BLOG: Neurological dry eye requires distinct treatment approach
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My journey into neurological dry eye began with the failure of my autonomic nervous system, a condition called dysautonomia.
Research into systemic inflammation and the autonomic nervous system culminated in answers for me and for many patients suffering with dry eye disease.
When the lacrimal functional unit (LFU) fails to produce an adequate aqueous layer of tears, dry eye disease (DED) results. In the setting of meibomian gland dysfunction, aqueous tear production can be adequate, but a suboptimal lipid layer leads to excessive tear evaporation. Chronic DED can also be caused by age or disease-related ocular surface inflammation.
Tear production is a neurological process that involves the autonomic nervous system. This aspect of DED is rarely explored by practitioners, however, due to a lack of treatment options.
The autonomic nervous system is comprised of sympathetic and the parasympathetic branches. The parasympathetic nervous system that regulates tear production has two neurotransmitters: acetylcholine and vasoactive intestinal peptide. DED models reveal that muscarinic nicotinic receptors in the LFU play a primary role in tear production, with nicotinic acetylcholine receptors playing a lesser role. When muscarinic acetylcholine receptors (mAChRs) on the LFU are damaged by autoimmunity, both the lipid and aqueous tear layers are decreased.
Effects of inflammation
Inflammation — both local and systemic — affects the autonomic nervous system. Take Sjögren's syndrome, for example. Early in the disease process, the parasympathetic receptors — mAChRs — maintain function, despite the fact the nerves serving the acinar cells are not effectively releasing acetylcholine. Interestingly, in a murine model of Sjögren'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. This is a good example of how inflammation affects the autonomic nervous system.
Because the receptors can maintain their function, however, the receptors offer additional therapeutic targets for dry eye, bypassing the ineffective lacrimal nerves. When the receptors themselves are therapeutic targets, there is no dependency on a functioning nerve for proper tear production.
Effects of ‘inflammaging’
Normal aging in the absence of autoimmune disease also causes chronic systemic inflammation, or so-called “inflammaging.” Type I and type II cytokines and nontraditional markers of inflammation are the most accurate measures of inflammaging.
Several proinflammatory, systemic cytokines are associated with increased morbidity and mortality in older patients, and, similarly, ocular concentrations of several cytokines correlate to the severity of DED.
Treatment options
To effectively treat DED, clinicians must dig deeper and determine if the ocular inflammation is indeed only local or an indication of systemic inflammation. If DED is but one manifestation of systemic inflammation, then the route to restoring wellness in both areas must include quelling inflammation at the systemic level. In healthy patients, the body's anti-inflammatory nerve, the vagus nerve, keeps inflammation in check via acetylcholine. When either the vagus nerve or acetylcholine release is dysfunctional, inflammation goes uncontrolled. Stimulating the nerve is ineffective, however — treatment must be directed to the receptors.
Inflammation can be controlled by stimulating nicotinic acetylcholine receptors on the vagus nerve, and tear production can be promoted by stimulating mAChRs on the parasympathetic nerves of the LFU. The result is tear homeostasis. Both of these things can be accomplished simultaneously.
This concept of DED (or NDED, neurological dry eye disease) as a localized manifestation of systemic inflammation is a dramatic departure from our traditional approach to this condition. Yet by listening closely to patients’ systemic symptoms, its presentation becomes obvious.
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