Stefano Meletti

Encephalopathy with electrical status epilepticus during slow sleep or ESES syndrome including the acquired aphasia

Encephalopathy with electrical status epilepticus during sleep or ESES is an age-dependent and self-limited syndrome whose distinctive features include a characteristic age of onset (with a peak around 4-5 years), heterogeneous seizures types (mostly partial motor or unilateral seizures during sleep and absences or falls while awake), a typical EEG pattern (with continuous and diffuse paroxysms occupying at least 85% of slow wave sleep) and a variable neuropsychological regression consisting of IQ decrease, reduction of language (as in acquired aphasia or Landau-Kleffner syndrome), disturbance of behaviour (psychotic states) and motor impairment (in the form of ataxia, dyspraxia, dystonia or unilateral deficit). Despite the long-term favourable outcome of epilepsy and status epilepticus during sleep (SES), the prognosis is guarded because of the persistence of severe neuropsychological and/or motor deficits in approximately half of the patients. No specific treatment has been advocated for this syndrome, but valproate sodium, benzodiazepines and ACTH have been shown to control the seizures and the SES pattern in many cases, although often only temporarily. Subpial transection is proposed in some instances as in non-regressive acquired aphasia. Recent data support the concept that ESES syndrome may include a large subset of developmental or acquired regressive conditions of infancy.

Central pattern generators for a common semiology in fronto-limbic seizures and in parasomnias. A neuroethologic approach.

Central pattern generators (CPGs) are genetically determined neuronal aggregates in the mesencephalon, pons and spinal cord subserving innate motor behaviours essential for survival (feeding, locomotion, reproduction etc.). In higher primates CPGs are largely under neocortical control. We describe how certain motor events observed in parasomnias and epileptic seizures could have similar features and resemble motor behaviours, which can be the expression of the same CPG. Both epilepsy and sleep can lead to a temporary loss of control of neomammalian cortex that facilitates through a common platform (arousal) the emergences of stereotyped inborn fixed action patterns. Therefore we suggest that, independently from the nature of the trigger, be it a seizure or a parasomnia, the same CPGs can be involved, “caught up”, leading to a common motor semiology (the “Carillon theory”).

Impaired facial emotion recognition in early-onset right mesial temporal lobe epilepsy.

Background: Anteromedial temporal lobe regions, particularly the amygdala, participate in the recognition of emotions from facial expressions. The authors studied the ability of facial emotion recognition (ER) in subjects with symptomatic epilepsy, evaluating whether mesial temporal lobe damage is related to an impairment in the recognition of specific emotions and whether the onset of seizures in a critical period of life could prevent the development of ER. Methods: Groups included patients with temporal lobe epilepsy (TLE) with MRI evidence of mesial temporal sclerosis (MTS) (n = 33); patients with TLE with MRI evidence of temporal lobe lesions other than MTS (n = 30); and patients with extratemporal epilepsy (n = 33). Healthy volunteers (n = 50) served as controls. ER was tested by matching a facial expression with the name of one of the following basic emotions: happiness, sadness, fear, disgust, and anger. A face-matching task was used to control visuoperceptual abilities with face stimuli. Results: No subject showed deficits in the face-matching task. ER was impaired in patients with right MTS, especially for fearful faces. Patients presenting left MTS, right or left temporal lobe lesions other than MTS, or extratemporal seizure foci showed ER performances similar to controls. In all subjects with right TLE, the degree of emotion recognition impairment was related to age at first seizure (febrile or afebrile) and age at epilepsy onset. Conclusions: Early-onset right-sided mesial temporal lobe epilepsy is the key substrate determining a severe deficit in recognizing emotional facial expressions, especially fear.

Motor pattern of periodic limb movements during sleep

Background: The pathophysiology of periodic limb movements in sleep (PLMS) in restless legs syndrome (RLS) is unclear. Objective: The authors neurophysiologically investigated PLMS in patients with idiopathic RLS in order to obtain information on the origin and pathophysiology of the movements. Methods: Ten patients with idiopathic RLS underwent electromyography with nerve conduction velocity (EMG-CV), somatosensory evoked potentials (SEPs), transcranial magnetic stimulation (TMS), nocturnal videopolysomnography, and multiple sleep latency test. The authors analyzed 100 consecutive PLMS for each patient to determine how frequently each muscle was involved in the PLMS; how frequently EMG activity started in a given muscle; and the time delay and pattern of activation between the first and the other activated muscles. Results: EMG-CV, SEPs, and TMS findings were all normal; in PLMS, leg muscles were those more frequently involved, often with alternation of side. Axial muscles were rarely and upper limb muscles sometimes involved. The tibialis anterior was the most frequent starting muscle. There was no constant recruitment pattern from one PLMS episode to another, even in the same patient. There was no ordinate caudal or rostral spread of the EMG activity. Conclusion: The recruitment pattern indicates the engagement of different, independent, and sometimes unsynchronized generators for each PLMS. The authors hypothesize an abnormal hyperexcitability along the entire spinal cord, especially its lumbosacral and cervical segments, as the primary cause of PLMS, triggered by sleep-related factors located at a supraspinal but still unresolved level.

