Sphenopalatine Ganglion Stimulation for Ocular and Oral Dryness

Study Overview
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Brief Summary
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Dry Eye Disease (DED) is a multifactorial pathology characterized by inflammation of the lacrimal functional unit that develops in ocular surface pathology, severely affecting patients quality of life. The core of the treatment relies at present in antinflammatory topical therapies, which are still scarce. The investigators hypothesize that osteopathy-based techniques may help these patients by influencing the central involvement regarding parasympathetic innervation of tear and saliva-secreting glands. The aim of this osteopathic treatment protocol is to release the involved structures in the tear-secreting system innervation, such as the sphenopalatine ganglion. In addition, this ganglion innervates the minor salivary glands, therefore it is intended to help patients suffering from xerostomia. The hypothesis then is that a systemic protocol treatment can help balance both parts of the vegetative nervous system (sympathetic and parasympathetic) with the objective of increasing the secretion of tear and saliva in patients with ocular and oral dryness (DED and xerostomia, respectively), thus improving their clinical situation. This osteopathic protocol does not have the potential to cause adverse effects. The main objective is to analyze the efficacy of this protocol application in terms of improving symptoms and signs of ocular and oral dryness, tear film quality and inflammation molecule levels in tears and saliva.

Detailed Description
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This clinical study intended to offer an alternative therapeutic tool for a disease, dry eye, that is highly prevalent, causes a decreased in the quality of life and work productivity, and whose pharmacologic treatment is very limited. The osteopathy protocol consists of an initial assessment of the cranial vault and 7 techniques through which the different structures involved are treated and are as follows: 1) balance of the cranio-sacral system; 2) reharmonization of sphenobasilar synchondrosis; 3) and 4) release of the bony components in the pterygo-palatine fossa (maxillas and sphenoid); 5) and 6) release of the bony components in relation with the main lacrimal gland (frontal and front-malar suture); and 7) sphenopalatine ganglion stimulation. The patient is always in supine position and the investigator is standing on the side. The proposed osteopathy protocol is innocuous, with no possible adverse effects. The main objective is to analyze the efficacy of this protocol application in terms of improving symptoms and signs of ocular and oral dryness, tear film quality and inflammation molecule levels in tears and saliva. Recruited patients will have dry eye disease (and subsequently ocular dryness) and oral dryness (xerostomia). Inclusion/exclusion criteria are detailed in the corresponding section below, as well as all outcome measures. All COVID19-related sanitary regulations will be strictly followed.

Official Title
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Efficacy of the Sphenopalatine Ganglion Stimulation Osteopathic Protocol in Patients With Ocular and Oral Dryness

Conditions
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Dry Eye Disease, Xerostomia

Intervention / Treatment
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* Other: Osteopathic protocol of Sphenopalatine Ganglion Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: > 18 years old. Patients diagnosed with Dry eye disease (DED) and suffering symptoms of ocular and oral dryness for at least 6 months. Dry eye symptoms must have a score of > 2 (0-4 range) in mSIDEQ questionnaire. Ocularly symptomatic patients (OSDI > 12) despite the medication, medical devices and/or therapeutic measures carried out until the inclusion. Symptomatic patients in terms of oral dryness (XI-Sp > 11) despite the medication, medical devices and/or therapeutic measures carried out until the inclusion. Schirmer I test, without topical anesthesia, must have an initial value of ≥ 1 mm and <10 mm. Not included in any other clinical pharmacological trial or study (medical devices are excluded) in the last 3 months. Signed informed consent and ability to complete all study visits. Exclusion Criteria: Irreversible anatomical alteration of the lacrimal glands (watery, sebaceous or mucinic) or salivary, surgeries or by healing processes that affect eyelids and/or conjunctiva. Alteration in the autonomic nervous system. Another active ocular surface disease different from that caused by DED. Oral diseases, inflammations or acute injuries in the mouth (trauma, surgical intervention, etc.) in the last month or healing processes of the oral mucosa. Use of cyclosporine or topical tacrolimus started within < 3 months and/or steroids or blood derivatives started within < 1 month and that will not be maintained during the study. Use of orally drugs with exocrine hyposecretory side effects or that may affect the parasympathetic nervous system, unless the dose is stable during the previous month to inclusion and whose dose is not expected to vary throughout this study. Patients may be using any other medication, topical or systemic, unless the dose are the same for the duration of the study. Patients may be using artificial tears, moisturizers in general or blood derivatives, unless the dose was the same in the last month and has to be maintained at the same dose for the duration of the study. To have had any in-office method to manage DED or Meibomian gland dysfunction (pulsed light, thermal massages, etc.) in the last 6 months. Occlusion of the lacrimal puncta in the last month. Local (in cranial sphere) or general anesthesia in the last 3 months. Use of contact lenses, unless they stop using them for at least one week before inclusion and one week before each visit

