A randomized controlled study evaluating medical treatment versus surgical treatment in addition to medical treatment of nasal polyposis.

BACKGROUND: Controlled prospective studies are needed to determine whether surgical treatment in fact has an effect additive to that of medical treatment of nasal polyposis. OBJECTIVE: We sought to compare the effect of medical treatment versus combined surgical and medical treatment on olfaction, polyp score, and symptoms in nasal polyposis. METHODS: Thirty-two patients with nasal polyposis and symmetrical nasal airways were randomized to unilateral endoscopic sinus surgery after pretreatment with oral prednisolone for 10 days and local nasal budesonide bilaterally for 1 month. Postoperatively, patients were given local nasal steroids (budesonide). Patients were evaluated with nasal endoscopy, symptom scores, and olfactory thresholds. They were followed for 12 months. RESULTS: The sense of smell was improved by the combination of local and oral steroids. Surgery had no additional effect. Symptom scores improved significantly with medical treatment alone, but surgery had additional beneficial effects on nasal obstruction and secretion. After surgery, the polyp score decreased significantly on the operated side but remained the same on the unoperated side. Twenty-five percent of the patients were willing to undergo an operation also on the unoperated side at the end of the study. CONCLUSIONS: Medical treatment seems to be sufficient to treat most symptoms of nasal polyposis. When hyposmia is the primary symptom, no additional benefit seems to be gained from surgical treatment. If nasal obstruction is the main problem after steroid treatment, surgical treatment is indicated. Selection of those who will benefit from surgery should be based on the patient's symptoms and not on the examiner's polyp score.

Results of transantral orbital decompression in patients with thyroid-associated ophthalmopathy.

PURPOSE: To present the results of orbital decompression in patients with thyroid-associated ophthalmopathy (TAO). METHODS: Transantral orbital decompression was performed in 63 patients with TAO. In 40 patients (63%) the operation was made because of progressive ophthalmopathy not responding to medical therapy, and in 23 patients (37%) the operation was made for rehabilitative reasons. The long-term hypesthesia engaging the infraorbital nerve was assessed with a questionnaire using a Visual Analogue Scale (VAS). RESULTS: The mean proptosis reduction was 3.2 mm (range 0-8 mm). Twenty-one patients had impaired visual acuity preoperatively, and 20 improved. Altogether 30 patients (40%) had worsened ocular motility postoperatively. Forty-three patients did not have diplopia in the primary position preoperatively, and new diplopia developed in 22 of these (51%). Hypesthesia in the infraorbital nerve area was reported for half of the operated sides, but was a major cause of distress (VAS-scoring >5) to eleven patients. CONCLUSIONS: Transantral orbital decompression is indicated in patients with progressive TAO or in patients with prominent exophthalmos, and results in a good proptosis reduction, but the risk of postoperative diplopia is significant. Postoperative hypesthesia is common but often not a major problem.

Capsaicin desensitization of the nasal mucosa reduces symptoms upon allergen challenge in patients with allergic rhinitis.

Patients with birch pollen allergic rhinitis were treated locally, out of season, in the nasal cavity with capsaicin (30 microM) or saline. The capsaicin treatment resulted in a statistically significant reduction of symptoms upon allergen challenge, which lasted for 2 months. Saline had no effect on the symptom score upon allergen challenge. Neither capsaicin nor saline treatment had any effect on allergen challenge-induced nasal mucosal swelling monitored by acoustic rhinometry. Allergen challenge-induced eosinophil migration to the nasal mucosa was affected by neither capsaicin nor the saline treatment. The finding that capsaicin treatment reduces allergic symptoms indicates that selective, non-peptide neurokinin receptor antagonists may be an alternative in the future in the treatment of nasal allergy. However, owing to the pain involved in local capsaicin treatment this treatment is unlikely to be of clinical use.

Basic mechanisms in autonomic nervous responses in specific and nonspecific nasal hyperreactivity.

The nasal mucosa and the autonomic nervous regulation of protective reflexes plays an important role for the protection of the lower airways. Increasing experimental evidence from both animal models and humans suggests that the organization of the autonomic nervous pathways is more complicated than previously assumed. Thus a number of biologically active peptides are known to be present in the autonomic pathways and coexist with the classical transmitters. The neuropeptides have experimentally been shown to play an important role in the pathophysiological events in both specific and nonspecific hyperreactivity.

Release of calcitonin gene-related peptide in the pig nasal mucosa by antidromic nerve stimulation and capsaicin.

