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I wrote this post in response to a question by Rebecca who asked me to explain better some statements in my previous posts regarding heat compresses anddry eye inflammation in general.
As I was posting in a hurry, I want to apologize that I failed to provide the proper back up explanation of what I was trying to say, so that is why I am post my reply to her here in a separate thread and will appreciate your feedback and thoughts, as we are all struggling to get a better understanding of this disease and the pros and cons of current treatments. Tha was my post:
Dear Rebecca,
I am taking this information from various textbooks on ophthalmology which I have been reading in a library, including their electronic database. That is why it s hard for me to keep a bibliography of what I have read.
But basically, to summarize, medical science defines dry eye, Keratoconjuctivitis sicca (KCS) as a chronic inflammatory disease notably characterized by the deficient production of the aqueous portion of the tear film (quantitative disorder) or the inadequate production of the lipid layer which leads to evaporative (qualitative disorder) or combination of the two.the disease causes damage to the corneal and conjuctval surface and varies in severity.
The corneal-conjuctival inflammation is mainly characterized by T-cell infiltration in the lacrimal glands (meiboian glands as well),and responds to immunosuppressive therapy with different agents, the only one of which approved for ophthalmic use in humans being cyclosporine A and various steroid preparations.
The pathogenesis of idiopathic KCS in humans has been established as follows--
epithelial cells of the conjuctiva regularly secrete antigens or cellular proteins. In normal states, these antigens are recognized by antigen-presenting cells (antigen presentation by Langerhans and dendritic cells) and then presented to effector lymphocytes on the ocular surface. In parallel, regulatory lymphocytes which are also present block the action of effector lymphocytes, thus preventing the development of an inflammatory state and maintaining local immunohomeostasis.
(topical immunosuppressants like CsA for ex. interfere with the antigen presentation as a first step in their immunomodulatry action;later on they deactivate other factors involved in the inflammation)
This pathway of antigen presentation is regulated by androgens which are responsible for the regulation of the production of transforming growth factor beta (TGF-beta), whose function is to reduce local prolactin concentration.Conditions such as senility and other idiopathic factors may reduce the production of androgen hormones, leading to changes in conjuctival homeostasis due to reduced production of TGF_beta and increased prolactin concentration in conjuctival epithelial cells. This alters local antigen detection, favoring the effector lymphocyte pathway and thus triggering local inflammation.
after the effector lymphocytes are activated they start an inflammatory cascade which involves many molecules and other cells and substances, like cytokines, TNF-alpha, etc. Various proinflammatory cytokines that may cause cellular destruction, including interleukin 1 (IL-1), interleukin 6 (IL-6), interleukin 8 (IL-8), TGF-beta, TNF-alpha, and RANTES, are altered in patients with KCS. IL-1 beta and TNF-alpha, which are present in the tears of patients with KCS, cause the release of opioids that bind to opioid receptors on neural membranes and inhibit neurotransmitter release through NF-K b production. IL-2 also binds to the delta opioid receptor and inhibits cAMP production and neuronal function. This loss of neuronal function diminishes normal neuronal tone, leading to sensory isolation of the lacrimal gland and eventual atrophy.(this is where doctors try to compensate by prescribing pilocarpine which is the substitute or acetylcholine, a major neurotransmitter stimulating the tear gland to excrete tears; cyclosporine also acts as a tear gland stimulator besides bein antiinflammatory).
Proinflammatory neurotransmitters (these are neurotransmitters that activate inflammatory cells), such as substance P and calcitonin gene related peptide (CGRP), are released, which recruit and activate local lymphocytes. Substance P also acts via the NF-AT and NF-K b signaling pathway leading to ICAM-1 and VCAM-1 expression, adhesions molecules that promote lymphocyte homing and chemotaxis to sites of inflammation. Cyclosporin A is an NK-1 and NK-2 receptor inhibitor that can downregulate these signaling molecules and is a prominent addition to the therapeutic armamentarium for dry eye, being used to treat both aqueous tear deficiency and meibomian gland dysfunction. It has been shown to improve the goblet cell counts and to reduce the numbers of inflammatory cells and cytokines in the conjunctiva.
These cytokines, in addition to inhibiting neural function, may also convert androgens into estrogens, resulting in meibomian gland dysfunction, as discussed above. An increased rate of apoptosis is also seen in conjunctival and lacrimal acinar cells, perhaps due to the cytokine cascade. Elevated levels of tissue-degrading enzymes called matrix metalloproteinases (MMPs) are also present in the epithelial cells. The latter can be deactivated with doxycyline or other tetracyclines that chelate substnces needed for the production of the enzymes.
There may be many reasons for the onset of dryness in the eye. But whatever the reason (for example surgery like LASIK disrupts the nerve signalling so in that case the inflammation starts after the neural isolation of the lacrimal gland), the inflammatory cascade that is involved is autoimmune and self-perpetuating in essence. Some new treatments may be developed involving stimulating the Nerve Growth Factor on the ocular surface to compensate the initial surgery damage or subsequent inflammatory damage of the corneal nerves.
