Nagai N, Oike Y, Noda K, Urano T, Kubota Y, Ozawa Y, Shinoda H, Koto T, Shinoda K, Inoue M, Tsubota K, Yamashiro K, Suda T, Ishida S
Invest Ophthalmol Vis Sci46p2925-31(2005 Aug)
It should be noted that some patients experience a drop in eye inflammation as soon as they start the ARBA drug which is an angiotensin receptor blocker. One of the ARBs is olmesartan (Benicar). Not all ARBs activate the Vitamin D Receptor. medication olmesartan. This is because aside from its ability to stimulate the innate immune system, olmesartan has significant anti-inflammatory properties. Benicar binds and blocks the Angiotensin Receptor, decreasing levels of Nuclear Factor Kappa B, a protein that stimulates the release of inflammatory cytokines - causing a drop in inflammation. For example, when researchers at the Keio University School of Medicine used a bacterial endotoxin to create a condition similar to uveitis in mice, they found that the eye inflammation of the animals decreased significantly after they were administered the ARB Telmisartan.1)
Normally the conjunctiva is clear white. Visibly red veins of the eye is a sign of vasculitis (inflammation of the veins) and is very common in patient with chronic inflammatory diseases. Because it is in the eye, it is very obvious and disconcerting. But it is also common in the skin, small varicose veins, easy bruising; in the gut, microscopic blood loss and in hidden areas.
Because immunopathology is a result of cytokine release and apoptosis (cell death) of infected cells caused by innate immune activation, this does occur as the bacteria as part of their life cycle will manifest in more typical forms causing immune identification and response. However, this is only a tiny fraction of the total bacterial load and unsupported, the immune system will not be able to eradicate the infection.
Various symptoms have been reported, including increased sensitivity to light, bloodshot (red) eyes, conjunctival bleeding, glazed vision, infection type symptoms and various visual disturbances. Vision exams may not reveal any abnormality.
Visual changes may also originate in the brain without organic change in the eyes. Eye muscles can also become weak as they heal. These eye symptoms could also be exacerbated by immunopathology.
Further, what may often feel like an allergic reaction in the eye is, in most cases, actually due to changes in immunopathology, meaning that no additional treatment is required.
Increased allergic-like reactions during the MP are fairly common and represent increased innate immune response.
Greg Blaney, M.D.
Main article: Photosensitivity
Abnormal sensitivity to sunlight and bright lights is known as photosensitivity and sometimes referred to as “sun flare” or photophobia. In the context of the MP, the ultimate cause of photosensitivity is the Th1 inflammatory disease process – not the treatment itself. Exposure to natural or bright artificial light in a photosensitiveAbnormal sensitivity to sunlight and bright lights. Also referred to as "sun flare" or "light flare." person can lead to flares of internal disease activity, including exacerbation of any inflammatory disease symptoms.
Photosensitivity can occur either when the skin is exposed to bright natural light or the eyes are exposed to either natural or artificial light. Photosensitivity symptoms can occur immediately after exposure or begin 1 to 3 days later, sometimes persisting 5 days or more.
Individuals who are photosensitive prior to the MP will likely become more photosensitive on the MP. Individuals who have no signs of photosensitivity may or may not become photosensitive on the MP. Individuals with limited inflammatory symptoms (suggesting early disease) are the most likely to be able to tolerate more light exposure while on the MP. There is no certain way to tell in advance precisely how photosensitive an individual will be while on the MP. Only after an individual has begun treatment can photosensitivity be assessed.
For many members but not all it is prudent to block sunlight from living space, work space and practice limited sunlight exposure and cover up skin with thick dark layers when going out as well as protect the eyes with the proper NOIRSpecial sunglasses worn by Marshall Protocol patients to block light. glasses.
When in doubt, patients should assume their intolerable symptoms are due to light exposure and reduce sunlight exposure and protect eyes with the proper NOIR sunglassesSpecial sunglasses worn by Marshall Protocol patients to block light..
Main article: Managing eye symptoms
Related article: Eye diseases
A variety of palliative medications and over the counter supplements are available to patients suffering from glaucoma, uveitis, cataracts, and eye inflammationThe complex biological response of vascular tissues to harmful stimuli such as pathogens or damaged cells. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue.. Perhaps the most important thing MP patients with eye symptoms can do is to protect the protect their eyes from the effects of light both indoors and outdoors while they exhibit the symptoms of photosensitivityAbnormal sensitivity to sunlight and bright lights. Also referred to as "sun flare" or "light flare.".
