How to best assess Plaquenil Toxicity: Briefly

There is still much confusion of how to follow patients who are on Plaquenil. All eyeMDs are scared of missing such toxicity but there

A. Check Patient’s Dose:

1. REAL Body Weight: Latest research (below) recommends to calculate dose based on REAL Body Weight.

2. No more than 6.5mg/kg/day

3. If dosing is calculating 300mg/day: alternate-day dosing recommended: Average dose over 2-3 days.

B. Assess Retinal Toxicity:

1. Baseline Screening within 1st year of use
2. Annual screening after 5 years of use:
Humphrey Visual Field: HVF White 10-2: yearly after 5 years (sooner if high risk patient–see below or suspicion of early toxicity). Have a low threshold for an abnormality and retest if abnormality is present. When in doubt, refer to Retina Specialist with Multifocal ERG, FAF (below).

3. Spectral Domain OCT: Annually especially if HVF is defective.

4. Multifocal ERG: (usually requires visit to eye hospital like Mass Eye & Ear, Johns Hopkins, Georgetown, etc). Recommended if any suspicion of early damage. Thought to show any damage earlier than visual field loss.

5. Fundus Autofluorescence (info below): Recommended if any suspicion of early damage. Shows damage earlier than visual field loss. (usually requires visit to eye hospital like Mass Eye & Ear, Johns Hopkins, Georgetown, etc).

Higher Risk:

1. Kidney disease

2. Taking Tamoxifen Citrate also

Prevalence of retinal damage

1. Plaquenil: 4.0-5.0mg/kg daily = 2% within 10 yrs

2. = 20% after 20 yrs

3. Only 20 cases reported of retinal damage with a dose <6.5mg/kg (Lee. Br J Ophthalmology 2005; 89: 521-522)

References:

The Risk of Toxic Retinopathy in Patients on Long-term Hydroxychloroquine Therapy.

Pediatric Critical Care MedicineNovember 15, 2014

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Importance:

Hydroxychloroquine sulfate is widely used for the long-term treatment of autoimmune conditions but can cause irreversible toxic retinopathy. Prior estimations of risk were low but were based largely on short-term users or severe retinal toxicity (bull’s eye maculopathy). The risk may be much higher because retinopathy can be detected earlier when using more sensitive screening techniques.

Objectives:

To reassess the prevalence of and risk factors for hydroxychloroquine retinal toxicity and to determine dosage levels that facilitate safe use of the drug.

Design, Setting, and Participants:

Retrospective case-control study in an integrated health organization of approximately 3.4 million members among 2361 patients who had used hydroxychloroquine continuously for at least 5 years according to pharmacy records and who were evaluated with visual field testing or spectral-domain optical coherence tomography.

Exposure:

Hydroxychloroquine use for at least 5 years.

Main Outcomes and Measures:

Retinal toxicity as determined by characteristic visual field loss or retinal thinning and photoreceptor damage, as well as statistical measures of risk factors and prevalence.

Results:

Real body weight predicted risk better than ideal body weight and was used for all calculations. The overall prevalence of hydroxychloroquine retinopathy was 7.5% but varied with daily consumption (odds ratio, 5.67; 95% CI, 4.14-7.79 for >5.0 mg/kg) and with duration of use (odds ratio, 3.22; 95% CI, 2.20-4.70 for >10 years). For daily consumption of 4.0 to 5.0 mg/kg, the prevalence of retinal toxicity remained less than 2% within the first 10 years of use but rose to almost 20% after 20 years of use. Other major risk factors include kidney disease (odds ratio, 2.08; 95% CI, 1.44-3.01) and concurrent tamoxifen citrate therapy (odds ratio, 4.59; 95% CI, 2.05-10.27).

Conclusions and Relevance:

These data suggest that hydroxychloroquine retinopathy is more common than previously recognized, especially at high dosages and long duration of use. While no completely safe dosage is identified from this study, daily consumption of 5.0 mg/kg of real body weight or less is associated with a low risk for up to 10 years. Knowledge of these data and risk factors should help physicians prescribe hydroxychloroquine in a manner that will minimize the likelihood of vision loss.

