Neurological Dry Eye Disease
Dry Eye Disease is more than just an eye problem.
Dry eye disease (DED) is traditionally seen as an eye problem, and treated as such. When viewed as a local manifestation of a systemic (body-wide) problem, treatment shifts. The vagus nerve is the anti-inflammatory nerve of the body and the parasympathetic nerves of the lacrimal functional unit are responsible for the majority of basal tear formation. These nerves share a neurotransmitter, that when supported by Parasym Plus EyesTM allows both the control of inflammation and increased tear production.
Dry eye is a multifactorial disease, however, with a significant inflammatory component, and all factors contributing to the condition, both local and systemic, need to be identified and treated for proper resolution of symptoms.1 If underlying systemic inflammation continues, DED and compromised overall health will also continue. Treatment based on local manifestations will offer limited relief of suffering and ocular damage.
The neurosensory and neurological component of chronic dry eye is closely involved in the inflammatory response. The neurology of tear production is complex, and when homeostasis is disrupted, symptoms can be difficult to control without addressing the underlying cause of the disruption. This underlying cause may not be a local, ocular issue (such as eczema, ocular rosacea, exposure due to thyroid disease, loss of sensitivity, or iatrogenic effects of topical medications). Systemic inflammatory conditions can also contribute to loss of homeostasis and to dry eye, and as inflammatory conditions, they can affect the neurology of tear production.
Inflammatory conditions that can cause DED include Sjogren’s syndrome, Lupus erythematosus, and rheumatoid arthritis. But chronic inflammation also affects a much larger population — the aging population, post-menopausal females, patients with metabolic syndrome, endocrine disorders, and inflammatory bowel disease also experience chronic inflammation.2,3,4,5,6,7,8 This is rarely recognized or addressed because the traditional markers of inflammation (CRP and SED rate) are often normal. Instead, measurements of inflammatory cytokines and chemokines will reveal the inflammation — difficult tests to perform and interpret clinically.
Chronic, systemic inflammation, then, often remains unrecognized, and its effect on neurological function is unaddressed. Instead, practitioners address resulting conditions such as DED locally, often resulting in incomplete recovery for the patient. Importantly, the patient’s quality of life is also diminished and additional conditions secondary to this chronic inflammation emerge.
Inflammation can have dramatic effects on neurological function, including the autonomic nervous system — the system of the body that should require no conscious effort.
Tear production is under tight neurological control, and the autonomic nervous system is at the heart of this control. This control is both a local and systemic process, and both need to be addressed in DED.
Parasympathetic Nervous System in Dry Eye
Severe dry eye often manifests as diminished tear production — the aqueous layer of tears, produced by the lacrimal gland and the accessory glands, is insufficient. Additionally, dry eye with normal (aqueous) tear production may occur due to meibomian gland dysfunction resulting in decreased formation of the lipid layer of the tears that normally prevents excessive evaporation of tears. Age or disease-related inflammation of the ocular surface can also result in chronic dry eye independent of aqueous deficiency or abnormal evaporation. 2
Aqueous tear production, meibomian gland function, and age or disease-related inflammation share common neurological processes involving the autonomic nervous system, and a close evaluation of autonomic function is warranted, but rarely considered by practitioners because of the paucity of treatment options.
The autonomic nervous system consists of the sympathetic nervous system and the parasympathetic nervous system. Tear production is primarily controlled by the parasympathetic nervous system, and involves the neurotransmitters acetylcholine and VIP (Vasoactive Intestinal Peptide).3 The parasympathetic nervous system involves minimal participation of the nicotinic acetylcholine receptors in the lacrimal functional unit — muscarinic nicotinic receptors are the type primarily responsible for tear production. This is evidenced by the use of scopolamine (a muscarinic nicotinic acetylcholine receptor antagonist) to induce dry eye in models of dry eye disease.4
Autoimmunity that damages the muscarinic acetylcholine parasympathetic receptors (mAChR) on the lacrimal gland, the accessory glands, and on the meibomian glands results in a decreased level of the lipid layer of tears as well as the aqueous component of tears.11 Poor tear production due to autoimmunity extends beyond its effect on the receptors and includes the neurological response to inflammation itself.
