Blinking and Yawning in Epilepsy: The Role of Dopamine
Blinking and Yawning in Epilepsy: The Role of Dopamine
The objective of the present study is to assess dopaminergic reactivity with behavioural
 markers (i.e. yawning and blinking) in patients with idiopathic generalized epilepsy compared
 to matched healthy controls, after injection of either low dose of apomorphine or placebo.

 Other parameters will be recorded: biochemical (prolactin, GH) and neurophysiological
 (Spike-Waves Discharge: SWD rating). Safety parameters will be recorded to assess tolerance.
Clinical data regarding the effects of dopaminergic drugs in idiopathic generalized
 epilepsies are scarce. The general observation that antipsychotic agents (dopaminergic
 antagonists) worsen seizures, has suggested that dopaminergic agonists would have
 antiepileptic effects. However, this has never been clearly demonstrated, besides in few
 limited studies (Mervaala, 1990 ; Quesney, 1980, 1981). More recently, Positron Emission
 Tomography (PET) investigations using dopaminergic markers (Fluoro-Dopa, SCH23390, DAT) have
 shown dopaminergic deficits in several epileptic syndromes: ring chromosome 20 syndrome
 (Biraben 2004), juvenile myoclonic epilepsy (Ciumas 2008), temporal lobe epilepsy (Bouilleret
 2008), frontal lobe epilepsy (Fedi 2008). These data give rise to a renewal of interest for
 the involvement of the dopaminergic neurotransmission in epilepsies. Based on our
 experimental data from animal studies (see Deransart and Depaulis, 2002), the investigators
 propose an original study investigating the involvement of the dopaminergic system in
 idiopathic generalized epilepsies using behavioural as well as neurophysiological markers of
 the dopaminergic response, in conditions where seizing activities in patients are facilitated
 (EEG follow-up after sleep deprivation). This approach is based on the concept developed in
 our laboratory concerning the involvement of the basal ganglia, and more precisely the
 dopaminergic pathways, in the control of spike-wave discharges in idiopathic generalized
 epilepsies.

 The primary objective is to assess dopaminergic reactivity using a behavioural marker (i.e.
 yawning) in patients with idiopathic generalized epilepsy compared to matched healthy
 controls after injection of either low dose of apomorphine or placebo. Other parameters will
 be recorded as secondary outcomes: behavioural (blinking), biochemical (prolactin, GH) and
 neurophysiological (Spike-Waves Discharge: SWD rating) markers. Safety parameters will be
 recorded to assess tolerance.

