Discussion
Various medical protocols for management of allergic rhinitis (AR) have been formulated in a stepwise manner. The mainstay of all treatments have been always conservative including antihistamines and intranasal steroids (10). However, for patients with AR refractory to medication therapy, a novel form of pharmacological treatment has been attempted, for controlling allergic symptoms, in form of intranasal injection of Botulinum toxin type A (BTX-A).
Since it provides a transient and reversible blockage of cholinergic transmission (11), BTX-A has been used recently in the symptomatic treatment of nasal hypersecretions (3),(9), that is controlled primarily by the parasympathetic nervous system (12). However, the effects of BTX-A on the suppression of sneezing and nasal congestion remain controversial; as besides the autonomic control of nasal mucosa, some sensory neuropeptides and sensory branches of the trigeminal nerve are also responsible for itching, sneezing and nasal congestion in allergic patients (13),(14).
Kim et al. showed that BTX-A effectively decreased nasal hypersecretions for 4 weeks, but did not affect nasal congestion and sneezing (3). Sapci et al. recorded a longer effect on nasal hypersecretions lasting for 8 weeks (9). The overall total nasal symptom score conducted by Zhang et al. showed greatest effect of BTX-A in subscales of nasal hypersecretions, followed by sneezing, nasal congestion, and itching, lasting all for 4 weeks (15). On the other hand, recent reports demonstrated effectiveness of intranasal BTX-A in improving all cardinal symptoms of AR including nasal hypersecretions, congestion and sneezing, with an effect lasting from 4 to 8 weeks (5),(6),(7),(8). Yang et al. study had the longest effect of BTX-A injection lasting for 20 weeks for all the allergic symptoms (16).
There is no universally accepted site of administration for the intranasal BTX-A usage; submucoperichondrial of nasal septum, inferior, middle turbinate, and posterior lateral nasal wall injections have been applied for the relief of allergic symptoms in different studies (2). Although inferior turbinate has been the commonest site for intranasal injection of BTX-A, some recent reports suggested that intraseptal injection had prolonged duration of effect. This could return to the lower blood flow in the submucoperichondrium of nasal septum that may lead to lesser clearance of BTX-A by bloodstream (6),(8).Ineffective infiltration of the area supplied by the anterior ethmoidal nerve has been postulated to be another reason for the limited effect in turbinate injections as compared to anterior nasal septum (9),(17). On contrary, Abtahi et al. concluded in their clinical trial that no differences in efficacy were noted between inferior turbinate and septal injections of BTX-A except a lower epistaxis rate in septal injections (8). A novel injection technique into the posterior lateral nasal wall, targeting parasympathetic innervation at the sphenopalatine ganglion, was described by Zhang et al. (15), however, the efficacy and safety of this technique require more investigations.
Although the toxic dose of BTX-A is known to be 2500-3000 units (18), 25–150 U is the range of BTX-A doses used in AR. There is no absolute agreement on the most suitable and effective dose for the intranasal injection. The efficacy of intra-turbinate injection of 40 U and 60 U of BTX-A did not differ significantly in their effectiveness on improving allergic symptoms, lasting for 8 weeks (5). Although Mozafarinia et al. (6) and Hashemi et al. (7) recorded improvement in allergic symptoms lasting for 4 and 8 weeks, after intraseptal injection of 80 U and intra-turbinate injection of 150 U of BTX-A, respectively, a long-lasting effect for 20 weeks had been reached in Yang et al. study using a lower dose of 50 U injected purely intra-turbinate (16). These results indorsed our praise to think that the effect of BTX-A in the nose is dose independent and it could be site dependent.
In our study, we proposed a different technique of combined intraseptal and intra-turbinate injection of BTX-A as; the intermediate part of inferior turbinate, anterior end of middle turbinate, and submucoperichondrial at the anterior part of nasal septum. A dose of 90 units was selected, in this study, as an average dose between the effective doses utilized for AR in the preceding studies. It was safely below the dose selected by Hashemi et al. (150 U), (7). The reason we chose this combined injection method was to reduce the parasympathetic tone to whole nasal mucosa. A recent anatomic study has redefined the nasal parasympathetic innervation suggesting that two main rami project from the sphenopalatine ganglion to innervate the nasal mucosa. The sphenoethmoidal ramus gain access to the nasal cavity via the sphenopalatine foramen to innervate the posterolateral part of nasal mucosa, blocked by the intra-turbinate injection and the orbitonasal ramus gain access to the nasal cavity via the anterior ethmoidal foramen to innervate the anterosuperior part of nasal mucosa, blocked by the intraseptal injection (19).
In our study, the combined injection method of BTX-A effectively reduced nasal hypersecretions in rates ranging from 27.5% to 62.5%. The effect displayed an increase starting from the first week and increased more reaching the maximum in the second and fourth weeks, which followed a statistically significant pattern for 12 weeks. These results are in accordance with those of Ozcan et al. in a clinical study (20), and Rohrbach et al. on an animal model (21), they have attributed the long duration of BTX-A effect to the recovery period of the degeneration in the nasal mucus glands that has been detected as 12 weeks. Another explanation for the long effect of BTX-A on nasal hypersecretions, in current study, was attributed to the multiple and different intranasal injections that enabled extensive distribution of the toxin to nasal mucosa and nasal glands, resulting in a more reduction of secretomotor innervation.
Although the combined injection method, in our study, effectively suppressed nasal hypersecretions, it lacked a similar efficacy on other allergic symptoms such as sneezing and nasal congestion. The significant effect of BTX-A on sneezing prominently decreased after the 4th week, while it was insignificantly different throughout the 12 weeks follow-up period for nasal congestion. The most likely explanation for these findings is that BTX-A does not have an essential role in the histamine-mediated allergic reactions (22). Minor sensory and parasympathetic efferent pathways exist in the nasal mucosa that may not be affected by the injected BTX-A, this may be another reason for the limited effect of BTX-A on nasal congestion and sneezing (19),(22).
Our study revealed the effect of combined septal and turbinate injection of BTX-A on the symptoms of AR. The greatest effect was seen in nasal hypersecretions lasted for 12 weeks, however effect on sneezing lasted only 4 weeks. The most important limitation of this study; that it was a subjective analysis after BTX-A injection, so further studies are required for the objective evaluation of the therapy efficacy. Moreover, further studies are required, to compare the combined injection technique with the other techniques reported in previous studies, to evaluate the effect of repetitive injections of BTX-A in the same patient, and to evaluate the optimal dose of BTX-A in allergic rhinitis.