Because they suppress the innate immune responseThe body's first line of defense against intracellular and other pathogens. According to the Marshall Pathogenesis the innate immune system becomes disabled as patients develop chronic disease. and contribute to disease relapse, MP patients should avoid immunosuppressive drugs such as eye drops with Prednisone except during emergencies. Opt instead for eye drops and medications which do not contain steroids such as Optive or artificial tears instead.
Patients who need temporary relief of their eye symptoms should contact their opthalmologist, physician or pharmacist for advice about palliative medications. Patients' opthalmologists who believe they need immunosuppressant eye drops to temorarily control inflammation may do so while on the Marshall ProtocolA curative medical treatment for chronic inflammatory disease. Based on the Marshall Pathogenesis. (MP).
Patients who are taking steroids should work with their physician to wean from the medication.
Cell wall deficient bacteria have been detected on multiple occasions in the eye. Researchers at Columbia under Emil Wirostko detected non-cultivable cell wall-deficient bacterial pathogens in patients with chronic ocular inflammatory disease. In one experiment, they injected these organisms into mouse eyelids, which subsequently caused the mice to develop inflammatory eye disease. They also found that these cell wall deficient pathogens could disseminate and cause similar inflammation in the heart, gut and lungs.2)
Additionally, photographs by Emil Wirostko show a substantial number of L-form bacteriaDifficult-to-culture bacteria that lack a cell wall and are not detectable by traditional culturing processes. Sometimes referred to as cell wall deficient bacteria. inside the immune system cells present in the vitreous of the eye. Several years later, his son, Dr. William Wirostko, implicated bacteria such as Staphylococcus hominis and Staphylococcus aureus in inflammatory diseases of the eye.3) 4)
Similarly, researchers at the Massachusetts Eye and Ear Infirmary found Chlamydia pneumoniae present in the diseased eye tissue of five out of nine people with age-related macular degeneration (AMD) - a disease in which the center of the inner lining of the eye, known as the macula area of the retina, suffers thinning, atrophy, and in some cases bleeding. However, the bacterium was not found in the eyes of more than 20 individuals without AMD.5)
AMD can result in loss of central vision, which entails the inability to see fine details, to read, or to recognize faces. According to the American Academy of Ophthalmology, it is the leading cause of central vision loss (blindness) in the United States today for people over 50 years of age. “The paper showed that C. pneumoniae is capable of modifying the function of important cell types involved in regulating normal eye function,” said lead author Murat Kalayoglu, MD, PhD.6)
Similarly, Wirostko’s group noted that cataracts developed in the eyes of 14 of the 15 mice who had been exposed to the cell wall deficient forms, whereas no cataracts developed in the eyes of 200 control mice that had not come in contact with the pathogens. This data led the team to suggest that cell wall deficient organisms can penetrate the lens capsule to produce cataracts, and that these same organisms could cause human cataracts.7)
In a prospective, non-randomised, comparative study, Kountouras et al found that the frequency of HP infection in a group of glaucoma patients was higher than in control subjects.8 In their study, HP infection was histologically confirmed in 88.2% of glaucoma patients.
Symptoms of uveitis include redness of the eye, blurred vision, photosensitivity (photophobia), dark floating spots along the visual field, and eye pain.
In a 2008 prospective study of 1,321 patients with uveitis, a team of French researchers used polymerase chain reaction (PCR) to search for evidence of microbes. Researchers found a variety of fastidious and difficult-to-grow bacteria including spirochetes, Bartonella species, intracellular bacteria (Chlamydia species, Rickettsia species, Coxiella burnetii), and Tropheryma whipplei along with herpes viruses and fungi. Bartonella quintana, Coxiella burnetii, Paracoccus yeei, Aspergillus oryzae, and Cryptococcus albidus were found to be associated with uveitis for the first time. The fact that PCR was not able to find microbes in all samples may be a tribute to this technology's weaknesses.9)
According to the Marshall PathogenesisA description for how chronic inflammatory diseases originate and develop., dysregulated vitamin D metabolism may contribute to loss of vision in several ways.
