Bronchial asthma as neurogenic paroxysmal and inflammatory disease
Scientific background of effective use of anticonvulsants for pharmacotherapy of bronchial asthma
Considering the bronchial asthma as a neurogenic paroxysmal and inflammatory disease having certain similar pathogenic mechanisms with epilepsy, migraine, trigeminal neuralgia and breath-holding spells, we successfully applied antiepileptic drugs for the treatment of bronchial asthma (Lomia et al, 2004; 2005; 2006).
New vision of asthma. According to the joint definition of WHO and US National Institute of Heart, Blood and Lung, «Bronchial asthma is a chronic inflammatory disorder of the airways in which many cells play a role, in particular mast cells, eosinophils, and T-lymphocytes. In susceptible individuals this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough particularly at night and/or in the early morning. These symptoms are usually associated with widespread but variable airflow limitation that is at least partly reversible either spontaneously or with treatment. The inflammation also causes an associated increase in airway responsiveness to a variety of stimuli» (Global
Initiative for Asthma, 1995).
New vision of asthma.
According to the joint definition of WHO and US National Institute of Heart, Blood and Lung,
«Bronchial asthma is a chronic inflammatory disorder of the airways in which many cells play a role, in particular mast cells, eosinophils, and T-lymphocytes. In susceptible individuals this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough particularly at night and/or in the early morning. These symptoms are usually associated with widespread but variable airflow limitation that is at least partly reversible either spontaneously or with treatment. The inflammation also causes an associated increase in airway responsiveness to a variety of stimuli» (Global Initiative for Asthma, 1995).
Some specialists even suppose that the cause of asthma is unknown, and it is not even clear whether asthma is a single disease with a single cause or a symptom complex with many separate causes (Reed, 1985).
We presume that bronchial asthma, epilepsy, migraine and trigeminal neuralgia have some similarities in pathogenic mechanisms.
This could be confirmed by the following facts:
1) All these diseases are neurogenic disorders with paroxysmal clinical manifestations. All these diseases have hereditary predisposition and manifestation of the symptoms depends on the influence of additional external factors. Some of these diseases (migraine, asthma, trigeminal neuralgia) are neurogenic inflammatory disorders with paroxysmal clinical picture.
2) The central nervous system plays the important role in the development of bronchial hyperreactivity (Gold et al., 1972; Nadel, 1973; Empey et al., 1976; Leff, 1982; Widdicombe, 2003). There are animal models of expiratory bronchospasm provoked by irritation of certain cerebral zones and some neurotropic pharmacological agents can decrease the severity of such bronchoconstriction (Khaunina, 1961; Pekker, Zhaugasheva, 1973; Pekker, Zhaugasheva, Balkhanova, 1975; Zhaugasheva, 1975, 1976).
3) Concomitant development of bronchial asthma and schizophrenia is very unusual (Ehrentheil, 1957; Dobrzanski, 1970), and this fact is in accordance with the well-known phenomenon of clinical antagonism of the epileptic seizures and schizophrenic psychosis (Meduna, 1937). In case of combination of bronchial asthma and schizophrenia, exacerbation of schizophrenia is accompanied with the amelioration of bronchial asthma symptoms and vise versa (Funkenstein, 1950; Lemke, 1992).
4) Epilepsy and seizure syndromes are present in anamnesis of children with bronchial asthma 2 - 6.5 times more often than among total children population (Ivanova, 1987; 1989). There are some correlations in the changes of concentration of neuroactive metabolites of tryptophan in biological fluids in children with epilepsy and bronchial asthma (Ivanova et al., 1988).
5) One of the main clinical symptoms of bronchial asthma is paroxysmally induced bronchoconstriction and breathlessness (dyspnea) with difficulties in expiration, while inspiration is almost intact. The asthmatic person usually can inspire quite adequately but has great difficulty expiring (Guyton, 1991). Expiratory dyspnea allows experienced clinicians to distinguish bronchial asthma from many other respiratory diseases (Mathow, 1981; Vinogradov, 1987). At the same time cyanotic breath-holding spells in children is another disease with paroxysmally induced difficulties in expiration – expiratory apnea. During pallid breath-holding attacks paroxysmal expiratory apnea usually is associated with reversible decrease of heart rate or asystole (Chutorian, 1991). Increased vagal tone and vagal reflex overactivity usually are the causes of these paroxysms (Korovin, 1984; Huttenlocher, 1987). Atropine and antiepileptic drugs are the first choice drugs in such patients (Chutorian, 1991; Silbert, Gibbay, 1992; Shanko, 1993). It is considered that breath-holding attacks have pathogenic relationship with epilepsy and seizure syndromes (Ratner, 1985; Kharitonov et al, 1990). 3.6% of persons with breath-holding spells in childhood lately became epileptic patients (Shanko, 1993) and this is 3.6-7.2 time more frequent prevalence of epilepsy in compare to total population - approximately 0.5-1% (Ehle, Homan, 1980; Zielinski, 1988; Shanko, 1993). Several authors report, that in children with breath-holding spells the epilepsy develops in 12% of cases (Ratner, 1985). According another data, among 700 patients with epilepsy the breath-holding spells were observed in anamnesis in 49 patients (7%) (Kharitonov et al., 1990). According to our observations 25% of children with bronchial asthma have breath-holding spells in anamnesis, which is 2.7-3.4 times higher in comparison with other total children population - 4-5% (Shanko, 1993). Consequently, we can hypothesize, that bronchial asthma, epilepsy and breath-holding spells have certain pathogenic interrelationships.