For now,treatment goes as follows: after doctors establish that eyelid hygiene, artificial tears,and removal of exacerbating factors is not enough to maintain the patient, they go on to add anti-inflammatory therapy which starts with topical steroids
and NSAIDS
and immunosuppressants like cyclosporine(which is also a potent lacrimostimulant)
and tetracyclines,
moisture chambers
and secretagogues like pilocarpine(which is a substitute for the neurotransmitter acetylcholine which stimulates the lacrimal glands to excrete tears; that also keeps them functional),
punctal occlusion.
In more severe cases that do not imrove on the latter therapy, the immunosuppressants are taken by mouth or intravenously.
Antiinflammatory therapy with lacrimostimulation is essential in the halting of the progression of the disease especially when it comes to corneal surface damage which is not only measured by staining and erosions; it is the loss of goblet cells and neural desensitization and isolation of the lacrimal glands.
However, as we all know,antiinflammatory therapy cannot remain the mainstay of dry eye treatment in the future, as it only controls the progress of the disease without curing it. The answer will most probably be a combination of hormone and nerve growth factor therapies with stem cell therapy. But that seems to be feasible in hte far future indeed. For now what doctors can do is firefight the consequences of an activated inflammatory cascade.
Doctors started me on antiinflammatories after my eyes were totally devastated-- I had developed filamentary keratitis (mucous strings and plaques set deep in the surface of th cornea that severely damage the corneal surface), prominent corneal oedema, severe erosions and ulcers, episcleritis, severe inflammation, etc. That is when they decided that I need something more than artificial tears an lid hygiene. It was too late. Now I have to live with the irreversible complications of this disease. If antiinflammatry therapy was started earlier, I would have been much better.
Oh, I forgot to mention for everyone-- never take sulfonamide antibiotics-- they are a direct cause of dry eye-- T cells respond to haptens generated by oxidative metabolites derived from these substances. So there you have another cause of dry eye. But whatever the cause is, it always involves an element of self-perpetuating inflammation and subsequent neural isolation of the lacrimal glands.
regarding heat compresses-- I can accept warm compresses, but about hot ones I don't know. All the processes I described above are intensified by heat and slowed down by cold. That patients get temporary symptomatic relief from the hot compress may be one thing, but the long-term impact on the actual underlying disease does not seem to be very good.I am not giving advice against using hot compresses.It is upt to every individual and how they feel to use or not to use something. There is hardly any medication for dry eye anyway, that does not have various degrees of potentially dangerous side effects.
And in the end,dear Rebecca, I would like to thank you for giving me the opportunity to share my experience on this wonderful forum, and for all your efforts that have helped ease so much suffering, including mine.
Please let me know your thoughts on my post. I truly appreciate your feedback.
As I was posting in a hurry, I want to apologize that I failed to provide the proper back up explanation of what I was trying to say, so that is why I am post my reply to her here in a separate thread and will appreciate your feedback and thoughts, as we are all struggling to get a better understanding of this disease and the pros and cons of current treatments. Tha was my post:
Dear Rebecca,
I am taking this information from various textbooks on ophthalmology which I have been reading in a library, including their electronic database. That is why it s hard for me to keep a bibliography of what I have read.
But basically, to summarize, medical science defines dry eye, Keratoconjuctivitis sicca (KCS) as a chronic inflammatory disease notably characterized by the deficient production of the aqueous portion of the tear film (quantitative disorder) or the inadequate production of the lipid layer which leads to evaporative (qualitative disorder) or combination of the two.the disease causes damage to the corneal and conjuctval surface and varies in severity.
The corneal-conjuctival inflammation is mainly characterized by T-cell infiltration in the lacrimal glands (meiboian glands as well),and responds to immunosuppressive therapy with different agents, the only one of which approved for ophthalmic use in humans being cyclosporine A and various steroid preparations.
The pathogenesis of idiopathic KCS in humans has been established as follows--
epithelial cells of the conjuctiva regularly secrete antigens or cellular proteins. In normal states, these antigens are recognized by antigen-presenting cells (antigen presentation by Langerhans and dendritic cells) and then presented to effector lymphocytes on the ocular surface. In parallel, regulatory lymphocytes which are also present block the action of effector lymphocytes, thus preventing the development of an inflammatory state and maintaining local immunohomeostasis.
(topical immunosuppressants like CsA for ex. interfere with the antigen presentation as a first step in their immunomodulatry action;later on they deactivate other factors involved in the inflammation)
This pathway of antigen presentation is regulated by androgens which are responsible for the regulation of the production of transforming growth factor beta (TGF-beta), whose function is to reduce local prolactin concentration.Conditions such as senility and other idiopathic factors may reduce the production of androgen hormones, leading to changes in conjuctival homeostasis due to reduced production of TGF_beta and increased prolactin concentration in conjuctival epithelial cells. This alters local antigen detection, favoring the effector lymphocyte pathway and thus triggering local inflammation.
after the effector lymphocytes are activated they start an inflammatory cascade which involves many molecules and other cells and substances, like cytokines, TNF-alpha, etc. Various proinflammatory cytokines that may cause cellular destruction, including interleukin 1 (IL-1), interleukin 6 (IL-6), interleukin 8 (IL-8), TGF-beta, TNF-alpha, and RANTES, are altered in patients with KCS. IL-1 beta and TNF-alpha, which are present in the tears of patients with KCS, cause the release of opioids that bind to opioid receptors on neural membranes and inhibit neurotransmitter release through NF-K b production. IL-2 also binds to the delta opioid receptor and inhibits cAMP production and neuronal function. This loss of neuronal function diminishes normal neuronal tone, leading to sensory isolation of the lacrimal gland and eventual atrophy.(this is where doctors try to compensate by prescribing pilocarpine which is the substitute or acetylcholine, a major neurotransmitter stimulating the tear gland to excrete tears; cyclosporine also acts as a tear gland stimulator besides bein antiinflammatory).
