Standard procedures for the diagnostic pathway of sleep-related epilepsies and comorbid sleep disorders: an EAN, ESRS and ILAE-Europe consensus review.

BACKGROUND AND PURPOSE: Some epilepsy syndromes (sleep-related epilepsies, SREs) have a strong link with sleep. Comorbid sleep disorders are common in patients with SRE and can exert a negative impact on seizure control and quality of life. Our purpose was to define the standard procedures for the diagnostic pathway of patients with possible SRE (scenario 1) and the general management of patients with SRE and comorbidity with sleep disorders (scenario 2). METHODS: The project was conducted under the auspices of the European Academy of Neurology, the European Sleep Research Society and the International League Against Epilepsy Europe. The framework entailed the following phases: conception of the clinical scenarios; literature review; statements regarding the standard procedures. For the literature search a stepwise approach starting from systematic reviews to primary studies was applied. Published studies were identified from the National Library of Medicine's MEDLINE database and Cochrane Library. RESULTS: Scenario 1: Despite a low quality of evidence, recommendations on anamnestic evaluation and tools for capturing the event at home or in the laboratory are provided for specific SREs. Scenario 2: Early diagnosis and treatment of sleep disorders (especially respiratory disorders) in patients with SRE are likely to be beneficial for seizure control. CONCLUSIONS: Definitive procedures for evaluating patients with SRE are lacking. Advice is provided that could be of help for standardizing and improving the diagnostic approach of specific SREs. The importance of identifying and treating specific sleep disorders for the management and outcome of patients with SRE is underlined.

Feline Temporal Lobe Epilepsy: Review of the Experimental Literature.

Accumulating evidence suggests that epileptic seizures originating from the temporal lobe (TL) occur in cats. Typically, affected animals have clinically focal seizures with orofacial automatisms including salivation, facial twitching, lip smacking, chewing, licking, and swallowing. Motor arrest and autonomic and behavioral signs also may occur. Many affected cats have magnetic resonance imaging (MRI) changes within the hippocampus or histopathologically confirmed hippocampal sclerosis or necrosis. From the 1950s to the 1980s, cats frequently were used as animal models for neurophysiological experiments and electrophysiological studies, from which important basic knowledge about epilepsy originated, but which has been rarely cited in clinical veterinary studies. These studies were reviewed. Experimental research on cats showed the widespread anatomical connections among TL structures. The ictal clinical signs originating from the hippocampus, amygdala, or lateral temporal cortex are similar, because of their dense interconnections. The ictal signs can be divided into autonomic, somatic, and behavioral. For research purposes, a 6-stage system was established, reflecting the usual sequential progression from focal to generalized seizure: attention response (1), arrest (2), salivation, licking (3), facial twitching (4), head turning or nodding (5), and generalized clonic convulsions (6). Knowledge of this data may help in recognizing low-stage (stage 1 or stage 2) epileptic seizures in clinical practice. Early experimental research data are in accordance with recent clinical observations regarding ictal clinical signs of TL epileptic seizures in cats. Furthermore, the research data supports the idea that TL epilepsy represents a unique clinical entity with a specific seizure type and origin in cats.

Bilateral Dentate Gyrus Structural Alterations in a Cat Associated With Hippocampal Sclerosis and Intraventricular Meningioma.

A 13-year-old cat had a history of seizures for 3 years that resembled temporal lobe epilepsy. Histologic examination of the brain revealed bilateral hippocampal alterations, including hypergyration and broadening of the dentate gyrus associated with hippocampal sclerosis and an intraventricular meningioma near the hippocampal region. The findings in the dentate gyrus were interpreted as a congenital malformation; however, it could not be ruled out that the alterations were induced by the seizures. Similar changes of the dentate gyrus have not been previously described in cats.

Epilepsy in cats: theory and practice.

The veterinary literature on epilepsy in cats is less extensive than that for dogs. The present review summarizes the most important human definitions related to epilepsy and discusses the difficulties in applying them in daily veterinary practice. Epileptic seizures can have a wide range of clinical signs and are not necessarily typical in all cases. Whether a seizure event is epileptic can only be suspected based on clinical, laboratory, and neuroimaging findings as electroencephalography diagnostic techniques have not yet been developed to a sufficiently accurate level in veterinary medicine. In addition, the present review aims to describe other diagnoses and nonepileptic conditions that might be mistaken for epileptic seizures. Seizures associated with hippocampal lesions are described and discussed extensively, as they seem to be a special entity only recognized in the past few years. Furthermore, we focus on clinical work-up and on treatment that can be recommended based on the literature and summarize the limited data available relating to the outcome. Critical commentary is provided as most studies are based on very weak evidence.