6) In bronchial asthma (GINA, 1995) as well as in epilepsy (Karlov, 1990) hyperventilation frequently provokes asthmatic attacks and seizures accordingly. Some other factors, such as emotions, intensive smell, meteorological and endocrine factors also could provoke paroxysms of epilepsy (Biniaurishvili, 1985) as well as that attacks of bronchial asthma (GINA, 1995).
7) Epilepsy most often develops at the age under 16-24 years (Fry, 1974; Brain, Walton, 1977; Sarajishvili, 1986; Goldensohn et al., 1989; Karlov, 1990), the next slight peak in morbidity is after the age of 40 -50 (Fry, 1974; Brain, Walton, 1977; Karlov, 1990). This is very similar to the age prevalence of bronchial asthma: in more than half of the cases bronchial asthma begins in childhood (Fry, 1974; Chuchalin, 1985, GINA, 1995). The second slight peak in asthma age prevalence comes after the age of 35 - 45 years (Fry, 1974; Fedoseev, Khlopotova, 1988, GINA, 1995). Decrease in seizure threshold, or convulsive predisposition (Biniaurishvili et al., 1985; Badalyan, Golubeva, 1985) as well as bronchial reactivity (O’Connor et al., 1986; GINA, 1995) is considerably decreased after the age of 16.
8) According to our data the state similar to aura can be observed before the asthmatic attacks. We have interviewed patients with bronchial asthma using special questionnaire designed for this purpose; 31.5% of patients reported the presence of symptoms, preceding the attacks by several minutes or seconds - more often sensation of compression or tickling in the throat and/or nasal cavity, or restrain and compression in chest. Besides, in several patients with bronchial asthma we observed prodromal syndromes preceding exacerbation of the disease by several days (mood disorders, irritability, anxiety, etc.), which can be analogues of the prodromal epileptic syndromes.
Bronchial asthma can be considered as disorder with paroxysmal clinical manifestations (Canadian asthma consensus report, 1999). Paroxysms of bronchial asthma can be considered as a condition, which has definite similarity to the simple partial seizure with autonomic manifestations (Commission, 1981). It can be considered, that reflexes from airways or from internal organs, metabolic processes or psychogenic factors can induce central neurogenic (vagal, and not only vagal) paroxysmal bronchoconstriction with predominantly expiratory dyspnoe and concomitant neurogenic bronchial inflammation due to decreased excitation threshold of the definite areas of central nervous system. As a rule, the bronchial spasm is partial - it almost never is generalized and never accompanied with the disturbances of consciousness. Similar to the epileptic status an asthmatic status could be developed.
Based on the above-mentioned considerations, we assume that:
Bronchial asthma is a neurogenic paroxysmal inflammatory disease with the complex pathogenic mechanism, including two level of components: 1) multiple trigger components and 2) central neurogenic generator component of paroxysmal attacks of bronchoconstriction and concomitant inflammation.
The possible trigger components are as follows: irritation of airways receptors (allergy, infections and other pathological changes in airways, hyperventilation, inspiration of dry or cold air, irritating substances, smells), physical exercises, psychogenic factors, meteorological factors, irritation of interoceptors, endocrine disorders, metabolism of NSAIDs, etc.
Under the influence of trigger components the paroxysmal generator component is induced and pathologic process appears 1) with manifestation of periodic paroxysmal bronchial smooth muscles spasms, induced by the central structures of autonomic nervous system, and 2) with concomitant chronic neurogenic inflammation.
The effect of generator component results in maintenance and stabilization of trigger components. This usually manifests in additional neurogenic induction and sustaining of chronic bronchial inflammation and in increase of reactivity of paroxysm-generating neuronal structures that results in appearance of the new secondary trigger components capable to provoke paroxysmal bronchoconstriction (so called “asthmatization” of the pathologic state (Fuchs, 1981)). This process is similar (but not equal) to the formation of the new secondary trigger foci of epileptic activity during epilepsy.
