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Non-abating vision damage associated with the use of the fluoroquinolones. Fluoroquinolone Toxicity Research Foundation June 2004 OBJECTIVE: To survey cases of fluoroquinolone-associated adverse events that included non-abating vision damage posted on two Internet Web Sites formed by people sustaining fluoroquinolone-related events or by those monitoring such events. METHODS: Cases were obtained by reviewing the various spontaneous reports by the members of The Quinolone Adverse Drug Reaction Forum hosted by GeoCities: and the adverse drug reactions to Levaquin as reported on: http://www.medications.com(Additional research material was utilized using the archives of fqresearch.org. This Web Site is dedicated to presenting the current information available regarding the severe adverse drug reactions associated with these chemotherapeutic agents: http://www.fqresearch.org)RESULTS: In contrast to the manufacturer sponsored reports suggesting that fluoroquinolone-associated vision problems are mild and short-term, the majority of the cases reviewed reported severe events that typically involved multiple vision problems that appear to be non-abating in nature and persist years after the drug therapy had been discontinued. Although many newer cases are continuing to evolve, symptoms have lasted more than four years in a number of these cases. Within the package inserts we commonly find that according to the manufacturers such events are self-limiting and cease upon discontinuation of therapy. We find that this is not correct. Onset of adverse events was usually rapid, with events beginning within anywhere from initiating of treatment to within several months after discontinuation. 118 individual reports were reviewed with a total of 234 adverse events being reported. The distribution of the drugs per patient is as follows: Levaquin (n = 61, adrs = 112) Cipro (n = 23, adrs=52) Cipro eye drops (n = 3, adrs = 9) Avelox (n = 5, adrs = 7) Tequin (n = 4, adrs = 10) Noroxin (n = 2, adrs = 3) Maxaquin (n = 1,adrs = 3) Floxin (n = 1, adrs = 4) Unidentified (n = 18, adrs = 34) [Other than the fact that it belong to the fluoroquinolone family.]
CONCLUSIONS: These cases appear to confirm the association between fluoroquinolone antibiotics and severe, long-term adverse effects involving the patient’s vision, as well as other neurological systems making up the visual pathway. The severity of these cases may reflect a far different population than typically reported to drug companies or MedWatch, as they are being reported by the patients who have suffered such events with the majority of such patients having failed in their attempt to receive the medical care so desperately needed when such events manifest. Web Sites such as those utilized in this report provide a forum for patients experiencing adverse effects that have not resolved promptly and provide an excellent database in which to document their ongoing progress. We believe that these cases warranted additional research regarding these events. Meanwhile, the manifestation of vision disturbances during fluoroquinolone therapy would mandate prompt and immediate discontinuation of the agent used to prevent the progression to total blindness or irreversible vision damage.
SOURCE OF CASES: Patient cases were obtained by reviewing the archives of the Quinolone Forum and selecting spontaneous reports of cases involving vision disturbing events that appeared to be non-abating in nature. The remaining cases were selected from the medications.com archives concerning such events that were reported for Levaquin. We also examined the reports regarding the other fluoroquinolones currently in use on that site as well and found only a handful of adverse events being reported, non of which involved vision problems, as compared to the thousands of reports regarding adverse reactions found for Levaquin (apart from vision damage), which also included a number of fatalities. Table 1 Avelox 8 post
Table 2 Source of cases presented Spontaneous reports found on the Quinolone Adverse Drug Reaction Forum (1999 to date): 97 Spontaneous reports found on the Medications.com Web Site for Levaquin (2002 to date) 21 Total number of reports reviewed: 118 INCLUSION OF CASES: Though an additional hundreds of such cases involving vision damage were found within the Quinolone Forum Archives only those in which the patient reports the non-abating nature together with the total and complete failure of the treating physician to recognize such events upon manifestation were utilized for this discussion. All cases involving symptoms suggestive of irreversible vision damage were included. Acceptable symptoms included sensory abnormalities (eye pain, blurring of vision, double vision, dilation, floaters, etc.) as well as documented damage to the optic nerve, muscles controlling eye movement, retina and the cornea. DATA REQUIRED: Cases are normally required to "…provide information that equaled or exceeded the standards of the FDA’s MedWatch program. Information normally requested includes the patients name (or another identification for patients preferring anonymity), age, gender, weight; date antibiotic was taken, reason for antibiotic use, specific antibiotic used, dosage, duration; time of use until onset of symptoms; symptoms of the adverse events and the degree of discomfort and/or impact, if any, on normal functioning; duration of events; prior medical problems and/or medications; subsequent treatment, if any, for adverse events; and whether a MedWatch report was submitted to the FDA" (Above criteria paraphrased from the criteria set forth by Dr. Jay S. Cohen; Peripheral Neuropathy Associated with Fluoroquinolones, 2001). However, due to the informal nature of this report, we did not seek such information from these patients. The event itself was found to be of a sufficient nature to be included in this report together with the non-abating nature of such an event. Further studies are planned in which detailed information meeting the above criteria will be utilized. IDENTIFICATION OF ADVERSE DRUG EVENT: Adverse events were defined according to the FDA’s current definition: "An undesirable effect, reasonably associated with the use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence." (54) The likelihood of the event being associated with fluoroquinolone treatment was judged based upon the information found within the spontaneous posting on these sites, rather than being rated by the author according to the Naranjo et al (55) probability scale. Further studies are planned in which the likelihood of the event will be rated by the criteria set forth by Naranjo et al.