There are a number of retinal protein genes which are transcribed by the VDRThe Vitamin D Receptor. A nuclear receptor located throughout the body that plays a key role in the innate immune response., which is the reason eyesight fails as these Th1 diseasesThe chronic inflammatory diseases caused by bacterial pathogens. advance, and with advancing age. This provides another pathway for the Th1 bacteria to inhibit the proper operation of the eyes.
Trevor Marshall, PhD
The Vitamin D ReceptorA nuclear receptor located throughout the body that plays a key role in the innate immune response. is involved in the transcription of several key proteins that form the structure of the retina. According to researchers at McGill University,10) these proteins include:
However, as microbial substances and 25-DThe vitamin D metabolite widely (and erroneously) considered best indicator of vitamin D "deficiency." Inactivates the Vitamin D Nuclear Receptor. Produced by hydroxylation of vitamin D3 in the liver. bind and decrease the activity of the VDR it cannot correctly transcribe the above genes. Also, higher than normal levels of 1,25-DPrimary biologically active vitamin D hormone. Activates the vitamin D nuclear receptor. Produced by hydroxylation of 25-D. Also known as 1,25-dihydroxycholecalciferol, 1,25-hydroxyvitamin D and calcitirol. may interfere with proper operation of receptors involved in vision:
The primary function of the retina is to act as host for the rhodopsins, which are GPCR receptors that sense light. A molecule of retinal is bound into rhodopsin, and it undergoes a conformational change when hit by a photon. The charge shift resulting from this phase change is conducted through the retina and aggregated, so that at some threshold (most experts seem to think about five triggered receptors), a sensory signal is then sent along the optic nerve to the brain.
1,25-D binds into rhodopsin and will competitively displace retinal (unpublished modeling work by yours truly). Thus, excess 1,25-D can directly interfere with the process of vision.
Trevor Marshall, PhD
Related section: Patients experiences (eye symptoms)
Consistent with the the theory of the Marshall Pathogenesis, some Marshall Protocol patients have reported that the treatment appears to clinically reveal markers of latent eye infections.
My wife, Carol, who has been on the Marshall Protocol since 8/2003 with rheumatoid arthritis, suffered an eye condition over a year ago that doctors said looked very much like Trachoma. Trachoma is a third world eye infection caused by Chlamydia. The eye doctor asked her if she had travelled to a foreign country recently, and she had not. They were then forced to conclude that it was not Trachoma, although we strongly suspected that it was.
She has had many IP reactions throughout the course of her treatment on the MP, and we knew that this was another one. It was successfully treated with antibiotic eye drops, although she also had to have some of her eyelashes removed. Trachoma causes the eyelashes to curl inward and irritate the eye surface.
At the time she posted her experiences on the MP website, and received confirmation from Trevor that this was in fact very likely to be trachoma, and that the eyedrops were the appropriate treatment. Trevor commented that Chlamydia is one of the bacteria linked to autoimmune diseases.
I went to the optometrist last week to get my very first prescription (I'm 52 years old) for reading glasses. He was very impressed with the quality of my eyes, particularly with my ability to read in the distance. I was able to read two lines below 20/20 vision. However for reading I needed glasses, which he said was normal at my age.
I had told the optometrist that I was suffering from uveitus about two and a half years ago and that the Doctors put me onto steroidal eye drops until I found the Marshall Protocol. The optometrist said you are fortunate having found an alternative therapy, as he has seen others with uveitus on the steroidal treatment that went on to develop shocking eye problems.
It was only when I heard him say this that it dawned on me, what future I had avoided for myself. How lucky I was to have stumbled onto the Marshall Protocol and spend the time to read firstly about the science and then the successes others have achieved.
Note: there have been few, if any, reports of cataracts in patients and physicians reporting on the MP. However, a temporary improvement in near vision is also a phenomenon of a beginning cataract. Age-related cataract formation can begin as early as age forty.
I had my annual eye exam, and my prescription is improving. For comparison, my prescription in January 2006 before I began the MP was OD: -3.25 -.75 x 50, OS: -3.50 -1.75 x 120. Now it is OD: -3.00 -.75 x 70, OS: -2.75 -1.25 x 130.
My doctor was so impressed with the healing of my right eye and eyes in general. I had severe corneal abrasion, infection with long hard recovery. Vision went from 20/20 to 20/400. Now back to 20/20. Dr. is most interested in MP and going to research it. He is president of the Florida Opthmathological Society and the best corneal specialist in South Florida.
