Chiara Pizzanelli

The role of norepinephrine in epilepsy: from the bench to the bedside.

This article provides a brief review of the role of norepinephrine (NE) in epilepsy, starting from early studies reproducing the kindling model in NE-lesioned rats, through the use of specific ligands for adrenergic receptors in experimental models of epilepsy, up to recent advances obtained by using transgenic and knock-out mice for specific genes expressed in the NE system. Data obtained from multiple experimental models converge to demonstrate the antiepileptic role of endogenous NE. This effect predominantly consists in counteracting the development of an epileptic circuit (such as in the kindling model) rather than increasing the epileptic threshold. This suggests that NE activity is critical in modifying epilepsy-induced neuronal changes especially on the limbic system. These data encompass from experimental models to clinical applications as recently evidenced by the need of an intact NE innervation for the antiepileptic mechanisms of vagal nerve stimulation (VNS) in patients suffering from refractory epilepsy. Finally, recent data demonstrate that NE loss increases neuronal damage following focally induced limbic status epilepticus, confirming a protective effect of brain NE, which has already been shown in other neurological disorders.

Citalopram as treatment of depression in patients with epilepsy.

Objectives:To assess the safety of citalopram as a treatment of depression in patients with epilepsy. Methods:This is an open, multicentered, uncontrolled study. Depressed epileptic patients on antiepileptic drugs (AEDs) took part in the study. Patients who had a mild frequency of seizures in the 4 previous months underwent treatment with citalopram (20 mg/d) for 4 consecutive months. A change in seizure frequency from the baseline was chosen as the primary measure for the safety of citalopram and efficacy against depressive symptoms was taken as secondary measure. Depression was rated using the Montgomery–Åsberg and Zung depression rating scales. Clinical assessments were performed at baseline, and at 2 and 4 months of citalopram therapy. Results:Forty-five patients were enrolled. Six patients dropped out of the study early: none of them because of a deterioration of seizure frequency. An overall improvement in seizure frequency was observed in the 39 patients who completed the study. Plasma AED concentrations were unchanged during therapy, and depressive symptoms improved markedly. Twenty-two patients complained of adverse effects, mainly headache, nausea, dizziness, somnolence, and fatigue. Conclusions:In this open, multicentered, uncontrolled study, 4 months’ of treatment with citalopram (20 mg/d) were associated with an improvement in depressive symptoms and reduction in seizure frequency.

The chemical neuroanatomy of vagus nerve stimulation

In this short overview a reappraisal of the anatomical connections of vagal afferents is reported. The manuscript moves from classic neuroanatomy to review details of vagus nerve anatomy which are now becoming more and more relevant for clinical outcomes (i.e. the therapeutic use of vagus nerve stimulation). In drawing such an updated odology of central vagal connections the anatomical basis subserving the neurochemical effects of vagal stimulation are addressed. In detail, apart from the thalamic projection of central vagal afferents, the monoaminergic systems appear to play a pivotal role. Stemming from the chemical neuroanatomy of monoamines such as serotonin and norepinephrine the widespread effects of vagal stimulation on cerebral cortical activity are better elucidated. This refers both to the antiepileptic effects and most recently to the beneficial effects of vagal stimulation in mood and cognitive disorders.

A damage to locus coeruleus neurons converts sporadic seizures into self-sustaining limbic status epilepticus

Various studies demonstrated that the neurotransmitter norepinephrine (NE) plays a relevant role in modulating seizures; in particular, a powerful effect consists in delaying the kindling of limbic areas such as the amygdala and hippocampus. Given the rich NE innervation of limbic regions, we selected a sensitive trigger area, the anterior piriform cortex, to test whether previous loss of noradrenergic terminals modifies sporadic seizures in rats. The damage to locus coeruleus terminals was produced by using the selective neurotoxin N‐(‐2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (DSP‐4, 60 mg/kg i.p.). In intact rats, bicuculline (a GABA‐A antagonist, 118 pmol) microinfused into this area produced sporadic seizures, while in rats previously injected with DSP‐4, bicuculline determined long‐lasting self‐sustaining status epilepticus. In intact rats, sporadic seizures were accompanied by a marked increase in norepinephrine release in the contralateral piriform cortex, while in locus coeruleus‐lesioned rats this phenomenon was attenuated. While bicuculline‐induced sporadic seizures were prevented by the focal infusion of amino‐7‐phosphonoheptanoic acid (AP‐7, a selective NMDA antagonist), or 1,2,3,4‐tetrahydro‐6‐nitro‐2,3‐dioxo‐benzo[f]quinoxaline‐7‐sulphonamide (NBQX, a selective non‐NMDA antagonist), status epilepticus obtained in norepinephrine‐lesioned rats was insensitive to AP‐7 but was still inhibited by NBQX. By using fluorescent staining for damaged (Fluoro‐Jade B) and intact (DAPI) neurons, as well as cresyl violet, we found that rats undergoing status epilepticus developed neuronal loss in various limbic regions. This study demonstrates a powerful effect of noradrenergic terminals in regulating the onset of limbic status epilepticus and its sensitivity to specific glutamate antagonists.