EXCLUSION OF CASES: Cases that in the judgement of the author appeared questionable, in which patients had other contributory conditions or were taking other medications that might help explain the adverse events, were also excluded, if such information had been provided by the patient and a reasonable likelihood that such medications or conditions were indeed responsible for the adverse event being reported. RESULTS: Distribution of the Drugs, Duration and Concurrent Medications Post Marketing Events as Reported on the Internet Duration of Non-Abating Adverse Events Onset of Non-Abating Adverse Events
PATIENTS CHARACTERISTICS:
ANTIBIOTIC USE Drug prescribed, duration of use and reason for prescribing SEVERITY OF SYMPTOMS: Severe adverse reactions reported Moderate/Mild Adverse Reactions Reported Table 10 Physicians response to the adverse events reported "…and to this day every Dr I meet I ask if they are away of the effects of FQ... and sadly to say the majority of them think I'm nuts... and say they never have heard of problems…." "…The ophthalmologist doesn't seem to be worried, and, of course, has never heard of FQs affecting vision. in December 1999. An ophthalmologist and an optometrist examined me and found nothing. In January, 2000, I visited another ophthalmologist who discovered that I had a plugged duct in my eyelid.." "…He diagnosed the shimmering and light sensitivity as migraine auras. I have never had migraine problems, and have never had a migraine headache…" "…eye exam unremarkable After a few days, my mother developed a serious rash and the Pharmacist told her to stop using Levaquin. Well, the eye appointment came out fine and the ENT specialist basically brushed aside the memory loss issues by saying it's a sign of aging. My mother is 59.In my heart I know Levaquin was the cause, but all the doctors I have mentioned this to have basically passed …" "…left knee had ruptured from prior exposure to Floxin, Tequin was the fifth FQ I've been on...fairly major reactions to no medical explanation…." "…I had several doctors (two of whom were neurologists) say that had the doctor read the insert, she would have known that I wasn't a candidate because I'd had a CNS injury and possible head injury in the past…." "…patient suffered severe adrs after third dose which continue to date of post…" "…was told to continue the Avelox so I did and the same thing happened within an hour after taking it the next day." "…no insert furnished with sample pack I asked my doctor if there were any potential interaction with the only other medication I’m currently taking. he assured me there wasn't. there were no warnings or advisories I checked the manufacturer's website again for information on these symptoms. I found nothing on the sample packages, or inside the box. though I also checked the manufacturers' websites of both drugs for interactions and side-effects…" "…pediatric patient who has been severely crippled by Levaquin for life. Her therapists said they have never seen anything like this before. They are horrified how it just keeps attacking different parts of her body every couple of weeks. We think and our orthopedic doctor believes it is because she is a kid and her body is having a very difficult time dealing with this miserable poison. She saw one of her pediatricians yesterday. He was horrified and couldn't believe her condition. He actually had tears in his eyes. He said the same old mantra: "She should never have been given this drug." He apologized at least a half a dozen times for recommending the idiot who gave it to her. …" "…Doctor stated that if drug is discontinued then he should not get worse. Had no idea an antibiotic could cause depression Dr. Stollo a sleep specialist did a study on quinolones and found that they caused depression, sponsor of the study cancelled it as a result…" "…severe adr after first dose but was told to keep taking it…" "… Well, I have just had an MRI and guess what? Yep...it's a severely torn rotator cuff. I was told I must have torn the tendon by some traumatic injury (sorry, doc, haven't had any) or by a repeated motion, such as an athletic movement...throwing a ball etc...(sorry again, I am a 62-year-old, overweight couch potato!)…" "…doctor wanted to inject me with a steroid/cortisone shot, I refused (steroids are contra indicated with fluoroquinolones) have now mentioned the quinolone adverse reactions to at least 8 physicians (including 2 orthopedic surgeons, an ENT doctor, an allergist, 4 general practitioners...NOT ONE of them has ever heard of these reactions. I failed to convince any of them, and they just looked at me as if I were an idiot I have been told by several of them not to believe anything on the internet...I have read that the FDA has sent all doctors a letter warning them of possible tendon rupture…" "…for 10 days. Plus, Flagyl (another antibiotic) for the diarrhea (500mg, 3 times per day for 10days). He also gave me Xanax for the anxiety…" "…Opthamologist says everything is fine... no nerve problems, vision is fine, peripheral fine. Said it must be a muscle problem. By now, I had found this site and asked if it could be Cipro. He said he thought is was the Ativan which is muscle relaxant…and may be causing the eye muscle to be weak. So, I stop the Ativan (which was .5 that I took at night to sleep... not much really). When I asked what I should do if the eye jerking continues, he said to see a Neurologist and get an MRI because it could be brain lesions or a tumor…." "…Back to the family doctor for follow-up. He looks at my back rash and says, 'Gee, this isn't shingles but an allergy to something. Did you change your soap recently??" He prescribes Ativan and sends me to an Opthamologist for my eye problem…" "…July 2002 rechallenged with Levaquin after severe adr in 2000…" "…I called my doc and asked if I should discontinue the Levaquin. Nurse said "NO"> I asked her to check with him again, and she said he felt I should keep taking it or else the infection that they were checking me for could worsen…" "…I saw an ophthalmologist an he said that my vision is good …" "…He was put on Prednesone to clear up rash, last two days it appears to be scaling off (shedding).As of this week the doctor who does feel it is a drug reaction, just not sure which one, has taken him off of vitamins, aspirin, antacids, shampoo, soap, detergent…" "…4th cycle of Levaquin treatment in 12 months I had noticed some side effects with Levaquin in past treatments, but attributed them to Prednison which I had been on Told doctor and he said stop Prednisone so I did. I took 1 and a half more Levaquin and still had problems so I stopped it to. Then he gave me Cipro. I took half and stopped it. I went to ER and they said I was having a reaction, so they gave me pepcid and more steroids by I.V…." "…I felt someone was pulling my eye from the backside with a pair of pliers. I kept asking if it was a reaction from the Avelox, and Dr. and asked if it was from all the antibiotic's that I had taken. Of course the answer was a flat "NO". …" "…was told that that wasn't a side affect of the drug! (upon manifestation of adrs to Cipro) I called the Dr.....he gave me Cipro for another 10 days and ordered CT scans of my whole body including my head....All clear...nothing....Then he ordered ultra sound of my body...nothing. I kept going back to the Dr. and was told it was menopause. He handed me Paxil and sent me home. I called him again and said I was no better. He suggested that I go to a Kidney specialist because I still had blood in it…" "…I have been to my eye doctor several times vision is excellent, but when I tell them about the flashes and floaters they blame it on age. That this happens as we grow older and most people don't even notice them. Yeah right!! I was 38 at the time. And they also told me they would go away…" "… If this was a Cipro reaction, why would things again take a turn for the worse, and why would I be getting new symptoms 'many months out from Cipro? I saw another neurologist who said MS was unlikely, based on another normal neurologic exam a normal visual test with a neuro-opthamologist…" "… I have had every test imaginable and they are all normal…" "… I've been to the eye doctor in Jan. and had a thorough exam…I was sent to the ER they did a CAT scan. They could find nothing but advised me to see an opthamolgist and neurologist in the morning. I called and set up an appt with a …" "… My eyes were