The overflow of calcitonin gene-related peptide like-immunoreactivity (CGRP-LI) in the nasal venous effluent upon antidromic stimulation of the maxillary division of the trigeminal nerve with 6.9 Hz for 3 min or upon capsaicin (0.3 mumol bolus injection) were analysed in the nasal mucosa of sympathectomized pentobarbital anaesthetized pigs. The overflow of CGRP-LI upon antidromic stimulation displayed a slower appearance in the venous effluent than the overflow upon bolus injection of capsaicin. The vascular effects as revealed by the arterial blood flow, the venous blood flow, the blood volume of the nasal mucosa, i.e., the filling of the capacitance vessels and the superficial mucosal blood flow as revealed by the laser-Doppler signal were also studied. Antidromic stimulation of the trigeminal nerve as well as capsaicin bolus injection induced a marked vasodilation which was parallel to the overflow of CGRP. However, capsaicin bolus injection also resulted in a marked increase in the mean arterial blood pressure which may be due to reflex activation of sympathetic fibers. In conclusion, we have demonstrated that chemical stimulation with capsaicin as well as antidromic stimulation of nasal sensory nerves in sympathectomized animals induces both vasodilation and overflow of CGRP-LI in vivo. This indicates that CGRP may contribute to the sensory regulation of the microcirculation in the nasal mucosa.

Compartment analysis of vascular effects of neuropeptides and capsaicin in the pig nasal mucosa.

The vascular effects of local infusion of capsaicin, substance P (SP), calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) were monitored in an experimental model on the pig nasal mucosa. Arterial, venous and superficial mucosal blood flow (laser-Doppler flowmetry) as well as mucosal volume, reflecting changes in capacitance vessels were studied in parallel. All substances induced concentration dependent increases in the parameters studied with the exception of the decrease in the superficial mucosal flow induced by vasoactive intestinal polypeptide. This latter finding was interpreted as a stealing phenomenon and suggests that vasoactive intestinal polypeptide mainly exerts its vasodilatory effect in the deeper glandular layers of the nasal mucosa. The vasodilatory effect of capsaicin, except the laser-Doppler signal, was markedly reduced by pretreatment with a combination of the ganglionic blocking agent chlorisondamine and atropine implying that capsaicin evokes a central reflex with a final parasympathetic pathway and release of agents like vasoactive intestinal polypeptide. The remaining capsaicin response may depend on a local effect with axon reflexes and the release of sensory neuropeptides with actions on superficial mucosal blood flow.

Lipoxin formation in human nasal polyps and bronchial tissue.

Chopped human nasal polyps and bronchial tissue produced lipoxin A4 and isomers of lipoxins A4 and B4, but not lipoxin B4, after incubation with exogenous leukotriene A4. In addition, these tissues transformed arachidonic acid to 15-hydroxyeicosatetraenoic acid. The capacity per gram of tissue to produce lipoxins and 15-hydroxyeicosatetraenoic acid was 3-5-times higher in the nasal polyps. Neither tissue produced detectable levels of lipoxins or leukotrienes after incubation with ionophore A23187 and arachidonic acid. Co-incubation of nasal polyps and polymorphonuclear granulocytes with ionophore A23187 led to the formation of lipoxins, including lipoxins A4 and B4. The results indicate the involvement of an epithelial 15-lipoxygenase in lipoxin formation in human airways.

Neuropeptide Y: presence in sympathetic and parasympathetic innervation of the nasal mucosa.

The occurrence of neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP) and peptide histidine isoleucine (PHI) in the sympathetic and parasympathetic innervation of the nasal mucosa was studied in various species including man. A dense network of NPY-immunoreactive (IR) fibres was present around arteries and arterioles in the nasal mucosa of all species studied. NPY was also located in nerves around seromucous glands in pig and guinea-pig, but not in rat, cat and man. The NPY-IR glandular innervation corresponded to about 20% of the NPY content of the nasal mucosa as revealed by remaining NPY content determined by radioimmunoassay after sympathectomy. These periglandular NPY-positive fibres had a distribution similar to the VIP-IR and PHI-IR nerves but not to the noradrenergic markers tyrosine hydroxylase (TH) or dopamine-beta-hydroxylase (DBH). The NPY nerves around glands and some perivascular fibres were not influenced by sympathectomy and probably originated in the sphenopalatine ganglion where NPY-IR and VIP-IR ganglion cells were present. The venous sinusoids were innervated by NPY-positive fibres in all species except the cat. Dense NPY and DBH-positive innervation was seen around thick-walled vessels in the pig nasal mucosa; the latter may represent arterio-venous shunts. Double-labelling experiments using TH and DBH, and surgical sympathectomy revealed that the majority of NPY-IR fibres around blood vessels were probably noradrenergic. The NPY-positive perivascular nerves that remained after sympathectomy in the pig nasal mucosa also contained VIP/PHI-IR. The major nasal blood vessels, i.e. sphenopalatine artery and vein, were also densely innervated by NPY-IR fibres of sympathetic origin. Perivascular VIP-IR fibres were present around small arteries, arterioles, venous sinusoids and arterio-venous shunt vessels of the nasal mucosa whereas major nasal vessels received only single VIP-positive nerves. The trigeminal ganglion of the species studied contained only single TH-IR or VIP-IR but no NPY-positive ganglion cells. It is concluded that NPY in the nasal mucosa is mainly present in perivascular nerves of sympathetic origin. In some species, such as pig, glandular and perivascular parasympathetic nerves, probably of VIP/PHI nature, also contain NPY.