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Mild dry eye disease<br>Osteopathic protocol of sphenopalatine ganglion stimulation | Other: Osteopathic protocol of Sphenopalatine Ganglion Stimulation<br>* Sphenopalatine Ganglion Stimulation to improve lacrimal and salivary gland secretion to improve ocular and oral dryness<br>|
| Other: Moderate dry eye disease<br>Osteopathic protocol of sphenopalatine ganglion stimulation | Other: Osteopathic protocol of Sphenopalatine Ganglion Stimulation<br>* Sphenopalatine Ganglion Stimulation to improve lacrimal and salivary gland secretion to improve ocular and oral dryness<br>|
| Other: Severe dry eye disease<br>Osteopathic protocol of sphenopalatine ganglion stimulation | Other: Osteopathic protocol of Sphenopalatine Ganglion Stimulation<br>* Sphenopalatine Ganglion Stimulation to improve lacrimal and salivary gland secretion to improve ocular and oral dryness<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ocular Surface Disease Index (OSDI) | Score value 0-48, where higher score means a worse outcome. | 6 Weeks | 
| Ocular Surface Disease Index (OSDI) | Score value 0-48, where higher score means a worse outcome. | 18 Weeks | 
| Modified Single-Item Score Dry Eye-Questionnaire (mSIDEQ) | Score value 0-28, where higher score means a worse outcome | 6 Weeks | 
| Modified Single-Item Score Dry Eye-Questionnaire (mSIDEQ) | Score value 0-28, where higher score means a worse outcome | 18 Weeks | 
| Visual analogue Scale (VAS) | Unique measurements 0-10, where higher score means a worse outcome | 6 Weeks | 
| Visual analogue Scale (VAS) | Unique measurements 0-10, where higher score means a worse outcome | 18 Weeks | 
| Change in Dry Eye Symptoms Questionnaire (CDES-Q) | First question compares how the patient is at the moment compared with last session in terms of Equal, Better or Worse. If better or worse is chose, two more questions measure how much improvement or worsening from a 0-10 scale, where higher score means a worse outcome. | 6 Weeks | 
| Change in Dry Eye Symptoms Questionnaire (CDES-Q) | First question compares how the patient is at the moment compared with last session in terms of Equal, Better or Worse. If better or worse is chose, two more questions measure how much improvement or worsening from a 0-10 scale, where higher score means a worse outcome. | 18 Weeks | 
| Statistically significant amelioration in oral symptoms | Enhancement in Xerostomia Inventory Spanish version (XI-Sp) test score 0-11, where higher score means a worse outcome. | 6 Weeks | 
| Statistically significant amelioration in oral symptoms | Enhancement in Xerostomia Inventory Spanish version (XI-Sp) test score 0-11, where higher score means a worse outcome. | 18 Weeks | 
| Statistically significant improvement in tear secretion | Schirmer I test, which test score is 0-35 mm, where lower score means a worse outcome. | 6 Weeks | 
| Statistically significant improvement in tear secretion | Schirmer I test, which test score is 0-35 mm, where lower score means a worse outcome. | 18 Weeks | 
| Statistically significant improvement in salivary discharge | Salivary flow rate, where flow rate below 0,1ml flow is considered hyposalivation. | 6 Weeks | 
| Statistically significant improvement in salivary discharge | Salivary flow rate, where flow rate below 0,1ml flow is considered hyposalivation. | 18 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Decrease in tear collection time | Statistically significant improvement in tear collection time, using a microcapillar of 1μl. | 18 Weeks | 
| Increased salivary flow rate | Statistically significant increased salivary flow rate, using Modified Fox Sreebny Technique. | 18 Weeks | 
| Lipiflow interferometry - lipid layer thickness | Statistically significant improvement in lipid layer thickness using Interferometry with Lipiview. | 18 Weeks | 
| Lipiflow interferometry - incomplete blink rate | Statistically significant improvement in incomplete blink rate using Interferometry with Lipiview. | 18 Weeks | 
| Lipiflow interferometry - c-factor | Statistically significant improvement in c-factor, using Interferometry with Lipiview. | 18 Weeks | 
| Enhancement in Break-Up Time Test | Statistically significant enhancement in Break-Up Time Test (normal >7 seconds) where lower score means a worse outcome. | 18 Weeks | 
| Corneal Staining | Statistically significant enhancement in Corneal Staining, using Oxford Scale and Cornea and Contact Lens Research Unit (CCLRU) Scale, score 0-5 where higher scores means worse outcome. | 18 Weeks | 
| Significant beneficial change in molecules evaluated in tear or saliva | The following putative salivary indicators of pain are assayed by enzyme-linked immunosorbent assay (ELISA): Cortisol (DRG Salivary Cortisol ELISA (DRG Instruments GmbH, Marburg, Germany), testosterone (DRG Instruments GmbH), sTNFαRII (Quantikine, Human sTNF RII/TNFRSF1B Immunoassay, R&D Systems, Minneapolis, MN, USA). sAA is | 18 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tear cytokines, dry eye disease, dryness, osteopathy, Keratoconjunctivitis sicca, Saliva cytokines, Saliva-producing glands, Sjögren´s syndrome, Sphenopalatine ganglion, Tear-producing glands, Tear film, Xerostomia