examined by an ophthalmologist, with no problems found…" "…sore itchy eye for a week, went to her doc who said, "you don't have an infection but it "wouldn't hurt" to use antibiotics …" "…I did not use the drops that night. I called my doctor's office the next day and told them of the reactions I had been having. I was advised to stop taking them and to call next day…" "…remains in the system - it never leaves. He says "You will either get better or you won't". "…The first doctor, the idiot who gave me Levaquin for a possible UTI", thought that the only adverse reactions were gastrointestinal… As soon as I said something about all my other problems with the Cipro and Floxin and fibromyalgia, he headed south…" "…Started on 21 days of Cipro June 2003 May 29 and had a thorough eye check then, both the Retinal specialist and his Ophthalmologist present, no new probs detected. Now this …" "… I called the doctor's office and spoke to the nurse. She said to stop the Levaquin and take Benadryl and she would call me back after she talked to the doctor. When she called back, she said he agreed with what she said…." "…I have been back to the original Levaquin prescribing doctor a couple of times and he dismisses my symptoms as normal arthritis pains and said the November episode couldn't have anything to do with what is happening …" "…dark like the same color like ice tea I mentioned the change on the color of my urine but I was told "Normal reaction because of Levaquin…" "…The color of my skin and eyes (white part of my eyes) were Yellow yes color Yellow. I called my PCP again asking if it was a normal reaction. He asked me to go to his office. He saw me and …" "…Almost immediately I began to have severe head and neck pain accompanied by ringing in my ears and double vision. I was at level ten pain that could not be relieved by any pain medication. I felt like I wanted to die; the pain was so intense. I returned to my doctor who said this was not a side effect from the medication I went to a massage therapist who did a test and advised me not to take my remaining pill (I had taken 9 0f 10 Since my vision was still abnormal, I was referred to an eye specialist. After hours of testing, it was determined that my brain had swelled. A quick check on his computer confirmed this was a side effect of the medication…" "…Three hospitalizations total, blood thinning to get blood to optic nerve, steroids, third time they said nothing further they could do. (This is a world renowned eye hospital in The neuro-opthalmologist says I have inflamed eye muscles, and possibly inflamed optic nerve due to the sinus infection…" "…and experienced tingling in both arms the night I took my first dose. I called my doctor's office the next day, but, of course, they said it was not drug related…." "… I go to local express care place being it the weekend, and they say I have a sprained shoulder. He mentions trapezoid muscle. I told him about my situation with Levaquin and he laughed and said that was irrelevant now since it would be out of my system. Well anyway sent me home told me to use ice and heat and it would heal in 6wks I told him about the info I have gotten and they look at you like your crazy. I did go back weeks ago to see the P.A that gave me the samples and he seemed concerned and he listened and agreed that these were very strong drugs and that I definitely had a bad reaction Is there anything I can do…" "… after finally making it in and telling the urologist about what this medicine had done to me, what does he do? He cuts me off and holds up his finger and says, "One percent. Just one percent of patients have side effects from this drug …" "…I specifically asked the MD if I was likely to experience side-effects. He replied that he often prescribed Levaquin and that it was usually very "well-tolerated' …" "…after just one pill I noticed many side-effects. I called the Dr and he said it was probably dose-related and to cut from 500 to 250. I had a 10-day prescription but stopped after 7 due to worsening tendon and joint problems…." "…This has been a major problem, and in no way has it ever been suggested by my eye specialist that there is any connection.13 years ago I had an acute angle glaucoma ended up having to have silicone shunts or plugs inserted into the tear ducts of both eyes …" "…the doctor finally said that is was from the adverse reaction from the Levaquin, My doctor does not believe that the Levaquin caused these problems but they began to happen almost immediately …" "…I took Levaquin in June for a sinus infection and had no side effects. Previous exposure to Levaquin 4/2003 with no side effects. I went to my GP and he told me it was "self-perpetuated" because the half-life of the drug had passed and the effects should have subsided quickly. (But he was surprised to see my liver enzymes were elevated even after the drug was stopped…" "…My doctor assured me that the antibiotic was perfectly safe…" "… Dr. David A. Flockhart, Chief of Clinical Pharmacology at IU School of Medicine. He was the only person that I read about that had background and experience in fluoroquinolone antibiotic adverse drug reactions. He told me that this class of drugs, when not eliminated from the body, binds to the nerve endings/gaba receptors in the brain. He stated that the drug does not metabolize much and sits in the brain and causes events to happen. He also stated that the drug binds to the nerve endings throughout the body…" "… I saw an ophthalmologist and he said that my vision is good and I only have some floaters in the vitreous…" "…I see an ophthalmologist and he said that everything is ok..I only have floaters…" "…My eye doctor was not familiar with the ADR's to FQ's…" "…The retina specialist was sure I had an autoimmune disease because this type of vision loss is usually associated with either arthersclerosis (older people) or retinal vasculitis (younger people). The results of the fluorescien photos of both eyes revealed nothing. He could not find an occlusion or inflammation, even at the sight of the loss…." "…The Opthamologist said that I had a "vitreous detachment". I also had large "floaters" in one eye that he said were cells torn off from the retina and optic nerve…." USE OF CASES COLLECTED VIA INTERNET:The Internet has allowed patients whose physicians have failed to recognize well known adverse drug reactions to the fluoroquinolones or even deliberately dismissed any such association without ever researching the subject matter an opportunity to meet and discuss these reactions with others who have suffered the same fate. Such interaction and reporting was unheard of when these drugs first came into use. The Med Watch program maintained by the FDA is a proven failure and totally unreliable when it comes to collecting such reports. Less than 4% of all such reactions are ever reported to the FDA. As noted above many physicians have been presented with information regarding such events found on the Internet only to dismiss such information out of hand. In this article, the use of the Internet to collect such reports naturally raises questions of reliability. However, all science begins with observation, and the Internet presents a unique opportunity to review patient-based information not previously available. As noted by Dr. Cohen in his report regarding peripheral neuropathy and the use of fluoroquinolones he stated "…Some precedent exists in the use of the Internet as a source of medically useful information. A common Web site and communication channel for patients with erythromelalgia, a rare and painful vascular disorder, spawned The Erythromelalgia Association (TEA); (available at www.erythromelalgia.com). This in turn facilitated the collection of data from the largest group of erythromelalgia patients ever assembled and the publication of a much-needed review article describing the diagnosis, pathophysiology, and treatment of this often-recalcitrant disorder…." Similarly, in this report, a the common occurrence of fluoroquinolone-related adverse events has led to the formation of numerous web sites in which thousands of individuals reporting severe adverse reactions and the sharing information in a manner that was impossible before the Internet. As such these and other Web sites represent different populations than what is normally utilized by traditional methods of collecting such reports. (IE: FDA, drug manufacturers, clinical trials, etc.) With the Internet