I am reading without contacts. I'm not sure my prescription has changed, but I don't recall doing this for years. However, yesteryear I wore hard contact lens, and now I'm using daily disposable contact lens. It was impossible to read after removing the hard contact lens from my eyes; and now I have no problem once the daily disposables are removed. I will have my eyes checked in the fall.
Sherry (Scooker48), MarshallProtocol.com
Nikki can read a book without her reading glasses - first time in a few years when she first starting needing reading glasses!
After about 8 months on MP, I was able to stop using my reading glasses that I had needed for almost 20 years. My vision problems started when I got sick, and I had always wondered if the two were connected somehow.
Sam (Shamutooth), MarshallProtocol.com
I went to read something this morning and I put on my glasses and I could not see, So I took off my glasses and I could see what I was reading.
My eyeglass prescription improved in one eye from O. D. -2.25/-1.50 to -2.00/-1.50.
Yesterday afternoon, before taking my abx, I did notice one symptom getting better that really surprised me.
Starting about 10 years ago - about age 40 - I started using reading glasses, first as weak as they came, but soon up to +2.50 or +2.75. About 4 years ago I started needing some very mild correction +1.25 for distance. Even things very far away were clearer with the +1.25, and they were essential within a typical sized room. I still needed the +2.50 for reading.
Yesterday when leaving work, I noticed some things in the distance weren't clear. So I took off my glasses, and whoo-hoo!! things were clearer with just my good old eyeball. Currently my eyes alone are only clearer than the glasses for objects over about 50' away… but it's a start!.
I don't want to jump the gun here but very excited to report something! Years ago when I first flared ('90)… I lost a good part of my central vision in my left eye. My right eye has compensated for this so it only seems to affect my reading…tire easily. Not knowing that I've had Sarc all these years my opthamologist examined this and told me it “appeared” to be a pit on my optic nerve and that there was not anything that could be done to regain my sight. I have had several visual field tests done and intend to make an appointment for a re-check to see what has changed. I have noticed that I am seeing in a wider field area that has come on gradual since being on MP! It is something big to me after all these years…I don't know if it is too much to hope for that I will regain this sight but I am hopeful! This loss of vision took up about 1/3 of my central vision in my eye, extending from side to side…there is now a very thin line of vision loss and is only centrally located as compared to before. So not only has the central vision improved but blindness on each side is gone. WOW! BIG WOW!
Deb Grabetz, MarshallProtocol.com
I've read comments by some folk on the MP regarding improvement in their vision and I am writing to report MY VISION HAS IMPROVED at 52!
I decided to try once again to get some prescription glasses to wear around the house (so I could stop looking 20+ years older with my NoIRSpecial sunglasses worn by Marshall Protocol patients to block light. fitovers), and because it had been 17 months since my last eye test, I decided it would be wise to have my eyes tested again. The doctor tested my old prescription and said he was surprised at how strong my biofocals were (I am farsighted and with farsighted people all over vision gets worse and worse with age, including close up, versus nearsighted people whose nearsightedness typically gets better while their close up vision gets worse).
The eye doc said he can normally predict how strong biofocals should be based on the person's distance vision and her age. He said my previous prescription had me pegged around age 60. So not only has my prescription gotten better, I've gotten younger!
He also told me that the quick decline in my vision (it took about two days to go from 1.25 bi-focal to 4.50 & 4.75 where it has stayed except for a slight worsening in the left eye) was not normal. This occurred a year and a few months before I became totally disabled–actually during a time when I should not have been working.
Additionally, I used to have noisy vision pre-MP. If you can imagine ink on the printed page being wet and have an extremely fine wire brush whisk some of the ink out from the letters, this is what I saw whether on the printed page or on the eye doctor's wall. I've noticed in the last year, that the noisy vision has gone away as well. Now when I select the clearest print in an eye test, the letters are nice and crisp (not looking like they are hairsuit).
I still have a ways to go vision wise (I'd be happy just to make it back to the kind of bi-focals one can pick up at 3 for $10), but I'm on my way!
I am a type 1 diabetic on MP, on an insulin pump. I have had DM for 46 years. Since being on MP, I have not experienced any negative issues with my diabetes. In fact, my A1C has improved, my eyes show no signs of retinopathy and I am checked every 6 months - she even took photos of my retinas they were so perfect!
