Can the Treatment of Normal-Pressure Hydrocephalus Induce Normal-Tension Glaucoma? A Narrative Review of a Current Knowledge.

Ventriculoperitoneal shunt placement is the most commonly used treatment of normal-pressure hydrocephalus (NPH). It has been hypothesized that normal-tension glaucoma (NTG) is caused by the treatment of NPH by using the shunt to reduce intracranial pressure (ICP). The aim of this study is to review the literature published regarding this hypothesis and to emphasize the need for neuro-ophthalmic follow-up for the concerned patients. The source literature was selected from the results of an online PubMed search, using the keywords "hydrocephalus glaucoma" and "normal-tension glaucoma shunt". One prospective study on adults, one prospective study on children, two retrospective studies on adults and children, two case reports, three review papers including medical hypotheses, and one prospective study on monkeys were identified. Hypothesis about the association between the treatment of NPH using the shunt to reduce ICP and the development of NTG were supported in all reviewed papers. This suggests that a safe lower limit of ICP for neurological patients, especially shunt-treated NPH patients, should be kept. Thus, we proposed to modify the paradigm of safe upper ICP threshold recommended in neurosurgery and neurology into the paradigm of safe ICP corridor applicable in neurology and ophthalmology, especially for shunt-treated hydrocephalic and glaucoma patients.

Prospective Clinical Study of Non-Invasive Intracranial Pressure Measurements in Open-Angle Glaucoma Patients and Healthy Subjects.

Background and Objective: Glaucoma is a progressive optic neuropathy in which the optic nerve is damaged. The optic nerve is exposed not only to intraocular pressure (IOP) in the eye, but also to intracranial pressure (ICP), as it is surrounded by cerebrospinal fluid in the subarachnoid space. Here, we analyse ICP differences between patients with glaucoma and healthy subjects (HSs). Materials and Methods: Ninety-five patients with normal-tension glaucoma (NTG), 60 patients with high-tension glaucoma (HTG), and 62 HSs were included in the prospective clinical study, and ICP was measured non-invasively by two-depth transcranial Doppler (TCD). Results: The mean ICP of NTG patients (9.42 ± 2.83 mmHg) was significantly lower than that of HSs (10.73 ± 2.16 mmHg) (p = 0.007). The mean ICP of HTG patients (8.11 ± 2.68 mmHg) was significantly lower than that of NTG patients (9.42 ± 2.83 mmHg) (p = 0.008) and significantly lower than that of HSs (10.73 ± 2.16 mmHg) (p < 0.001). Conclusions: An abnormal ICP value could be one of the many influential factors in the optic nerve degeneration of NTG patients and should be considered as such instead of just being regarded as a "low ICP".

The effect of nebulized dorzolamide/timolol fixed combination mist versus drops on retrobulbar blood flow and intraocular pressure in glaucoma patients.

OBJECTIVE: The aim of this study was to evaluate intraocular pressure (IOP), retrobulbar blood flow (RBF), and ocular side effects after the application of topical dorzolamide/timolol fixed combination (DTFC) drops vs topical nebulized DTFC mist in patients with primary open-angle glaucoma. MATERIAL AND METHODS: A total of 15 POAG patients were enrolled in a prospective study. Retrobulbar blood flow was measured in the ophthalmic (OA) and central retinal (CRA) arteries using color Doppler imaging. DTFC mist or drops were applied to the experimental eye, and it was examined after 15 and 60 minutes. DTFC mist was applied 6 times for 30 seconds using a misting device. RESULTS: DTFC mist significantly increased peak-systolic (PSV) and end-diastolic (EDV) velocities after 15 and 60 minutes in both the arteries (OA: increase of 12.5% and 9.6% in PSV, P=0.01; increase of 25.8% and 23.1% in EDV, P=0.03; CRA: increase of 11.5% and 8.7% in PSV, increase of 32% and 21.6% in EDV, respectively, P<0.05). DTFC drops had a similar effect on PSV and EDV in the CRA after 15 and 60 minutes (increase of 8.1% and 9.6% in PSV; increase of 17.1% and 23% in EDV, respectively, P=0.03), but a significant effect on PSV and EDV in the OA was documented only after 15 minutes (increase of 9% and 21.4%, respectively, P=0.02). DTFC mist reduced the resistance index in the CRA after 15 and 60 minutes (decrease of 8.5% and 10.2%, respectively, P=0.04). Both methodologies showed a significant decrease in IOP after 15 and 60 minutes (P<0.05). All patients complained of ocular irritation after drop application, and 1 patient complained of general weakness after mist treatment. CONCLUSIONS: Nebulized DTFC mist significantly reduced IOP and increased blood flow in the OA and the CRA, causing no ocular irritation as compared with traditional DTFC drop methodology.

