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.