Thus, vicious cycle is formed: trigger components provoke activity of generator component and vice versa. This is a mechanism of sustaining of asthma as a chronic disease. Abnormally increased vagal tone during asthma prevents generalization of paroxysmal activity into other parts of CNS. Constitutional predisposition to the development of neurogenic generator component is necessary for asthma development.
Syndrome of bronchial hyperreactivity, or latent bronchospasm (Leff, 1982; Williamson, Schultz, 1987), airway resistance, edema and chronic neurogenic inflammation of airways can be considered as increased asthmatic susceptibility (predisposition), induced by the central neurogenic generator component. This increased asthmatic susceptibility (predisposition) can be considered as analogue of the increased seizure susceptibility (predisposition) in epilepsy, and asthmatic status can be considered as a certain analogue of the epileptic status. Attenuation of the trigger, as well as the generator central neurogenic paroxysmal and inflammatory component induces disappearance of clinical manifestations of asthma. The possible trigger factors are as follows: allergy and infection in airways, pathological changes in nasopharyngeal area (adenoids, rhinitis, sinusitis, etc.), physical exercises, hyperventilation, inspiration of dry or cold air, psychogenic factors, intensive smells, inspiration of irritating substances, influence of meteorological factors, non-respiratory allergy, irritation of interoceptors, endocrine disorders, metabolism of non-steroidal anti-inflammatory drugs, etc. Very often it is not possible to determine exact nature of the trigger factors (especially with their variety), which makes it difficult to influence them by pharmacological agents or other methods. Consequently, therapeutic intervention aimed at the paroxysm - generating factors and neurogenic inflammation generating factors is easier, and it is possible by some anticonvulsive agents. This kind of medication has been successfully applied in our trials (Lomia et al, 2004, 2005): in more than 70% of patients with asthma some antiepileptic drugs induced complete and stable remission.
Exact location of central neurogenic generating structures of bronchial asthma is still unknown. We do not know in which limited neuronal populations the increased activity and/or paroxysmal discharges occur and which structures of CNS have relationship to this process. We can suppose that vagus nerve system, central suprasegmental structures of parasympathetic autonomic nervous system, some structures of brain stem, limbic system, certain areas of hypothalamus and some cortical structures are involved in this process.
Generalization of paroxysmal activity never occurs in bronchial asthma. It may be explained by abnormally increased vagal tone, which prevents the spreading of the convulsive activity into other parts of CNS: it is known that vagus nerve stimulation is successful for the management of drug resistant epilepsy (Schachter, Saper, 1998).
It is possible that efficacy of anticonvulsants in bronchial asthma is not due to only central neurogenic influence. Local influence of aniconvulsants on airways is also possible. Antiepileptic drugs can reduce the sensitivity of local nerve terminals, and also can inhibit of axon reflexes, which probably are involved in sustaining of neurogenic inflammation in airways (Rihoux, 1993). Antiepileptic agents may also inhibit of neuropeptide release from axon terminals in airways, and reduce of peripheral neuromuscular transmission (Rutledge et al, 1971; Gandhi et al, 1976, Zaidat et al, 1999). Anticonvulsants also can stabilize of cells membranes and also can induce direct relaxation on the bronchial smooth muscles and inhibition of post-tetanic depolarization (Julien, Halpern, 1970; Hackman et al., 1981).
It should be considered also, that anticonvulsants inhibit neuronal discharges of any kind: epileptogenic or non-epileptogenic. This property of anticonvulsants explains their efficacy in variety of non-epileptic conditions (Kryzhanovskii, 1980). It is also possible, that anticonvulsants act via neurogenic control of immune reactions. Neurogenic control of immune reactions was first described at the beginning of the 20th century (Besredka, Steinhardt, 1907), and confirmed later (Spiegel, Kubo, 1923; Filipp, Szentivanyi, 1952, 1957; Hall, Goldstein, 1981; Spector, Korneva, 1981; Maclean, Reichlin, 1981; Besedovsky, Sorkin, 1981). Antiepileptic drugs can decrease the concentration of various immunoglobulins and activity of immunocompetent cells (Basaran et al., 1994; Callenbach et al, 2003), and due to this can interfere in asthma immune mechanisms.
Until today, management of bronchial asthma was held in two main directions: 1) modification of factors inducing allergic reaction and interference on the certain stages of allergic reaction; and 2) interference with peripheral bronchial receptors. Both these directions do finally affect the trigger factors.