Debbie Y., MarshallProtocol.com
I am in Phase 3 and have been on MP 2 years. I am also a diabetic so when I started having flashes of light also zigzag, I got panicky. The moderator is correct. Go to your ophthalmologist and have your eyes examined. They found nothing on my exam and in fact, took pictures of my retinas because they were perfect even after 45 yrs. of diabetes! This is unusual for most diabetics. But, the exam was thorough and relieved my fears greatly. And, I had it in both eyes, and it did eventually fade away.:D
Debbie Y., MarshallProtocol.com
I had my yearly eye exam and after a rather comprehensive check, was told “there is not any sign of Uveitis or Iritis and your occular pressure is 14 in each eye…the lowest it's been in years and years and years.” I am so thrilled!!!
I was completely cured of severe uveitis by the very first stages of the Marshall Protocol. In fact I hadn't even started the full MP with Benicar when my eyes began to heal quite dramatically, just on minocycline.
Most doctors only have experience with patients who are not on the MP. People with uveitis who are not on the MP don't usually get the degree of healing that is possible on the MP. At a recent ophthalmologist visit, my daughter's doctor wanted to show her intern my daughter's pupil. Her right pupil had become irregular in shape because of adhesions related to inflammation. When the doctor went to look at it, she (the doctor) was surprised to see how the pupil was no longer so distended. She said she never would have expected the change. For treating and curing uveitis, we have seen much more benefit from the Marshall Protocol.
My daughter [who is an MP patient] has never been free of using steroid eye drops during the four years she has had chronic uveitis – the lowest dose she has been on is four drops per day. She also had one steroid injection, at the time of her first cataract surgery.
Despite using the steroid eye drops, her systemic symptoms have gotten so much better on the MP. We also never noticed eye herxing. I would suggest that someone with uveitis be closely monitored by an eye doctor while on the MP, and be prepared to adjust antibiotic dosing if it seems that there are any problems related to eye herxes.
Her eye symptoms improved while on the MP. Her second cataract surgery, after one more year on the MP, had a much easier recovery period than the first. Over time on the MP, her uveitis has slowly gotten better. We think that each eye surgery, and related medications, stalled her progress on the MP by at least 6 months. (She has had three eye surgeries, due to severe cataracts. Unfortunately, cataracts are a risk of prednisolone/prednisone use as well as of uveitis.)
I had developed uveitis over the last year with a significant bulge in my right eye as well as the iris/pupil area moving to the right and becoming off center and the color being black (my eyes are medium brown). In the last couple of days I have noticed that my right eye is now almost normal; the bulge has gone, the darker color as well as the off centeredness! I have only been on the mp for 5 months and look what has happened:D. My doctor noticed the difference in my right eye when I first went to him, so it is documented.
Toni girl, MarshallProtocol.com
Uveitis specialist available for consult
Because uveitis is relatively rare, many eye doctors have treated very few patients with the disease. If you ask how many patients (over how many years) the doctor has treated with uveitis, and how many with your type of presentation, you may be shocked.
Any ophthalmologist can express an interest in treating uveitis; their experience and expertise vary. If you aren't able to travel to see someone, you can ask your doctor to consult by phone (or email) with another specialist.
Dr. Stephen Foster, in Boston, is a top specialist, and is very willing to consult with other physicians. (He won't know anything about the MP, but he has lots of experience treating uveitis and controlling iflammation after surgery in uveitis.)
If your eye doctor is reluctant to contact Dr. Foster, your family doctor can also consult with him, or can urge the eye doctor to do so. Dr. Foster will consult by phone or email. (You can write him directly, as well.) Dr. Foster's contact info:
Dr Stephen Foster (Uveitis Specialist) Massachusetts Eye Research and Surgery Institute 5 Cambridge Center 8th Floor Cambridge, MA 02142 http://www.mersi.us. Phone 617-621-6377 Fax 617-494-1430
Dr. Foster wrote a book on uveitis; he and his research group have published a huge number of articles on it. Because he is such a well-known specialist, he has seen more cases of uveitis than pretty much anyone else.
Here is a link to his background and publication details:
You can also contact the online patient support group that Dr. Foster supports. People there may have recommendations for doctors to see in your area.
