| Cardiovascular regulation in epilepsy with emphasis on the interictal state | ||
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In the present study, the values of cardiovascular reflex tests did not differ in patients with untreated recently diagnosed epilepsy from those of the control subjects. These patients had experienced at least two recent partial or generalized epileptic seizures and were otherwise healthy. However, in two patients, two measurements of cardiovascular reflex tests were outside the reference range, although they did not complain any symptoms of ANS dysfunction. This observation gives further evidence to the hypotheses that epilepsy related autonomic cardioregulatory dysfunction is associated with the chronic nature of epilepsy, with the possible modifying effect of long-lasting antiepileptic medication on the ANS function (Quint et al. 1990).
In the present study, patients with idiopathic generalized epilepsies had diminished values of SD of RR intervals, whereas patients with partial epilepsy showed decreased BP responses in isometric tests in cardiovascular reflex tests compared to the control subjects. Patients with idiopathic generalized epilepsies were mainly using VPA as an AED, whereas the majority of the patients with partial epilepsy had CBZ as their AED. Based on these results, it can be concluded that patients with idiopathic generalized epilepsies seem to have mild alterations of autonomic cardiovascular regulation, but these changes may be more subtle than in patients with partial epilepsies. This apparent yet conclusive difference between idiopathic generalized and partial epilepsies may be due to the different nature of the two epilepsy types but may also relate to differences in AED therapy (Quint et al. 1990, Devinsky et al. 1994, Tomson et al. 1998).
Cardiovascular dysfunction has previously been demonstrated in a small group of patients with progressive myoclonus epilepsy (Kälviäinen et al. 1990). The majority of these young progressive myoclonus epilepsy patients complained symptoms of ANS dysfunction and had diminished values of the max-min ratio of the cardiovascular reflex tests compared to their controls. However, progressive myoclonus epilepsy is a degenerative disease of the CNS different from any other epilepsy type, which makes the comparison of the results difficult. Autonomic dysfunction has been demonstrated in patients with JME using tradional analysis of HRV from 24-hour ECG-registration (Tomson et al.1998). In the same study, patients with TLE were also investigated, and altered autonomic control of the heart was more evident in TLE patients. Patients with JME were mainly on VPA therapy and patients with TLE were mainly on CBZ therapy. Patients with JME differed only little from the controls, showing reduced HF/LF ratio, suggesting decreased sympathetic, or alternatively an increased vagal tone, since LF oscillations are associated with negative feedback from the baroreflex arc mediated both by sympathetic and parasympathetic activity and HF power reflects respiratory sinus arrhythmia and is mainly related to parasympathetic activity (Tomson et al. 1998).
The major finding of the present study was that both cardiovascular reflexes and tonic autonomic cardiovascular regulation are altered in patients with partial epilepsy. There are few previous studies focusing on interictal ANS dysfunction in patients with partial epilepsy (Frysinger et al. 1993, Devinsky et al. 1994, Faustmann & Ganz 1994, Massetani et al. 1997, Tomson et al. 1998, Druschky et al. 2001). The methods and parameters used, as well as study designs, are different in these studies, and, therefore, the results are difficult to compare. To our knowledge, this is the first study to evaluate the association between altered HRV and the severity of TLE. Moreover, dynamic measures that are able to describe long term tonic oscillations of HRV have not been previously used to evaluate autonomic dysfunction in TLE. The present study agrees with the previous findings of abnormal HR regulation in patients with partial epilepsy and suggests that the degree of abnormality may not be related solely to the severity of TLE. Based on these results, it also seems that in addition to the conventional measures of HRV, new dynamic measures not related to means and variance are useful in detecting altered HR behavior in patients with TLE.
In cardiovascular reflex tests, the patients with partial epilepsy had diminished BP responses to isometric work, whereas patients with with well controlled TLE had decreased values of the 30:15 ratio compared to the control subjects. Refractory TLE, however, was associated with decreased values of SD of RR intervals and the 30:15 ratio compared to the control subjects. Although statistical significance was not reached when these different subgroups of patients were compared to each other, a uniform trend towards lower values of all parameters of cardiovascular reflex tests were detected in patients with refractory TLE, compared to the patients with well controlled TLE. However, the most significant finding was that both refractory and well controlled TLE seem to be associated with altered cardiovascular reflexes.
It is also noteworthy that clinically significant changes in cardiovascular reflexes were detected in two patients with well controlled and three patients with refractory TLE. Interestingly, four of these five patients were male. This raises the question whether epilepsy per se may be associated with altered function of the ANS, and whether male gender may predispose to the observed changes.
In the analysis of HRV, all parameters of the traditional and frequency domain measures were lower in patients with TLE compared to the control subjects. In addition, the slope of the power law and the values of dynamic measurements were decreased in TLE patients compared to the control subjects. Patients with refractory TLE had a lower value of ApEn from the dynamic measures compared to the patients with well controlled TLE, whereas the long term correlation value α2 of the fractal correlation properties was decreased in patients with well controlled TLE compared to that of refractory TLE patients. These broad changes of nearly all parameters of HRV together with the above mentioned altered values of cardiovascular reflex test suggest multidimensional affection of the ANS for TLE in particular.
