O. Mameli

Neurogenic myocardial arrhythmias in experimental focal epilepsy

Summary: The potential for cardiac arrhythmia was studied in an experimental focal epilepsy induced in hemispherectomized rats by topical application of buffered penicillin G onto the thalamus. The epileptic burst triggered cardiac and hemodynamic responses, as simultaneously monitored by arterial pressure, and hypothalamic and heart activity. During interictal epileptic activity, the single burst triggered a short‐latency cardiac arrhythmia, characterized by sinus bradyarrhythmia and junctional rhythm, and lengthening of intervals between sphygmic waves with significant reduction of diastolic pressure. When the epileptic burst stopped, the cardiac activity resumed normal rhythm, and diastolic pressure returned to basal value. During ictal epileptic activity, the sinus and junctional bradyarrhythmic episodes lasted longer, and supraventricular extrasystoles, sinus arrest, and bigeminal ventricular extrasystoles were observed. Both systolic and diastolic pressures decreased from 120/85 to 100/65 mm Hg. The end of the ictal episode always marked resumption of normal cardiac rhythm and systemic pressure. Considering the absence of metabolic complications (blood‐gas analytic parameters and acid‐base balance being controlled) and the short latency of the cardiac and hemodynamic responses, it is suggested that during paroxysmal hypothalamic activity the observed cardiac arrhythmias and the hemodynamic modifications were neurogenic in origin. A role for cardiovascular alterations in sudden unexplained epileptic death is postulated.

Sudden death in epilepsy: An experimental animal model

INTRODUCTION The physiopathogenetic mechanisms possibly involved in sudden unexplained epileptic death (SUDEP), were investigated in the hemispherectomized rat. METHODS For this purpose, paroxysmal activity, vagal nerve firing, systemic blood pressure (BP), pulmonary artery pressure, and ECG were simultaneously recorded in an experimental animal model of epilepsy. Recordings were performed in basal conditions and during paroxysmal activity induced by topical application of penicillin-G at hypothalamic and mesencephalic level. During the experiment were also performed hemogas analysis and at end, samples of lung tissue were processed for histology. RESULTS Activation of hypothalamic (HEF) and mesencephalic (MEF) epileptic foci induced a significant increase of spontaneous vagal nerve firing that was strictly correlated to ECG impairments and hypotension. When paroxysmal activity extinguished, vagal nerve activity and cardiovascular parameters returned to basal conditions. However, in 25% of the animals, co-activation of HEF and MEF always triggered a vagal hypertone which was temporally correlated to cardiac arrhythmias, but also to hyperkalemia, acidosis, pulmonary hypertension and to animal death. Histological control in lungs of deceased animals showed an alveolar and perivessel oedema with an oedematous infiltration in the alveolar and bronchial spaces and mucous secretion. During ictal activity, comparison between survived and deceased animals showed significant differences in the incidence of ECG impairment of pulmonary artery pressures, pO2, and pCO2 pressures, and [K+], [HCO3-], and [pH], concentrations. DISCUSSION A possible explanation of the above observations is discussed in relationship to SUDEP physiopathogenesis.

The brainstem cardioarrhythmogenic triggers and their possible role in sudden epileptic death.

The cardiovascular effects of simultaneous activation of hypothalamic and mesencephalic cardioarrhythmogenic triggers were studied in hemispherectomized rats. Paroxysmal activity of hypothalamic neurons (HEF), elicited by topical application of penicillin G on the thalamus, triggered short-lasting bradyarrhythmic episodes, up to a maximum of 6 s, and alterations in repolarization. In the hypothalamic neurons, an additional penicillin G epileptic focus at mesencephalic level (MEF) induced the enhancement of paroxysmal activity by a recruitment of new units and potentiation of their background activity. HEF+MEF triggered second-degree 2:1-8:1 atrioventricular (A-V) blocks, impairment of the A-V conduction, alterations in the recovery phase and bundle branch blocks. After HEF, the arterial blood pressure decreased by 4-6%. HEF+MEF induced a further reduction of 17% in systolic pressure only. It is possible that the enhancement of the HEF following MEF could depend on MEF spreading upward. The HEF, in turn, by spreading downward could influence the MEF and so activate, between HEF and MEF, a circuitry with reciprocal co-excitation that could explain the more serious cardiovascular alterations observed during HEF+MEF compared with those observed during HEF only or during MEF only. However, this cardiovascular impairment, which must be neurogenic in origin as it was observed in animals with normal acid-base and blood parameter values, did not induce heart death. Thus, additional concomitances must be considered, such as metabolic derangement which can occur during seizures, to explain sudden death in epileptic patients. Some aspects of metabolic complications in cardiac activity during epilepsy are also discussed.

Autonomic nervous system activity and life threatening arrhythmias in experimental epilepsy

In the present study the possible derangement of the autonomic system and its influence in life threatening arrhythmias were analysed during paroxysmal activity. In hemispherectomized rats a paroxysmal activation of the hypothalamic and mesencephalic cardioarrhythmogenic triggers was performed by topical application of penicillin-G. Blood gas parameters and electrical activity of the thalamus, hypothalamus, vagal nerve fibre, ECG and arterial blood pressure were simultaneously monitored in basal conditions and repeated after the appearance of paroxysmal activity. Temporal correlation analysis was carried out. Results showed that during activation of these triggers, the spontaneous vagal nerve fibre activity significantly increased and triggered the appearance of cardiac arrhythmias which could become life threatening and induce animal death when blood gas and electrolytic parameters were simultaneously impaired. These experiments suggest that fatal evolution of the heart impairment is related not only to an autonomic cardiac trigger, but also to a concomitant metabolic derangement, which most likely shares the same autonomic origin.