Suspected limbic encephalitis and seizure in cats associated with voltage-gated potassium channel (VGKC) complex antibody.

BACKGROUND: Treatment-resistant complex partial seizures (CPS) with orofacial involvement recently were reported in cats in association with hippocampal pathology. The features had some similarity to those described in humans with limbic encephalitis and voltage-gated potassium channel (VGKC) complex antibody. HYPOTHESIS/OBJECTIVES: The purpose of this pilot study was to evaluate cats with CPS and orofacial involvement for the presence of VGKC-complex antibody. ANIMALS: Client-owned cats with acute orofacial CPS and control cats were investigated. METHODS: Prospective study. Serum was collected from 14 cats in the acute stage of the disease and compared with 19 controls. VGKC-complex antibodies were determined by routine immunoprecipitation and by binding to leucine-rich glioma inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2), the 2 main targets of VGKC-complex antibodies in humans. RESULTS: Five of the 14 affected cats, but none of the 19 controls, had VGKC-complex antibody concentrations above the cut-off concentration (>100 pmol/L) based on control samples and similar to those found in humans. Antibodies in 4 cats were directed against LGI1, and none were directed against CASPR2. Follow-up sera were available for 5 cats in remission and all antibody concentrations were within the reference range. CONCLUSION AND CLINICAL IMPORTANCE: Our study suggests that an autoimmune limbic encephalitis exists in cats and that VGKC-complex/LGI1 antibodies may play a role in this disorder, as they are thought to in humans.

Pharmacokinetics of eslicarbazepine acetate at steady-state in adults with partial-onset seizures.

OBJECTIVE: To evaluate the pharmacokinetics of eslicarbazepine acetate (ESL) at steady-state in adults with partial-onset seizures who have taken ESL for at least 1 year with one or two concomitant antiepileptic drugs (AEDs). METHODS: Blood samples for the pharmacokinetic assessment were taken at pre-dose, and 1, 2, 3, 4, 6, 8, 12 and 24h post-dose at steady-state in 51 patients stabilised on chronic (beyond 1 year) treatment with ESL 400mg (n=7), 800mg (n=26) or 1200mg (n=18) once-daily. Most patients (n=29, 56.9%) were receiving 2 concomitant AEDs, and most frequent co-medications were carbamazepine (n=34, 66.7%) and valproic acid (n=19, 37.3%). Plasma concentrations of ESL and its metabolites eslicarbazepine, R-licarbazepine and oxcarbazepine (OXC) were determined by a validated chiral method using liquid chromatography coupled to mass spectrometry. RESULTS: Similarly to earlier findings in healthy subjects, plasma ESL concentrations were consistently below the lower limit of quantification (50ng/mL). The major compound in plasma was the active metabolite eslicarbazepine, which reached maximum concentrations (C(max)) 2h post-dose; thereafter, its plasma concentrations declined with a mean apparent half-life of 13, 14, and 20h in patients receiving ESL doses of 400, 800, and 1200mg once daily, respectively. Eslicarbazepine C(max) were 9.7, 15.5 and 23.0µg/mL, and areas under the plasma concentration-time curve over the dosing interval (AUC(0-24)) were 132.5, 205.4 and 336.1µgh/mL in patients receiving ESL doses of 400, 800 and 1200mg once-daily, respectively. Eslicarbazepine main pharmacokinetic parameters (C(max) and AUC(0-24)) were dose-proportional. R-licarbazepine and OXC were minor metabolites. CONCLUSIONS: Following once-daily oral administration of ESL 400mg, 800mg and 1200mg to epilepsy patients treated concomitantly with one or two other AEDs, ESL was rapidly converted to eslicarbazepine, which was the primary active compound found in plasma. Systemic exposure to eslicarbazepine was dose-proportional.

Phase coupling between rhythmic slow activity and gamma characterizes mesiotemporal rapid-eye-movement sleep in humans.