The Relationship between Intracranial Pressure and Visual Field Zones in Normal-Tension Glaucoma Patients.

Growing evidence suggests that intracranial pressure (ICP) plays an important role in the pathophysiology of glaucoma, especially in normal-tension glaucoma (NTG) patients. Controversial results exist about ICP's relationship to visual field (VF) changes. With the aim to assess the relationship between ICP and VF zones in NTG patients, 80 NTG patients (age 59.5 (11.6) years) with early-stage glaucoma were included in this prospective study. Intraocular pressure (IOP) (Goldmann), visual perimetry (Humphrey) and non-invasive ICP (via a two-depth Transcranial Doppler, Vittamed UAB, Lithuania) were evaluated. Translaminar pressure difference (TPD) was calculated according to the formula TPD = IOP − ICP. The VFs of each patient were divided into five zones: nasal, temporal, peripheral, central, and paracentral. The average pattern deviation (PD) scores were calculated in each zone. The level of significance p < 0.05 was considered significant. NTG patients had a mean ICP of 8.5 (2.4) mmHg. Higher TPD was related with lower mean deviation (MD) (p = 0.01) and higher pattern standard deviation (PSD) (p = 0.01). ICP was significantly associated with the lowest averaged PD scores in the nasal VF zone (p < 0.001). There were no significant correlations between ICP and other VF zones with the most negative mean PD value. (p > 0.05). Further studies are needed to analyze the involvement of ICP in NTG management.

Quality of life in patients with age-related macular degeneration.

UNLABELLED: The aim of this study was to evaluate the quality of life in persons affected by age-related macular degeneration. MATERIAL AND METHODS: The study was performed in the Clinic of Ophthalmology, Hospital of Lithuanian University of Health Sciences. A total of 140 patients completed the Visual Functioning Questionnaire and the Hospital Anxiety and Depression Scale (HADS) during this prospective study. The patients were divided into two groups: patients with age-related macular degeneration (70 patients) and control patients (70 patients). RESULTS: There was a significant difference in the quality of life between groups (P<0.0001). Analyzing patients with age-related macular degeneration within the group (patients with monocular or binocular disorders), significant differences in near vision (P=0.003), far vision (P=0.04), color vision (P=0.01), and social functioning (P=0.02) were observed. Mental health (r=0.326, P=0.02), dependency (r=0.340, P=0.02), and role difficulties (r=0.355, P=0.01) were found to be significantly associated with general vision in the age-related macular degeneration group. CONCLUSIONS: Age-related macular degeneration appeared to have a great impact on the quality of life. General vision impairment caused by age-related macular degeneration affects patient's mental health, dependency, and role difficulties.

Prospective Pilot Clinical Study of Noninvasive Cerebrovascular Autoregulation Monitoring in Open-Angle Glaucoma Patients and Healthy Subjects.

PURPOSE: To analyze the cerebrovascular autoregulation (CA) dynamics in patients with normal-tension glaucoma (NTG) and high-tension glaucoma (HTG) as well as healthy subjects using noninvasive ultrasound technologies for the first time. METHODS: The CA status of 10 patients with NTG, 8 patients with HTG, and 10 healthy subjects was assessed, using an innovative noninvasive ultrasonic technique, based on intracranial blood volume slow-wave measurements. Identified in each participant were intraocular pressure, ocular perfusion pressure, and CA-related parameter volumetric reactivity index (VRx), as well as the duration and doses of the longest cerebral autoregulation impairment (LCAI). In addition, we calculated the associations of these parameters with patients' diagnoses. RESULTS: The VRx value, the LCAI dose, and duration in healthy subjects were significantly lower than in patients with NTG (P < 0.05). However, no significant differences were noted in these parameters between healthy subjects and HTG and between NTG and HTG groups. CONCLUSIONS: NTG is associated with the disturbed cerebral blood flow and could be diagnosed by performing noninvasive CA assessments. TRANSLATIONAL RELEVANCE: The VRx monitoring method can be applied to a wider range of patient groups, especially patients with normal-tension glaucoma.