2. From: http://www.aao.org/publications/eyenet/201105/retina1.cfm

Clinical Update: Retina Screening

Rx Side Effects: New Plaquenil Guidelines and More

By Miriam Karmel, Contributing Writer
Interviewing Frederick W. Fraunfelder, MD, Anne E. Fung, MD, and Michael F. Marmor, MD

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(PDF 370 KB)

Drug-induced ocular side effects are back in the spotlight, thanks to the Academy’s revision of its recommendations on screening for retinal toxicity from chloroquine and its analogue hydroxychloroquine (Plaquenil).¹

There are hundreds of drugs with potential retinal toxicity—so many that the National Registry of Drug-Induced Ocular Side Effects doesn’t stratify them by incidence or effect, said Frederick W. “Rick” Fraunfelder, MD, director of the Registry and associate professor of ophthalmology at Oregon Health & Science Universityin Portland. “Plaquenil toxicity isn’t even in the top 10, or the top 100” if you’re looking at incidence, he said. “It’s a pretty rare thing.” Nevertheless, he urged doctors to master the Academy’s new guidelines, because the effects from chloroquine and hydroxychloroquine, when they do occur, are severe and often irreversible. (Note that chloroquine is not used frequently in the United States and has been replaced by the use of hydroxychloroquine because the latter has fewer side effects.) Also, watch for June’s Ophthalmic Pearls for more on spotting and treating Plaquenil toxicity.

The Plaquenil Problem

“Plaquenil toxicity is very distinctive,” said Michael F. Marmor, MD, professor of ophthalmology at Stanford University. Dr. Marmor, who chaired the Academy’s screening guidelines committee, said the goal in Plaquenil screening is to catch changes at a very early stage when there’s just a minimal amount of loss of vision. “Then, when you stop the drug, the damage won’t progress enough to cross the fovea and affect reading vision.”

Plaquenil, widely used to treat lupus, rheumatoid arthritis and other inflammatory and dermatologic conditions, is very effective, and “the risk of toxicity in the first five years for someone without special risk factors is very low,” Dr. Marmor said. However, risk increases with duration of use, and the guidelines call for annual screening after five years, or sooner if there are “unusual risk factors or a suspicion of early toxicity.”

Anne E. Fung, MD, a retina specialist at Pacific Eye Associates in San Francisco, averages one Plaquenil screening a week, due to her close affiliation with the medical center’s rheumatology and dermatology clinics. Still, in 10 years of practice, she’s seen just one case of toxicity. Dr. Marmor, on the other hand, has seen at least 10 cases in the past year.

Dr. Fung’s case involved a 48-year-old woman with lupus. Nine years after discontinuing medical therapy, the patient had new scotomas, difficulty reading and progression of bull’s-eye maculopathy. Plaquenil’s long half-life in the body can cause irreversible and progressive damage, Dr. Fung said.

Similarly, one study reported that 16 women who’d taken hydroxychloroquine or chloroquine, or a combination of the agents, showed no improvement seven years after stopping drug therapy, and progression occurred in six of the cases.²

The Revised Guidelines

The Academy’s new guidelines represent “a paradigm shift from subjective to objective measures,” said Dr. Fung. “It’s a new algorithm, very much a new concept in Plaquenil screening.” Some points to consider:

Preferred screening methods. 10-2 visual fields, but not Amsler grids, are still acceptable for screening if read with caution. Dr. Marmor said, “We also recommend use of objective tests such as spectral domain OCT, multifocal ERG and fundus autofluorescence.” He added that older time domain OCT units lack enough sensitivity for Plaquenil toxicity.

Go by ideal, not real, weight. Dr. Marmor stressed the importance of not overdosing, which greatly accentuates the risk of toxicity. Therefore, the new guidelines suggest using a person’s height as a dosing factor. By the old standards, obese people, if dosed by their actual weight, could be overmedicated, Dr. Marmor said. If you’re short, the standard prescription of 200 mg of Plaquenil, twice daily, is too much, he said.

The recommended dosage is no more than 6.5 mg/kg/day, using the standard known as “ideal weight,” which factors in height. Dr. Marmor suggested calculating this as follows:

For women, the ideal weight is 100 lbs for 5 feet, plus five lbs per extra inch of height.
For men, the ideal weight is 110 lbs for 5 feet, plus five lbs per extra inch of height.

What if the ideal dose is 300 mg/day? Both Drs. Marmor and Fung suggested alternate-day dosing. “It’s possible to average a dose over the course of two or three days,” Dr. Fung said. “Take two one day and one the next.”