Neurotoxic effect of lead at low concentrations

The effects of lead exposure at low concentrations were evaluated by studying the post-rotatory nystagmus (PRN) in two groups of rats exposed for 3 months to 50 parts per million (ppm) of sodium acetate and 50 ppm of lead acetate, respectively, in the drinking water. Only animals treated with lead acetate showed changes of the PRN parameters which were significantly related to the concentration of lead in the blood and in brain structures. The patterns of PRN responses were characterized and classified into four types: progressively inhibitory (40%), prematurely inhibitory (25%), late inhibitory (25%), and excitatory-inhibitory (10%). No alterations of the PRN parameters were observed in the animals treated with sodium acetate. The results show that exposure to lead, even at low concentrations, impairs both sensory and motor functions. The findings also point out that the vestibular system and brain stem structures which generate and control the PRN represent targets of the action of this heavy metal. Finally, the results indicate that the evaluation of the vestibulo-ocular-reflex can provide a test suited for the screening of the neurotoxic effects of lead even in the absence of clinical signs typical of lead intoxication.

Vestibular ampullar modulation of hypoglossal neurons

This paper describes preliminary observations on vestibular ampullar involvement in the control mechanism of the hypoglossal nucleus activity. Thermic stimulation of the labyrinth, performed by irrigating the external auditory meatus with cold water (20 degrees C), significantly modified the spontaneous electrical activity of hypoglossal neurons localized in the medio-caudal part of the nucleus. Tonic spontaneous discharge of the units following labyrinthine stimulation was modified into a phasic activity and bursts with multi-unit recruitment appeared. This modified activity was observed during 5-6 minutes after the onset of ear irrigation. Similar response patterns, but with shorter duration, were recorded following contralateral stimulation of the labyrinth. These results show that hypoglossal neurons are triggered by the vestibular system following dynamic conditions in response to every spatial head displacement.

Labyrinthine projection to the hypoglossal nucleus

Evoked potentials and responses of single hypoglossal neurons were recorded in response to electrical stimulation of the labyrinth. In addition, the spontaneous electrical activity of hypoglossal neurons was significantly modified in response to ipsi- and contralateral static tilt of the whole animal and thermic stimulation of the labyrinth. The experiment showed that the labyrinth modulates the electrical activity of hypoglossal neurons with phasic inputs in response to ampullar stimulation and with tonic inputs in response to macular stimulation. The vestibular phasic influence of hypoglossal neurons represents the most adequate functional pattern to obtain a quick, short lasting response of the tongue muscles instantly modifiable with every abrupt head displacement. On the contrary, the vestibular tonic influence of hypoglossal neurons represents the most adequate functional pattern to obtain not only adjustment but also maintenance of the muscular lingual response to static displacement of the head.

Improvement of Vestibular Plasticity in the Guinea Pig with a Calcium Entry Blocker

The influence of flunarizine on vestibular compensation was investigated in hemilabyrinthectomized guinea pigs. The results showed that the vestibular deficits from hemilabyrinthectomy disappeared more rapidly in the treated animals than in the controls. To elucidate the mechanism by which the drug could affect the compensatory process, further studies on the spontaneous and evoked activity of vestibular nuclei were performed in normal, labyrinthectomized and labyrinthectomized-cerebellectomized animals. These electrophysiological data implied that flunarizine improved the vestibular compensation by inhibiting the receptor and nuclear activities of the intact labyrinth. The drug excited the cerebellar cortex, which modulated the activity of the vestibular nuclei of both sides, restoring the balance disrupted by hemilabyrinthectomy.

Visual input to the hypoglossal nucleus

Photic stimulation of the retina elicits in the mediocaudal part of the XIIth nucleus the appearance of pronounced field potentials and responses of single hypoglossal units. The latency of the evoked potentials, characterized by a complex sequence of positive-negative waves, was 32.75 +/- 2.5 ms for the initial component p1, 42.25 +/- 3.30 ms for n1, 49.75 +/- 3.09 ms for p2, and 67 +/- 3.94 ms for n2. The hypoglossal neurons, antidromically identified by electrical stimulation of the XIIth nerve, responded with several combinations of excitation-inhibition at various latencies. Nineteen percent of the units responded to both retinae and 10% only to one retina, mainly to the contralateral one. As the mediocaudal part of the hypoglossal nucleus receives vestibular information, it can be concluded that the hypoglossal units adjust their firing in relation to head position and also by using visual information.

Focal and secondarily generalised convulsive status epilepticus induced by thiocolchicoside in the rat

The objective of this study was to document the convulsant properties of thiocolchicoside in rats, and to characterise the electroclinical pattern of epileptic seizures. Experiments were carried out in three groups of male Wistar rats: in group A, thiocolchicoside was applied topically to the pia, or given by microinjection to the cerebral cortex (2 microg/microl); in group B, the drug was administered parenterally (6 mg/kg) to rats with minimal lesions of the dura and arachnoid membranes; in group C, thiocolchicoside was administered parenterally (up to 12 mg/kg) to intact rats. In all animals, electroclinical activity was continuously monitored for at least 3 hours after thiocolchicoside injection or application. In group A, electrographic and behavioural activity of focal motor seizures occurred in 100% of animals, developing into a focal status epilepticus; in group B, a multifocal epileptic pattern with secondary generalisation, clinically characterised by clonic or tonic-clonic seizures occurred in 100% of animals, until a secondarily generalised convulsive status epilepticus; in group C, none of animals showed either electrographic or behavioural seizure activity. Our study documents that thiocolchicoside has a powerful convulsant activity in the rat, perhaps due to an antagonistic interaction of the compound with a cortical subtype of the GABA(A) receptor.