In the human sleep literature there is much controversy regarding the existence and the characteristics of hippocampal rhythmic slow activity (RSA). Generally the human RSA is believed to occur in short bursts of theta activity. An earlier study, however, reported mesiotemporal RSA during rapid-eye-movement (REM) sleep that instead of theta fell in the delta frequency band. We conjectured that if this RSA activity is indeed a human analogue of the animal hippocampal theta then characteristics associated with the animal theta should also be reflected in the human recordings. Here our aim was to examine possible phase coupling between mesiotemporal RSA and gamma activity during REM sleep. The study relied on nine epilepsy surgery candidates implanted with foramen ovale electrodes. Positive half-waves of the 1.5-3 Hz RSA were identified by an automatic algorithm during REM sleep. High-frequency activity was assessed for 11 consecutive 20 Hz-wide frequency bands between 20 and 240 Hz. Increase in high frequency activity was phase coupled with RSA in most frequency bands and patients. Such a phase coupling closely resembles that seen between theta and gamma in rodents. We consider this commonality to be an additional reason for regarding delta rather than theta as the human analogue of RSA in animals.

Lateralizing value of postictal automatisms in temporal lobe epilepsy.

PURPOSE: To describe clinical characteristics and lateralizing value of postictal automatisms in patients with temporal lobe epilepsy (TLE). METHODS: One hundred and ninety-three videotaped seizures of 55 consecutive patients with refractory TLE and postoperatively seizure-free outcome were analyzed. Ictal as well as postictal (manual, oral and speech) automatisms were monitored. RESULTS: Thirty-four (62%) of the 55 patients showed PA at least once during their seizures. Postictal automatism was observed in 70 (36%) attacks as manual (21%), oral (13%) or speech (9%) automatisms. Fifteen seizures contained a combination of two different postictal automatisms. The presence of postictal oral automatisms did not lateralize the seizure onset zone (p=0.834). Speech automatisms (repetitive verbal behavior) occurred more frequently after left-sided seizures (p=0.002). Postictal unilateral manual automatism showed no lateralizing value occurring by the ipsilateral hand in 10 and the contralateral upper limb in 6 seizures (p=0.454). CONCLUSION: : Postictal automatism is a relatively frequent phenomenon in TLE. Postictal speech automatism lateralizes the seizure onset zone to the left hemisphere. Our observation can help the presurgical evaluation of TLE because verbal perseveration frequently occurs spontaneously, even in seizures without appropriate postictal language testing.

Electrode manipulation automatism during temporal lobe seizures.

OBJECTIVE: To describe clinical characteristics and lateralizing value of peri-ictal electrode manipulation automatism (EMA) in patients with temporal lobe epilepsy (TLE) and compare our data with ictal manual automatisms described in the literature. METHODS: Two-hundred and five videotaped seizures of 55 consecutive patients with refractory TLE and postoperatively seizure-free outcome were analyzed and EMA (tugging, scratching or adjusting the electrodes and cables) were monitored. RESULTS: Twenty-eight (51%) patients showed EMA during 47 (23%) seizures. Ictal start was noted in 22 seizures and in 19/22 cases EMA finished before the end of seizure. Ictal EMAs were always associated with automotor seizure components. During 25 seizures, exclusively postictal EMAs were observed. Electrode manipulation was presented during 24/112 left-sided and 23/93 right-sided seizures (p = 0.742). Peri-ictal EMA was unilateral (completed by one hand) in 24/47 seizures (10 ictal, 14 postictal); it was done by the hand ipsilateral to the seizure onset zone in 17/24 and by contralateral hand in 7/24 cases (p = 0.064). We observed concomitant contralateral dystonic posturing during 3/10 seizures with unilateral ictal EMA. Unilateral hand automatism, temporally independent from the EMA appeared in 30 (64%) of the 47 seizures. CONCLUSION: Peri-ictal EMA is a frequent phenomenon but shows no lateralizing value in TLE. The mechanism of EMA is in many ways dissimilar from that of earlier described manual automatisms.

EFNS guideline on the diagnosis and management of alcohol-related seizures: report of an EFNS task force.

