RICERCA ITALIANA     

CLINICAL, GENETIC AND DEVELOPMENTAL CHARACTERIZATION OF SLEEP-RELATED EPILEPTIC SEIZURES AND AROUSAL DISORDERS

Università degli Studi di Bologna

Abstract

NFLE is a syndrome that includes paroxysmal episodes with variable semeiology, intensity and duration, occurring during sleep. NFLE may be familial with a mendelian autosomal dominant inheritance (ADNFLE). The known mutations responsible for ADNFLE are in genes coding for neuronal Ach Receptor subunits (CHRNA4, CHRNB2) but, in the majority of the cases, NFLE is cryptogenic. NFLE is therefore a complex disease whose etiology is probably determined by the interaction of genetic and environmental factors in the majority of cases (multifactorial-polygenic disease), but, so far, the relevant risk factors are unknown. Ad hoc designed epidemiological (case-control or cohort) studies for the assessment of the genetic and environmental risk factors are needed. Due to the bizarre clinical features and the frequent normality of even ictal EEG, the diagnosis of NFLE is a significant challenge for the clinician, with the differentiation of NFLE from non-epileptic arousal parasomnias often the primary concern. Indeed, NFLE seems to coexist in affected patients or their family relatives with nocturnal parasomnic attacks, suggesting that common pathogenic mechanisms may exist between NFLE and arousal disorders such as the parasomnias. There is, therefore, a need to establish the reliability of the clinical and polysomnographic features in distinguishing NFLE seizures from parasomnias in those situations in which video-EEG and polysomnography are impracticable or unhelpful. This research project is therefore aimed at trying and answer some of the diagnostic and pathogenetic challenges posed by NFLE by establishing a collaboration among 3 research Units with long standing commitment to sleep and NFLE studies. The project is articulated into a mainly clinical and epidemiological set of studies, aimed at establishing a diagnostic instrument for the differential diagnosis of NFLE vs the arousal parasomnias (comprising a study on the diagnostic accuracy of the clinical and videopolygraphic features of NFLE and parasomnias, a study on the inter-observer reliability of the proposed criteria for the diagnosis of NFLE, a prospectic validation of the criteria for the diagnosis of NFLE, a study on the risk factors of NFLE, and a study on the prevalence of arousal parasomnias in relatives of patients with NFLE and relatives of general population controls). To these mainly clinical studies will be added neurophysiological and neuropsychological studies aimed at assessing the consequences of the nocturnal attacks on daytime cognition, and functional MR imaging studies assessing the eventual structural lesions underlying the focal origin of the nocturnal attacks and their correlation with the neuropsychological tests. Finally, a genetic characterization study will be performed in regard to known genes responsible for ADNFLE, and in the aim of identifying possible new genes and loci for genetic determination of NFLE and arousal disorders. An instrument for genetic counselling will be developed, and the expression pattern in brain tissue of several neuronal Ach receptor subunits will be analysed. <<<