cases utilized within this report the information is derived directly from patients rather than with the healthcare providers that report to the FDA and the manufacturers. As noted within the physicians statements regarding such adverse events listed in table 9 the physician appears to be dismissing such events out of hand which results in such reports never being made. Internet cases are, therefore, likely to present a different perspective and possibly more in tune with reality regarding these events. As stated by Dr. Cohen "…It should be noted, however, that patient-based reporting is accepted, indeed encouraged, by the FDA, so these reports are a legitimate source of information. Indeed, the ability to contact patients to clarify and confirm information provided a degree of completeness of information often lacking in reports submitted to the FDA…." As such we feel that these reports, though not authenticated by traditional means, is a true and correct sampling of such events which the treating physician adamantly refuses to recognize, treat and report. As such they are worthy of our consideration. NEUROTOXICITY AND FLUOROQUINOLONE ANTIBIOTICS First and foremost one must understand that fluoroquinolones are NOT a true antibiotic but a man made chemotherapeutic agent, genetically engineered to destroy the DNA of the bacterial agent. They are not and cannot be put in the same class as antibiotics, which are substances produced as metabolic products of one microorganism, which inhibit or kill other microorganisms. Antibiotics may exhibit adverse drug reactions but such reactions resolve upon cessation of therapy or modification of the therapeutic dose. The toxic adverse drug reactions associated with fluoroquinolones do not appear to be dose dependent and do NOT resolve upon cessation of therapy in some cases. In most cases such adverse drug reactions do not even manifest until weeks, months and even years after such therapy has been terminated. These latent reactions also do NOT appear to resolve and become chronic conditions to which there is no known treatment protocol. In spite of the overwhelming evidence of the non-abating nature of such injuries, the FDA continues to approve new drugs within this class together with new indications for those already on the market. Ignoring the 5,276 reports that include 473 associated deaths and 19,792 total reactions found within the AERS reports for Levofloxacin. Together with the 4,995 reports which include 480 associated deaths and 20,890 total reactions for Ciprofloxacin found within the AERS reports as well. Almost fifty percent of such chemotherapeutic agents have been removed from clinical practice or their use severely curtailed, due to toxicity issues Table 12 Adverse drug reactions, MedWatch November 1997 – November 2001 (four years) Drug ADR rate Associated Fatality Cipro 12,444 328 Floxin 7,255 173 Levaquin 11,656 273 . It has been established that fluoroquinolones can be neurotoxic, (56-58, 59-61) and that these drugs can produce spontaneous tendon rupture together with peripheral neuropathy. In contrast to the tendon events, fluoroquinolone-associated vision problems are not widely recognized. Adverse events such as these have been reported by the manufacturers to occur at a rate of less than 1%. The only previous report in the medical literature involving reversible vision loss can be found in an article written by Vrabec et al which describes the bilateral acute visual loss which manifested in a patient receiving a large oral doses of Ciprofloxacin which reversed upon cessation of therapy. (62) The Canadian Adverse Reaction Newsletter (Volume 12, Issue 4, October 2002) describes Optic Neurititis manifesting in a 22 year old woman after receiving ONE dose of Moxifloxacin. After 4 days of treatment she lost vision in her left eye and it was reported that her vision would not return. Rubin et al reports on a 43-year-old male with rapid vision loss of the left eye following a two-week course of Levaquin, which manifested as endogenous endophthalmitis of the left eye. (63) Direct association is suspect in this case but due to other medical complications such an association was not firmly established. Orcutt et al studied 68 patients, which presented with benign intracranial hypertension (BIH), another documented adverse reaction to drugs within this class, with an average follow-up of 4.1 years. Definite loss of visual function occurred in 49% of the patients studied in which 6% within this group the damage was considered to be severe. (64) Vasculitis is also strongly suspected in the more severe adverse reactions, which manifest as peripheral neuropathy and tendon damage. More than a few cases of fluoroquinolone-related neuropathies was published in 1996 by the Swedish Adverse Drug Reactions Advisory Committee. (65) This report listed 37 cases of peripheral sensory disturbances submitted to the Swedish authorities over a period of seven years (1987–1993). The most recent report in which serious complications such as corneal perforations, evisceration, or enucleation of the affected eye occurred in 16.7% of patients receiving fluoroquinolone eye drops is reported by Daniell et al, 2000. (66) Optic neuropathy and optic neuritis, sometimes progressing to total blindness, have been associated with the class of chemotherapeutic agents commonly referred to as Fluoroquinolones, since the introduction of the "Father" of the quinolones, Nalidixic Acid in 1962 (1). Although severe and at time fatal adverse reactions have been associated with this class, including spontaneous tendon ruptures (years after therapy had been discontinued), peripheral neuropathy and multiple organ failure, we will restrict the discussion at hand to the irreversible and permanent vision disturbances being reported with these agents. (4) Any patient who notes changes in visual acuity or peripheral vision should be referred for ophthalmologic evaluation. However the over whelming majority of the treating physicians fail to recognize, treat and report such events and as such no such evaluation ever takes place. The neurologic toxicity of these chemotherapeutic agents has been grossly under estimated both in scope and severity for more than forty years. A review of the AERS for Ciprofloxacin Levaquin and Floxin, maintained by the FDA reveals 789 individual reports of severe visual disturbances ranging from blurred vision, conjunctivitis, eye pain, diplopia, eyelid edema, corneal erosion, visual field defects and total blindness.
Postmarking Surveillance VIA Adverse Event Reporting System (FDA) In addition the literature reveals numerous reports of vision loss, some of which are irreversible following a course of therapy involving these agents (2.3). In some cases such reactions manifested upon ingestion of just ONE dose (3). Diminished eyesight, decreased vision, blurred vision (loss of visual acuity – sharpness of vision), blind spots (scotomas), floaters, retinal detachment, etc., are a significant threat to ones quality of life and ones vision. Table 14 Adverse Visual Drug Reactions as listed within the Package Inserts Nalidixic Acid Overbrightness of lights, change in color perception, difficulty in focusing, decrease in visual acuity, and double vision. They usually disappeared promptly when dosage was reduced or therapy was discontinued.Cipro Blurred vision, disturbed vision (change in color perception, overbrightness of lights) decreased visual acuity, diplopia, eye pain. Decreased visual acuity, flashing lights, change in color perception, overbrightness of lights, Most of the adverse events reported were described as only mild or moderate in severity, abated soon after the drug was discontinued, and required no treatment.Floxin The most frequently reported drug-related adverse reaction was transient ocular burning or discomfort. Other reported reactions include stinging, redness, itching, chemical conjunctivitis/keratitis, foreign body sensation, photophobia, blurred vision, tearing, dryness, and eye pain, diplopia, nystagmus, visual disturbances such as blurred vision, double vision and abnormal color vision, usually reversible following discontinuation.Levaquin Abnormal vision, diplopia, ophthalmologic abnormalities, including cataracts and multiple punctate lenticular opacities, conjunctivitis.Tequin Eye pain, abnormal vision Grepafloxacin (Removed from clinical use due to severe toxicity) Disturbances in vision. Amblyopia, conjunctivitis, dry eyes, eye pain, photophobia.Lomefloxacin Ophthalmologic: abnormal vision, conjunctivitis, photophobia, eye pain, abnormal lacrimation.Sparfloxacin Amblyopia, photophobia, conjunctivitis, diplopia, abnormality of accommodation, eye pain, lacrimation disorder.Trovan (Restricted use due to severe liver toxicity) Eye pain, abnormal vision, conjunctivitis, photophobia, conjuctival hemorrhage, hyperacusis, scotoma, visual field defect, diplopia, xerophthalmia.* Note: More than 50% of the quinolone and fluoroquinolone agents have been removed from clinical practice or their use severely restricted due to toxicity issues. (1)