If you are faced with eye surgery or complicated-to-manage inflammatory eye conditions , it would be a good idea to get Dr. Foster's input. You and your doctor may not want to do what he says, but he has much more experience in this area than almost anyone else. He is unfamiliar with the MP, and, in fact, considers most inflammatory eye disease to be autoimmuneA condition or disease thought to arise from an overactive immune response of the body against substances and tissues normally present in the body in nature (not caused by active bacterial infection). However, for managing essential eye surgery, we have also consulted doctors trained by Dr. Foster.
Study Shows Bacterium Present in Eyes with “Wet” Age-Related Macular Degeneration http://www.meei.harvard.edu/what/press.php
ARB reduces Uveitis due to bacterial toxin Suppression of Ocular Inflammation in Endotoxin-Induced Uveitis by Blocking the Angiotensin II Type 1 Receptor
Uveitis is one name for inflammation in the eyes. (Uveitis is inflammation of the eye structure called the uvea. Other parts of the eye can also become inflamed, caused conditions such as scleritis. They are included in the umbrella name “ocular inflammatory disease.”)
“Uveitis is a symptom, and has many identified causes and associations at this point. Some cases are widely accepted to be due to bacteria or viruses. Other cases are associated with “autoimmune diseases” like Crohns disease and rheumatic arthritis. I suspect that these other cases are due to CWD bacteria. There are several interesting papers that explore this. The researchers found cell-wall deficient bacteria (sometimes called mollicute-like organisms) in the vitreous fluid of patients with sardoidosis, Crohn’s disease, ulcerative colitis, juvenile rheumatoid arthritis, etc.” Dr. Trevor Marshall, Ph.D
Trans Am Ophthalmol Soc. 1993;91:85-94; discussion 95-8.
Mycoplasma-like organisms and ophthalmic disease. Wirostko E, Johnson LA, Wirostko BM, Farris RL. Columbia-Presbyterian Medical Center, New York. PMID: 8140710
There is an article in PubMed Central in which Wirostko explains how mollicutes, transfected from humans, infected first the eyes of mice, then their whole bodies. Somehow it has slipped my attention since I first saw it. You might be interested to take a look. The images are not as compelling as the the original publications from the 1980's, however
Reconsidering the connection between vitamin D levels and age-related macular degeneration.Golan S, Shalev V, Treister G, Chodick G, Loewenstein A Eye (Lond) Aug 2011; Full text via publisher | Download citation Affiliation 1] Department of Ophthalmology Tel Aviv Medical Center, Tel Aviv, Israel  Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Abstract PurposeRecent evidence has suggested a correlation between reduced vitamin D levels and delayed angiogenesis and reduced inflammatory response, which are known to have a major role in the development and progression of age-related macular degeneration (AMD).DesignCross-sectional study.ParticipantsMembers of the Maccabi Healthcare Services (MHS, one of the four largest Israeli Health Maintenance Organization) aged ≥60 years, whose vitamin D levels were taken as part of routine examinations between 2000 and 2008.MethodsAll data for this study were obtained from MHS databases that include medical information on 1.8 million subscribers.Main outcome measuresSerum 25-OH vitamin D levels.ResultsThe total study population comprised of 1045 members diagnosed as having AMD, and 8124 as non-AMD, for whom there was information on vitamin D levels. The mean±SD level of 25-OH vitamin D was 24.1±9.41 ng/ml (range 0.8-120) for the AMD patients and 24.13±9.50 ng/ml (range 0.0-120) for the controls (P=ns). One-third (33.6%) of the AMD patients and 32.86% of the controls had a 25-OH vitamin D level <16 ng/ml, and the proportions of tests in which the 25-OH vitamin D level was >74 ng/ml were 0.19 and 0.14%, respectively (P=ns)ConclusionsNo association was detected between vitamin D levels and the presence of AMD in this cross-sectional study. These results raise some doubt about an association between reduced vitamin D levels and the prevalence of AMD.Eye advance online publication, 5 August 2011; doi:10.1038/eye.2011.174.
Age-related macular degeneration is an inflammatory disease possibly treatable with minocycline (link)
# Emil Wirostko Columbia University, College of Physicians and Surgeons, New York, USA # William J. Wirostko Medical College of Wisconsin, Milwaukee, Wisconsin # Barbara M. Wirostko Columbia University, College of Physicians and Surgeons, New York, USA Letter to the editor
Sir, Age-related macular degeneration (AMD) is a major medical problem. It remains the most common cause of blindness for older patients in developed nations, and is expected to become even more prevalent as the population ages Ryan & Schacht 2001). Its economic and psychological costs are staggering, both for those responsible financially for treatment, and for those suffering blindness.