In Sjogren’s syndrome, for example, autoimmune cells cause infiltration of inflammatory cells into the lacrimal gland and these ultimately damage the acinar cells and their receptors, resulting in organ atrophy and dry eye. Early in the disease process, however, the parasympathetic receptors (muscarinic acetylcholine receptors) continue to function, but the postganglionic nerves do not release the neurotransmitter, acetylcholine. Interestingly, in a murine model of Sjogren’s syndrome, stimulation of these nerves did not result in release of the neurotransmitter when the nerves were infiltrated with lymphocytes. This poor response to stimulation was not due to a defect in the acinar cells because the addition of exogenous secretagogue resulted in proper secretion by these cells. Instead, the neurotransmitter release was effectively blocked by the lymphocytes (or the inflammatory cytokines and chemokines produced by these cells).12 Because the receptors can maintain their function, these receptors offer additional therapeutic targets for dry eye, bypassing the ineffective lacrimal nerves.4 When the receptors themselves are therapeutic targets, there is no dependency on a functioning nerve for proper tear production.
Systemic Inflammation in Dry Eye
Significant systemic inflammation occurs in conditions beyond autoimmune conditions, including normal aging (or “inflammaging”). Inflammaging was first named by Franceschi et al. in 2000 and includes the concept of increased and uncontrolled chronic inflammation and oxidation with normal aging. This inflammation can be most accurately measured via measurement of Type I and Type II cytokines (not by the traditional markers of CRP or SED rate). Proinflammatory, systemic cytokines, including IL-6, TNF-alpha, Il-1, IL-8, IFN-y, and IFN-b, are associated with increased morbidity and mortality in the elderly.13
Likewise, in dry eye disease, numerous studies demonstrate significantly increased ocular concentrations of cytokines IL-1b, IL-6, IL-8, IL-17, and TNF-alpha, whose levels reflect the severity of the disease.6 Is this ocular inflammation a local inflammatory state, or is it a local manifestation of a systemic inflammatory state? The distinction is critical not only for resolution of the dry eye condition, but for optimal health of the patient.
If DED is just one manifestation of systemic inflammation, supporting the body’s ability to regulate systemic inflammation is significant for both dry eye recovery and systemic wellness. In a normal, healthy patient, chronic inflammation is managed by the vagus nerve — the anti-inflammatory nerve of the body. Its release of acetylcholine controls the production of inflammatory cytokines via the alpha-7 subunit nicotinic acetylcholine receptors on inflammatory cells. When release of acetylcholine is inhibited, or the vagus nerve is damaged for any reason, this receptor is no longer able to control these inflammatory cells, resulting in chronic inflammation and the continued release of damaging inflammatory cytokines and chemokines.14
Stimulation of this nerve via a vagus nerve stimulator is an ineffective means of releasing the neurotransmitter when neurotransmitter release is affected by lymphocytes — similar to the ineffective stimulation of the lacrimal nerve in Sjogren’s syndrome. The lymphocytes (or their cytokines or chemokines) block the release of the neurotransmitter despite stimulation of the nerve. Interestingly, although the lacrimal and salivary parasympathetic receptors are primarily muscarinic and the vagus nerve receptors are nicotinic, the neurotransmitter is the same — acetylcholine. When release is not blocked by inflammatory cells, the same neurotransmitter can stimulate both types of receptors.
Stimulation of the nicotinic acetylcholine receptors (on the vagus nerve) helps to control inflammation. Stimulation of the muscarinic acetylcholine receptors (on the parasympathetic nerves of the lacrimal functional unit) promotes tear production. The combination of these two actions helps to maintain normal, moist eyes. When the neurotransmitter is not released due to (systemic) inflammation, two things occur simultaneously. Tear quantity and quality suffers, and inflammation is no longer controlled — a devastating combination to ocular and systemic health.