Animal Studies Baytril (Enrofloxacin) was first approved for veterinary use in 1989. In July of 2000 Bayer issued a "Dear Doctor Letter" in regards to reports of feline blindness induced by this drug. (71) In this letter Bayer states that they believed such events to be dosed related. Gelat et al states within his study that ". All cats had diffuse retinal degeneration as evidenced by increased tapetal reflectivity and retinal vascular attenuation. Absence of recordable electroretinographic responses suggested diffuse and extensive outer retinal disease. Vision returned in a few cats, but the retinal degeneration persisted or even progressed. Histopathology of two eyes revealed primarily outer retinal degeneration, with diffuse loss of the outer nuclear and photoreceptor layers, and hypertrophy and proliferation of the retinal pigment epithelium." (72) Nomura et al describes ototoxicity in regards to nalidixic acid when administered to Long Evan rats. (73) Hendrix et al upon the testing of Cipro on canine epithelial cells in tissue cultures describes the manifestation of rounding, shrinkage and detachment from plates upon the administration of Cipro. (74) In a human study of four corneal transplant patients Eiferman et al finds crystalline precipitates that were pure Ciprofloxacin which where biocactive and bioavailable after 24 and 48 hours Though Bayer continues to deny any such association claiming that "…Prior to FDA approval in 1989, Baytril underwent mandatory toxicological testing in dogs and cats. Pre-approval target animal safety studies in both dogs and cats demonstrated safety at 25 mg/kg/day x 30 days…" (71) One uses animal studies as a basis of comparison when such events manifest in the human population. As such the relationship between the fluoroquinolones and severe vision damage has been demonstrated on animal models gives additional weight to the assertion that such events have manifested within the population being reported upon within this report. TREATMENT CONSIDERATIONS The large number of patients stating that their adverse reactions were missed or dismissed by their physicians confirms the fact that the majority of the treating physicians are unaware that fluoroquinolones have been associated with serious vision problems. Alternately, the physicians may have been unconvinced that the events were related to treatment due to the lack of reports to be found within the literature. In some cases, the severity and multiplicity of these symptoms may have produced a confusing picture that suggested unrelated conditions, especially since fluoroquinolone- associated vision problems are typically described by the manufacturers as mild and reversible by discontinuation of the drugs. (67-69) It may be that there are as many or even more patients encountering similar problems, but who obtained prompt treatment having such reactions promptly recognized and the drug discontinued. Clarification of these issues is beyond the scope of this report and the author strongly suggest that immediate discontinuation is required for patients presenting with fluoroquinolone-related vision problems and further antibiotic therapy should be provided from a different antibiotic group. Physicians should be aware that fluoroquinolone-associated events may occur after a single dose. (70) However, in this survey, the majority of severe cases occurred in patients who continued or restarted fluoroquinolones after adverse events had occurred. Thus, prompt recognition and withdrawal appears imperative, especially because there is no recognized treatment for the majority of these events and, according to this survey, supportive treatment is often not highly effective and irreversible vision problems appear to be the norm. LIMITATIONS AND FUTURE STUDY CONSIDERATIONS: The very nature of this report, because of its limitations, is not intended or capable of establishing a cause and effect association between the adverse events reported and the use of these chemotherapeutic agents. No statistical tests were performed, no data complying with the FDA standards was secured from the patients and no direct contact made with those reporting such events was attempted. Instead, the purpose of the article is to report the existence of large concentrations of patients in which the physician denied any such association, failed to recognize, treat and report such events, presenting a group of individuals with strikingly similar descriptions of adverse events which manifested upon such therapy, and to suggest that further investigation regarding their complaints is warranted. It is the sole intention of this report to bring to the attention of healthcare providers who provide medical care regarding the patient’s vision, the possible association of fluoroquinolone therapy with these events in a population of generally young, previously healthy and active people with no history or disease state that would result in such damage to their vision. Upon manifestation of such events it is to be deemed prudent to terminate such therapy and a viable alternative sought. HISTORY OF THE DRUGS BEING STUDIED: Table 15 History of the development of the Flouroquinolones
(Corneal verticillata & whorls, mechanisms of production of corneal & lens changes are drug deposition. Some reactions e.g. cancers, retinopathy and retroperitoneal fibrosis, may manifest months or years after exposure. Reported to cause prolongation of the QT interval or torsades de pointes. Some of the observed neuropsychiatric reactions are depression and suicidal ideation, anxiety, panic, confusion, hallucinations, paranoid delusions and convulsions.)
1967 Oxolinic Acid (quinoleine) German Patent Warner/Lambert 1973 Flumequine (benzo quinolizine) German Patent Rikker Labs 1974 Pipemidic Acid (pyrido-2-3-pyrimidine) German Patent Roger Bellon 1978 Norfloxacin (6-fluoro-7-pyrididino-quinoleine) Belgium Patent Kyorin 1979 Pefloxacin German Patent Roger Bellon/Dainippon 1982 Ofloxacin European Patent Daiichi 1983 Ciprofloxacin German Patent Bayer AG 1985 Sparfloxacin Daiichippon 1987 Levofloxacin European Patent Daiichi 1987 Clinafloxacin Kyorin 1988 Temafloxacin Toyama 1988 Gatifloxacin Kyorin 1989 Grepafloxacin Otskuda 1993 Trovafloxacin Pfizer 1994 Moxifloxacin Bayer AG 1994 Gemifloxacin LG Chemicals LTD Korea Table 16 Fluoroquinolones removed from clinical practice or use restricted 1962 Nalidixic Acid 1973 Flumequine 1985 Sparfloxacin 1988 Temafloxacin 1989 Grepafloxacin
2000 Factive (originally denied but recently received approval) Table 17 Severe adverse drug reactions associated with fluoroquinolone currently in use
[Severe peripheral neuropathy, spontaneous tendon rupture, CNS and PNS events, vision damage] 1983 Ciprofloxacin [Severe peripheral neuropathy, spontaneous tendon rupture, CNS and PNS events, vision damage] 1987 Levofloxacin [Severe peripheral neuropathy, spontaneous tendon rupture, CNS and PNS events, vision damage] 1994 Moxifloxacin [Severe peripheral neuropathy, spontaneous tendon rupture, CNS and PNS events, vision damage]