Analysis of RR variability in drug-resistant epilepsy patients chronically treated with vagus nerve stimulation

Vagus nerve stimulation (VNS) has been suggested as an adjunctive treatment for drug-resistant epilepsy when surgery is inadvisable. The overall safety profile of VNS seems to be favorable as only minor adverse effects have been described. The purpose of this study was to determine if cardiac vagal tone is eventually modified by short- and long-term VNS. The effects of short- and long-term VNS were evaluated in seven subjects with intractable epilepsy. Autonomic cardiac function has been carried out by means of a 24-h analysis of RR variability at baseline (t(0)), 1 month (t(1), short-term VNS) and 36 months after VNS initiation (t(2), long-term VNS). Frequency- and time-domain parameters were calculated. Periodic cardiological and neurological evaluations were performed.Clinically relevant cardiac effects were not observed throughout the study. Despite the limited number of patients and the variety of data among them, for all the patients, a common trend towards a nocturnal decrease in the high-frequency (HF) component of the spectrum was observed after long-term VNS (mean+/-S.D.: 40+/-18 normalized units (nu) at t(0), 38+/-17 nu at t(1), 18+/-10 nu at t(2); p<0.05 of t(2) vs. either t(0) or t(1)). The day-to-night changes in the power of low-frequency (LF) and HF components were significantly blunted after long-term VNS (LF day-to-night change: +16+/-13 nu at t(0) and +15+/-8 nu at t(1) vs. +3+/-13 nu at t(2), p<0.02; HF day-to-night change: -18+/-13 nu at t(0) and -13+/-11 nu at t(1) vs. +3+/-12 nu at t(2), p<0.003). No significant changes were observed with regard to the time-domain parameters of the heart rate variability. Throughout the neurological follow-up, one subject became seizure-free, three experienced a seizure reduction of >50%, two patients of <50% and one had no changes in his seizure frequency. Our findings suggest that long-term VNS might slightly affect cardiac autonomic function with a reduction of the HF component of the spectrum during night and a flattening of sympathovagal circadian changes, not inducing, however, clinically relevant cardiac side effects.

Daytime Sleepiness in Epilepsy Patients Receiving Topiramate Monotherapy

Summary:  Purpose: Limited research has focused to date on objective neurophysiological evaluation of daytime sleepiness in patients treated with newer antiepileptic drugs (AEDs), especially when used as monotherapy. This study was aimed at assessing occurrence of daytime sleepiness in newly diagnosed, drug‐naïve patients with partial epilepsy receiving initial topiramate (TPM) monotherapy.

Antimyoclonic effect of levetiracetam in MERRF syndrome

The treatment of progressive myoclonic epilepsy (PME) is largely empirical, even though valproic acid (VPA) is usually considered the drug of first choice. However, VPA should be used with caution in PME due to mitochondrial dysfunction, i.e. in MERRF (myoclonic epilepsy with ragged red fibers) syndrome, because of its interaction with mitochondrial respiration and metabolism. Levetiracetam (LEV) treatment was started in combination with VPA in a patient with typical clinical, histological, and biochemical features of MERRF due to a mutation on the tRNA of Phenilalanine gene. The average myoclonus score improved dramatically, as well as the quality of life and no side effects were observed, even after having withdrawn VPA. LEV may benefit myoclonus in PME of mitochondrial origin without altering mitochondrial function, and it could be considered the drug of first choice for the treatment of myoclonus in MERRF.

Circulating levels of allopregnanolone, an anticonvulsant metabolite of progesterone, in women with partial epilepsy in the postcritical phase.

Summary:  Purpose: Several lines of evidence indicate that there exists a relation between ovarian hormones and epilepsy. Estrogens decrease seizure threshold and increase brain excitability, whereas progesterone has an inhibitory effect and reduces epileptiform activity. Recently considerable interest has turned to neuroactive steroids, a group of progesterone metabolites, as endogenous modulators of excitability of the central nervous system (CNS). Their ability to alter neuronal firing rapidly occurs through interaction with γ‐aminobutyric acid (GABA) A receptor complex. In a previous experience, serum allopregnanolone (3α‐OH‐5α‐pregnan‐20‐one) levels were measured in 15 women with partial epilepsy in the intercritical phase, and no significant differences were found between patients and control subjects.

Mismatch negativity analysis in drug-resistant epileptic patients implanted with vagus nerve stimulator

It is well known that some epileptic patients does not respond to conventional treatments, despite multiple combination of antiepileptic drugs, and they are therefore considered drug-resistant. For these patients, vagal nerve stimulation (VNS) represents a successful alternative to traditional therapy, and it is generally well tolerated; beside benefits on seizure frequency, VNS showed positive effects on cognition and mood. Aim of this study was to investigate short-term memory changes in a group of 12 patients implanted with VNS, through Mismatch Negativity wave (MMN). After 1 year of follow-up, MMN latencies and amplitudes did not show significant changes following VNS implantation, independently on current intensity, as compared with pre-implantation values. In two patients, MMN values, which were abnormal before VNS implantation, showed a major reduction in latency and an increase in amplitude after implantation, suggesting a likely positive effect of VNS on pre-attentive processes investigated by MMN.

Lack of α1b‐adrenergic receptor protects against epileptic seizures

Purpose:  The role of α1b‐adrenergic receptor (α1b‐AR) in relation with neuronal degeneration, drug addiction, and seizure susceptibility has recently emerged. In particular, mice that overexpress α1b‐AR undergo spontaneous epileptic seizures and progressive neuronal loss in a variety of brain areas. Therefore, one should expect that the blockade of α1b‐AR leads to anticonvulsant and neuroprotective effects. However, the lack of α1b‐AR antagonists does not allow testing of this hypothesis.