Unfortunately, prescribing doctors often don’t consider the ocular threshold, said Dr. Fung. “I have had many patients on doses above the safe ocular threshold. So ophthalmologists are doing our patients a disservice if we are not vigilant.”

Share Your Data

The National Registry of Drug-Induced Ocular Side Effects was founded in 1976 by Dr. Fritz Fraunfelder as a place where doctors could solicit information about and contribute reports of suspected drug toxicities.

How does it work? If you suspect that an ocular condition is drug-related, the Registry, a nonprofit organization, may help confirm that suspicion. For example, you may have a patient with eye inflammation who recently was vaccinated for hepatitis B. Is there a connection, as was reported last year?¹

“Doctors can call us and we can search” for similar cases, said Dr. Rick Fraunfelder. Patient information is protected, so access is restricted. “We’ll give the physician available literature and all the current spontaneous reports.” (The Registry includes data from the FDA and the World Health Organization’s spontaneous database.) Dr. Fraunfelder also encourages doctors to enter their spontaneous reports into the database. For example, if a patient on a statin experiences double vision, you can submit that information to the Registry. At some point, if enough spontaneous reports are submitted, the computer issues a signal that further investigation may be warranted, Dr. Fraunfelder said.

To access the Registry, go to www.eyedrugregistry.com. The service is free, although Academy membership is required for entry.

1 Fraunfelder, F. W. et al. Cutan Ocul Toxicol 2010;29:26–29.

Beyond Plaquenil: Other Drugs, Other Problems

If you’re looking for a comprehensive assessment of drug reactions that relate to the eye, Dr. Fraunfelder and his father, Frederick T. “Fritz” Fraunfelder, MD, along with Wiley A. Chambers, MD, literally wrote the book.³

“So many drugs can cause ocular side effects that if you’re trying to make a point about which drugs to watch out for, you can’t really pick [just] one,” Dr. Fraunfelder said. However, he has narrowed the list for a course he teaches at the Academy’s Annual Meeting and for a published review of adverse ocular drug reactions.⁴

Here are some drugs to watch out for, based on recent reports.

Bisphosphonates are used to manage osteoporosis and other conditions that involve loss of bone mass. Multiple clinical concerns include blurred vision, anterior uveitis and episcleritis.
Cetirizine (Zyrtec and others), an antihistamine, can cause pupillary changes, blurred vision and keratoconjunctivitis sicca. Of nine cases reported to the Registry, eight involved children.
Erectile dysfunction drugs cause a range of side effects that are common, dosage-dependent and, thus far, fully reversible. They include changes in color and light perception, blurred vision, conjunctival hyperemia, ocular pain and photophobia.
Ethambutol (Myambutol), used to treat pulmonary tuberculosis, has generated over 800 reports to the Registry. Ethambutol is associated with optic or retrobulbar neuritis, affecting one or both eyes. An unusual form of the toxicity causes peripheral constriction of the visual field. Monthly ophthalmic exams are recommended for doses of ethambutol exceeding 15 mg/kg/day.
Fluoroquinolones are associated with side effects not seen in other classes of antibiotics. Topical administration may cause precipitates in the cornea and, possibly, uveitis.
Hepatitis B vaccine may have an association with uveitis.
Herbal medicines and nutritional supplements generated $60 billion in sales worldwide in 2004, according to the World Health Organization.⁵ WHO has published guidelines on the use of herbal medicine, and the Registry lists common supplements and their visual symptom reactions.
Retinoids, used to treat severe, recalcitrant acne and psoriasis and to induce remission of leukemia, have been linked to intracranial hypertension and papilledema when used in prescribed therapeutic doses.
Tamsulosin (Flomax), used to treat benign prostatic hyperplasia and hypertension, has been associated with intraoperative floppy iris syndrome.
Topiramate (Topamax) is used to treat epilepsy and migraines. The drug also is used off-label for a number of concerns, including weight loss, bipolar disorder and depression. It has been associated with acute angle-closure glaucoma and transient myopia.
Statins may be associated with diplopia, ptosis and ophthalmoplegia, and they may exacerbate myasthenia gravis and cataracts.

Final Thoughts: Quick Tips

Some quick tips to consider when you are diagnosing and managing ocular toxicity:

Dr. Fraunfelder: “One of the main rules, but not a hard rule, is if it’s a drug toxicity, it usually is bilateral.”