 Experimental data: hyperdopaminergic response in a model of absence-epilepsy in the rat.
 Since the late 80's, our laboratory has demonstrated the existence of an endogenous neural
 mechanism that controls the occurrence of epileptic seizures in different animal models, a
 system based on the hypothesis that the basal ganglia modulate the synchronisation of
 epileptic rhythmic activities (Depaulis 1994). The studies performed in GAERS (Genetic
 Absence Epilepsy Rats from Strasbourg, a validated model of absence-epilepsy in rat) have
 shown that inhibition of the main output structure of basal ganglia (i.e., the substantia
 nigra pars reticulata) had antiepileptic effects (Depaulis 1994; Deransart 1996). Similarly,
 deep brain stimulation of the substantia nigra pars reticulata as well as of the subthalamic
 nucleus interrupts seizures (Vercueil 1998; Feddersen 2007). Systemic and intrastriatal
 dopamimetics injections in GAERS also suppress seizures, whereas antagonists worsen them
 (Warter et al, 1988; Deransart et al., 2000). Electrophysiological data showed respectively
 decreased and increased activity of DA neurons during and at the end of absence-seizures
 (Lücking et al. 2002). An increase in D3 receptor transcripts was also observed in adult
 GAERS as compared to inbred non epileptic control rats (NEC), within the ventral striatum
 (Deransart et al. 2001). These data suggest changes in the DA tone in GAERS with fully
 developed epileptic phenotype. According to the key role of DA D3 neurotransmission in the
 foetal cortical development (Levant B, 1995) and modulation of DA tone (Nissbrandt et al.,
 1995; Gilbert et al., 1995; Kreiss et al., 1995), the researchers investigated whether the
 putative impaired DA tone in GAERS correlates with functional changes in spontaneous and
 quinpirole-induced yawning behaviour (Kurashima et al. 1995; Collins et al.2005). The
 hypothesis of an increased dopaminergic tone in GAERS was thus addressed using pharmacology
 and microdialysis. In GAERS and NEC (i) spontaneous and quinpirole-induced yawning behaviour
 and (ii) changes in intra-accumbens dopamine contents induced by amphetamine and K+ and
 measured by microdialysis were investigated. Spontaneous yawning was significantly decreased
 in GAERS (0.3±0.2 yawn/hr, n=9) as compared to NEC (5.4±1.2, n=8) and Wistar Harlan rats
 (9.7±2.3, n=7). Quinpirole-induced yawning was significantly increased in GAERS (29.4±4.9) as
 compared to NEC (10.5±2.7) and Wistar-Harlan rats (22.6±3.5). Quinpirole also increased the
 number of absence-seizures in GAERS (+47.4±8.6%). When compared to NEC, basal levels of DA
 were 40% lower in GAERS whereas amphetamine and K+ produced a higher increase in
 extracellular dopamine in GAERS. The increased quinpirole-induced yawning in GAERS may
 account for an overexpression in D3 transcripts. The increased responsiveness of dopamine
 transmission observed in GAERS after pharmacological manipulations, as compared to NEC,
 suggests a " hyperdopaminergic " phenotype of GAERS. Altogether, these data support that
 GAERS have an impaired DA tone that may be associated with the development of mechanisms
 controlling absences seizures (Deransart et al, in preparation).

 Altogether, these data suggest that a phasic involvement (" on request ") of the basal
 ganglia - notably under the influence of the dopaminergic neurotransmission - may underlie
 the rapid changes in extracellular activity recorded in output structures of the basal
 ganglia at the end of seizures in this model (Deransart 2003). Such a phasic functioning of
 the dopaminergic system in the control of seizures could also reconcile with the apparent
 discrepancy regarding the fact that seizures appear to escape chronic high-frequency
 stimulations of the substantia nigra (Feddersen 2007). These data strengthen the need for a
 re-appraisal of clinical approaches, especially based from a dynamic point of view regarding
 the involvement of the dopaminergic system in epilepsy.

 Clinical data:

 -  Involvement of the dopaminergic system in idiopathic generalized epilepsies. Exposure to
 dopaminergic antagonists, like antipsychotic drugs, increases the risk for the patients
 to display epileptic seizures. The mechanism by which these treatments may lead to such
 an aggravation remains unknown and, up to date, there is no pharmacological strategy to
 decrease such a risk. Recent data suggested the involvement of the dopaminergic pathways
 in several epileptic syndromes: a significant homogeneous decrease in striatal dopamine
 uptake has been shown using PET in patients with epileptic seizures associated with ring
 chromosome 20 mosaicism (Biraben, 2004). In this epileptic syndrome, patients display
 prolonged seizures, reminiscent of an absence status epilepticus. A similar study, using
 a marker for the dopamine transporter, recently reported a decrease in dopamine
 re-uptake at the level of the substantia nigra in patients with idiopathic generalized
 epilepsies (Ciumas, 2008). These data differ from what is observed in neurodegenerative
 pathologies involving the dopaminergic system (e.g., Parkinson disease) where imaging
 studies of the dopaminergic transmission show a decrease in synaptic terminals linked to
 a progressive degenerative process. Data from epileptic patients rather suggest a
 modulation of the expression of some dopaminergic receptors as well as dynamic changes
 in the synaptic transmission. In line with our experimental data and the recently
 published neuroimaging studies, the investigators propose that the reactivity of the
 dopaminergic system displays special features specific to epileptic patients and may
 constitute a risk-level marker for epileptic seizures. The conceptual framework of the
 proposed translationnal study lies on the dynamic involvement of the dopaminergic system
 and the assessment of its reactivity in epileptic patients.

