Blinking and Yawning in Epilepsy: The Role of Dopamine
Condition: Idiopathic Generalized Epilepsy
MeSH terms: Epilepsy; Epilepsy, Generalized
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Apomorphine (Experimental product)
Intervention type(s): Other
Intervention description(s): Dosage Form: Injection Dosage: 1 or 5 mg / kg
Route of administration: Subcutaneous
Duration of treatment: two injections of apomorphine followed by two injections of a placebo one week after or vice versa.
Two injections will be made by visiting during visits 2 and 3.
The study was conducted cross-over with two visits EEG recording, the order will be randomized injections:
Sequence A during visit 2 followed by sequence B during visit 3
or sequence B during visit 2
Intervention MeSH terms: Apomorphine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: Epilepsy,; dopamine; yawning,; blinking eyelids,; electroencephalography