The wide clinical spectrum of nocturnal frontal lobe epilepsy

doi:10.1053/smrv.2000.0109

Sleep Medicine Reviews

Volume 4, Issue 4, August 2000, Pages 375-386

https://doi.org/10.1053/smrv.2000.0109 Get rights and content

Abstract

Nocturnal frontal lobe epilepsy (NFLE) has become clinically relevant in recent years. NFLE represents a spectrum of clinical manifestations, ranging from brief, stereotyped, sudden arousals, often recurring several times per night, sometimes with a quasi-periodic pattern, to more complex dystonic–dyskinetic seizures and to prolonged “somnambulic” behaviour. Episodes of increasing intensity have been labelled as paroxysmal arousal (PA), nocturnal paroxysmal dystonia (NPD) and episodic nocturnal wandering (ENW). NFLE affects both sexes with a higher prevalence for men, is frequently cryptogenetic and displays a strong familial trait for parasomnias and epilepsy (NFLE). Seizures appear more frequently between 14 and 20 years of age, but can affect any age and tend to increase in frequency during life. Interictal and ictal scalp electroencephalography (EEG) are often normal, the use of sphenoidal leads may be helpful. Carbamazepine taken at night is often effective at low doses, but a third of the patients are resistant to anti-epileptic drugs (AED) treatment. A familial form, characterized by an autosomal dominant transmission, has also been described. Autosomal dominant nocturnal frontal lobe epilepsy is a genetic variant of NFLE, in itself both clinically and biologically heterogeneous. NFLE should be suspected in the presence of frequent stereotyped paroxysmal nocturnal motor events arising or persisting into adulthood. Videopolysomnography is mandatory to confirm the diagnosis.

