New Findings Lead to Revised Therapeutic Regimen to Slow RP
By Alan Laties, M.D. Chairman of the FFB Scientific Advisory Board
The Berman-Gund Laboratory for the Study of Retinal Degenerations, at Harvard
Medical School, has just completed the second in an ongoing series of clinical
trials testing nutritional or other supplements as potential therapies for
retinitis pigmentosa (RP). The first clinical trial completed in 1993
demonstrated a beneficial effect on visual function of Vitamin A and a
deleterious effect of Vitamin E. As a result, the Foundation Fighting Blindness
and the National Eye Institute jointly recommended for most adults the daily
administration of 15,000 units of Vitamin A palmitate. Not fully understood,
either then or now, the beneficial effect of Vitamin A was slow to take effect,
becoming evident in the original clinical trial only after several years of
administration.
Just completed, a second study was designed to test whether a lipid of special
relevance to vision, DHA, taken as a dietary supplement would enhance the
already recognized sight-saving benefit of Vitamin A. The results of the second
trial are published in two reports in the September 2004 issue of the American
Medical Association’s Archives of Ophthalmology. The lead author of the report,
Eliot L. Berson, M.D., is a member of the Scientific Advisory Board of The
Foundation Fighting Blindness.
The results are complex and are best understood when it is kept in mind that the
benefit to vision observed in the original trial took several years to become
evident. In fact, some wondered at the announcement of the results of the first
clinical trial if treatment effects so delayed were indeed valid.
The second trial sheds new light as it demonstrates an interaction between
Vitamin A and DHA such that DHA apparently foreshortens the time for Vitamin A
to become effective. This became evident when it was recognized that two groups
of participants took part in the second clinical trial: subjects already taking
Vitamin A and subjects not taking Vitamin A. Among many other considerations,
this distinction was not recognized in the original study design and, hence, no
notice of it was taken in the original randomization. However, early in the
course of the just reported clinical trial an interaction was recognized.
Thereafter, the clinical course of the two categories of participants was
followed annually. At the conclusion of the clinical trial, subgroup analyses
clearly documented that DHA accelerated the onset of visual benefit for those
who were newly started on Vitamin A. But in participants who had already taken
Vitamin A for a period of time long enough to achieve its full benefit, DHA did
not add to that benefit.
The second clinical trial included a careful survey of dietary practices of all
participants. When these were analyzed, it was discovered that intake once or
twice a week of fish with a high fat content (such as tuna, mackerel, sardines,
salmon or herring) conferred an additional visual benefit.
The study from the Berman-Gund Laboratory also showed that patients with higher
red blood cell levels of DHA experienced a substantially slower loss of vision
field sensitivity than did patients with lower levels. These results are
consistent with findings from a previous FFB-sponsored trial by Dr. Dennis
Hoffman of the University of Texas Southwestern Medical Center and colleagues in
subjects with X-linked RP showing that increased DHA levels in the blood were
associated with a decreased rate of decline in visual function.
Based on the findings of these clinical trials, Dr. Berson and his colleagues
have issued an advisory letter. The letter follows and is also available on the
Foundation Fighting Blindness web site (blindness.org). It contains specific
recommendations and cautions. These include obtaining blood tests periodically
as well as information on sources of appropriate Vitamin A and DHA supplements.
The research was supported by grants from The Foundation Fighting Blindness and
the National Eye Institute.
HARVARD MEDICAL SCHOOL * MASSACHUSETTS EYE AND
EAR INFIRMARY
BERMAN-GUND LABORATORY
FOR THE STUDY OF RETINAL DEGENERATIONS
243 Charles Street Boston Massachusetts 02114
September 23, 2004
New Treatment Regimen for Patients with Retinitis Pigmentosa
In June 1993, we reported in the Archives of Ophthalmology that vitamin A
palmitate 15,000 IU/day helped to preserve retinal function while vitamin E 400
IU/day appeared to hasten the loss of retinal function among patients with
retinitis pigmentosa (RP). This led to the recommendation that most adults with
the typical forms of RP should take vitamin A palmitate 15,000 IU/day and avoid
high dose vitamin E supplements such as the 400 IU/day used in this study. This
recommendation remains the same today.
In September 2004, the Archives of Ophthalmology has just published two reports
that summarize the results of 8 years of work to evaluate the effects of
docosahexaenoic acid (DHA) for adults with typical RP also receiving vitamin A
palmitate 15,000 IU/day. The results are complex.