Graphical and statistical analyses of the oculocardiac reflex during a non-invasive intracranial pressure measurement.

PURPOSE: This study aimed to examine the incidence of the oculocardiac reflex during a non-invasive intracranial pressure measurement when gradual external pressure was applied to the orbital tissues and eye. METHODS: Patients (n = 101) and healthy volunteers (n = 56) aged 20-75 years who underwent a non-invasive intracranial pressure measurement were included in this retrospective oculocardiac reflex analysis. Prespecified thresholds greater than a 10% or 20% decrease in the heart rate from baseline were used to determine the incidence of the oculocardiac reflex. RESULTS: None of the subjects had a greater than 20% decrease in heart rate from baseline. Four subjects had a greater than 10% decrease in heart rate from baseline, representing 0.9% of the total pressure steps. Three of these subjects were healthy volunteers, and one was a glaucoma patient. CONCLUSION: The incidence of the oculocardiac reflex during a non-invasive intracranial pressure measurement procedure was very low and not associated with any clinically relevant effects.

Cognitive functions and normal tension glaucoma.

PURPOSE: Only a few studies have analyzed the potential link between glaucoma and cognitive function impairment. They have found controversial results. This study aims to perform quick cognitive function assessment with clock drawing test (CDT) using two different scoring systems and compare between normal tension glaucoma (NTG) and cataract patients. METHODS: Totally, 30 NTG and 30 patients with cataracts were included in a prospective, pilot study. The predrawn circle was given, and patients were asked to draw the clock showing a time of 11:10. The test was evaluated using two methods - Freund method using a 7-point scoring scale (optimal cutoff ≤4) and Rakusa using a 4-point scoring scale (optimal cutoff ≤3). The level of significance was set at P < 0.05. RESULTS: CDT result was significantly better in cataract group than in NTG group: 3.5 (2) versus 2 (2) by Freund, (P = 0.003) and 6.5 (1) versus 4.5 (2.75) by Rakusa, respectively (P = 0.004). Sixty percent (n = 18) of NTG group and 10% (n = 3) of cataract group patients completed the CDT in the specific picture manner (the short hand on 11 and the long hand between 11 and 12), (P = 0.001). CONCLUSIONS: Lower CDT results were seen in NTG patients according to two different scoring systems. NTG patients showed a specific manner of drawing. Further prospective studies are needed to investigate the CDT reliability as fast screening test of cognitive function impairment in glaucoma patients.

Location of the internal carotid artery and ophthalmic artery segments for non-invasive intracranial pressure measurement by multi-depth TCD.

The aim of the present study was to locate the ophthalmic artery by using the edge of the internal carotid artery (ICA) as the reference depth to perform a reliable non-invasive intracranial pressure measurement via a multi-depth transcranial Doppler device and to then determine the positions and angles of an ultrasonic transducer (UT) on the closed eyelid in the case of located segments. High tension glaucoma (HTG) patients and healthy volunteers (HVs) undergoing non-invasive intracranial pressure measurement were selected for this prospective study. The depth of the edge of the ICA was identified, followed by a selection of the depths of the IOA and EOA segments. The positions and angles of the UT on the closed eyelid were measured. The mean depth of the identified ICA edge for HTG patients was 64.3 mm and was 63.0 mm for HVs (p = 0.21). The mean depth of the selected IOA segment for HTG patients was 59.2 mm and 59.3 mm for HVs (p = 0.91). The mean depth of the selected EOA segment for HTG patients was 48.5 mm and 49.8 mm for HVs (p = 0.14). The difference in the located depths of the segments between groups was not statistically significant. The results showed a significant difference in the measured UT angles in the case of the identified edge of the ICA and selected ophthalmic artery segments (p = 0.0002). We demonstrated that locating the IOA and EOA segments can be achieved using the edge of the ICA as a reference point. ABBREVIATIONS: OA: ophthalmic artery; IOA: intracranial segments of the ophthalmic artery; EOA: extracranial segments of the ophthalmic artery; ICA: internal carotid artery; UT: ultrasonic transducer; HTG: high tension glaucoma; SD: standard deviation; ICP: intracranial pressure; TCD: transcranial Doppler.

