPOTHESIS: Sleep related violence needs thorough diagnostic evaluation for preventing life-threatening consequences. Violent somnambulism appears to be a distinct NREM sleep-related overlap parasomnia.

Clinical experiences with Creutzfeldt-Jakob disease: three case studies.

The clinical picture, electroencephalographic, imaging and cerebrospinal fluid parameters as well as the molecular background of Creutzfeldt-Jakob disease have been well explored. The diagnostic criteria, offering clinicians a fair chance to identify these patients in vivo, have recently been updated. However, the diagnosis is still a challenge in everyday neurological routine. We report on three of our Creutzfeldt-Jakob patients for calling attention to the classical and the recently defined features of the disease. We conclude that based on the rapidly progressing neuropsychiatric syndrome Creutzfeldt-Jakob disease may be suspected; follow-up EEG may reveal the typical (pseudo)-periodic pattern with progressive deterioration of the background activity. In addition, diffusion-weighted brain MRI imaging (DWI) has high diagnostic value. Detection of 14-3-3 protein in the cerebrospinal fluid supports the in vivo diagnosis.

Our clinical experience with zonisamide in resistant generalized epilepsy syndromes.

PURPOSE: Zonisamide is licensed in the European Union for adjunctive therapy for partial epilepsy, but its efficacy in generalized epilepsy was less explored. METHODS: This prospective observational study included 47 patients (mean age 29 years, range 3-50) with different resistant generalized epilepsy syndromes: idiopathic generalized syndromes (IGE) 15 patients, (juvenile myoclonic epilepsy four, absence epilepsy four, myoclonic absence two, unclassified IGE five), progressive myoclonic epilepsy type 1 (PME1) four, severe myoclonic epilepsy of infancy (SMEI) three, borderline SMEI three, Lennox-Gastaut syndrome/secondary generalized epileptic encephalopties 23 patients. All patients were followed up for at least six months. The mean dose given was 367 mg/day (range 100-600 mg/day), the patients received at least one and no more than two concomitant AE. Response was defined as more than 50% seizure reduction or seizure freedom. RESULTS: The best effect was achieved in PME one, all the patients were responders. Myoclonic seizures were reduced 80%, none of the patients had generalized tonic clonic (GTC) seizures. In two of the four patients all other antiepileptics were tapered of (including piracetam), so they were GTC seizure and almost myoclonia free on zonisamide only. Responder rates were in GEFS +/- SME 62.5%, in resistant IGE 62.5%, and in epileptic encephalopathies 33.3% patients. Tolerance after initial efficacy developed in six patients. Adverse effects were mild: weight loss, somnolence and confusion were repeatedly reported. Three patients reported cognitive improvement. CONCLUSION: Clinical benefit of a broad spectrum antiepileptic zonisamide extends across seizure types, ages and epilepsy syndromes. The efficacy in PME proved to be excellent.

Interhemispheric propagation of seizures in mesial temporal lobe epilepsy.

OBJECTIVES: To investigate interhemispheric propagation of mesial temporal lobe epilepsy seizures in patients undergoing long-term video-EEG monitoring with combined scalp and foramen ovale electrodes. AIM OF THE STUDY: To reveal possible interhemispheric propagation patterns in mesial temporal lobe epilepsy, to improve presurgical evaluation of temporal epileptic patients. METHODS: Sixty-five seizures from 20 patients were analyzed. We defined two contralateral seizure propagation patterns: Type I for those seizures that spread to the contralateral foramen ovale electrodes earlier than to the contralateral scalp electrodes, and type II for the opposite. PARTICIPANTS: Twenty drug resistant epileptic patients were investigated in frame of their presurgical evaluation. RESULTS: The majority of seizures (80%) were classified as type I. Inter-foramen ovale electrode propagation time was significantly shorter for type I compared to type II seizures. Ninety percent of patients had either type I or type II seizures only. Patients with type I seizures significantly more often had mesiotemporal structural alterations evident on magnetic resonance imaging scans, and became more often seizure-free after surgery compared to patients with type II seizures whose surgical outcome was less favorable or surgery could not be indicated because of independent bilateral ictal seizure-onset. CONCLUSIONS: The two types of contralateral propagation patterns we are describing seem to represent two subtypes of mesial temporal lobe epilepsy with different morphological and prognostic features. The predominance of type I over type II seizures together with shorter propagation times for type I seizures indicate a role of a more direct and dominant interhemispheric pathway in mesial temporal lobe epilepsy.

Late-life absence status epilepticus: a female disorder?

We report on three women and a review of the literature on absence status epilepticus over the age of 50 years. Our aim was to characterize the male-female ratio in this condition. Out of 16 studies on absence status epilepticus over the age of 50, including our cases, a female dominance was found in 15. We found altogether, 104 (71%) females and 42 (29%) males. This gender difference is highly significant (p < 0.00001). We conclude that absence status epilepticus over the age of 50 is predominantly a female disorder.

The risk of paradoxical levetiracetam effect is increased in mentally retarded patients.

PURPOSE: Incidental paradoxical antiepileptic effect of levetiracetam has been described. The aim of the present study was to identify the epilepsy patients at risk. METHODS: We performed a retrospective analysis in 207 patients treated with levetiracetam. This entailed evaluation of patient notes and patient interviews. A paradoxical effect was defined as an increased seizure frequency or the experience of more severe seizures including generalized tonic-clonic seizures (GTCS) within 1 month after starting levetiracetam (LEV). RESULTS: Thirty patients (14%) experienced a paradoxical effect. Eight of them (4%) developed de novo GTCS. We could not demonstrate any association between the paradoxical effect of levetiracetam and type of epilepsy or the antiepileptic comedication used. However we found that the paradoxical effect developed preferentially (p < 0.001) in mentally retarded patients. CONCLUSION: Because there is an increased risk of worsening epilepsy when starting levetiracetam treatment of mentally retarded epileptic patients, there is a need for caution and close observation during the first weeks of therapy.