Identifying Low Parasympathetic Nervous System Function
Dramatically reduced parasympathetic nervous system function due to low acetylcholine levels occurs in anticholinergic syndrome (poisoning with an anticholinergic drug). If patients have not been poisoned, but are suffering with low release of acetylcholine at parasympathetic nerves due to inhibition of release by inflammatory mediators, symptoms similar to anticholinergic poisoning (but milder) should become evident. These symptoms may include constipation, gastroparesis, dry eyes, dry mouth, difficulty concentrating, light sensitivity due to large pupils, and easy agitation.
A patient population that can be used as a model of dramatically poor parasympathetic nervous system function is those with Postural Orthostatic Tachycardia Syndrome (“POTS” — a form of dysautonomia, or autonomic dysfunction).
A review of symptom checklists received by POTS patients over 5 years included 156 potential symptoms, including 36 symptoms of anticholinergic syndrome.15 Chronic dry eye was reported by 78% of these patients. A close evaluation of these symptoms revealed the following frequency of autonomic symptoms related to low release of acetylcholine, as seen in anticholinergic syndrome:
|Lack of perspiration||46|
|Decreased blood pressure when standing||78|
|Bradycardia or tachycardia||81|
|Increased body temperature||57|
|Central Nervous System Symptoms||%|
|Abnormal mood swings – almost bipolar presentation||41|
|Peripheral Nevous System Symptoms and Miscellaneous||%|
|Wakeful myoclonic jerks||74|
|Loss of coordination (ataxia)||77|
|Seeing periodic flashes of light||63|
|Seeing “dancing lines, spiders or insects||42|
|Hallucinations – auditory or visual||28|
|Warping or waving of surfaces and edges||29|
|Sensitivity to sudden sounds||96|
When viewed as a whole, these symptoms suggest, but cannot prove, low release of acetylcholine affecting the autonomic, central, and peripheral nervous systems.
The Vagus Nerve and Inflammation
Because many of the autonomic symptoms affecting POTS patients reflect poor vagus nerve function and because the vagus nerve is the anti-inflammatory nerve of the body, it is critical to understand the origin of vagus nerve problems for maximum treatment response. Concerning the vagus nerve, we must differentiate two distinct possibilities: are the nicotinic acetylcholine receptors (nAchR) damaged, or is the neurotransmitter is not being produced or released adequately for any reason (including nerve damage).
To test the nicotinic acetylcholine receptors, the author utilized an agonist for acetylcholine at the site of the postganglionic vagus nerve receptors (acetylcholine is not a drug that can be used with precision inside the human body — an agonist is required). The agonist for acetylcholine at the vagus nerve is nicotine (hence the name “nicotinic acetylcholinergic nerve” for the vagus nerve). Use of a nicotine patch immediately restored vagus nerve function in POTS patients, exhibited by reversal of constipation, gastroparesis, and gallbladder dysfunction. When the agonist for the neurotransmitter effectively stimulates the receptors, we can conclude that the receptors on the organs are viable and can be a target for treatment. This allows us to bypass the need for a functioning vagus nerve for treatment.
The symptoms affecting these patients reach beyond vagus nerve symptoms, however, suggesting that the problem with acetylcholine is a more global issue than a vagus nerve problem, involving three systems of the body — the autonomic, central, and peripheral nervous systems.
Are dry eye patients a similar, albeit more mildly affected patient population? In dry eye patients, is chronic inflammation simultaneously interfering with the release of acetylcholine at the site of the lacrimal functional unit (reducing tear production) and the vagus nerve (resulting in increased inflammation)? Is chronic DED one symptom of a systemic inflammatory problem resulting in parasympathetic nervous system dysfunction? And if so, could systemic inflammation be controlled while simultaneously increasing tear production?
Is dry eye a localized manifestation of systemic inflammation, rather than an ocular disorder alone?
Restoring Acetylcholine Levels for Nicotinic and Muscarinic Receptors
To test the hypothesis that DED is a local manifestation of systemic inflammation due to reduced release of acetylcholine, an over-the-counter supplement patented to stimulate the postganglionic vagus nerve or the nicotinic receptors on the organs served by the vagus nerve (Parasym Plus EyesTM) was used for dry eye.