Principal Investigator

Pasquale Montagna Università degli Studi di BOLOGNA

Research Objectives

The principal objective of the research project is to try and define the differential features in the clinical and natural history characteristics of the frontal lobe seizures arising during sleep versus the arousal parasomnias. This objective stems from the recognized inability to sometimes differentiate the 2 conditions even under optimal conditions, such as the recording of the actual ictal event, and from the current lack of knowledge about the precise risk factors (mainly genetic versus environmental ones) for NFLE. The differentiation of the clinical and videopolysomnographic characteristics of the seizures arising from the frontal lobe compared to the arousal parasomnias cannot be achieved in the absence of a clinical instrument (e.g. questionnaire) which is at the same time accurate, reliable (e.g. applicable by any physician involved in the diagnostic question) and validated across a spectrum of conditions, ranging from NFLE to several kinds of parasomnias to other potentially confounding sleep disorders. Such an instrument is at the moment lacking. Therefore the first objective of the project is to try and provide such a clinically reliable instrument and to validate it, and the task is to be performed in collaboration by the 3 Units involved in the project according to standard validation procedures. Videorecording of the ictal event will remain of course the “gold standard”. This clinical instrument will also be used in defining the eventual co-morbidity of NFLE with the arousal parasomnias (in an epidemiological case-control study), something which is very intriguing and that we do not yet know whether it represents a true finding, a chance association or a bias. The nosological implications of this are very important, and may be utterly significant not only for the patients but also for the scientific definition of arousal. Characterization of the clinical differential features of the ictal event and of the natural history of NFLE (risk factors for NFLE, evolution and prognostic factors, including response to drug treatment) represents, however, just the first step of the project. The project also aims at defining the eventual cognitive co-morbidity of the conditions, in particular whether it is associated with significant daytime impairment. This cannot be achieved without a fine definition of the night-time sleep characteristics, examined in their macro- and micro-structural features, and their correlation with daytime measurements of sleepiness. At the same time the neuropsychological, especially the executive functions of the NFLE patients will be examined in order to determine whether specific patterns exist which characterize these patients and may help with etiology and differential diagnosis. In this regards, it is worth remarking that no consistent study of frontal lobe functions is available in NFLE. Such a clinical analysis of frontal lobe functions will be associated with functional imaging studies performed by means of MRI, whereby the frontal lobes of such patients will be examined non invasively at the functional level (MRI, diffusion and tensor imaging) in order to detect potential abnormalities. Remarkably again, such data, which are lacking in the NFLE literature, will hopefully help in the detection of abnormal frontal lobe features characterizing such patients. The final branch objective of the project concerns itself with the genetic characterization of patients, again a controversial issue in the NFLE. Even though several genes have been found implicated in some families with autosomal dominant NFLE (in nicotinic Ach receptor subunit genes), the relevance of these mutations for the majority of the sporadic NFLE cases is not clear. Likewise, their relevance in the arousal parasomnias, which also carry a significant genetic risk, has never been explored. Therefore the project aims at a comprehensive characterization of the clinical material in regard to known mutations, and eventually at defining new genes implicated in suitable families. Expression patterns of nicotinic Ach receptor subunits performed in brain tissues derived from normal individuals will finally help in detecting anatomic patterns eventually of relevance in neural pathways implicated in the physiological regulation of arousal. <<<