Despite being a considerable problem in neurological practice and responsible for one-third of seizure-related admissions, there is little consensus as to the optimal investigation and management of alcohol-related seizures. The final literature search was undertaken in September 2004. Consensus recommendations are given graded according to the EFNS guidance regulations. To support the history taking, use of a structured questionnaire is recommended. When the drinking history is inconclusive, elevated values of carbohydrate-deficient transferrin and/or gammaglutamyl transferase can support a clinical suspicion. A first epileptic seizure should prompt neuroimaging (CT or MRI). Before starting any carbohydrate containing fluids or food, patients presenting with suspected alcohol overuse should be given prophylactic thiamine parenterally. After an alcohol withdrawal seizure (AWS), the patient should be observed in hospital for at least 24 h and the severity of withdrawal symptoms needs to be followed. For patients with no history of withdrawal seizures and mild to moderate withdrawal symptoms, routine seizure preventive treatment is not necessary. Generally, benzodiazepines are efficacious and safe for primary and secondary seizure prevention; diazepam or, if available, lorazepam, is recommended. The efficacy of other drugs is insufficiently documented. Concerning long-term recommendations for non-alcohol dependent patients with partial epilepsy and controlled seizures, small amounts of alcohol may be safe. Alcohol-related seizures require particular attention both in the diagnostic work-up and treatment. Benzodiazepines should be chosen for the treatment and prevention of recurrent AWS.

Overnight verbal memory retention correlates with the number of sleep spindles.

Despite strong evidence supporting a role for sleep in the consolidation of newly acquired declarative memories, the contribution of specific sleep stages remains controversial. Based on electrophysiological studies in animals, synchronous sleep oscillations have been long proposed as possible origins of sleep-related memory improvement. Nevertheless, no studies to date have directly investigated the impact of sleep oscillations on overnight memory retention in humans. In the present study we provide evidence that overnight verbal memory retention is highly correlated with the number of sleep spindles detected by an automatic algorithm over left frontocentral areas. At the same time, overnight retention of newly learned faces was found to be independent of spindle activity but correlated with non-rapid-eye-movement sleep time. The data strongly support theories suggesting a link between sleep spindle activity and verbal memory consolidation.

Surviving CA1 pyramidal cells receive intact perisomatic inhibitory input in the human epileptic hippocampus.

Temporal lobe epilepsy (TLE) is known to be linked to an impaired balance of excitation and inhibition. Whether inhibition is decreased or preserved in the human epileptic hippocampus, beside the excess excitation, is still a debated question. In the present study, quantitative light and electron microscopy has been performed to analyse the distribution, morphology and input-output connections of parvalbumin (PV)-immunopositive interneurons, together with the entire perisomatic input of pyramidal cells, in the human control and epileptic CA1 region. Based on the degree of cell loss, the patients with therapy-resistant TLE formed four pathological groups. In the non-sclerotic CA1 region of TLE patients, where large numbers of pyramidal cells are preserved, the number of PV-immunopositive cell bodies decreased, whereas axon terminal staining, and the distribution of their postsynaptic targets was not altered. The synaptic coverage of CA1 pyramidal cell axon initial segments (AISs) remained unchanged in the epileptic tissue. The somatic inhibitory input is also preserved; it has been decreased only in the cases with patchy pyramidal cell loss in the CA1 region (control, 0.637; epileptic with mild cell loss, 0.642; epileptic with patchy cell loss, 0.424 microm synaptic length/100 microm soma perimeter). The strongly sclerotic epileptic CA1 region, where pyramidal cells can hardly be seen, contains a very small number of PV-immunopositive elements. Our results suggest that perisomatic inhibitory input is preserved in the epileptic CA1 region as long as pyramidal cells are present. Basket and axo-axonic cells survive in epilepsy if their original targets are present, although many of them lose their PV content or PV immunoreactivity. An efficient perisomatic inhibition is likely to take part in the generation of abnormal synchrony in the non-sclerotic epileptic CA1 region, and thus participate in the maintenance of epileptic seizures driven, for example, by hyperactive afferent input.

Postoperative interictal spikes during sleep contralateral to the operated side is associated with unfavourable surgical outcome in patients with preoperative bitemporal spikes.

PURPOSE: To correlate the persistence of contralateral spikes during sleep after unilateral surgery with seizure outcome in a temporal lobe epilepsy (TLE) population and to test the existing hypotheses about the origin of the contralateral spikes in temporal lobe epilepsy. METHODS: In the 19 patients selected for this study unilateral temporal lobe surgery was performed. To investigate the course of bilateral interictal epileptiform discharges observed before surgery in awake or sleep over the temporal lobe contralateral to surgery, 24 h mobile 12 channel EEG recording was performed at minimum two, in average 4.6 (2-10) years after the surgery. RESULTS: The association of postoperative contralateral spikes and non-seizure free outcome was highly significant. The existence of unilateral pathology before surgery was highly predictive for good outcome and disappearance of contralateral spikes. The association between good seizure outcome, disappearance of contralateral spikes and the existence of unilateral pathology before surgery was also significant. Our data partially satisfies the expectations of both the "seizure induced" and mirror type secondary epileptogenesis hypotheses concerning origin of contralateral spikes, but were not completely congruent with either of them. CONCLUSIONS: Unfavourable surgical outcome in a temporal lobe epilepsy group with preoperative independent bilateral interictal spikes was associated with the persistence of postoperative contralateral spikes and lack of unilateral pathology. Compared with seizure outcome the presence/absence and distribution of postoperative interictal spikes in NREM sleep not entirely fit to the predictions of existing secondary epileptogenesis hypotheses.