Tachykinins and calcitonin gene-related peptide: co-existence in sensory nerves of the nasal mucosa and effects on blood flow.

The presence and co-existence of calcitonin gene-related peptide (CGRP)- and substance P (SP)-like immunoreactivity (-LI) in sensory neurons of the nasal mucosa and trigeminal ganglion in several vertebrate species, including man, were established using immunohistochemistry. In the nasal mucosa the CGRP- and SP-immunoreactive (IR) nerve fibers were localized within the epithelium, around arteries, arterioles, venules, venous sinusoids and close to exocrine elements, mainly ducts. Double-staining experiments revealed that the CGRP-LI-containing nerve profiles and cell bodies also contained SP-LI. In the pig, CGRP- and SP-IR fibers were also detected in the maxillary portion of the trigeminal nerve and around the sphenopalatine artery and vein, as well as around the nasal dorsal vein. The nasal mucosal content of CGRP-LI, as determined by radioimmunoassay, was almost 5-fold higher in the pig and guinea pig compared to man. The nasal CGRP-IR nerves disappeared after capsaicin pretreatment in the guinea pig. In the cat, local intra-arterial infusions of capsaicin, SP, neurokinin A (NKA), neuropeptide K (NPK) and CGRP caused a concentration-dependent increase in nasal blood flow. CGRP caused a longer-lasting vasodilatation than the tachykinins. In conclusion, the morphological findings of co-localization of CGRP-LI and SP-LI in capsaicin-sensitive nerve fibers of the nasal mucosa and trigeminal ganglia of different species including man, coupled with the in vivo description of the high vasodilator potency of CGRP and tachykinins, imply co-release of several vasoactive agents upon activation of the nasal sensory nerves. Furthermore, the similarity of the morphological findings among the different species indicates that experimental data from animals may reflect the existence of similar mechanisms in humans.

Capsaicin and nicotine-sensitive afferent neurones and nasal secretion in healthy human volunteers and in patients with vasomotor rhinitis.

1. Applications of capsaicin, nicotine and methacholine were made locally onto the nasal mucosa in human controls and patients suffering from hyperreactive nasal disorders. Perception of sensation was registered as a sympton score and secretion quantified. The sensory reaction (irritation - pain) to capsaicin was similar in the three groups studied, i.e. controls, a group of patients with the diagnosis of vasomotor rhinitis and a group of patients with increased nasal secretion as the main symptom of the hyperreactive disorder. Nicotine induced only a mild itching sensation in the three groups. However, capsaicin and nicotine challenge caused a significantly larger secretory response in the last group than in the unselected vasomotor rhinitis group and in the control group. 2. Pretreatment with muscarinic receptor antagonists almost completely abolished the secretory response to both capsaicin and nicotine, and blocked methacholine-induced secretion. Furthermore, pretreatment with a combination of local anaesthetic and vasoconstrictor agent abolished the capsaicin-induced irritation, as well as the capsaicin- and nicotine-induced secretion on both the ipsilateral and the contralateral side. Therefore, no clearcut contribution seems to be exerted by locally released peptides from sensory neurones as direct trigger substances for the secretory response to capsaicin. 3. In conclusion, the nasal secretory response, in man, to both capsaicin and nicotine, seems to be mediated via cholinergic parasympathetic reflexes. In patients with hyperreactive non-allergic disorders of the nasal mucosa with rhinorrhea as the main complaint, the enhanced secretion may be due to a hyperreactive efferent cholinergic mechanism rather than hypersensitive irritant receptors on capsaicin- and nicotine-sensitive sensory neurones. Challenge with irritant agents seems a useful test for the evaluation of both afferent and efferent reflexogenic responses in hyperreactive disorders of the nasal mucosa.

Sympathetic vascular control of the pig nasal mucosa (III): Co-release of noradrenaline and neuropeptide Y.