Table 18 Systemic symptoms in Cogan’s syndrome Nervous system Headache, meningismus, encephalitis, psychosis, cerebral infarction, cavernous sinus thrombosis, psychosis, peripheral nerve involvement Musculoskeletal Arthralgia, arthritis, myalgia Gastrointestinal Abdominal pain, gastric hemorrhage Cardiac Aortic insufficiency, arrhythmias, ventricular hypertrophy, valvular defects Skin Nodules, non-specific rash, palpable purpura, Genitourinary Abnormal urinalysis, hematuria, proteinuria, testicular pain Pulmonary Pleuritis, pulmonary nodules, Lymphoreticular Lymphadenopathy, splenomegaly, hepatomegaly Discussion: The manifestation of strikingly similar adverse events as well as the ocular involvement has lead us to hypothesize that Cogan’s syndrome is an autoimmune disease mediated by hypersensitivity response to one or more of the fluoroquinolones as the manifestations of these symptoms which mimic Cogan’s syndrome appears to be a universal complaint of those undergoing such therapy. All of the above is pure speculation on our part and is being offered for further discussion and debate and not intended to be considered proven fact. (See additional reference material items 1-19) The 118 cases reflected here were found within the archives of the forums indicated above and were provided voluntarily by patients motivated enough to seek information via the Internet after an exhaustive search for further information. The majority of the cases clearly indicate the failure on the part of the physician to recognize, treat and report such events. These factors may explain the preponderance of severe cases in this survey and on Web sites for fluoroquinolone-related reactions that differ markedly from previous published information. Internet groups such as this provide a different perspective on the long-term vision events associated with fluoroquinolones as well as with other drugs. The secondary Web site from which the remaining cases were reviewed consists mainly of cases involving Levofloxacin as the other fluoroquinolones on that site did not receive any such reports, but the main Web site that provided the majority of such cases included all fluoroquinolones. The preponderance of Levofloxacin-associated cases also cannot be explained by prescribing trends. Thus, this trend may reflect a previously unrecognized tendency toward greater vision problems with Levofloxacin. However the reports found within the Med Watch database seems to indicate a far greater infinity toward this manifestation with Floxin and Cipro. The fluoroquinolone antibiotics are one of the most over prescribed and abused drugs available to the physician for the treatment of bacterial infections. This has been done since the introduction of such agents in spite of the fact that such chemotherapeutic agents were never intended to be used as first line agents and only to be used as a drug of last resort when all other therapies have failed. With the rapidly expanding use for the treatment of bacterial induced eye infections it is imperative that both the patient and the physician be made aware of the adverse drug reactions involving the patient’s vision. Fluoroquinolone adverse events involving the central nervous system (e.g., dizziness, headache, seizures, psychosis) (5-18) as well as spontaneous tendon rupture and damage (19-52) are often times dismissed out of hand by the treating physician. Such events have been reported for over forty years and are only now beginning to gain prominence due to the efforts of the members of these web sites. However, less recognized are fluoroquinolone-associated vision damage and even though there are numerous reports and several articles that have been published in the medical literature regarding such events, (which are usually described as mild and of short duration, diametrically opposed to what the victims have reported on these sites) such an association appears to be unrecognized. (such reports can be found at www.fqresearch.org). Also to be noted is when we review the package inserts for a number of such agents currently in use we find repeatedly listed ALL of the adverse events being reported by these individuals as being associated with such therapy. Together with the following statement "…Most of the adverse events reported were described as only mild or moderate in severity, abated soon after the In contrast, in recent years, hundreds of reports involving fluoroquinolone-associated events involving their vision, which has not abated, have been posted on Internet Web sites by patients or concerned family members. Many of these events are described as severe and long lasting, causing substantial pain, impairment of functioning, and, in some cases, long-term disability or total blindness. In February 1999 the Quinolone Antibiotics Adverse Reaction Forum was established at www.geocities.com/quinolones/ to provide a central forum for individuals to self-report adverse events experienced in association with fluoroquinolones. This Web site also encourages people to use its link to the Food and Drug Administration’s (FDA’s) MedWatch program for filing official reports. As of May 2004, the Quinolone Adverse Drug Reaction Forum has received more than 18,5000 posts and currently has over 750 members. Utilizing the archives of this forum a survey of cases involving vision damage was conducted in order to examine the number and characteristics of these adverse events in this population. Events since September 11, 2001, there has been a heightened awareness by the physician and the public regarding the serious adverse effects associated with fluoroquinolones as a result of the anthrax threat associated with the events of that day. The media, generally, have presented only a few stories regarding the fluoroquinolone adverse effects and they are usually described as mild and self-limiting. Despite being inundated by those who have suffered severe adverse reactions the media has shown no interest in providing such information to the general public. The FDA has refused to date to take any action to inform the prescribing physician as well, despite the urgent plea by Public Citizen, in 1996, regarding spontaneous tendon ruptures (53) and the reporting of the events contained within this report which had been forwarded to the FDA as well. Even more disturbing is the fact that in the majority of the cases reviewed there was no clinical rational for the use of these agents. The treatment of prostatitis was not an approved use of Levaquin at the time that such therapy was started. Minor urinary tract infections, minor respiratory infections, and even a bee sting we find listed as the reasons for such therapy. The futility of the use of antibiotics to treat bronchitis has been firmly established as well as the use of these agents to treat viral infections. Even when the laboratory results clearly indicated that there was no bacterial infection present such therapy was continued. When the patient presented with adverse reactions in the majority of the cases therapy was continued or the patient switched to a different drug within the same class. The 118 cases presented in this report, as well as previous published articles about the neurotoxicity and effects of fluoroquinolones on the eyes, should give patients and physicians pause before using fluoroquinolones without specific indication. Moreover, the physician needs to be intimately aware of the possible adverse events regarding such therapy as well as what to do if potentially serious fluoroquinolone adverse effects occur involving the patient’s vision. If the reports found within the two databases being utilized are any indication such information is grossly lacking by the prescribing physician. Rarely, if ever, has it been reported that such vision disturbances are being recognized as being induced by the fluoroquinolone being utilized. SUMMARY: Fluoroquinolones are to be considered drugs of last resort when the patient has failed to respond to traditional therapy. They are not, and can not, due to their severe manifestation of life threatening and non-abating adverse reactions be considered first line agents. Serious adverse drug reactions involving the CNS, PNS and musculoskeletal systems have been reported but not recognized as such by the treating physician. This report adds severe vision damage to the never-ending list of adverse reactions that the physician has no prior knowledge of. Further, better controlled investigation we believe to be warranted. If the occurrence of fluoroquinolone-associated adverse drug reactions of this severity and duration is confirmed, physicians need to be informed and warnings added to the drugs’ product information regarding the non abating nature of such injuries. In the meantime, healthcare providers need to be more vigilant regarding the adverse events associated with fluoroquinolones and refrain from denying any such association to the patient. Even mild events involving the patient’s vision should prompt immediate discontinuation of such therapy and a viable alternative sought. A copy of this report was forwarded to The
National Registry of Drug Induced Ocular Side-Effects, F.T.
Fraunfelder, M.D.