Neuroretinal rim area and ocular haemodynamic parameters in patients with normal-tension glaucoma with differing intracranial pressures.

PURPOSE: To assess the differences in the neuroretinal rim area (NRA) and ocular haemodynamic parameters in patients with normal-tension glaucoma (NTG) with differing intracranial pressure (ICP) values. METHODS: 40 patients (11 males) with NTG (age 61.1 (11.5)) were included in the prospective study. Intraocular pressure (IOP), non-invasive ICP, retrobulbar blood flow (RBF) and confocal laser scanning tomography for optic nerve disc (OND) structural parameters were assessed. Non-invasive ICP was measured using a novel two-depth Transcranial Doppler device. RBF was measured using colour Doppler imaging in the ophthalmic artery (OA). The patients were divided into two groups, ICP ≥ and <8.3 mm Hg, based on the statistical median of ICP. p Values <0.05 were considered statistically significant. RESULTS: Patients with NTG had mean ICP 8.8 (2.5) mm Hg, IOP 13.6 (2.1) mm Hg, OND size 2.3 (0.6) mm(2), NRA 1.2 (0.4) mm(2). Lower ICP was correlated with decreased NRA (r=0.51, p=0.001). Patients with NTG having lower ICP (N=20) had significantly lower NRA 1.0 (0.3) mm(2), than patients with NTG having higher ICP (N=20) 1.3 (0.3) mm(2), p=0.002, although there were no significant differences in OND size (accordingly, 2.2 (0.5) and 2.3 (0.6) mm(2), p=0.55) and IOP (accordingly, 13.5 (2.4) and 13.7 (1.8) mm Hg, p=0.58). Patients with NTG having lower ICP had significantly lower OA blood flow velocities (peak systolic volume (PSV) 28.7 (8.0), end-diastolic volume (EDV) 6.9 (3.0) cm/s), compared with patients with NTG having higher ICP (PSV 35.5 (10.2), EDV 9.4 (4.1) cm/s), p<0.04. CONCLUSIONS: Patients with NTG having lower ICP have decreased neuroretinal rim area and OA blood flow parameters compared with patients having higher ICP. Further longitudinal studies are needed to analyse the involvement of ICP in NTG management.

Update in intracranial pressure evaluation methods and translaminar pressure gradient role in glaucoma.

Glaucoma is one of the leading causes of blindness worldwide. Historically, it has been considered an ocular disease primary caused by pathological intraocular pressure (IOP). Recently, researchers have emphasized intracranial pressure (ICP), as translaminar counter pressure against IOP may play a role in glaucoma development and progression. It remains controversial what is the best way to measure ICP in glaucoma. Currently, the 'gold standard' for ICP measurement is invasive measurement of the pressure in the cerebrospinal fluid via lumbar puncture or via implantation of the pressure sensor into the brains ventricle. However, the direct measurements of ICP are not without risk due to its invasiveness and potential risk of intracranial haemorrhage and infection. Therefore, invasive ICP measurements are prohibitive due to safety needs, especially in glaucoma patients. Several approaches have been proposed to estimate ICP non-invasively, including transcranial Doppler ultrasonography, tympanic membrane displacement, ophthalmodynamometry, measurement of optic nerve sheath diameter and two-depth transcranial Doppler technology. Special emphasis is put on the two-depth transcranial Doppler technology, which uses an ophthalmic artery as a natural ICP sensor. It is the only method which accurately and precisely measures absolute ICP values and may provide valuable information in glaucoma.

Effect of Trabeculectomy on Ocular Hemodynamic Parameters in Pseudoexfoliative and Primary Open-angle Glaucoma Patients.

