Idiopathic Generalized Epilepsy Clinical Trial
Official title:
Dopaminergic Reactivity In Idiopathic Generalized Epilepsy: A "Proof Of Concept" Clinical, Pharmacological And Neurophysiological Study
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.
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Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Basic Science
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