"Your data on increased vitreous floaters has me baffled and is something that goes along with posterior vitreous detachment. Both have similar etiology; it is something I would like to monitor and follow with you..." The National Registry of Drug Induced Ocular
Side-Effectswas founded in 1976 in Little Rock, Arkansas by Dr.
Frederick (Fritz) T. Fraunfelder. The goal was to create an
international clearinghouse of drug information on adverse ocular
events associated with drugs and biologics. The underlying principle
of the Registry is to generate early signals of adverse ocular
reactions secondary to medications based on suspicions of practicing
clinicians. Citations and References 1. Safety of the Fluoroquinolone Antibiotics: Focus on Molecular Structure Stacy J. Childs, MD, University of Colorado Health Sciences Center, Denver[Infect Urol 13(1):3-10, 2000. © 2000 Cliggott Publishing Co., Division of SCP/Cliggott Communications, Inc.] 2. Reversible visual loss in a patient receiving high-dose ciprofloxacin.Vrabec TR, Segott RC, Jaeger EA, Savino PJ, Bosley TM Neuro-Ophthallmology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia PA Ophthalmology, 1991 3. Canadian Adverse Drug Reaction Newsletter, Volume 12, Issue 4, October 2002 Optic Neuritis with permanent vision loss after ONE dose of Moxifloxacin (Avelox) 4. Patients receiving fluoroquinolones developed visual disturbances including color distortions and diplopia. (Ball, 1989) 5. Wolfson JS, Hooper DC. Fluoroquinolone antimicrobial agents. Clin Microbiol Rev 1989;2:378- 424. 6. Stahlmann R, Lode H. Toxicity of quinolones. Drugs 1999;58(suppl2):37- 42. 7. Thomas RJ. Neurotoxicity of antibacterial therapy. South Med J 1994;87:869-74. 8. Christ W. Central nervous system toxicity of quinolones: human and animal findings. J Antimicrob Chemother 1990;26(suppl B):219-25. 9. Schwartz MT, Calvert JF. Potential neurologic toxicity related to ciprofloxacin.DICP 1990;24:138- 40. 10. Lietman PS. Fluoroquinolone toxicities. An update. Drugs 1995;49(suppl2):159-63. 11. Schmuck G, Schurmann A, Schluter G. Determination of the excitatory potencies of fluoroquinolones in the central nervous system by an in vit-ro model. Antimicrob Agents Chemother 1998;42:1831-6. 12. Mulhall JP, Bergmann LS. Ciprofloxacin-induced acute psychosis. Urology 1995;46:102-3. 13. Lipsky BA, Baker CA. Fluoroquinolone toxicity profiles: a review focusing on newer agents. Clin Infect Dis 1999;28:352-64. 14. Traeger SM, Bonfiglio MF, Wilson JA, Martin BR, Nackes NA. Seizures associated with ofloxacin therapy. Clin Infect Dis 1995;21: 1504-6. 15. North DS, Fish DN, Redington JJ. Levofloxacin, a second-generation fluoroquinolone. Pharmacotherapy 1998;18:915-35. 16. 1983 Peddie BA: Norfloxacin induced rhuematic disease RR, JA 17. 1986 JG, Sports Med: tendon lesions 18. 1987 Goodchild MC: Arthropathy in a patient with Cystic
Fibrosis …(context) 19. 1987 Schluter G: Ciprofloxacin review of potential
toxicological effects 20. 1988 Davey PG: Ciprofloxacin and tenosynovisits (context) 21. 1991 Wolfson JS: Fluoroquinolone antimicrobial agents (context) 22. 1991 Jorgenson, Anya: Arthropathy wich Achilles tendon
involvement induce by perflosacin (context) 23. 1991 Weinstabl, Stiskal et al : Classifying calcaneal
tendon injury according to MRI findings (context) 24. 1991 Ribard, Audisis: Seven Achilles tendinitis including three
complicated by rupture 25. 1991 Chaslerie, Bannwarth: Rupture tendisneuse et
fluoroquinolones: Un effet undesirable 26. 1992 Ribard P, Audisio F, Kahn MF, et al: Seven Achilles
tendinits including 3 complicated by rupture 27. 1992 Lee WT, Collins JF: Ciprofloxacin associated bilateral
Achilles tendon rupture 28. 1993 Collins JF: Ciprofloxacin associated bilateral Achilles'
tendon rupture 29. 1993 Lafon M: Tendonopathies et fluoroquinolones 30. 1993 Gillet P, Blum A, Pierfitte C et al: Fluoroquinolone
associated Achilles tendinitis 31. 1993 Falt-Rolachon, Pireyre et al: Rupture bilaterale de coiffe
des rotateurs lors d'un tratitem… 32. 1993 Borderie, Marcelli et al: Spontaneous rotator cuff tear
during fluoroquinolone therapy 33. 1994 Hestin, Mainard et al: Spontaneous bilateral rupture of
the Achilles Tendon… 34. 1994 R J Netter: Features of tendon disorders with
fluoroquinolones… 35. 1995 Gillette, Hestin et al: Fluoroquinolone induced
tenosynovisitis of the wrist 36. 1995 FDA, Blum M.D. : More on fluoroquinolone antibiotics and
tendon rupture… 37. 1995 J C Chauveaux: Epidondylitis after treatment with
fluoroquinolone antibiotics 38. 1996 Zabraniecki, Negrier et al: Fluoroquinolone induced
tendinopathy report of 6 cases 39. 1996 HRG Publication #1399: Petition to require a warning of
all fluoroquinolones antibiotics 40. 1996 Szarfman et al: Labeling changes British National
Formulary 41. 1996 FDA Medical Bulletin October 1996 Volume 26 Number 3;
Reports of adverse events with fluoroquinolones 42. 1997 Movin, Gad et al: Pathology of the achilles tendon in
association with Ciprofloxacin 43. 1997 Andujar et al: Tendinitis associated with ciprofloxacin 44. 1998 Levadouxe M, Carli P, Gadea J F: Repeated rupture of the
extensor tendons of the hand… 45. 1999 Van der Linden PD: Achilles tendinitis associated with
fluoroquinolones 46. 1999 Harrell R M: Fluoroquinolone induced tendinopathy: What do
we know? 47. 2000 Stahlmann: Arthropathies 48. 2000 Williams R: Ciprofloxacin associated with destructive
enzymes 49. 2001 Van Der Linden et al: Tendon disorders attributed to
fluoroquinolones a study of 42 cases 50. 2001 Malaguti et al: Ciprofloxacin associated Achilles tendon
rupture in a hemodialyis patient 51. 2002 Rudzinski: Toctoc Response, since 1983 fluoroquinolones