[Clinical experience with levetiracetam for adults with epilepsy]. / Klinikai tapasztalatok levetiracetamkezeléssel felnottkori epilepsziákban.

OBJECTIVE: A retrospective study to evaluate the efficacy of levetiracetam in the treatment of adult pharmacoresistant epilepsy. METHOD: Retrospective work up of our treatment-experiences with 55 pharmacoresistant patients treated with levetiracetam (11 of them on monotherapy) for 6-39 months. Three treatment groups were analysed: idiopathic generalised epilepsy (9 patients); partial epilepsy (30 patients); malignant or malignated epileptic syndromes (16 patients). RESULT: Seven idiopathic generalised patients (77%) and 5 partial epilepsy patients (16%) became seizure free. One idiopathic generalised epileptic patient, 10 partial epilepsy patients (33%) significantly improved. Six patients (37%) from the group of malignant or malignated epileptic syndromes also significantly improved. Five of the improved idiopathic generalised epilepsy patients and 6 of the improved partial epilepsy patients received levetiracetam monotherapy. Altogether seven patients (12% of the whole population) relapsed after a 4-15 months improved period. Fifteen patients (27%) suffered side effects (mainly somnolence, headache, dizziness and irritability) improving after dose reduction of levetiracetam (generally below 2000 mg pro day). CONCLUSION: Levetiracetam is an effective, well tolerable, broad-spectrum drug as adjunctive treatment or monotherapy in adult patients unsuccessfully treated with other antiepileptic drugs.

[Sudden death and mortality in epilepsy]. / Hirtelen halál es mortalitás epilepsziában.

Mortality in epilepsy is 2-3 times higher than in the age- and sex-matched general population. It is the highest in young male epilepsy patients with generalised tonic-clonic seizures living in low socio-economical situation. The main factors of early mortality unrelated to seizures are the neurological conditions underlying epilepsy. Suicide is an important factor first of all in temporal lobe epilepsy. The group of mortality directly related to epilepsy is made up of the high-mortality grand mal status epilepticus rarely seen in treated epilepsy; the accidents related to seizures and sudden unexpected death (SUDEP). The reasons directly related to epilepsy make up about 40 per cent of epilepsy mortality. There is a 20-24-fold increase of the risk of sudden death in epilepsy compared to sudden death in the general population. The main risk of SUDEP is the "severity" of epilepsy signaled by generalized tonic-clonic seizures, resistance to antiepileptic drugs, polytherapy and frequent drug-modifications in adulthood epilepsy. Seizure-dependent autonomic changes as cardiac rhythm and breathing disturbances as well as some antiepileptic drugs and treatment modifications may contribute to the development of SUDEP. The data suggest that the main tools helping to decrease mortality in epilepsy nowadays are as follows: optimal seizure control, effective treatment of concomitant psychiatric conditions and monitoring for potentially dangerous heart dysrhythmias as well as respiration disorders.

[Supplementary sensory-motor seizures--symptomatology, etiology, and surgical management with illustrative case reports]. / A szupplementer szenzomotoros rohamok tünettana, kóreredete és mutéti kezelhetosége, illusztratív esetismertetésekkel.

In the past decade, owing to the advance of epilepsy surgery, growing knowledge has accumulated on the role of the supplementary motor area, described by Penfield and coworkers in the early fifties, in movement regulation and on the characteristics of seizures involving this area. In the Hungarian neurological literature this topic--despite its neurophysiological and practical clinical importance--has been hardly touched. The authors, based on their own experience obtained from surgeries performed within the framework of the "Co-operative Epilepsy Surgery Program", describe the electrophysiological features of this area, its role in movement regulation and the symptoms of epileptic seizures stemmed from or spread onto this area. Using cases as illustrations, they demonstrate the reasoning and various algorithms of the multidisciplinary examination necessary to explore the seizure onset zone and the pathways of seizure spread. Details of the surgical solution are also described.

Generalised paroxysmal fast activity (GPFA) is not always a sign of malignant epileptic encephalopathy.

PURPOSE: Generalised paroxysmal fast activity (GPFA) consists of 8-26 (most frequently around 10 Hz), 2-50 seconds (usually below 10 seconds) bursts of generalised rhythmic discharges with frontal predominance, appearing most frequently during NREM sleep. The pattern is traditionally linked to Lennox-Gastaut (LGS) or late LGS (LLGS) syndrome and associated with tonic-axial seizures, pharmaco-resistency and poor prognosis including mental deterioration. We present here four patients with GPFA, who had neither LGS/LLGS syndrome, nor mental deterioration, two of them are seizure-free, two had infrequent seizures on medication. METHODS: All the patients had neurological work-up and high resolution MRI studies. They were followed for years including repeated EEGs in awake state and during sleep. RESULTS: The main seizure-type was generalised tonic-clonic seizure in three patients and absence in one. Onset of epilepsy varied from 7 to 21 years. No MRI lesion was found. All of them had generalised spike-and-wave discharges during the course of their epilepsy but some had also focal clinical or EEG features, were more difficult to treat, as atypical features compared to the classic generalised epilepsies with generalised spike-wave pattern. CONCLUSIONS: Although GPFA should remain an important diagnostic feature of both the classical and late variant of LGS, our cases clearly demonstrate that GPFA could represent a possible electrographic variant in certain generalised epilepsies showing atypical features; better treatability and outcome than in LGS and no mental deterioration.