The overflows of noradrenaline (NA) and neuropeptide Y like immunoreactivity (NPY-LI) and vascular responses upon sympathetic nerve stimulation were analysed in the nasal mucosa of pentobarbital anaesthetized pigs. In controls, a frequency-dependent increase in NA overflow was observed whereas detectable release of NPY-LI occurred only at 6.9 Hz. Parallel decreases in blood flow in the sphenopalatine artery and vein and in nasal mucosa volume (reflecting blood volume in the venous sinusoids) were observed. The laser Doppler flowmeter signal (reflecting superficial blood flow) increased upon low and decreased upon high frequency stimulation. Twenty-four hours after reserpine pretreatment and preganglionic decentralization, the NA overflow was abolished while a frequency-dependent release of NPY-LI occurred. Forty, 60 and 80% of the vasoconstrictor responses then remained upon stimulation with a single impulse, 0.59 and 6.9 Hz, respectively. Both the vasoconstriction and NPY-LI overflow, however, were subjected to fatigue upon repeated stimulation. In reserpinized animals release of NPY-LI and vasoconstrictor responses were larger upon stimulation with irregular bursts at 0.59 Hz compared to effects seen at stimulation with continuous impulses. Pre-treatment with the alpha-adrenoceptor antagonist phenoxybenzamine or the monoamine reuptake inhibitor, desipramine, enhanced NA overflow by 2-3 and 1.5 times at 0.59 and 6.9 Hz, respectively. Phenoxybenzamine significantly reduced the nerve-evoked vascular responses while the release of NPY-LI at 6.9 Hz was increased. Desipramine increased the functional responses but reduced the NPY-LI overflow. During tachyphylaxis to the vasoconstrictor effects of the stable adenosine 5'-triphosphate (ATP) analogue alpha-beta-methylene ATP (mATP) in controls, the vasoconstrictor responses as well as the NA and NPY-LI overflow to nerve stimulation were unmodified. In reserpinized animals, however, the vascular responses and the overflow of NPY-LI were reduced after mATP tachyphylaxis. These data show that both NA and NPY are released upon sympathetic nerve stimulation in the nasal mucosa in vivo and this release seems to be regulated via prejunctional alpha-adrenoceptors. The lack of effect of mATP tachyphylaxis under control conditions makes it less likely that ATP serves as a major mediator of the large nonadrenergic vasoconstrictor component.

Sympathetic vascular control of the pig nasal mucosa (2): Reserpine-resistant, non-adrenergic nervous responses in relation to neuropeptide Y and ATP.

The possible occurrence of non-adrenergic mechanisms in the sympathetic vascular control of the nasal mucosa was studied in vivo using reserpine-treated pigs (1 mg kg-1, i.v., 24 h earlier) in combination with pharmacological blockade of alpha-adrenoceptors by local phenoxybenzamine (1 mg kg-1, i.a.) infusion. The nasal mucosal depletion (99%) of the content of noradrenaline (NA) in reserpinized animals was not influenced by preganglionic denervation while the depletion (44%) of neuropeptide Y (NPY) was prevented. Upon stimulation with single shocks, 25% of the arterial blood flow reduction and 47% of the nasal mucosal volume reduction (reflecting contraction of venous sinusoids) were still present after reserpine as compared with controls. In reserpinized animals, the vascular responses were slow developing and long-lasting, and about 60% remained at 0.59 Hz and more than 80% at 6.9 Hz. The vascular effects after reserpine were, however, subjected to fatigue, which may explain why phenoxybenzamine treatment still reduced the functional effects in the absence of NA. Local intra-arterial injections of NA, NPY and the metabolically stable adenosine-5'-triphosphate analogue alpha, beta-methylene ATP (mATP) caused reduction in both arterial blood flow and nasal mucosal volume. The C-terminal fragment of NPY (NPY 13-36) also induced nasal vasoconstriction although with a fivefold lower potency than NPY 1-36. Adenosine-5'-triphosphate caused a biphasic vascular effect with vasodilatatory actions at low doses and a short-lasting vasoconstriction followed by vasodilatation at very high doses (100-fold higher than the threshold response to mATP). In contrast to the response to NA, the long-lasting vascular effects of NPY and mATP were resistant to phenoxybenzamine treatment. In conclusion, although NA is likely to mediate most of the sympathetic vascular responses to low-frequency stimulation in the pig nasal mucosa, a large resistance and capacitance vessel component upon high-frequency stimulation seems to be non-adrenergic and mimicked by NPY rather than ATP.

Sympathetic vascular control of the pig nasal mucosa: (I). Increased resistance and capacitance vessel responses upon stimulation with irregular bursts compared to continuous impulses.

