Mr Edison Bittencourt, from Brazil, whose daughter suffered from Stevens-Johnson Syndrome caused by Lamotrigine, makes the following comments :

The folate observation and Stevens Johnson Syndrome

Since different drugs for very different pathologies are associated with Stevens Johnson Syndrome, I researched the literature trying to find some common mechanism of action in those drugs, utilized in very different pathologies , and I found as a possible common mechanism the anti -folate action, which I believe deserves to be studied. Lamotrigine , one of the most known drugs associated with Stevens Johnson Syndrome , “…was initially developed as a folate antagonist after the observation that patients with epilepsy treated with AEDs had diminished levels of folic acid (106). However, no correlation between antifolate activity and AED activity has ever been established . “ ( Rho and Sankar , 1999) . According to this paper Lamotrigine is considered to have a weak anti-folate action in vitro.

Very recently , I found a paper , “Skin Manifestations of Folic Acid Defficiency “ ( Nagaraju et al. 1971 ), which could tie the anti folate action with low levels of folic acid in the blood . The case report is :


“A man aged 63 was admitted to Dundee Royal Infirmary in November 1967, complaining of weakness and unsteadiness on walking for 4 weeks and a generalized rash for 2 weeks.”


This man had been, years before, diagnosed with pernicious anemia.


Although Stevens Johnson Syndrome is not mentioned in the report ( the term “erithematous lesions “, is used ), photos shown , suggest a case related to Stevens Johnson Syndrome . The paper mentions that “ The majority of the lesions were papules covered by fine scales but there were some macules On the extensor aspects of the limbs there were larger plaques of variable size and shape, covered by heavy scale. The skin between the lesions appeared to be normal. There was clubbing of the fingers. There were stomatitis, glossitis and pharingitis , with dysphagia and hoarseness of voice. “


According to this study “ It is well known that deficiency of folic acid from any cause produces megaloblastic anaemia ..” and “Folic acid deficiency is found to be associated with various dermatoses (Knowlea et al., 1963; Shuster et al., 1907), but there has been no report of folic acid deficiency actually causing skin manifestations” . The author proposed that folic acid deficiency was the cause of the skin problems since,


“ 1. Megaloblastic anaemia was associated with megalocytosis of the skin epithelium in the absence of vitamin Bjg deficiency.
2. There was no response to normal diet with additional vitamin B12 therapy.
3. The response to folic acid therapy was dramatic. The folic acid fiefioiency in our patient is thought to be the result of malabsorption, the cause of whicli Is unknown.


Folic acid was , in this case, used in the therapy , and it is reported that “The skin lesions showed a remarkable improvement and completely cleared over the next 3 weeks “.

It is well known that folic acid prevents congenital abnormalities in offsprings, and as mentioned by Kjær et al ( Kjær et al, 2007) , “The prevalence of major congenital abnormalities in newborns exposed to antiepileptic drugs (AEDs) in utero ranges from 3.3 to 9.0%, two- to three-fold higher than that among nonexposed newborns” . So again the anti-folate action of a group of drugs and undesirable consequences is demonstrated. An excellent presentation on antifolate drugs is in Update on Antifolate Drugs Targets ( Costi and Ferrari, 2001 ) .Antifolate drugs are used in chemotherapy, to inhibit the cancer cells growth. It should be pointed out that antifolate drugs work by different mechanism, and therefore interfere with humans in different ways.


According to Kjarer et al, “Some AEDs ( antiepileptic drugs) , such as carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), and primidone (PRI), alter the folic acid metabolism, and folic acid blood levels decrease with increasing plasma levels of AEDs .


Supplementation is generally utilized, although some studies find no protective action of the folic acid supplementation. However , the authors find the risk of abnormalities reduced , but not eliminated. Anti epiletic drugs ( AEDs) are also associated with Hyperhomocysteinemia, and excess of homocysteine ( Huemer et al, 2005 ) a compound which is associated with heart problems. The authors conclude that “Hyperhomocysteinemia is present in 15.5% of children receiving long-term AED treatment. Multidrug treatment and long duration of therapy enhance the risk for hyperhomocysteinemia. Folic acid supplementation significantly reduces tHcy. We recommend assessment of serum folate and plasma tHcy in children receiving AEDs. “


“ A folate deficiency could be a contributing cause of anorexia, cancer, cervical dysplasia, chronic fatigue, constipation, diarrhea, elevated homocysteine, glossitis, gum disease, hair loss, headache, heart disease, hypersegmentation of neutrophils and with severe deficiency- intestinal lesions, increased infections, insomnia, megaloblastic anemia (identical in appearance to a vitamin B12 deficiency), memory impairment, nausea, neural tube defects and other birth defects, paranoia, and restless legs. Folate deficiency also harms DNA metabolism which caused abnormal cellular development, especially in cells with the most rapid rates of turnover (epithelial cells of the stomach, intestine, vagina and uterine cervix, leukocytes and red blood cells).”




And, mostly important ,


“Further, individuals at highest risk for a folate deficiency include alcoholics, anti-convulsant therapy (barbiturates, phenytoin, primidone), vitamin B12 deficiency, elderly, folate antagonist therapy (5-fluorouracil, methotrexate, pyrimethamine), increased rate of cellular division (burns, haemolytic anemia, malignancies, trauma), infants, inherited folate disorders, malabsorption, malnourished, oral contraceptive users, pregnant and lactating women, sulfasalazine therapy, tuberculosis therapy (isoniazid plus cycloserine).