The first new report on all participants taken together showed that DHA
supplementation by capsules (600 mg twice each day) did not, on average, slow
the course of RP over a four-year interval. Therefore, we cannot make any
general recommendation for DHA supplementation by capsules for patients already
taking vitamin A palmitate.
The second new report describes the results in subgroups of the participants.
Here we observed that DHA supplementation did provide a benefit. However, the
benefit was limited to the subgroup of patients starting vitamin A palmitate for
the first time. In a comparison among randomized patients in this subgroup, DHA
supplementation by capsules slowed the course of RP for two years.
In addition, a dietary benefit of omega-3 rich food became evident as stated in
the second report. We observed that patients taking vitamin A palmitate (but not
on DHA capsules) with a higher omega-3 rich diet intake (i.e., equivalent to
eating 1-2 three-ounce servings per week of omega-3 rich fish, such as salmon,
tuna, mackerel, herring, or sardines, which contain among other constituents
considerable DHA) had, on average, a 40 - 50% slower annual rate of loss of
visual field than patients with a lower omega-3 rich diet intake. The results in
the second report lead us to offer the following general recommendations.
(1) For adults with typical RP already on vitamin A palmitate 15,000 IU/day, we
advise that they continue vitamin A palmitate and eat 1-2 three-ounce servings
per week of omega-3 rich fish. Including this amount of fish in the diet is
consistent with current American Heart Association recommendations. About three
months after starting omega-3 rich fish, we advise a measurement of fasting red
blood cell (RBC) DHA through their physician to confirm that the RBC DHA level
is at least 4% of total RBC fatty acids, as we reported that such patients have,
on average, a slower rate of decline of visual field than patients with lower
levels. If the RBC DHA level is not at least 4%, we advise patients to consult
with their physician on how best to reach this level through food. If the level
is 4% or greater, this test could be repeated annually thereafter.
2) For adults with typical RP who plan to start
vitamin A palmitate 15,000 IU/day for the first time, the results support the
following. If fasting serum vitamin A and liver function profile are normal, we
advise that they take this dose of vitamin A palmitate and also supplement with
DHA capsules 600 mg twice each day (i.e., three 200 mg capsules in both the AM
and PM with meals) for two years. After two years patients should discontinue
DHA supplementation by capsules because no evidence was found for continued
benefit and because a slight tendency toward adversity on ocular function was
observed over the longer term among patients concurrently on vitamin A palmitate.
After stopping DHA capsules after two years, patients should continue vitamin A
palmitate 15,000 IU/day and also eat 1-2 three-ounce servings of omega-3 rich
fish each week. Then, about three months after starting omega-3 rich fish, we
advise measurement of fasting RBC DHA as described above. It should be noted
that combining an omega-3 rich fish diet with DHA capsules did not provide any
additional benefit.
The study results reported in the second paper show that the potential benefit
of combining vitamin A palmitate with dietary intake of 1-2 servings of omega-3
rich fish per week is substantial: the rate of decline of loss of visual field
sensitivity was reduced by 40 - 50% per year. Therefore, combining vitamin A
palmitate with this diet regimen could achieve a gain of almost two decades of
visual preservation. For example, we have estimated that an average patient age
37 with typical RP already on vitamin A palmitate 15,000 IU/day who maintains an
omega-3 fatty acid food intake of at least 0.2 grams per day (i.e., equivalent
to eating 1-2 three ounce servings of omega-3 rich fish per week) would be
expected to lose virtually all central visual field sensitivity by age 78,
whereas an average patient who eats less than 0.2 grams per day would be
expected to lose all central visual field sensitivity by age 59.
It should be noted that beta-carotene is not vitamin A. It is the precursor of
vitamin A, but it is not predictably converted into vitamin A. Therefore
beta-carotene is not a suitable substitute for vitamin A palmitate in the
context of this treatment regimen. Although no toxic side effects have been
observed among adults with RP in good general health on vitamin A palmitate
15,000 IU per day (Sibulesky et al., Safety of Less Than 25,000 IU Vitamin A
Daily in Adults with Retinitis Pigmentosa, Am J Clin Nutr 69:656-663 1999), we
continue to advise that patients obtain a fasting serum vitamin A and liver
function profile annually and continue vitamin A palmitate only if these tests
are normal. We have observed no toxic side effects among adults with RP in good
general health on DHA supplementation by capsules.
The results apply to most adult patients with typical RP including those with
partial hearing loss. The results do not apply to patients with RP and profound
congenital deafness, RP as part of the Bardet-Biedl syndrome, or atypical or
rare forms of RP as such patients were not included in this study. Women with RP
who are pregnant or planning to be pregnant should not take the combination of
vitamin A palmitate and DHA by capsules because high vitamin A intake has been
associated with an increased risk of birth defects. We did not study patients
under age 18 or patients with best-corrected visual acuity of less than 20/100
in both eyes; therefore, we cannot make any formal recommendation for such
patients.