Age-related macular degeneration exists in both non-exudative and exudative forms. The non-exudative form involves atrophy of the central retina with a slow and progressive loss of central vision. The exudative form is characterized by the growth of new blood vessels through Bruch's membrane into the subretinal space, with often sudden and profound vision loss. Both forms may coexist, and the presence of AMD in one eye suggests the likelihood of disease in the other (Ryan & Schacht 2001).
Because it lacks an aetiology, treatment for AMD remains limited. Laser photocoagulation and photodynamic therapy are helpful in a select minority, but often cannot prevent further vision loss, central scotomata formation or recurrent neovascularization (Ryan & Schacht 2001). Repeat treatments are often necessary at a financial cost to society.
High dose antioxidants with zinc can also help retard disease progression, but may not prevent further vision loss either (Age-Related Eye Disease Study Research Group 2001). The effect of vitamin supplementation on mild disease remains unclear.
Ischaemic vascular disease is probably involved in the pathology of AMD. Risk factors common to both include increasing age, cigarette smoking, hypertension, angina, positive family history, and use of thyroid medication, oral antacids and hydrochlorthiazide (Ryan & Schacht 2001). An association between ischemia and AMD is not surprising as the macula has only a single blood supply, the eye is an end organ, and the retina has the highest uptake of oxygen in the body. A recent study by Kalayoglu et al. (2003) demonstrated that the prokaryotic pathogen Chlamydia pneumoniae, which is emerging as a risk factor for cardiovascular disease, may play a role in AMD. The authors demonstrated a serological association between AMD and anti C. pneumoniae antibodies (Kalayoglu et al. 2003).
Pathogenesis of AMD also involves chronic granulomatous inflammation. A series of elegant studies has documented the involvement of giant cells and monocytes in both non-exudative and exudative disease (Penfold et al. 1986, 1987). In exudative disease, lymphocytes appeared to be intimately involved with the growth of choroidal capillaries through Bruch's membrane. It is likely that they represent the source of supply of the potent lytic enzymes, including matrix metalloproteinases, collagenases and lipases, necessary for neovascularization and the degradation of Bruch's membrane. The source of inflammation may be drusen. Drusen represent cellular remnants from degenerate retinal pigment epithelial cells, and contain inflammatory stimuli, including acute phase reactants, immunoglobulins, fibrinogen and complement. Their formation may be analogous to that in Alzheimer's disease and atherosclerosis, where the accumulation of extracellular plaques and deposits elicits an inflammatory response that exacerbates the effects of the primary pathogenic stimulus (Anderson et al. 2002). Inflammation can exacerbate underlying ischaemia by inducing vascular endothelial hyperplasia and hypertrophy.
Implicating inflammation in the pathogenesis of AMD suggests that oral tetracyclines may help retard disease progression. Tetracyclines inhibit lymphocyte proliferation, suppress leucocyte chemotaxis, inhibit angiogenesis, limit inflammatory cytokines and inactivate matrix metalloproteinases, collagenases and lipases. They have proven effective for controlling inflammation in a wide variety of idiopathic inflammatory diseases, including rheumatoid arthritis, scleroderma, acne rosaea and vulgaris, where many patients have used them safely for long durations. In a randomized, double-blind, controlled study of 48 weeks duration, minocycline (100 mg po bid) (a semisynthetic tetracycline) was found to be safe and effective for improving clinical and chemical parameters of chronic rheumatoid arthritis (Tilley et al. 1995). A year of therapy was necessary to achieve response, with improvements continuing thereafter (O'Dell et al. 1999). Minocycline is also beneficial in arresting scleroderma (Robertson et al. 2003), and may be beneficial for treating the inflammation of multiple sclerosis (Brundula et al. 2002).
The authors propose a trial of minocycline as treatment for AMD. Oral minocycline is rapidly absorbed, demonstrates a prolonged half-life, possesses antioxidant capabilities, is lipid soluble, and attains high concentrations within the eye (Tilley et al. 1995; O'Dell et al. 1999). With chronic therapy, we believe minocycline will be helpful for arresting disease progression in early AMD, and be beneficial for retarding neovascularization in advanced disease.