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SHE may respond to carbamazepine (CBZ) therapy, which completely abolishes seizures in ∼20% of patients and reduces seizures in another 48% [2]. However, despite receiving active pharmacologic therapy, approximately one-third of patients do not achieve satisfactory seizure control [2,4,5]. Spontaneous remissions of SHE are unusual; in cases responding to treatment, withdrawal of anti-seizure medications (ASMs) is often followed by seizure recurrence [2].
This study aimed to evaluate the efficacy and tolerability of perampanel (PER) as adjunctive therapy in patients with pharmacoresistant sleep-related hypermotor epilepsy (SHE). Patients diagnosed with SHE who received PER treatment between 2016 and 2019 were included, and their data were reviewed retrospectively. Diagnosis was based on reports of patients or family members witnessing the events and clinical characteristics of seizures captured by video or during video-electroencephalography monitoring. Among 36 SHE patients, 20 with pharmacoresistant SHE (six female; mean age: 34.1 ± 9.0 years) who received PER as adjunctive therapy were included in this study. Fourteen out of the 20 patients received PER with mean length of PER exposure of 24.6 ± 15.7 months: 10 of them were responders and four non-responders. The remaining six patients discontinued PER for adverse events (n = 5) and patient choice (n = 1). Among the 10 responders, six (60%) reported seizure-free periods lasting ≥6 months. The most common PER-associated adverse event was dizziness (25%) followed by malaise (10%). Clinical experience with these patients demonstrated that PER might be considered as an add-on anti-seizure medication for patients with highly pharmacoresistant SHE.
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The classical three ADSHE mutations of CHRNA4, S280F, S284L and insL, affect to differ significantly with respect to their neuropsychiatric comorbidity and antiepileptic drug sensitivity. Usually, carbamazepine (CBZ) is a first-choice anticonvulsant for ADSHE/SHE syndrome, in relatively low doses leads to remission in approximately 60 % of ADSHE/SHE patients, including S280F and insL mutations [4,16,17]. However, ADSHE patients with S284L mutation are resistant to CBZ but responsive to other anticonvulsants such as zonisamide (ZNS) [5,12–14,18].
To study the pathomechanism and pathophysiology of nocturnal paroxysmal dystonia of autosomal dominant sleep-related hypermotor epilepsy (ADSHE), this study determined functional abnormalities in thalamic hyperdirect pathway from reticular thalamic nucleus (RTN), motor thalamic nuclei (MoTN), subthalamic nucleus (STN) to substantia nigra pars reticulata (SNr) of transgenic rats (S286L-TG) bearing S286 L missense mutation of rat Chrna4 gene, which corresponds to the S284 L mutation in the human CHRNA4 gene. The activation of α4β2-nAChR in the RTN increased GABA release in MoTN resulting in reduced glutamatergic transmission in thalamic hyperdirect pathway of wild-type. Contrary to wild-type, activation of S286L-mutant α4β2-nAChR (loss-of-function) in the RTN relatively enhanced glutamatergic transmission in thalamic hyperdirect pathway of S286L-TG via impaired GABAergic inhibition in intra-thalamic (RTN-MoTN) pathway. These functional abnormalities in glutamatergic transmission in hyperdirect pathway contribute to the pathomechanism of electrophysiologically negative nocturnal paroxysmal dystonia of S286L-TG. Therapeutic-relevant concentration of zonisamide (ZNS) inhibited the glutamatergic transmission in the hyperdirect pathway via activation of group II metabotropic glutamate receptor (II-mGluR) in MoTN and STN. The present results suggest that S286L-mutant α4β2-nAChR induces GABAergic disinhibition in intra-thalamic (RTN-MoTN) pathway and hyperactivation of glutamatergic transmission in thalamic hyperdirect pathway (MoTN-STN-SNr), possibly contributing to the pathomechanism of nocturnal paroxysmal dystonia of ADSHE patients with S284L mutant CHRNA4. Inhibition of glutamatergic transmission in thalamic hyperdirect pathway induced by ZNS via activation of II-mGluR may be involved, at least partially, in ZNS-sensitive nocturnal paroxysmal dystonia of ADSHE patients with S284L mutation.
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These sleep movements, seen in non REM sleep, have been classified into two main types, based upon their duration and semiology. They include: paroxysmal arousals- comprising stereotyped head or trunk elevation, lasting 5–10 s and minor motor events (MMEs)- brief (<5 s) limb, trunk or face movements (Tinuper et al., 1990; Provini et al., 1999; Provini, Plazzi, Montagna and Lugaresi, 2000; Gibbs et al., 2016). Initially, MMES were considered to be attributable to epileptic phenomena for a variety of reasons.
Paroxysmal nocturnal movements in epilepsy are a recognised phenomenon, however, the mechanisms that produce them and the effect of the underlying epilepsy still remains elusive. In this study, 10 patients were studied to define the cerebral networks corresponding to these movements and explore how epileptiform activity modulated them.
We compared the change in power of the 25–250 Hz frequency band using event-related synchronization of all stereo-EEG electrodes implanted, during a baseline segment, during nocturnal movements and seizures.
The underlying network activated during these paroxysmal movements comprised the insula, anterior cingulate, premotor areas and orbitofrontal regions. Three groups emerged, (1) complete overlap, (2) no overlap and (3) partial overlap of ERS changes of the epileptogenic zone within the proposed network and correlation of semiology between nocturnal movements and seizures.
We conclude that nocturnal movements are due to a complex interplay within this physiological network of defined anatomical regions. Epileptic activity had significant impact on nocturnal movements but was not required for generation.
Where the semiology of the first clinical sign of a seizure consistently matches a patient’s nocturnal movements, we suggest that the underlying epileptogenic zone is potentially located within this defined network.
Brain functional connectivity in sleep-related hypermotor epilepsy
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To evaluate functional connectivity (FC) in patients with sleep-related hypermotor epilepsy (SHE) compared to healthy controls.
Resting state fMRI was performed in 13 patients with a clinical diagnosis of SHE (age = 38.3 ± 11.8 years, 6 M) and 13 matched healthy controls (age = 38.5 ± 10.8 years, 6 M).
Data were first analysed using probabilistic independent component analysis (ICA), then a graph theoretical approach was applied to assess topological and organizational properties at the whole brain level. We evaluated node degree (ND), betweenness centrality (BC), clustering coefficient (CC), local efficiency (LE) and global efficiency (GE). The differences between the two groups were evaluated non-parametrically.
At the group level, we distinguished 16 RSNs (Resting State Networks). Patients showed a significantly higher FC in sensorimotor and thalamic regions (p < 0.05 corrected). Compared to controls, SHE patients showed no significant differences in network global efficiency, while ND and BC were higher in regions of the limbic system and lower in the occipital cortex, while CC and LE were higher in regions of basal ganglia and lower in limbic areas (p < 0.05 uncorrected).
The higher FC of the sensorimotor cortex and thalamus might be in agreement with the hypothesis of a peculiar excitability of the motor cortex during thalamic K-complexes. This sensorimotor-thalamic hyperconnection might be regarded as a consequence of an alteration of the arousal regulatory system in SHE. An altered topology has been found in structures like basal ganglia and limbic system, hypothesized to be involved in the pathophysiology of the disease as suggested by the dystonic-dyskinetic features and primitive behaviours observed during the seizures.
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During the last decade, many clinical and pathophysiological aspects of sleep-related epileptic and non-epileptic paroxysmal behaviors have been clarified. Advances have been achieved in part through the use of intracerebral recording methods such as stereo-electroencephalography (S-EEG), which has allowed a unique “in vivo” neurophysiological insight into focal epilepsy. Using S-EEG, the local features of physiological and pathological EEG activity in different cortical and subcortical structures have been better defined during the entire sleep-wake spectrum. For example, S-EEG has contributed to clarify the semiology of sleep-related seizures as well as highlight the specific epileptogenic networks involved during ictal activity. Moreover, intracerebral EEG recordings derived from patients with epilepsy have been valuable to study sleep physiology and specific sleep disorders. The occasional co-occurrence of NREM-related parasomnias in epileptic patients undergoing S-EEG investigation has permitted the recordings of such events, highlighting the presence of local electrophysiological dissociated states and clarifying the underlying pathophysiological substrate of such NREM sleep disorders. Based on these recent advances, the authors review and summarize the current and relevant S-EEG literature on sleep-related hypermotor epilepsies and NREM-related parasomnias. Finally, novel data and future research hypothesis will be discussed.
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^☆: Correspondence to be addressed to: Federica Provini, MD, Istituto di Clinica Neurologica, Via Ugo Foscolo 7, 40123 Bologna, Italy. Fax: +39 51 6442165; E-mail: [email protected]