Timescale

24 months

National and international background

Paroxysmal events in sleep represent a significant challenge for the clinician: in particular distinguishing nocturnal epilepsy originating from the frontal lobe (NFLE) from paroxysmal non-epileptic sleep disorders (so-called arousal parasomnias) is often difficult and sometimes impossible on clinical grounds alone, especially since NFLE is a syndromic entity that includes paroxysmal episodes with variable semeiology, intensity and duration comparable with the parasomnias, with onset mainly during adolescence and with seizures appearing during non-REM sleep just like the parasomnias. Interictal and even ictal EEG moreover often fail to disclose epileptiform abnormalities in a substantial percentage of the NFLE. At the moment, some historical and clinico-polysomnographic features have been proposed by some research groups, which may distinguish NFLE from parasomnias, but the value of these features has not been systematically assessed. Also, both the International Classification of Sleep Disorders (ICSD) and the International League Against Epilepsy (ILAE) Classification include nosographic delineations of the NFLE, however, their features again have never been validated. Video-polysomnography together with a careful clinical history remain mandatory for a correct diagnosis, but the nocturnal episodes may still be confused and misdiagnosed as parasomnias, nocturnal panic attacks or hysterical episodes. Moreover video EEG-polysomnography, the “gold standard” diagnostic test, is expensive and inconvenient investigation and does not always capture the event. There remains thus the need to establish the reliability of historical features in distinguishing nocturnal frontal lobe seizures from parasomnias, especially when video-EEG and polysomnography are impracticable or unhelpful.
As to the semeiology of the different kinds of seizures, while some ictal features are thought to be originated in the mesial frontal zones, other manifestations seem to involve the orbito-frontal regions or even the subcortical structures. Seizures moreover with clear cut “frontal lobe” characteristics have been shown to originate in the temporal lobes, and to give rise to ictal manifestations typical of NFLE when they involve frontal lobe regions. Therefore the semeiological characteristics of the seizures in NFLE are not yet clear and invasive studies by means of deep implanted electrodes performed in drug-resistant NFLE patients could help in clarifying the precise semeiology of the different types of NFLE and maybe even help in the interpretation of the manifestations of the arousal parasomnias. These differential diagnosis characteristics of NFLE versus the parasomnias, however, represents just one of the several problematic issues. Another is represented by the etiopathogenesis of NFLE. Most cases of NFLE remain indeed criptogenic, since a symptomatic etiology is present only in 13% of cases (Provini et al 1999). However, a family history of epilepsy can be present and a clear mendelian autosomal dominant inheritance has been described in some families (so-called autosomal dominant NFLE, ADNFLE). ADNFLE is linked to mutations in the genes which code for the a4 and b2 subunits of the acetylcholine receptors (CHRNA4 and CHRNB2) in some ADNFLE families and an increased acetylcholine sensitivity has been found in receptors containing these mutated subunits. The neuronal nicotinic acetylcholine receptors (nAChR) are ion channels distributed widely on the membranes of neurons and glia, and, when functional, display a modulatory effect on arousal at both thalamic and cortical levels. Therefore they could be implicated in the peculiar association of NFLE with sleep, but could also represent plausible mechanisms in the origins of the arousal parasomnias. Even while, however, the precise pathophysiological mechanisms of ADNFLE remain elusive, these mutations in the nAChR genes are not usually found in large samples of sporadic and even familial NFLE cases and thus remain a rare cause even of ADNFLE. Probably NFLE is a complex disease with both genetic and environmental factors (multifactorial-polygenic model, Ottmann 2005). Case-control studies of the relative risk factors are however lacking for NFLE and genetic studies of NFLE cases, both sporadic and familial, are warranted with the aim of not only clarifying the puzzle of the sporadic cases and possibly finding new genes and mutations responsible for the familial NFLE, but also to determine whether genetic factors play a significant role in the origin of arousal disorders and thus cast some light on pathogenetic mechanisms possibly common to NFLE and arousal disorders. Remarkably enough, another controversial issue is indeed the possible coexistence in affected patients or their families of nocturnal parasomnic attacks (Provini et al 1999). Moreover, a third of the patients with NFLE have a personal history of co-presence of night terrors, sleepwalking, sleep talking, rhythmic movement disorder and enuresis. This could be a mere coincidence since parasomnias are rather frequent in the general population, or a bias due to patients’ recollection of nocturnal episodes of any nature. It may, however, represent also a link between unusual sleep episodes and epileptic seizures during sleep, and there is the possibility that in a predisposed individual, parasomnias in infancy are replaced by frontal lobe seizures during life, suggesting a common cortical substrate (Tinuper and Lugaresi 2002). The issue is even more controversial since parasomnias too have a clear familial aggregation (Hublin and Kaprio 2003). Finally, some NFLE patients complain of poor sleep quality and daytime sleepiness, and some may actually come to observation because of excessive daytime tiredness rather than because of the nocturnal attacks. It is indeed possible to conceive of a relation between sleep fragmentation, nocturnal motor seizures and daytime symptoms. While sleep macrostructure in NFLE is generally preserved, sleep microstructure studies reveal an increase in sleep instability with periodicity of the nocturnal seizures related to the Phase A of the Cyclic Alternating Pattern (CAP) cycle. Apart from such sleep particularities however, which may bear on the daytime symptoms of NFLE, the cognitive deficits, in particular of the executive functions, associated with NFLE, if any, have not been explored in any detail either at the clinical or at the functional imaging level. This may represent a useful effort in the clinical characterization of the syndrome, and may even have an interest in the differential diagnosis. <<<