Dr. Fung: “I’m always concerned that the prescribing doctors are not completely aware of the dose-related toxicity of chloroquine and hydroxychloroquine. So I always check and calculate the dose. Also, communication with the prescribing doctor is very important. I have a form letter where I fill in the current dose, weight and goals.”

Dr. Marmor: “Stop the drug [Plaquenil] if you detect parafoveal thinning. But you do have to discuss this with the patient and his or her rheumatologist to be sure you’re not affecting the medical care. I’ve had a few patients continue because they think the drug is so critical for their quality of life. But the vast majority is happy stopping. There are alternatives.”
___________________________

1 Marmor, M. F. et al. Ophthalmology 2011;118:415–422.
2 Michaelides, M. et al. Arch Ophthalmol 2011;129:30–39.
3 Clinical Ocular Toxicity (Philadelphia: W. B. Saunders, 2008).
4 Fraunfelder, F. W. and F. T. Fraunfelder. Ophthalmology 2004;111:1275–1279.
5 National Policy on Traditional Medicine and Regulation of Herbal Medicines—Report of a WHO Global Survey(Geneva: WHO, 2005).

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Clinical Update: Retina

The Nuts and Bolts of Fundus Autofluorescence Imaging

By Annie Stuart, Contributing Writer
Interviewing Szilárd Kiss, MD, Srinivas Sadda, MD, and Richard F. Spaide, MD

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(PDF 242 KB)

With the introduction of fluorescein angiography decades ago, ophthalmologists observed that, even without the use of fluorescein, parts of the fundus showed areas of fluorescence in certain conditions. Although this faint, so-called autofluorescence was at first considered to be a distraction, it was later found to have potential as a diagnostic indicator and a tool for monitoring disease progression. New instrumentation and techniques have been developed to begin harnessing its potential.¹

We now know that fundus autofluorescence (FAF) imaging can provide information about the health and function not just of the central retina but in the periphery as well.

The Fluorescent Fundus

What causes fundus autofluorescence? The retinal photoreceptors contain light-sensing molecules, a class of retinoids that are susceptible to damage and cross-linking, said Richard F. Spaide, MD, in private practice with Vitreous-Retina-Macula Consultants of New York. The photoreceptors shed their damaged outer segments, which the retinal pigment epithelium (RPE) ingests through phagocytosis. The molecules are stored in liposomes and form lipofuscin (LF).¹

Accumulation of lipofuscin. “Over years, each RPE cell will eventually phagocytize 3,000,000,000 outer segments, and up to 25 percent of the cell volume will be occupied by lipofuscin,” said Dr. Spaide. In addition to age, disease states and potentially increased oxidative damage can contribute to the buildup of LF in RPE cells.

LF can be made to fluoresce by a fairly broad range of wavelengths, about 500 to 800 nm.¹ “After excitation, the molecule will spontaneously release a photon of light of a somewhat longer wavelength, efficiently recorded with a variety of imaging methods,” said Dr. Spaide.

Hyper- and hypofluorescence. Areas of excess LF accumulation will appear hyperfluorescent. But when RPE cells die or are absent, LF disappears, leading to hypofluorescence.

Not just the RPE. Fluorescence comes from other layers of the retina as well. “With age and under certain pathologic conditions, this autofluorescence increases dramatically and adds to the signal produced by the lipofuscin in the RPE,” said Dr. Spaide.

Fundamentals of FAF

Two main methods are used to record autofluorescence: confocal scanning laser ophthalmoscopy (cSLO) and standard fundus camera photography, said Szilárd Kiss, MD, director of clinical research and assistant professor of ophthalmology at Weill Cornell Medical College in New York City.

cSLO systems. The first method developed for clinical FAF imaging, cSLO uses a laser to rapidly and precisely scan the retina, said SriniVas Sadda, MD, associate professor of ophthalmology at the University of Southern California and the Doheny Eye Center in Los Angeles. Among the cSLO systems equipped for FAF imaging are the Heidelberg Retina Angiograph, which uses blue light, and the Optos OCT
SLO, which uses green light.

You can acquire images at nearly a video rate and add them together, Dr. Sadda said, which improves the signal-to-noise ratio and provides higher-quality images. “More important, you’re able to image structures that may be relatively weak in terms of their autofluorescence.”