Our conclusions are based on group averages and, therefore, we cannot provide
assurance that this regimen will benefit a specific patient or that it is
appropriate for any particular patient.
Sources of vitamin A palmitate 15,000 IU as well as DHA in 200 mg gelcaps and
the procedure for obtaining a RBC DHA level are attached. Please share this
information with your ophthalmologist and family physician to determine if this
regimen is appropriate for you. This treatment regimen should be done only under
medical supervision. You are referred to the Archives of Ophthalmology Volume
122, pages 1297-1305 and pages 1306-1314, 2004 if you or your doctors wish to
review the details of our research. If you still have questions, please write to
us at the above letterhead address.
Known Sources of Vitamin A Palmitate
Vitamin A palmitate 15,000 IU/day has been
recommended for most adults with typical forms of retinitis pigmentosa (see
Berson et al; Archives of Ophthalmology 111:761-772, 1993). Patients with
retinitis pigmentosa should consult with their doctor concerning whether vitamin
A is appropriate for them before ordering this supplement. Adults planning to
take vitamin A palmitate should have a normal fasting serum vitamin A and liver
function profile before starting this treatment and annually thereafter. It is
important to note that beta-carotene (the precursor of vitamin A) is not
predictably converted into vitamin A; therefore beta-carotene is not a suitable
substitute for vitamin A palmitate in the context of this treatment. The
recommended dose of vitamin A palmitate is not available in most food stores.
Some known sources are listed below.
Sources of 15,000 IU of vitamin A palmitate
FREEDA VITAMINS, INC.
36 East 41st Street
New York, NY 10017
1–800–777–3737 (outside NY) or
1–212–685–4980; FAX 1-212-685–7297
AKORN OPHTHALMICS
2500 Millbrook Drive
Buffalo Grove, IL 60089
1–800–932–5676
A–Palmitate–15
100 Tablets $5.90/bottle
250 Tablets $11.65/bottle
Shipping & Handling $4.95
Will ship outside USA for extra postage Palmitate–A 15000
100 Tablets/Bottle $7.50/bottle
(minimum order of two bottles)
Shipping & Handling included
J.R. CARLSON LABORATORIES, INC.
15 College Drive
Arlington Heights, IL 60004–1985
1–888–234–5656 (outside Chicago) or
1–847–255–1600
Products #1101 and 1102
120 Gel-caps $6.90/bottle
240 Gel-caps 12.90/bottle
Shipping & Handling 4.50
Will ship outside USA for extra postage
Precautions: Women who are pregnant or planning to be pregnant should not take
this dose of vitamin A because of the increased risk of birth defects among
women on high-dose vitamin A supplements. Because of a slight increase (1% or
less) in the risk of developing a hip fracture noted in post-menopausal women
not on hormones but taking vitamin A supplements (Feskanich et al: JAMA
287:47-54, 2002) and in men age 49 or older with high serum vitamin A levels (Michaelsson
et al: NEJM 348:287-294, 2003), such patients should have a periodic evaluation
of bone health with their physician. This dose should not be used in children or
young adolescents with RP because of a potential for toxicity.
Disclaimer: The listing of these suppliers and their products should not be
misinterpreted as a recommendation or indication of proprietary interest in any
of these companies.
Eliot L. Berson, M.D.
Known Sources of Neuromins® DHA 200mg
DHA in a dose of 600 mg twice a day has been recommended for most adult patients
with typical retinitis pigmentosa who are starting vitamin A palmitate 15,000 IU/day
for the first time (see Berson et al; Archives of Ophthalmology 122: 1306-1314,
2004). Patients with retinitis pigmentosa should consult with their doctor
concerning whether DHA is appropriate for them before ordering this supplement.
Neuromins® DHA 200 was the form of DHA used in this study. Neuromins® DHA 200 is
available in many health food stores across the country. Brands of Neuromins®
DHA 200 include Nature’s Way, Source Naturals, Solaray, Natrol, and Solgar. The
above brands are sold directly to retail stores and clearing houses (two listed
below) rather than to individual consumers. However, both Nature’s Way
(1-800-962-8873 or www.naturesway.com) and Natrol (1-800-262-8765 or
www.natrol.com) will help you locate a local supplier. The dose recommended is
600 mg twice each day (3 in the AM and 3 in the PM with meals) only for 2 years.