Kufs Disease, the Major Adult Form of Neuronal Ceroid Lipofuscinosis, Caused by Mutations in CLN6

The molecular basis of Kufs disease is unknown, whereas a series of genes accounting for most of the childhood-onset forms of neuronal ceroid lipofuscinosis (NCL) have been identified. Diagnosis of Kufs disease is difficult because the characteristic lipopigment is largely confined to neurons and can require a brain biopsy or autopsy for final diagnosis. We mapped four families with Kufs disease for whom there was good evidence of autosomal-recessive inheritance and found two peaks on chromosome 15. Three of the families were affected by Kufs type A disease and presented with progressive myoclonus epilepsy, and one was affected by type B (presenting with dementia and motor system dysfunction). Sequencing of a candidate gene in one peak shared by all four families identified no mutations, but sequencing of CLN6, found in the second peak and shared by only the three families affected by Kufs type A disease, revealed pathogenic mutations in all three families. We subsequently sequenced CLN6 in eight other families, three of which were affected by recessive Kufs type A disease. Mutations in both CLN6 alleles were found in the three type A cases and in one family affected by unclassified Kufs disease. Mutations in CLN6 are the major cause of recessive Kufs type A disease. The phenotypic differences between variant late-infantile NCL, previously found to be caused by CLN6, and Kufs type A disease are striking; there is a much later age at onset and lack of visual involvement in the latter. Sequencing of CLN6 will provide a simple diagnostic strategy in this disorder, in which definitive identification usually requires invasive biopsy.

The system epilepsies: a pathophysiological hypothesis.

We postulate that “system epilepsies” (SystE) are due to an enduring propensity to generate seizures of functionally characterized brain systems. Data supporting this hypothesis—that some types of epilepsy depend on the dysfunction of specific neural systems—are reviewed. The SystE hypothesis may drive pathophysiologic and clinical studies that can advance our understanding of epilepsies and can open up new therapeutic perspectives.

Facial emotion recognition impairment in chronic temporal lobe epilepsy.

Purpose:  To evaluate facial emotion recognition (FER) in a cohort of 176 patients with chronic temporal lobe epilepsy (TLE).

Impaired fear processing in right mesial temporal sclerosis: a fMRI study

Lesion and neuroimaging studies have demonstrated that the mesial temporal lobe is crucial for recognizing emotions from facial expressions. In humans, bilateral amygdala damage is followed by impaired recognition of facial expressions of fear. To evaluate the influence of unilateral mesial temporal lobe damage we examined recognition of facial expressions and functional magnetic resonance (fMRI) brain activation associated with incidental processing of fearful faces in thirteen mesial temporal lobe epilepsy (MTLE) patients (eight with right MTLE, five with left MTLE). We also examined the effect of early versus later damage, comparing subjects with hippocampal-amygdalar sclerosis (MTS) and seizures occurring before five years of age to epilepsy patients with late onset seizures. Fourteen healthy volunteers participated as controls. Neuropsychological testing demonstrated that the ability of right MTLE patients to recognize fearful facial expressions is impaired. Patients with early onset of seizures were the most severely impaired. This deficit was associated with defective activation of a neural network involved in the processing of fearful expressions, which in controls and left MTLE included the left inferior frontal cortex and several occipito-temporal structures of both hemispheres.

Increased cortical BOLD signal anticipates generalized spike and wave discharges in adolescents and adults with idiopathic generalized epilepsies

Purpose:  Electroencephalography–functional magnetic resonance imaging (EEG‐fMRI) coregistration has recently revealed that several brain structures are involved in generalized spike and wave discharges (GSWDs) in idiopathic generalized epilepsies (IGEs). In particular, deactivations and activations have been observed within the so‐called brain default mode network (DMN) and thalamus, respectively. In the present study we analyzed the dynamic time course of blood oxygen level–dependent (BOLD) changes preceding and following 3 Hz GSWDs in a group of adolescent and adult patients with IGE who presented with absence seizures (AS). Our aim was to evaluate cortical BOLD changes before, during, and after GSWD onset.

Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy.

Focal epilepsies are the most common form observed and have not generally been considered to be genetic in origin. Recently, we identified mutations in DEPDC5 as a cause of familial focal epilepsy. In this study, we investigated whether mutations in the mammalian target of rapamycin (mTOR) regulators, NPRL2 and NPRL3, also contribute to cases of focal epilepsy.