Pharmaceutical drugs that can cause a folate deficiency include aspirin, barbiturates, carbamazepine, celecoxib, cholestyramine resin, choline magnesium trisalicylate, choline salicylate, cimetidine, colestipol, corticosteroids, cycloserine, ethosuximide, famotidine, 5-fluorouracil, fosphenytoin, hydrochlorothiazide and triamterene, indomethacin, isoniazid, methotrexate, methsuximide, nizatidine, non-steroidal anti-inflammatory drugs, oral contraceptives, phenytoin, primidone, pyrimethamine, ranitidine bismuth citrate, ranitidine hydrochloride, salsalate, sulfasalazine, triamterene, trimethoprim and valproic acid and derivaties “ One can identify here several substances capable of inducing Stevens Johnson Syndrome .


If you are interested in making sure that we supply your body with folates ,


“Dietary sources richest in folate (per serving) include beet, broccoli, brussel sprouts, cabbage, cantaloupe, cauliflower, egg, dark green leafy vegetables, legumes (beans [particularly kidney and lima], lentils, peas, soybeans), liver, nutritional supplements, nutritional yeasts, nuts, orange juice, seeds, wheat germ, and whole grains and grain products. Folate is easily destroyed by heat, light and oxygen, and substantial losses occur in cooking and storage.” ( Same site as above). It should be pointed out that folate deficiency may be caused by malabsorption due to different internal mechanisms. Read also ( www.news-journal.com) , specially on B complex to sped up recovery in case of burns. In this site also, is pointed out that , about precautions “




“Because of the potential for side effects and interactions with medications, dietary supplements should be taken only under the supervision of a knowledgeable healthcare provider.Side effects from folic acid are rare. Very high doses (above 15,000 mcg) can cause stomach problems, sleep problems, skin reactions, and seizures. Folic acid supplementation should always include Vitamin B12 supplementation (400 to 1000 mcg daily) because folic acid can mask an underlying vitamin B12 deficiency, which can cause permanent damage to the nervous system. In fact, taking any one of the B complex vitamins for a long period of time can result in an imbalance of other important B vitamins. For this reason, it is generally important to take a B complex vitamin with any single B vitamin.”


Folic acid supplementation is defended for pregnant women .See “Antifolate antibodies: another reason for pregnant women to take folic acid” , (http://findarticles.com), where is stated that


“Periconceptional administration of folic acid reduces the incidence of neural tube defects (NTDs) in the offspring. This benefit occurs among pregnant women who have no clinical evidence of folic acid deficiency, suggesting that some women have a higher-than-normal requirement for folic acid that cannot be met by a typical diet. Part of this increased requirement may be explained by genetic variations in the 5,10-methylenetetrahydrofolate reductase allele; however as less than 20% of humans have the variant allele, that factor alone cannot explain the 70-80% reduction in NTDs that results from folic acid supplementation. “


We should point out , again, “ …. that some women have a higher-than-normal requirement for folic acid that cannot be met by a typical diet”. Therefore , it is possible that some people have also , considering other situations , “more-than-normal requirement for folic acid “ . Even if serum levels may be normal, but still more is needed in special situations.


Note that “The importance of folic acid supplementation prior to and during pregnancy has been amplified by recent evidence that folic acid taken during the first 6 weeks of gestation may reduce the incidence of congenital heart defects (ventricular septal defects and conotruncal defects) by more then 50% (Fam Pract News, December 15, 2003, p. 10.). “


I would like to add that , among antibiotics, “Trimethoprim-sulfamethoxazole (Bactrim, Septra, Bactrim DS, Cotrim) -- Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. (http://www.emedicine.com)” Also , “Ciprofloxacin (Cipro) -- Fluoroquinolone that inhibits bacterial DNA synthesis and, consequently, growth “ . A good presentation on antibiotics which work inhibiting protein synthesis is given in “Survey of Antibiotics. Protein Synthesis Inhibitors “ in (pathmicro.med.sc.edu/2005-bacppt/Antibioticsmayer05.ppt) . Although I have researched for almost 3 years and collected much more literature on the subject than presented here, I decided to present this discussion as a motivator to more competent investigators, knowing that this is only an observation and not a theory, considering that I am not e medical doctor . I am a Chemical Engineer who saw how devastating SJS can be, and the suffering that comes ,certainly when it affects somebody you love. I also saw how the adequate therapy help, how the follow up is important , and how , if you are blessed by a miracle, we should blend reason and faith.


Edison Bittencourt


Campinas , Brasil, February of 2009


M.P. Costi* and S. Ferrari , Update on Antifolate Drugs Targets, Current Drug Targets,
2001, 2, 135-166
M. NAGARAJU,* D. G. ADAMSON AND J. ROGERS , Skin Manifestations of Folic Acid Defficiency , Br.J. De.r7, . (1071)84, 32


Martina Huemer, _Bernd Ausserer, Gunther Graninger, Michael Hubmann, Christian Huemer, Kurt Schlachter, Arthur Tscharre, Hanno Ulmer, and Burkhard Simma,
“Hyperhomocysteinemia in Children Treated with Antiepileptic Drugs Is Normalized by Folic Acid Supplementation “, Epilepsia, 46(10):1677–1683, 2005


Rho, J. M., and Sankar, R., “The Pharmacologic Basis of Antiepileptic Drug Action”,
Epilepsia, 40 (11), 1999, 1471- 1473.



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