Therefore, patients ordering Neuromins® DHA 200 will be taking six softgels per
day. For example, a one-month supply would be 180 softgels and patients should
plan accordingly. The following are sources of Neuromins® DHA 200 readily
accessible by toll-free phone or via their websites.
SWANSON HEALTH PRODUCTS
P.O. Box 6003
Fargo, ND 58108-6003
1–800–437-4148
www.swansonvitamins.com
(search Neuromins® on the homepage)
30 softgels (SWU092) 200mg
12.49/bottle
Shipping & Handling 4.95
Ship abroad for additional fee. THE VITAMIN SHOPPE
Customer Care Department
2101 91st Street
North Bergen, NJ 07047
1-800-223-1216
www.vitaminshoppe.com
(search Neuromins® on the
homepage)
60 softgels (SR-5558) 200mg
30.80/bottle
120 softgels (SR-5559) 200mg
59.98/bottle
Shipping & Handling 4.99
Ship abroad with restrictions for added fee
Precautions: Please be reminded that DHA supplementation in a dose of 600 mg
twice a day for adults with typical retinitis pigmentosa (RP) on vitamin A
palmitate was reported to be effective for only two years and only in patients
starting vitamin A for the first time. The products described above in this dose
have not been tested or evaluated to determine their safety or effectiveness in
children or adolescents with RP.
Stopping instructions: This dose of DHA should not be continued beyond two years
because no evidence was found of a continued benefit and also because a slight
tendency toward adversity on ocular function was observed over the longer term
among patients on vitamin A palmitate 15,000 IU/day (see Archives of
Ophthalmology, Volume 122, pages 1306-1314, 2004). This supplement in
combination with vitamin A palmitate should not be taken by women who are
pregnant or planning to become pregnant because of an increased risk of birth
defects among women on high dose vitamin A intake.
Disclaimer: The listing of these suppliers and their products should not be
misinterpreted as a recommendation or indication of proprietary interest in any
of these companies.
September 23, 2004
PROCEDURE FOR OBTAINING A RED BLOOD CELL DOCOSAHEXAENOIC ACID (DHA) LEVEL
1. Patients should fast overnight. If not feasible, fast at least 4 hours prior
to the blood draw.
2. Use a 5 ml EDTA - Lavender top vacutainer tub (Becton Dickenson Catalog
#DB366452 or #DB367863). Collect about 3 ml of blood in an EDTA tube. The tube
should be labeled with the PATIENT'S NAME and the DATE THE BLOOD WAS DRAWN.
3. The patient's blood should be packaged in a Specimen Collection Kit provided
by the laboratories below only on request from your physician. Your physician
should fill in the required information on a Test Requisition Form, available at
the websites of the laboratories listed below, and request a RBC DHA level which
is part of a RBC total lipid fatty acid profile.
4. Send the lavender EDTA tube of whole blood at room temperature by same day
courier on the day collected (Mondays through Thursdays only) in a Specimen
Collection Kit following kit instructions for packaging and shipping along with
the Test Requisition Form to either one of the three laboratories listed below
to arrive within 24 hours after the specimen was drawn via DHL or Federal
Express:
Peroxisomal Diseases Laboratory
Kennedy Krieger Institute
707 North Broadway, Room 530
Baltimore, MD 21205
Tel # 443-923-2788
Fax# 443-923-2755
www.genetics.kennedykrieger.org
$150.00 with specimen
(pre-pay)
Great Smokies Diagnostic Laboratory
63 Zillicoa Street
Asheville, NC 28801
Tel# 800-522-4762
Fax# 828-252-9303
www.gsdl.com
$150.00 with specimen
(pre-pay)
Metametrix Clinical Laboratory
4855 Peachtree Ind. Blvd
Norcross, GA 30092
Tel# 800-221-4640
Fax#770-441-2237
www.metametrix.com
$150.00 with specimen
(pre-pay)
A report will be sent within about 1 month. Adults with typical retinitis
pigmentosa on vitamin A palmitate 15,000 IU/day and an omega-3 rich diet should
strive to have a RBC DHA level of 4% or greater of total RBC fatty acids. If the
level is 4% or greater, the level could be rechecked annually. Patients who have
not achieved this level should consult with their physician on ways to increase
their RBC DHA level through food intake and then recheck their level about 3
months after changing their food intake (See Archives of Ophthalmology
122:1306-1314, 2004).
Disclaimer: The listing of these suppliers and their tests should not be
misinterpreted as a recommendation or indication of proprietary interest in any
of these companies.