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REVIEW ARTICLEThe wide clinical spectrum of nocturnal frontal lobe epilepsy☆

Abstract

Lancet

Am J Hum Genet

Electroencephalogr Clin Neurophysiol

ElectroÍencephalogr Clin Neurophysiol

Electroencephalogr Clin Neurophysiol

Episodic nocturnal wanderings responsive to anticonvulsant drug therapy

Ann Neurol

Episodic nocturnal wandering responsive to antiÍconvulsant drug therapy

Ann Neurol

Episodic nocturnal wandering

Sleep

Epileptic nocturnal wanderings

Sleep

Hypnogenic paroxysmal dystonia; epileptic seizures or a new syndrome?

Sleep

Nocturnal paroxysmal dystonia

J Neurol Neurosurg Psychiatry

Nocturnal paroxysmal dystonia with short-lasting attacks: three cases with evidence for an epileptic frontal lobe origin of seizure

Epilepsia

Is nocturnal paroxysmal dystonia a form of frontal lobe epilepsy?

Mov Disord

Nocturnal paroxysmal dystonia: a clinical form of focal epilepsy

Neurophysiol Clin

Autosomal dominant nocturnal frontal lobe epilepsy: electroclinical picture

Epilepsia

Paroxysmal awakenings from sleep associated with excessive daytime somnolence: a form of nocturnal epilepsy

Neurology

Paroxysmal arousals during sleep

Neurology

Nocturnal paroxysmal dystonia and nocturnal wandering

Neurology

Familial paroxysmal hypnogenic dystonia

Neurology

Hypnic tonic postural seizures in healthy children provide evidence for a partial epileptic syndrome of frontal lobe region

Epilepsia

Autosomal dominant nocturnal frontal lobe epilepsy. A distinctive clinical disorder

Brain

Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q13.2

Nat Genet

A missense mutation in the neuronal nicotinic acetylcholine receptor (4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy)

Nat Genet

An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy

Hum Mol Genet

Autosomal dominant nocturnal frontal lobe epilepsy in a Spanish family with a Ser252Phe mutation in the CHRNA4 gene

Arch Neurol

A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy

Neurology

REVIEW ARTICLE
The wide clinical spectrum of nocturnal frontal lobe epilepsy☆