have been associated with tendon pathology… 52. 2003 Gold et al: Levofloxacin-Induced Tendon Rupture: A Case Report and Review of the Literature 53 Petition to Require a Warning on All Fluoroquinolone Antibiotics (HRG Publication #1399) August 1, 1996 54. US Department of Health and Human Services, Food and Drug Administration. Requirements on content and format of labeling for human prescription drugs and biologics: proposed rule. Federal Register, Dec. 22,2000;65(247):81081-124. 55 Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239- 45. 56 Stahlmann R, Lode H. Toxicity of quinolones. Drugs 1999;58(suppl 2):37- 42. 57 Thomas RJ. Neurotoxicity of antibacterial therapy. South Med J 1994; 87:869-74. 58 Christ W. Central nervous system toxicity of quinolones: human and ani-mal findings. J Antimicrob Chemother 1990;26(suppl B):219-25. 59 Schmuck G, Schurmann A, Schluter G. Determination of the excitatory potencies of fluoroquinolones in the central nervous system by an in vit-ro model. Antimicrob Agents Chemother 1998;42:1831-6. 60. von Keutz E, Schluter G. Preclinical safety evaluation of moxifloxacin, a novel fluoroquinolone. J Antimicrob Chemother 1999;43(suppl B):91-100. 61 Fluoroquinolone toxicities. An update. Drugs 1995;49(suppl 2):159-63. 62 Reversible visual loss in a patient receiving high-dose
ciprofloxacin hydrochloride (Cipro) 63 Case 7-2003 — A 43-Year-Old Man with Fever, Rapid Loss of Vision in the Left Eye, and Cardiac Findings: Robert H. Rubin, M.D., Mary Etta King, M.D., and Eugene J. Mark, M.D. 64.Factors affecting visual loss in benign intracranial
hypertension. 65 Hedenmalm K, Spigset O. Peripheral sensory disturbances related to treatment with fluoroquinolones. J Antimicrob Chemother 1996;37: 831-7. 66 Br J Ophthalmol 2000;84:378-384."Fluoroquinolone Effective In Treating Corneal Ulcer But Should Be Used With Caution" May 4, 2000 WESTPORT (Reuters Health) 67 Lietman PS. Fluoroquinolone toxicities. An update. Drugs 1995;49(suppl2):159-63. 68 Fluoroquinolone toxicities. An update. Drugs 1995;49(suppl 2):159-63. 69 Bertino J Jr, Fish D. The safety profile of the fluoroquinolones. Clin Ther 2000;22:798-817. 70.McEvoy GK. American Hospital Formulary Service, Drug information 1999. Bethesda, MD: American Society of Health-System Pharmacists,1999. 71 Bayer Agriculture Division Animal Health Bayer Corporation
P.O. Box 390 Shawnee Mission, KS 66201-0390 Phone: 913 268-2000
July 6, 2000 Dear Doctor Letter regarding vision loss associated
with Baytril® (enrofloxacin) 72 Enrofloxacin-associated retinal degeneration in cats. 73 Ophthalmotoxicity and ototoxicity of the new quinolone
antibacterial agent levofloxacin in Long Evans rats.Nomura M,
Yamada M, Yamamura H, Kajimura T, Takayama S. 74 Effects of antibiotics on morphologic characteristics and
migration of canine corneal epithelial cells in tissue culture.
Hendrix DV, Ward DA, Barnhill MA. Additional Reference Material 1. Cogan DG. Syndrome of non syphilitic interstitial keratitis and vestibuloauditory symptoms. Arch Ophthalmol 1945; 33: 144-49. 2. Vollertsen RS et al. Cogan’s syndrome: 18 cases and a review of the literature. Mayo Clin Proc 1986; 61: 344-61. 3. Morgan GJ et al. Cogan’s syndrome: acute vestibular and auditory dysfunction with interstitial keratitis. Am J Otolaryngol 1984; 5: 258-61. 4. Garcia Berrocal JR et al. Cogan’s syndrome: an oculo-audiovestibular disease. Postgrad Med 1999; 75: 262-64. 5. Vollertsen RS et al. Cogan’s syndrome: audiovestibular involvement and prognosis in 18 patients. Laryngoscope 1985; 95: 650-54. 6. Schuknecht HF et al. Temporal bone pathology in a case of Cogan’s syndrome. Laryngoscope 1994; 104: 1135-42. 7. Allen NB et al. Use of immunosuppressive agents in the treatment of severe ocular and vascular manifestations of Cogan’s syndrome. Am J Med 1990; 88: 296-301. 8. Ho AC et al. Cogan’s syndrome with refractory abdominal aortitis and mesenteric vasculitis. J Rheumatol 1999; 26: 1404-07. 9. Helmchen C et al. Cogan’s syndrome: clinical significance of antibodies against the inner ear and cornea. Acta Otolaryngol 1999; 119: 528-36. 10. Heinemann MH et al. Cogan’s syndrome. AnnOphthalmol 1980; june: 667-74. 11. Cogan DG et al. Late corneal opacities in the syndrome of interstitial keratitis and vestibulo-auditory symptoms. Acta Ophthalmol 1989; 67: 182-87. 12. Cheson BD et al. Cogan’s syndrome: a systemic vasculitis. Am J Med 1976; 60: 549-55. 13. Majoor MHJM et al. Corneal autoimmunity in Cogan’s syndrome? Report of two cases. Ann Otol Laryngol 1992; 101: 679-84. 14. Del Carpio J et al. Cogan’s syndrome and HLA-BW17. Letter to the editor. N Engl J Med 1976; 25: 1262-63. 15. Hughes GB et al. Autoimmune reactivity in Cogan’s syndrome: a preliminary report. Otol Head and Neck Surg 1983; 91: 24-32. 16. Eisenstein B et al. Non syphilitic interstitial keratitis and bilateral deafness (Cogan’s syndrome) associated with cardiovascular disease. N Engl J Med 1958; 258 (22): 1074-79. 17. Cogan DG et al. Nonsyphilitic interstitial keratitis with vestibuloauditory symptoms: a case with fatal aortitis. Arch Ophthalmol 1964; 71: 172-75. 18. Cobo LM et al. Early corneal findings in Cogan’s syndrome. Ophthalmology 1984; 91: 903-07. 19. Gilbert WS et al. Cogan’s syndrome: signs of periarteritis nodosa and cerebral venous sinus thrombosis. Arch Ophthalmol 1969; 82: 633-36. 20. THE JAPAN LAWLETTER, December, 1982. By Roderick Seeman 21. THE JAPAN LAWLETTER, April 1987. By Roderick Seeman 22.eMedicine Journal, May 25 2001, Volume 2, Number 5 Authored by Manolette Rangel Roque, MD Chief of Service, Immunology and Uveitis Service, Consulting Staff, Cornea and Refractive Surgery Service, Q.C. Eye Center, Cavite Eye and ENT Center, Makati Eye Laser Center |
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