PURPOSE: To evaluate the effects of trabeculectomy on ocular hemodynamic parameters in pseudoexfoliative glaucoma (PXG) and primary open-angle glaucoma (POAG) patients and to analyze serum antiphospholipid antibody levels (APLAs) in PXG. METHODS: Thirty open-angle glaucoma patients were included in the prospective study. Intraocular pressure (IOP), ocular perfusion pressure (OPP), blood pressure, and pulsatile ocular blood flow (POBF) were measured. Retrobulbar blood flow (RBF) was measured using the color Doppler imaging. Venous blood samples were obtained from PXG patients; APLAs IgG levels were assessed. The level of significance was P<0.05. RESULTS: IOP decreased significantly in both groups after trabeculectomy [from 30.1 (7.2) to 15.0 (5.1) in PXG; from 29.1 (7.7) to 13.1 (5.5) in POAG, P<0.05]. OPP increased from 38.9 (10.3) to 55.5 (8.6) in PXG and from 40.9 (11.0) to 56.7 (8.9) in POAG group, P<0.05. Both groups showed significant increase in CRA PSV [from 8.75 (2.27) to 9.79 (2.31) in PXG and from 8.55 (2.59) to 10.11 (2.64) in POAG, P<0.05]. Both groups showed an increase in POBF [from 13.09 (3.41) to 18.81 (5.70) in PXG and from 11.89 (5.79) to 19.29 (9.02) in POAG, P<0.05). Patients with normal APLAs levels showed significant decrease in IOP [from 30.7 (8.1) to 15.2 (5.9)] and increase in POBF [from 13.24 (3.69) to 19.94 (5.03)], CRA PSV [from 8.78 (2.39) to 9.46 (2.17)], and tSPCA PSV [from 7.61 (2.15) to 8.35 (1.98)], P<0.05. CONCLUSIONS: Trabeculectomy resulted in a significant decrease in IOP and increase in ocular blood flow. Effects of trabeculectomy in PXG patients were significantly less compared with POAG. Patients with normal APLA levels had a significant increase in ocular hemodynamic parameters compared with patients with higher APLAs levels.

The difference in translaminar pressure gradient and neuroretinal rim area in glaucoma and healthy subjects.

Purpose. To assess differences in translaminar pressure gradient (TPG) and neuroretinal rim area (NRA) in patients with normal tension glaucoma (NTG), high tension glaucoma (HTG), and healthy controls. Methods. 27 patients with NTG, HTG, and healthy controls were included in the prospective pilot study (each group consisted of 9 patients). Intraocular pressure (IOP), intracranial pressure (ICP), and confocal laser scanning tomography were assessed. TPG was calculated as the difference of IOP minus ICP. ICP was measured using noninvasive two-depth transcranial Doppler device. The level of significance P < 0.05 was considered significant. Results. NTG patients had significantly lower IOP (13.7(1.6) mmHg), NRA (0.97(0.36) mm(2)), comparing with HTG and healthy subjects, P < 0.05. ICP was lower in NTG (7.4(2.7) mmHg), compared with HTG (8.9(1.9) mmHg) and healthy subjects (10.5(3.0) mmHg); however, the difference between groups was not statistically significant (P > 0.05). The difference between TPG for healthy (5.4(7.7) mmHg) and glaucomatous eyes (NTG 6.3(3.1) mmHg, HTG 15.7(7.7) mmHg) was statistically significant (P < 0.001). Higher TPG was correlated with decreased NRA (r = -0.83; P = 0.01) in the NTG group. Conclusion. Translaminar pressure gradient was higher in glaucoma patients. Reduction of NRA was related to higher TPG in NTG patients. Further prospective studies are warranted to investigate the involvement of TPG in glaucoma management.

Ophthalmic drug delivery in glaucoma-a review.

Glaucoma is a progressive optic neuropathy and medical therapy is the initial option for the treatment of this potentially blinding condition. Topical instillation of eye drops from the bottle is the most common glaucoma drug delivery form. Due to limited permeability of anterior ocular surface, natural clearance and drainage, eye drops contain large amounts of inactive ingredients. Effective penetration enhancers are known as irritants causing ocular discomfort. Although drug efficacy is determined by active ingredients, inactive agents can affect tolerance and can result in conjunctival irritation and hyperemia and influence patients' adherence and quality of life.

Photodynamic therapy and central serous chorioretinopathy.

Central serous chorioretinopathy is a common acquired maculopathy. Multiple studies showed that photodynamic therapy is useful treatment for acute and chronic central serous chorioretinopathy. The exact mechanism of photodynamic therapy in treating central serous chorioretinopathy is not clear, but it is thought to be caused by short-term choriocapillaris hypoperfusion and long-term choroidal vascular remodeling, leading to a reduction in choroidal congestion, vascular hyperpermeability and extravascular leakage. Furthermore, photodynamic therapy seems to be an effective means of improving or stabilizing visual acuity in patients with central serous chorioretinopathy.