A small initial group of 18 patients with dry eye were selected to participate in a double-blind placebo-controlled study using Parasym Plus EyesTM or a placebo (both oral capsules). Ocular Surface Disease Index (OSDI®) scores, corneal staining, and Tear Breakup Time (TBUT) were evaluated before treatment and one month later.
Results of testing for the treatment group:
|Initial TBUT||Final TBUT||Initial corneal staining||Final corneal staining||Initial OSDI score||Final OSDI score|
Results for the placebo group:
|Initial TBUT||Final TBUT||Initial corneal staining||Final corneal staining||Initial OSDI score||Final OSDI score|
|Improved corneal staining: 92%||Improved OSDI score: 83%|
|Improved TBUT: 75%|
|Improved corneal staining: 60%|
|Improved OSDI score: 40%|
|Improved TBUT: 60%|
Results of treatment were strongly positive. A larger study is warranted and is currently being completed. Importantly, comments by patients included systemic improvements, including normalization of bowel movements and dramatically improved cognition and short-term memory.
Dry Eye as a Systemic Inflammatory Condition
Viewing chronic dry eye as a local manifestation of systemic inflammation requires a shift in viewpoint. No longer an “eye disease”, the presentation of DED requires consideration of the patient’s general health beyond the well understood inflammatory conditions such as rheumatoid arthritis and Sjogren’s syndrome.
If DED is just one manifestation of a systemic inflammatory disorder, the quality of life of dry eye patients may be reduced beyond ocular pain and visual compromise. Patients may be suffering with diminished health they incorrectly blame on stress, a poor diet, or being tired. Fluctuating symptoms of poor concentration or constipation may be attributed to lack of rest or just getting old. Depression can be attributed to having chronic dry eyes or just not feeling good, rather than as an effect of systemic inflammation. But when corrected, renewed wellness and energy can be life-changing.
Importantly, patients with chronic dry eye may recognize few if any symptoms of low acetylcholine release beyond that of dry eye. And yet Parasym Plus EYESTM offers vagus nerve support that helps ensure their bodies can fight unwanted chronic inflammation contributing to dry eye by controlling the release of inflammatory cytokines, while also supporting the parasympathetic nerves of the lacrimal functional unit allowing normal tear production.
Treatment of DED with neurotransmitter support such as Parasym Plus EyesTM is not a panacea. Such treatment will not replace damaged meibomian glands or exposure from thyroid disease, for example. But when the problem with the neurotransmitter is not recognized and treated, response to other dry eye treatments may be incomplete, and more importantly, the patient’s quality of life will be unnecessarily reduced beyond the symptoms of dry eye.
Support for both the vagus nerve (to control inflammation) and the parasympathetic nerves of the lacrimal functional unit (to promote tear production) utilizing Parasym Plus EYESTM should be a part of every doctor’s dry eye armamentarium and can easily dove-tail into current treatment paradigms.
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2. Di Zazzo A, Micera A, Coassin M, et al. InflammAging at Ocular Surface: Clinical and Biomolecular Analyses in Healthy Volunteers. Invest Ophthalmol Vis Sci. 2019;60(5):1769-1775. doi:10.1167/iovs.18-25822
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4. Dartt DA. Neural regulation of lacrimal gland secretory processes: relevance in dry eye diseases. Prog Retin Eye Res. 2009;28(3):155-177. doi:10.1016/j.preteyeres.2009.04.003
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7. Farid M, Agrawal A, Fremgen D, et al. Age-related Defects in Ocular and Nasal Mucosal Immune System and the Immunopathology of Dry Eye Disease. Ocul Immunol Inflamm. 2016;24(3):327-347. doi:10.3109/09273948.2014.986581
8. Wang H, Yu M, Ochani M, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003;421(6921):384-388. doi:10.1038/nature01339
9. Driscoll, D. (2016). Correcting the Missing Piece in Chronic Fatigue Syndrome [white paper]. Genetic Disease Investigators, LLC. https://vagusnervesupport.com/wp-content/uploads/2017/11/Chronic-Disease-Digest-Text-Correcting-the-Missing-Piece-in-Chronic-Fatigue-Syndrome.pdf