Because light is forced through the confocal pinhole, this method allows you to selectively isolate a signal from one plane only. “This method has the advantage of rejecting spurious fluorescence from other structures in the eye, such as the lens, which has many fluorophores and fluoresces in the same wavelengths as lipofuscin,” said Dr. Spaide.

However, because only one plane can be seen, he added, conditions that increase fluorescence from the neurosensory retina, including almost any condition causing a serous or tractional detachment, will not be detected well with a cSLO-based system.

Fundus camera. In contrast, “The fundus camera shows a summation of fluorescence from the fundus and consequently can image fluorescence from the retina and RPE at the same time,” said Dr. Spaide. “The signal strength is sufficiently powerful so that only one photograph needs to be taken, instead of averaging images over time.”

Based on modifications pioneered by Dr. Spaide, the fundus camera FAF-imaging method uses filters exciting in the green spectrum and recording emission in the yellow-orange spectrum, said Dr. Sadda.

Does color matter? Noting that some systems use blue and others green light for excitation, Dr. Kiss said, “These provide essentially corresponding information about the retina. However, the green spectrum may provide some additional detail in the fovea, as the blue light tends to be absorbed by the high concentration of xanthophyll pigments.” Dr. Sadda added, “One advantage of longer-wavelength [green] light is that there is less absorption by the crystalline lens of the eye, which is quite autofluorescent with blue light, especially in patients with cataracts.”

Near-infrared. Light outside of the visible spectrum can also be used. “Near-infrared FAF imaging uses very long wavelengths of light—about 790 nm—just beyond the ability of the human eye to detect,” said Dr. Sadda. These wavelengths excite molecules other than LF, most notably, melanin. The distribution of melanin in the eye, he said, provides a different type of information about the disease process than LF alone.

Wide-field imaging. FAF imaging can be used to view only the posterior pole or all the way out to the periphery of the retina. For the latter, “You need a wide-field imaging platform such as the Optos system, which has the capability of scanning to 200 degrees,” said Dr. Kiss. The Optos uses an ellipsoidal mirror in the image pathway, said Dr. Spaide, which deflects light across a wide field of the ocular fundus.

In a retrospective review, Dr. Kiss and colleagues found peripheral autofluorescent abnormalities in nearly 64 percent of eyes in patients with age-related macular degeneration (AMD), compared with about 36 percent of control eyes, suggesting potential implications for diagnosing and treating different subtypes of the disease.²A retrospective analysis by Dr. Sadda found similar abnormal peripheral patterns in a majority of patients with a wide range of diseases.³

Because the Optos scans such a large area of the retina, however, it cannot capture images quite as rapidly as the Heidelberg, said Dr. Sadda. It is also less confocal, which may create some “noise” in the image due to autofluorescence from other structures.

Which Conditions to Test?

Unlike other imaging modalities, said Dr. Kiss, FAF provides functional information about retinal cells. According to Dr. Spaide, it is useful for almost any fundus disorder, including AMD, retinal detachment, inherited dystrophies, central serous chorioretinopathy, vitelliform lesions, and acute zonal occult outer retinopathy (AZOOR). Dr. Kiss noted that FAF is also helpful in screening for medication toxicity, including eye problems related to hydroxychloroquine (Plaquenil).

AMD. FAF imaging allows functional evaluation of geographic atrophy in dry AMD, said Dr. Kiss, making it possible to assess emerging therapies and monitor response to medication as well as progression of the disease.

“Areas of geographic atrophy are hypofluorescent because there are no photoreceptors and no lipofuscin within the RPE cells,” he said. However, hyperfluorescence shows up in junctional zones around geographic atrophy where the RPE is working overtime—a foreshadowing of imminent atrophy.

“Of the studies using autofluorescence as a secondary end point, the most prominent one is AREDS 2,” said Dr. Kiss. The results may have a strong effect on the application of FAF imaging in the future, he added, just as OCT now influences clinicians’ treatment of patients with wet AMD.

Retinal detachment. Hyperfluorescence in areas immediately adjacent to a retinal detachment can demarcate its extent and help explain visual problems in patients, said Dr. Kiss. “In a small series using ultra-wide-field FAF imaging, we also showed that these areas can remain abnormal, even after the retina is reattached.”