Proinflammatory neurotransmitters (these are neurotransmitters that activate inflammatory cells), such as substance P and calcitonin gene related peptide (CGRP), are released, which recruit and activate local lymphocytes. Substance P also acts via the NF-AT and NF-K b signaling pathway leading to ICAM-1 and VCAM-1 expression, adhesions molecules that promote lymphocyte homing and chemotaxis to sites of inflammation. Cyclosporin A is an NK-1 and NK-2 receptor inhibitor that can downregulate these signaling molecules and is a prominent addition to the therapeutic armamentarium for dry eye, being used to treat both aqueous tear deficiency and meibomian gland dysfunction. It has been shown to improve the goblet cell counts and to reduce the numbers of inflammatory cells and cytokines in the conjunctiva.
These cytokines, in addition to inhibiting neural function, may also convert androgens into estrogens, resulting in meibomian gland dysfunction, as discussed above. An increased rate of apoptosis is also seen in conjunctival and lacrimal acinar cells, perhaps due to the cytokine cascade. Elevated levels of tissue-degrading enzymes called matrix metalloproteinases (MMPs) are also present in the epithelial cells. The latter can be deactivated with doxycyline or other tetracyclines that chelate substnces needed for the production of the enzymes.
There may be many reasons for the onset of dryness in the eye. But whatever the reason (for example surgery like LASIK disrupts the nerve signalling so in that case the inflammation starts after the neural isolation of the lacrimal gland), the inflammatory cascade that is involved is autoimmune and self-perpetuating in essence. Some new treatments may be developed involving stimulating the Nerve Growth Factor on the ocular surface to compensate the initial surgery damage or subsequent inflammatory damage of the corneal nerves.
For now,treatment goes as follows: after doctors establish that eyelid hygiene, artificial tears,and removal of exacerbating factors is not enough to maintain the patient, they go on to add anti-inflammatory therapy which starts with topical steroids
and NSAIDS
and immunosuppressants like cyclosporine(which is also a potent lacrimostimulant)
and tetracyclines,
moisture chambers
and secretagogues like pilocarpine(which is a substitute for the neurotransmitter acetylcholine which stimulates the lacrimal glands to excrete tears; that also keeps them functional),
punctal occlusion.
In more severe cases that do not imrove on the latter therapy, the immunosuppressants are taken by mouth or intravenously.
Antiinflammatory therapy with lacrimostimulation is essential in the halting of the progression of the disease especially when it comes to corneal surface damage which is not only measured by staining and erosions; it is the loss of goblet cells and neural desensitization and isolation of the lacrimal glands.
However, as we all know,antiinflammatory therapy cannot remain the mainstay of dry eye treatment in the future, as it only controls the progress of the disease without curing it. The answer will most probably be a combination of hormone and nerve growth factor therapies with stem cell therapy. But that seems to be feasible in hte far future indeed. For now what doctors can do is firefight the consequences of an activated inflammatory cascade.
Doctors started me on antiinflammatories after my eyes were totally devastated-- I had developed filamentary keratitis (mucous strings and plaques set deep in the surface of th cornea that severely damage the corneal surface), prominent corneal oedema, severe erosions and ulcers, episcleritis, severe inflammation, etc. That is when they decided that I need something more than artificial tears an lid hygiene. It was too late. Now I have to live with the irreversible complications of this disease. If antiinflammatry therapy was started earlier, I would have been much better.
Oh, I forgot to mention for everyone-- never take sulfonamide antibiotics-- they are a direct cause of dry eye-- T cells respond to haptens generated by oxidative metabolites derived from these substances. So there you have another cause of dry eye. But whatever the cause is, it always involves an element of self-perpetuating inflammation and subsequent neural isolation of the lacrimal glands.
regarding heat compresses-- I can accept warm compresses, but about hot ones I don't know. All the processes I described above are intensified by heat and slowed down by cold. That patients get temporary symptomatic relief from the hot compress may be one thing, but the long-term impact on the actual underlying disease does not seem to be very good.I am not giving advice against using hot compresses.It is upt to every individual and how they feel to use or not to use something. There is hardly any medication for dry eye anyway, that does not have various degrees of potentially dangerous side effects.
And in the end,dear Rebecca, I would like to thank you for giving me the opportunity to share my experience on this wonderful forum, and for all your efforts that have helped ease so much suffering, including mine.
Please let me know your thoughts on my post. I truly appreciate your feedback.
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