We suggest 3rd direction in the management of bronchial asthma: application of anticonvulsive agents for the control of activity of generator neurogenic mechanisms of bronchial asthma. This new approach leads to the prevention of asthmatic attacks and opens up new perspectives for the management of this disease.
Bronchial asthma is not the only disease having pathogenic mechanisms related to that of epilepsy. Trigeminal neuralgia also has certain pathogenic relationship with epilepsy (Karlov et al., 1983; Kryzhanovskii et al., 1992; Pagni, 1993; Jensen, 2002). It is considered that paroxysmal pain attacks in trigeminal neuralgia are associated with epileptic-like pacemaker activity in brain stem trigeminal nucleus (Pagni, 1993), which is induced by slight tactile stimulation of trigger zone, sensory (tactile, auditory, photo or thermal stimulus), and also by emotional factors. Sometimes specific paraesthetic aura is observed by patients before the paroxysm (Grechko et al, 1985). It is supposed that not only trigeminal nuclei but also other upper regions of CNS may play a role in the generation of pain paroxysms (Kryzhanovskii, 1980; Jensen, 2002). Some authors suppose that trigeminal neuralgia has a peripheral cause and a central pathogenesis (Fromm et al., 1984). Chronic irritation of the peripheral trigeminal nerve leads to failure of segmental inhibition in the trigeminal nucleus and to production of ectopic action potentials in the trigeminal nerve. Increased neuronal discharge and reduced inhibitory mechanism produce a hyperactive sensory circuit, leading eventually to paroxysmal discharges in the trigeminal nucleus (Dalessio, 1987). The main reason for the efficacy of anticonvulsants in both epilepsy and trigeminal neuralgia may be the related pathogenic mechanism of these conditions (Karlov, Savitskaia, 1976; Kryzhanovskij, 1980). As in the case with bronchial asthma, one of the pathogenic mechanisms of trigeminal neuralgia is the neurogenic inflammation in which neuropeptides play a significant role (Strittmatter et al., 1997).
Migraine as a paroxysmal disease also has relationship with epilepsy. Several investigators consider that migraine and epilepsy have certain similar pathogenic mechanisms (Donnet, Bartolomei, 1997; Terwindt et al., 1998). The aura is often observed before the migraine attacks, and migrenous status (status migraine) also may develop. Central structures of the nervous system are involved in pathogenesis of migraine paroxysms (Shtok, 1987). Migraine paroxysms can be triggered by auditory and photo stimulus, smells, psychoemotional factors, etc. As in bronchial asthma and trigeminal neuralgia the neurogenic inflammation is an important pathogenic mechanism of migraine (Hardebo, 1992). Besides, it is known that migraine is more common in patients with bronchial asthma, than it is in the entire population, and vice versa (Chen, Leviton, 1990). Epilepsy is more common in patients with migraine, then in the general population, and vice versa (Alberca, 1998).
Some neuromediators and bioactive substances have the same influence in provoking or suppressing of asthme attacks, epileptic seizure, migraine and trigeminal neuralgia.
So, GABA and its agonists have protective effect against asthma attacks (Dicpinigaitis, 1999), epileptic seizures (Karceski et al, 2005), migraine (Spina, Perigi, 2004) and trigeminal pain (Spina, Perigi, 2004).
Glycine has protective effect against asthma attacks (Fogarty et al, 2004), epileptic seizures (Liu et al, 1990), and trigeminal pain (Megdiatov et al, 1991).