 -  Reactivity of the dopaminergic system in idiopathic generalized epilepsies. Low doses of
 apomorphine, a dopaminergic agonist, induce yawning and palpebral winking in healthy
 subjects (Blin, 1990). Similarly, higher therapeutic doses induce yawning immediately
 before therapeutic effect in patients with Parkinson's disease. These data suggest that
 higher affinity of apomorphine to presynaptic receptor could be involved in promoting
 yawning and blinking. The study of dopaminergic system response to low doses of
 apomorphine, below the side-effects threshold (nausea, vomiting, hypotension) represent
 an original, well-tolerated approach in both patients with epilepsy and healthy
 subjects. Similar studies have already been published in patients with migraine (Cerbo,
 1997) and cocaine users (Colzato, 2008) in order to study dopaminergic reactivity in
 selected populations. The investigators propose to study dopaminergic reactivity in
 patients with idiopathic generalized epilepsy compared to matched healthy volunteers,
 during prolonged EEG after sleep-deprivation, using apomorphine doses of 1 µg/kg and 5
 µg/kg. Indeed, apomorphine 0.5 to 2 µg/kg increased spontaneous blinking rate and
 yawning in healthy volunteers (Blin, 1990). However, a 10 µg/kg dose induced symptoms
 such as nausea, vomiting, sweating and dizziness in migraineurs (Cerbo, 1997). The study
 will focus on behaviour (spontaneous and apomorphine-induced yawning and blinking) and
 EEG (spontaneous and apomorphine induced SWD) as compared to placebo. Prolactin and GH
 dosing after apomorphine injection will provide a biochemical validation of dopaminergic
 stimulating effect. Indeed, prolactin secretion is inhibited by dopamine from the
 hypothalamus, while Growth hormone (GH) is stimulated. Thus, a decrease in prolactin and
 an increase in GH reflect central dopamine availability. Dosing prolactin and GH
 response to apomorphine subcutaneous injection represents a way to document the synaptic
 effects of the drug, as previously described (Aymard, 2003; Friess, 2001).

 This project arises from concepts developed in our laboratory from experimental data obtained
 in an animal model of epilepsy and from recent clinical data from the literature. It aims at
 improving understanding of dopaminergic transmission dynamics in patients with epilepsy. It
 could therefore promote the emergence of new markers of susceptibility to epileptic seizures
 and constitute an opportunity to develop new pharmacological approaches based on dopaminergic
 neuromodulation.
Inclusion Criteria:

 For patients:

 -  Men and women aged between 18 and 40

 -  Person affiliated to social security or beneficiary of such a regime

 -  idiopathic generalized epilepsy treated with lamotrigine, an association of
 lamotrigine, topiramate, levetiracetam, lamotrigine or levetiracetam alone (group
 patients) for at least 14 days without changing doses The idiopathic generalized
 epilepsy is defined by generalized seizures: generalized tonic-clonic seizures,
 absences or myoclonic seizures, excluding any other type of seizure, and
 electroencephalographic appearance following: presence of interictal EEG discharge
 generalized to type of spikes, spike-wave or wave polyspikes generalized, sporadic or
 rhythmic> or = 3 Hz background activity is normal.

 For healthy volunteers:

 -  Men and women aged between 18 and 40

 -  Person affiliated to social security or beneficiary of such a regime

 Exclusion Criteria:

 -  Topic wrongly included

 -  Deflecting protocol that can skew the primary endpoint

 -  Primary endpoint missing

 -  If the investigator considers the health of the subject is incompatible with the
 continuation of the study.

 Criteria for non-inclusion

 -  For patients:

 -  The presence of interictal focal discharges on EEG previous

 -  The emergence of partial seizures

 -  Restless Leg Syndrome

 -  All non-antiepileptic treatment may affect levels of dopamine

 -  Current use of illicit drugs.

 -  A person deprived of liberty by judicial or administrative person being a measure
 of legal protection.

 -  Pregnant, parturient, lactating mother.

 -  For women, lack of effective contraception

 -  For healthy volunteers:

 -  Any medical treatment associated

 -  Current use of illicit drugs

 -  Pregnant, parturient, lactating mother

 -  For women, lack of effective contraception

 -  A person deprived of liberty by judicial or administrative person being a measure
 of legal protection.