Comparison of intraocular pressure, blood pressure, ocular perfusion pressure and blood flow fluctuations during dorzolamide versus timolol add-on therapy in prostaglandin analogue treated glaucoma subjects.

OBJECTIVE: To compare the effects of dorzolamide and timolol add-on therapy in open-angle glaucoma (OAG) patients previously treated with prostaglandin analogue (Pg), by evaluating fluctuations in the intraocular (IOP), blood (BP), ocular perfusion pressures (OPP) and retrobulbar blood flow (RBF) parameters. METHODS: 35 OAG patients (35 eyes), 31 women (88.6%) age 63.3 (8.9) years were evaluated in a 3 month randomized, cross-over, single-masked study. During the experiments BP, heart rate, IOP and OPP were assessed 4 times per day (8-12-16-20 h). RBF was measured twice per day (8-20 h) using Color Doppler imaging in the ophthalmic (OA), central retinal (CRA), nasal (nSPCA) and temporal (tSPCA) posterior ciliary arteries. In each vessel, peak systolic velocity (PSV) and end-diastolic velocity (EDV) were assessed and vascular resistance (RI) calculated. RESULTS: Both add-on therapies lowered IOP in a statistically significant manner from 15.7 ± 2.4 mmHg at latanoprost baseline to 14.9 ± 2.2 mmHg using dorzolamide (p < 0.001) and 14.2 ± 1.9 mmHg using timolol (p < 0.001). The IOP lowering effect was statistically significant at 20 h, favoring timolol as compared to dorzolamide (1.4 ± 2.4 vs. 0.2 ± 2.1 mmHg), (p < 0.05). Dorzolamide add-on therapy showed smaller IOP (2.0 ± 1.4), SPP (13.3 ± 7.9), systolic BP (13.5 ± 8.7) and diastolic BP (8.4 ± 5.4) fluctuations as compared to both latanoprost baseline or timolol add-on therapies. Higher difference between morning and evening BP was correlated to decreased evening CRA EDV in the timolol group (c = -0.41; p = 0.01). With increased MAP in the morning or evening hours, we found increased evening OA RI in timolol add-on group (c = 0.400, p = 0.02; c = 0.513, p = 0.002 accordingly). Higher MAP fluctuations were related to impaired RBF parameters during evening hours-decreased CRA EDV (c = -0.408; p = 0.01), increased CRA RI (c = 0.576; p < 0.001) and tSPCA RI (c = 0.356; p = 0.04) in the dorzolamide group and increased nSPCA RI (c = 0.351; p = 0.04) in the timolol add-on group. OPP fluctuations correlated with increased nSPCA RI (c = 0.453; p = 0.006) in the timolol group. OPP fluctuations were not related to IOP fluctuations in both add-on therapies (p < 0.05). CONCLUSIONS: Both dorzolamide and timolol add-on therapies lowered IOP in a statistically significant fashion dorzolamide add-on therapy showed lower fluctuations in IOP, SPP and BP. Higher variability of daytime OPP led to impaired RBF parameters in the evening.

The Effect of Diluted Penetration Enhancer in Nebulized Mist versus Liquid Drop Preparation Forms on Retrobulbar Blood Flow in Healthy Human Subjects.

The aim of this study was to compare the effects of nebulized mist and liquid drop applications on retrobulbar blood flow. A prospective, non-randomized clinical trial was used to collect data from 40 healthy human eyes. Color Doppler Imaging determined peak systolic (PSV) and end diastolic (EDV) blood flow velocities and resistance index (RI) in the ophthalmic artery after both applications. Measurements were taken at baseline and at 1 min post-treatment in both eyes with 5 min measurements in the treatment eye only. p values ≤ 0.05 were considered statistically significant. Mist application to treatment eye produced an increase in 1 min and 5 min PSV and EDV (0.001 < p < 0.03) and a decrease in 5 min RI (p = 0.01), with no significant changes in PSV, EDV or RI of control eye or in treatment eye 1 min RI (p > 0.05). Drop application to treatment eye produced an increase in PSV (p < 0.001) and EDV (p = 0.01) at 1 min, with an increase in control eye 1 min PSV and EDV (p = 0.03). There were no statistically significant changes in treatment eye PSV, EDV and RI after 5 min (p > 0.05). The use of nebulized mist may provide an effective alternative to liquid drop medication application.