Intentional seizure interruption may decrease the seizure frequency in drug-resistant temporal lobe epilepsy.

We investigated the nature of preictal subjective phenomena and whether they had any effect on the seizure frequency in 95 adult patients with medial temporal lobe epilepsy. Seventy-three (77%) patients indicated that they experienced seizure-provoking factors. Ten patients (11%) had prodromas independent of auras, while auras occurred in 89%. Forty-four patients (46%) reported that that they had tried to stop their seizures in the presence of prodroma or aura and this action had resulted in success at least once. Twenty-one patients (22%) regularly tried to stop their seizures because this effort was often successful according to their interpretation. Patients who reported that they could frequently inhibit their seizures had 1.8 +/- 1.6 seizures/month, a significantly lower mean seizure frequency than those 74 patients who did not do it regularly (4.6 +/- 4.8 seizures/month, P<0.001). Patients who reported regular experience in inhibiting intentionally their seizures more often had affective (P=0.05) and vertiginous auras (P<0.01) as well as isolated auras (P<0.05). Patients who experienced provoking factors showed the same seizure frequency as those who did not. Our results suggest that intentional seizure inhibition had an impact on the severity of drug-resistant epilepsy.

Clinical differences in patients with unilateral hippocampal sclerosis and unitemporal or bitemporal epileptiform discharges.

PURPOSE: To investigate factors determining the presence of bilateral interictal epileptiform discharges (IEDs) in temporal lobe epilepsy (TLE) with unilateral hippocampal sclerosis (HS). METHODS: We analysed data of 243 TLE patients with unilateral HS who had long-term video-EEG. Eighty-one patients (33%) had bitemporal IEDs. RESULTS: We categorised patients into a unilateral group (UG), a bilateral group (BG) according to presence of bitemporal IEDs. We found no difference between UG and BG regarding epilepsy duration, secondarily generalised seizures, and history of febrile seizures. Mean seizure frequency was significantly higher in the BG (UG: 7.7+/-14.7 seizures/month; BG: 13+/-35 seizures/month, P=0.01). We found a significant correlation between late epilepsy onset and the presence of bitemporal IEDs. The mean age at epilepsy onset in UG was 10.1+/-7.9 years, while in BG it was 13+/-9.2 years (P=0.02). CONCLUSIONS: The traditional concept of the evolution of mirror focus cannot apply for humans because the duration of epilepsy does not influence the evolution of bitemporal IEDs. Other factors, i.e. age at onset and seizure frequency may play a role in this process. The association between the higher seizure frequency and mirror foci indicates that the development of mirror focus depends on seizures and not on a progressive 'interictal' epileptogenesis.

Misleading hallucinations in unrecognized narcolepsy.

OBJECTIVE: To describe psychosis-like hallucinatory states in unrecognized narcolepsy. METHOD: Two patients with hypnagogic/hypnapompic hallucinations are presented. RESULTS: Both patients had realistic and complex - multi-modal and scenic-daytime sexual hallucinations leading, in the first case, to a legal procedure because of false accusation, and in the second, to serious workplace conflicts. Both patients were convinced of the reality of their hallucinatory experiences but later both were able to recognize their hallucinatory character. Clinical data, a multiple sleep latency test, polysomnography, and HLA typing revealed that both patients suffered from narcolepsy. CONCLUSION: We suggest that in unrecognized narcolepsy with daytime hypnagogic/hypnapompic hallucinations the diagnostic procedure may mistakenly incline towards delusional psychoses. Daytime realistic hypnagogic/hypnapompic hallucinations may also have forensic consequences and mislead legal evaluation. Useful clinical features in differentiating narcolepsy from psychoses are: the presence of other narcoleptic symptoms, features of hallucinations, and response to adequate medication.