The prognostic value of the changes in autonomic cardiovascular regulation in TLE is unknown. Cardiovascular reflex tests and traditional spectral measurements of the analysis of HRV have proved useful in determining autonomic regulatory dysfunction in various clinical conditions (Huikuri 1995c). Similar to our findings in TLE patients, altered autonomic cardiovascular function using cardiovascular reflex test and analysis of HRV has also been described in various cardiac diseases. Several studies have shown that reduced HRV is an independent risk factor for arrhythmic sudden death post myocardial infarction (Oppenheimer 1993, Bigger et al. 1996, Huikuri et al. 1996, Mäkikallio et al. 1997). A study on a large number of elderly people showed that the slope of the power-law relationship of HRV most strongly predicts cardiovascular mortality in a general population of elderly subjects (Huikuri et al. 1997). The slope of the power law is also especially deep in patients with denervated transplanted heart, suggesting abnormal postganglionic adrenergic innervation of the heart (Bigger et al. 1996). Therefore, it is possible that changes in these parameters may also predict the cardiovascular risk in patients with TLE. Furthermore, the steep power law relation slopes refers to the pathology of the sympathetic cardiac innervation.
The physiological and clinical applicability of fractal and complexity measures of HR dynamics are not yet completely understood, but they are suggested to reveal abnormal patterns of RR interval behavior that are not easily detected by commonly used moment statistics of HRV (Mäkikallio et al. 1996). Reduced ApEn indicates larger predictability in HR behavior and it has previously been described to correlate with various pathological conditions, e.g. risk of the sudden infant death syndrome (Pincus 1991, Pincus &Viscarello 1992, Fleisher et al. 1993, Pincus & Goldberger 1994, Mäkikallio et al. 1996, Rosenstock et al. 1999). It is possible, therefore, that cardiovascular autonomic dysfunction, in the form of decreased HR responses to certain stimuli and tonic oscillations of HRV, could be a prognostically unfavorable phenomenon in TLE as well. Reduced ApEn has also been found to be associated with the onset of paroxysmal atrial fibrillation in subjects without any structural heart disease (Vikman et al. 1999) and infusion of norepinephrine (Tulppo et al. 1999) possibly reflecting concomitant, accentuated sympathetic and vagal outflow to the sinus node. The mean values of ApEn and the slope of the power law relationship of HRV, did not correlate with the traditional spectral measures of HRV, showing that these new indices may be more sensitive than conventional methods in detecting altered cardiovascular regulation in patients with TLE. Reduced ApEn in patients with refractory TLE compared to the patients with well controlled TLE and the control subjects may reflect the sympathetic imbalance due to repetitive seizures in these patients and could be prognostically unfavorable phenomenon.
The pathophysiological basis of the cardiovascular autonomic dysfunction in TLE is not completely understood. The insular cortex is considered the most important cortical area controlling cardiovascular regulation, and it has extensive connections with other cardiovascular control centers (Cechetto 1990, Oppenheimer 1993, Cechetto 2000). In TLE, the epileptic focus close to these frontal and temporal regulatory areas may interfere with their function. Oppenheimer et al have demonstrated in humans that stimulation of the left insular cortex produces bradycardia, and stimulation of the right insular cortex produces tachycardia (Oppenheimer et al 1992). Moreover, potentially life threatening vagotonic cardiovascular dysfunction can be associated with unilateral mesiotemporal epileptogenic discharges (Schraeder & Lathers 1989). Recently, Druschky et al showed an impaired post-ganglionic cardiac sympathetic innervation and autonomic imbalance towards increased parasympathetic activity in cardiovascular reflex test in patients with TLE (Druscky et al. 2001).
Interestingly, in the present study, changes in cardiovascular regulation were seen both in refractory and in well controlled partial epilepsy, especially TLE, although the changes seem to be more evident in patients with refractory epilepsy. However, as the duration of epilepsy was longer in patients with refractory TLE, it can not be excluded that the duration of epilepsy may affect these result as well. Moreover, the slope of the power law was steeper in patients with TLE compared to the control subjects, thus reflecting impaired postganglionic sympathetic innervation of the heart in this study as well. Therefore, according to the present results, TLE itself may be implicated, but long-lasting antiepileptic medication may also modify the ANS function.
It is difficult to distinguish the effects of AEDs on the ANS function from the effects of epilepsy itself. In the present study abnormal cardiovascular reflexes appeared to be associated with CBZ medication, but statistical significance was reached only when compared to the control subjects. However, on the contrary to some earlier studies (Quint et al. 1990, Devinsky et al. 1994, Tomson et al. 1998), an analysis of HRV did not show alteration in relation to any specific drug regimen. This does not exclude the possibility that AEDs could have effects on cardiovascular regulatory function. Many AEDs taken by the patients in the present study act by blocking sodium channels like many antiarrhythmic agents, e.g. flecainide, that are associated with increased arrhythmogenic mortality (The Cardiac Arrhytmias Suppression Trial 1989, The Cardiac Arrhytmias Suppression Trial II Investigators 1992). Therefore, AEDs may have effects on cardiac conduction system as well as on centrally mediated cardiovascular control system function and contribute to the observed changes. Moreover, CBZ is mainly used in the treatment of patients with TLE. Both CBZ medication and TLE may contribute to the observed abnormal cardiovascular reflexes.
However, the effects of AEDs on cardiovascular regulation are still poorly outlined and further studies are needed to establish the effects of CBZ and other AEDs on the ANS function. The present study was not designed to assess the effects of the AEDs on the function of the ANS and the results can not give unambigous data to support the view that CBZ has a more potent effect on the cardiac regulatory system than the other commonly used AEDs.