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Nocturnal frontal lobe epilepsy and sleep spindles

English title Nocturnal frontal lobe epilepsy and sleep spindles
Applicant Picard Fabienne
Number 104190
Funding scheme Project funding (Div. I-III)
Research institution Division of Dermatology/ PATIM Lab Dermato-Oncology Unit University Hospital of Geneva
Institution of higher education University of Geneva - GE
Main discipline Neurophysiology and Brain Research
Start/End 01.07.2004 - 31.03.2007
Approved amount 106'292.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Neurology, Psychiatry

Keywords (3)

frontal lobe epilepsy; sleep spindles; brain mapping

Lay Summary (English)

Lead
Lay summary
The syndrome of nocturnal frontal lobe epilepsy (NFLE) consists in frequent brief nocturnal seizures with essentially motor (hyperkinetic or dystonic) components in patients with a normal cerebral MRI. The pathophysiological mechanisms of NFLE are still unknown though causal genes (coding for nicotinic receptor subunits) have been identified in familial forms. The occurrence of NFLE seizures nearly exclusively during non-rapid eye movement sleep stage 2 constitutes a characteristic of this syndrome, and very often seizures apparently begin on sleep spindles, which are transient physiological EEG oscillations specific of this sleep stage. Transformation of these physiological oscillations generated by thalamocortical circuitry into generalized spike-and-wave activity has been proposed in absence epilepsy, based on animal models, but a direct relationship between sleep spindles and NFLE has never been stated in the literature. As the nicotinic receptors which are mutated in familial NFLE are mostly localized in the thalamus (and the cortex) and as nicotinic receptors have been shown to be involved in the cessation of sleep spindles at the time of an awakening in animals, a defect of these receptors could disturb the normal dynamics of sleep spindles. The hypothesis that is at the root of our project is that a defect of sleep spindles' interruption may transform into pathological oscillations with a motor clinical expression. We focused on the analysis of the EEG recordings made in two NFLE patients who benefited from a presurgical evaluation of their epilepsy, which included intracerebral stereo-EEG ictal recordings. We aimed to demonstrate that the last sleep spindle before the seizure had an abnormally prolonged duration. The EEG of each lead of the different stereotactically implanted intracerebral electrodes was transformed into the frequency domain by Fast Fourier Transform (2 second-epochs, overlapping ratio 75%, frequency resolution 0.5 Hz). The further analysis was confined to the 12 Hz frequency as the analyzed sleep spindles had a predominantly frontal distribution, with a frequency peak at 12 Hz. For all studied seizures the duration of the 12 Hz activity of the pre-seizure sleep spindle was always longer than that of any of the 10 preceding interictal sleep spindles. These results may suggest a lack of normal sleep spindle interruption at seizure onset, related to a thalamocortical loop dysfunction (possibly of genetic origin) expressing itself at the time of arousals.In parallel of this electrophysiological work, we decided to investigate the nicotinic receptor (nAChR) brain distribution by positron emission tomography (PET) using the radiotracer [18F]-F-A-85380 in a group of patients with familial NFLE, who all carried a mutation in a nicotinic receptor subunit. A group of eight non-smoking NFLE patients was compared to a group of seven age-matched non-smoking healthy control subjects. Statistical parametric mapping (SPM) showed clear regional differences between patients and controls: patients had a statistically significant increase in nAChR density in the epithalamus, ventral mesencephalon and cerebellum, but decreased nAChR density in the right dorsolateral prefrontal region. The demonstration of a regional nAChR density decrease restricted to the prefrontal cortex, despite the known distribution of these receptors throughout the cerebral cortex, is consistent with focal epilepsy involving the frontal lobe. In addition, based on the known biochemical and cellular circuits in the brainstem, we suggest that the nAChR density increase in the mesencephalon is involved in the pathophysiology of familial NFLE, through the role of brainstem ascending cholinergic systems in arousal. Lastly, by investigating the influence of tobacco habits in 22 patients from two pedigrees with nAChR mutations, we were able to demonstrate a clear relationship between the nicotine consumption and the seizure frequency. We concluded that tobacco appears to be an environmental factor which influences the course of familial NFLE.
Direct link to Lay Summary Last update: 21.02.2013

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