An in vivo model is described in which pentobarbital anaesthetized pigs were used to study the sympathetic nervous control of the nasal mucosal vascular bed. Changes in blood flow in the sphenopalatine artery (representing nasal blood flow) and in the volume of the nasal cavity (mainly reflecting blood content in venous sinusoids), upon electrical stimulation of the cervical sympathetic trunk, were recorded simultaneously. Single impulses (15V, 5 ms) reduced both the arterial flow and the volume of the nasal mucosa. The effects of nerve stimulation with a continuous train of impulses at 0.59, 2 and 6.9 Hz were compared with those caused by stimulation with the irregular bursting pattern, triggered by recorded human sympathetic vasoconstrictor nerve activity, with the same average frequencies. Both types of stimulation reduced nasal blood flow and volume, but the responses were significantly larger with burst stimulation at 0.59 Hz. The volume reduction was already maximal at 0.59 Hz while the blood flow response increased further higher frequencies. Local intra-arterial pretreatment with the alpha-adrenoceptor antagonist phenoxybenzamine significantly attenuated the flow and volume responses to single impulses, while clear-cut reductions in blood flow (by 40%) and volume (by 80%) remained, upon stimulation, at 6.9 Hz. Noradrenaline given intra-arterially caused a dose-dependent reduction in nasal blood flow and volume. The noradrenaline effects were blocked by phenoxybenzamine treatment. The results show that the pig nasal mucosa represents a model where both blood flow and volume changes can be studied in parallel in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuropeptide Y and non-adrenergic sympathetic vascular control of the cat nasal mucosa.

Neuropeptide Y (NPY) coexists with noradrenaline (NA) in a population of perivascular nerves in the cat nasal mucosa. In the present study, NPY was found to exert non-adrenergic nasal vasoconstrictor actions. Postganglionic sympathetic nerve stimulation induced a release of NPY-like immunoreactivity (LI) concomitant with vasoconstriction in the nasal mucosa. About 60 and 70% of the vasoconstrictor responses upon sympathetic stimulation at 2 and 10 Hz, respectively, remained after pretreatment with phenoxybenzamine and propranolol which abolished the effects of exogenous NA. Preganglionic denervation one week prior to the experiments did not change the vasoconstrictor response to sympathetic nerve stimulation or the NA or NPY contents of the nasal mucosa. The levels of NPY-LI in the superior cervical ganglion were however reduced. After reserpine treatment, which depleted the nasal NA content by almost 90% and the NPY content by 50%, a vasoconstrictor response to nerve stimulation was still present. After reserpine treatment combined with preganglionic denervation, nerve stimulation simultaneously induced an increased output of NPY-LI and a marked long-lasting vasoconstriction which was not influenced by phenoxybenzamine and propranolol. The reserpine-induced depletion of NA was not influenced by preganglionic denervation while the reduction in the nasal content of NPY-LI was prevented. In conclusion, NPY could be a non-adrenergic mediator of sympathetic vascular effects in cat nasal mucosa.

Neuropeptide Y and noradrenaline mechanisms in relation to reserpine induced impairment of sympathetic neurotransmission in the cat spleen.

The mechanisms underlying the reserpine-induced impairment of the functional responses to sympathetic nerve stimulation and output of noradrenaline (NA) and neuropeptide Y (NPY)-like immunoreactivity (-LI) were studied using the isolated blood-perfused cat spleen. Splenic nerve stimulation (10 Hz for 2 min) during control conditions caused perfusion-pressure increase, volume reduction and an increased output of NA and NPY-LI. After administration of phenoxybenzamine, the nerve stimulation-induced perfusion-pressure increase was almost abolished, the volume reduction inhibited and the output of NPY-LI enhanced. After subsequent addition of propranolol, a clear-cut increase in perfusion pressure upon nerve stimulation reappeared. Local infusion of NPY caused a potent, long-lasting, adrenoceptor-resistant increase in perfusion pressure and a relatively smaller volume reduction of the spleen. Twenty-four hours after reserpine pretreatment (1 mg kg-1 i.v.), which depleted the splenic content of NA greater than 95% and NPY-LI by about 50%, the functional responses upon nerve stimulation were markedly reduced. Preganglionic denervation or pretreatment with the ganglionic-blocking agent chlorisondamine did not influence the NA depletion after reserpine treatment. A considerable, adrenoceptor antagonist-resistant, long-lasting functional response as well as a markedly enhanced output of NPY-LI then occurred upon nerve stimulation. In conclusion, reserpine treatment combined with interruption of preganglionic impulse flow reveals non-adrenergic, nerve stimulation evoked splenic functional responses which could be mediated by release of a cotransmitter peptide like NPY.