Taurine has protective effect against asthma attacks (Cortijo et al, 2001), epileptic seizures (Birdsall, 1998), and migraine (Martinez, 1993). Dopamine has protective effect against asthma attacks (Cabezas, 2003) and epileptic seizures (Starr, 1996). Cyclic adenosine monophosphate (cAMF) has protective effect against asthma attacks (Hidi, 2000) and epileptic seizures (Ferrendelli, 1983). Kynurenines have provocative effect in asthma attacks (Ivanova et al, 1988), epileptic seizures (Lapin, 2004), migraine (Velling et al, 2003) and trigeminal pain (Knyihar-Csillik, 2004). Monosodium glutamate has provocative effect in asthma attacks (Allen et al, 1987, GINA 2004), epileptic seizures (Meldrum, 1994), migraine (Peres et al, 2004). Cytokines have provocative effect in asthma attacks (GINA, 2004), epileptic seizures (Vezzani et al, 2004), migraine (Reuter et al, 2001). Substance P has provocative effect in asthma attacks (Tomaki et al, 1995), epileptic seizures (Liu et al, 1999), migraine (De Vane, 2001) and trigeminal pain (De Vane, 2001). Leukotrienes have provocative effect in asthma attacks (GINA, 2004), epileptic seizures (Phillis et al, 2006), migraine (Sheftell et al, 2000). Some prostaglandines have provocative effect in asthma attacks (Nishimura et al, 2001; GINA, 2004), epileptic seizures (Bhaduri et al, 1995), migraine (Bic et al, 1998, Al-Waili, 2000). Acetylcholine has provocative effect in asthma attacks (Popa, 1986) and in epileptic seizures (Sergienko et al, 1979) and trigeminal pain (Lundblad et al, 1983). Some bioactive substances have not the same influence on these diseases, but number of such substances are significantly less in comparison with similar acting substances. It is quite natural: all of these diseases are in close relationship, but nevertheless there are different diseases. In our opinion, bronchial asthma, trigeminal neuralgia and migraine can be included in the distinct group of paroxysmal neurogenic inflammatory diseases, having pathogenic mechanisms similar to epilepsy. There may be approaches at different levels for the management of these diseases: 1) peripheral trigger level with specific effective groups of medications (e.g. non-steroidal anti-inflammatory drugs are effective for the treatment of migraine and trigeminal neuralgia, but at the same time they are contraindicated in bronchial asthma; beta-adrenomimetics are effective for bronchial asthma, but beta-adrenoblockers - for migraine, and in the same time they are contraindicated in bronchial asthma. 2) on the level of central neurogenic paroxysmal factors: in bronchial asthma (Lomia et al, 2004, 2005), migraine (Wauquier, 1986; Ziegler, 1987; Shelton, Conelly, 1987) and trigeminal neuralgia (Dalessio, 1987) administration of some antiepileptic agents significantly decrease frequency and intensity of disease attacks. _________________ References:
Taurine has protective effect against asthma attacks (Cortijo et al, 2001), epileptic seizures (Birdsall, 1998), and migraine (Martinez, 1993).
Dopamine has protective effect against asthma attacks (Cabezas, 2003) and epileptic seizures (Starr, 1996).
Cyclic adenosine monophosphate (cAMF) has protective effect against asthma attacks (Hidi, 2000) and epileptic seizures (Ferrendelli, 1983).
Kynurenines have provocative effect in asthma attacks (Ivanova et al, 1988), epileptic seizures (Lapin, 2004), migraine (Velling et al, 2003) and trigeminal pain (Knyihar-Csillik, 2004).
Monosodium glutamate has provocative effect in asthma attacks (Allen et al, 1987, GINA 2004), epileptic seizures (Meldrum, 1994), migraine (Peres et al, 2004).
Cytokines have provocative effect in asthma attacks (GINA, 2004), epileptic seizures (Vezzani et al, 2004), migraine (Reuter et al, 2001).
Substance P has provocative effect in asthma attacks (Tomaki et al, 1995), epileptic seizures (Liu et al, 1999), migraine (De Vane, 2001) and trigeminal pain (De Vane, 2001).
Leukotrienes have provocative effect in asthma attacks (GINA, 2004), epileptic seizures (Phillis et al, 2006), migraine (Sheftell et al, 2000).
Some prostaglandines have provocative effect in asthma attacks (Nishimura et al, 2001; GINA, 2004), epileptic seizures (Bhaduri et al, 1995), migraine (Bic et al, 1998, Al-Waili, 2000).
Acetylcholine has provocative effect in asthma attacks (Popa, 1986) and in epileptic seizures (Sergienko et al, 1979) and trigeminal pain (Lundblad et al, 1983).
Some bioactive substances have not the same influence on these diseases, but number of such substances are significantly less in comparison with similar acting substances. It is quite natural: all of these diseases are in close relationship, but nevertheless there are different diseases.
In our opinion, bronchial asthma, trigeminal neuralgia and migraine can be included in the distinct group of paroxysmal neurogenic inflammatory diseases, having pathogenic mechanisms similar to epilepsy. There may be approaches at different levels for the management of these diseases:
1) peripheral trigger level with specific effective groups of medications (e.g. non-steroidal anti-inflammatory drugs are effective for the treatment of migraine and trigeminal neuralgia, but at the same time they are contraindicated in bronchial asthma; beta-adrenomimetics are effective for bronchial asthma, but beta-adrenoblockers - for migraine, and in the same time they are contraindicated in bronchial asthma.
2) on the level of central neurogenic paroxysmal factors: in bronchial asthma (Lomia et al, 2004, 2005), migraine (Wauquier, 1986; Ziegler, 1987; Shelton, Conelly, 1987) and trigeminal neuralgia (Dalessio, 1987) administration of some antiepileptic agents significantly decrease frequency and intensity of disease attacks.
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