Dystrophies and degenerations. Retinal dystrophies and degenerations also show abnormal autofluorescence, said Dr. Kiss. As with dry AMD, retinal dystrophies such as retinitis pigmentosa demonstrate areas of both hyper- and hypofluorescence, a sign that the retina is burning out.

“Always test Best disease,” said Dr. Kiss, “which is characterized by macular or submacular accumulation of lipofuscin material and has a sharp, characteristic hyperfluorescent region in the macula.” Dr. Spaide added, “We are familiar with Best disease causing a yellow egg yolk–like lesion in kids and young adults, but with time that will go away. However, FAF imaging shows widespread abnormalities in the fundus and also can find areas of atrophy within the lesions.”⁴

Dr. Sadda finds FAF particularly useful in diagnosing Stargardt disease, in which pisciform lesions are readily apparent.

Central serous chorioretinopathy (CSC). According to Dr. Spaide, the extent of CSC is best seen with autofluorescence, not just in the area of the subretinal fluid but also in other parts of the macula or even the other eye.

As with diseases that cause a buildup of vitelliform material, said Dr. Spaide, CSC accumulates outer segments that have been shed but not yet phagocytized. “In central serous chorioretinopathy, it is common to see subretinal accumulation of material,” he said. “Some ophthalmologists will call that ‘subretinal protein’ without giving the material much thought. However, it is highly autofluorescent in the wavelengths used to excite retinoids. Proteins do not efficiently autofluoresce in these wavelengths, so the hypothesis that the material is protein does not fit the available facts.”

A Complementary Tool

The role of FAF imaging is still evolving, but it provides unique information to complement that obtained through other imaging modalities. With practice, it is possible to seamlessly integrate FAF imaging with other methods to gain a more complete understanding of a patient’s condition, said Dr. Spaide, just as someone learning tennis first individually practices serves, backhands, volleys, and forehand shots—and then uses them together fluidly in a tennis match.

FAF and fluorescein angiography. For example, both FAF imaging and fluorescein angiography provide useful and complementary information. “On the one hand, fluorescein angiography provides information about flow and the structure of blood vessels in ways autofluorescence can’t,” he said. “FAF imaging, on the other hand, captures fluorescence that is largely proportional to RPE lipofuscin accumulation and is a means to gauge certain aspects of physiology as well as topographic anatomic information.”

An overlooked method? Sometimes imaging modalities offer overlapping information, said Dr. Spaide, adding that, in such cases, it make sense to choose the one that is the least invasive, risky, or expensive. However, he noted, even seasoned clinicians may overlook FAF imaging—even though it’s an easy, safe, and cheap method that is particularly useful in establishing a difficult diagnosis.

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1 Holz FG, Schmitz-Valckenberg S, Spaide RF, Bird AC. Atlas of Fundus Autofluorescence Imaging. Berlin:Springer-Verlag; 2007.

2 Witmer M et al. Acta Ophthalmol. 2012 May 11; doi: 10.1111/j.1755-3768.2012.02434.x.

3 Sadda SR et al. Widefield autofluorescence: a new tool to study macular and retinal disease. Presented at: AAO Retina Subspecialty Day; Oct. 22, 2011; Orlando, Fla.

4 Spaide RF et al. Ophthalmology. 2006;113(8):1392-1400.

Marmar. Ophthalmology 2011: 118: 415-422

A. Check Patient’s Dose:

For my EMR record for MDs:

Since this patient is on Hydroxychloroquine, we recommend the following:
1. REAL Body Weight be used to calculate dose (see eyedoc2020@blogspot.com for reference from 2014).

2. No more than 6.5mg/kg/day

3. If dosing is calculating 300mg/day: alternate-day dosing recommended: Average dose over 2-3 days.

EyeMDs recommend the following yearly eye screening:

1. Baseline Screening within 1st year of use

2. Annual screening after 5 years of use with Humphrey Visual Field: HVF White 10-2

3. Spectral Domain OCT: Annually especially if HVF has any defect.

4. If we have any suspicion of damage, we will request a Multifocal ERG and Fundus Autofluorescence. Please let us know if your patient has any history of Kidney Disease or is taking Tamoxifen Citrate which increases the risk of retinal toxicity. Prevalence of retinal toxicity with 4.0-5.0mg/kg daily dose is 2% within 10 yrs and 20% after 20 yrs