I.    Introduction:

Over the past six years, amid reports of an explosion of new cases of attention deficit disorder (ADD), production of methylphenidate (Ritalin^®) and amphetamines has increased almost sixfold. While advocates see the expanded use of these stimulants as an appropriate response to a legitimate medical condition, critics allege that they are prescribed inappropriately to children whose behaviors fail to satisfy adult expectations, but do not conform to strict diagnostic criteria.

Professionals who treat children with ADD, hyperactivity, and related disorders should of course be aware of the advantages of stimulant medicines. It is incumbent upon them also to understand the limitations and risks of these controlled substances, even when given to children accurately diagnosed with ADD, and to maintain familiarity with the considerable scientific literature supporting a range of effective non-stimulant medical strategies, including, for example, diet restriction and allergy treatment.

II.   Effects of Stimulant Treatment in ADD

Swanson and his co-authors, in a comprehensive literature review,[1] indicate that the proven advantages of stimulant medications (Ritalin^® and the amphetamines) for patients with ADD are modest. Accumulated evidence reveals that, when they work, stimulants produce only temporary improvement in overactivity, inattention, impulsivity, deportment, aggression, social interactions, and academic productivity. Adverse drug effects, such as increasing tics and problems with eating, sleeping, cognition, and mood, must be weighed against these limited benefits. In most cases, stimulant treatment is stopped within two years. Stimulants do not improve reading or other skills, and ameliorate neither long term academic achievement nor eventual social functioning.

III.  Non-stimulant Medical Strategies

A.  Elimination Diets

Recent years have seen the publication of a body of scientific research supporting the effectiveness of elimination diets, most commonly targeting artificial food colors and preservatives, cow's milk, wheat, and soy, for ADD and hyperactivity. Experimental neurotoxic effects of synthetic food colors have been demonstrated in both invertebrate[2] and vertebrate[3] [4] animal systems. Controlled human experiments investigating the consequences of ingestion of food dyes by hyperactive children have yielded evidence of adverse effects on learning[5] and behavior.[6] A number of well-designed double-blind, placebo controlled trials have demonstrated the effectiveness of dietary elimination for the control of behavioral symptoms in hyperactivity and ADD.[7] [8] [9] [10] The percentage of ADD or hyperactive children who improve on an open elimination diet varies among these reports from 58%[8] to 82%. [7] The percentage of subjects whose food-induced behavioral symptoms are confirmed by double-blind placebo-controlled food challenges ranges from 60%[9] to 75%.[7]

It is possible that selection bias factitiously elevates the percentage of diet responders in some or all of these reports, since parents who consent to participation in diet studies may include a disproportionate number who believe they have observed food-induced problems in their children. As Carter et al. have shown, controlled food challenge usually validates parental suspicions of food-induction of behavioral symptoms.[9]

On the other hand, lower percentages of subjects with food sensitivities confirmed on double-blind food challenges, compared to percentages responding in open diet trials, are due in part to the failure of some subjects who complete the preliminary open phase of the study to participate in the final double-blind phase; food sensitivities of those subjects who complete the open trial but do not participate in double-blind food challenge are counted (with non-responders) as non-confirmed by double-blind challenge.

These reports demonstrate that there is no single dietary regimen that is best for all children with hyperactivity and/or ADD. Each subject underwent a period of dietary elimination followed by oral challenges with specific foods, to determine his or her "ideal" diet. Many children in these studies reacted not only to one food, but to several.

B.  Allergy Desensitization Treatment

To determine whether food-induced hyperactivity would respond to allergy desensitization treatment, Egger, Stolla, and McEwen carried out a double- blind trial of enzyme potentiated desensitization (EPD) treatment in a group of children diagnosed with this condition.[11] Open food challenges were conducted before and after a series of EPD injections. All 16 children who completed three active EPD injections at intervals of 2 months became tolerant of provoking foods, compared with only 4 of the 20 children who completed the same number of placebo injections (p<0.001). Adverse effects of EPD injections were limited to transient local discomfort at injection sites. In those actively treated subjects whose food sensitivity returned after completion of the trial, desensitization was restored by additional EPD injections.

C.  Ritalin^® vs. Vitamin B6

Coleman et al. have published a report comparing methylphenidate (Ritalin^®) with pyridoxine (vitamin B6), for the treatment of hyperactivity.[12] Only 6 subjects participated, and these children were selected on the basis of their low blood serotonin levels and their previous positive responses to methylphenidate. All subjects received a 3-week trial each of placebo, low dose pyridoxine, high dose pyridoxine, low dose methylphenidate, and high dose methylphenidate. In this group, behavioral improvement on pyridoxine exceeded that on methylphenidate, both in magnitude and in persistence of improvement after cessation of treatment; both active treatments were superior to placebo. Blood serotonin, while not consistently affected by methylphenidate or placebo, rose with pyridoxine treatment, and remained increased during the post-pyridoxine persistence of behavioral improvement. The intriguing results of this study, which has yet to be repeated with a larger sample, have remained unchallenged since publication in 1979.

D.  Prevention of Hyperactivity

A positive correlation between recurrent middle ear infections (otitis media) in infancy and the later diagnosis of hyperactivity has been demonstrated by Hagerman and Falkenstein, who postulate that effective strategies to reduce the incidence of otitis media might actually serve to prevent cases of hyperactivity.[13] The authors' suggestion that, in order to reduce the prevalence of hyperactivity, antibiotics should be given vigorously to prevent otitis media (page 256) assumes not only that otitis media is a cause of hyperactivity and not merely an associated condition, but also that aggressive antibiotic treatment can reduce the incidence of otitis media. The former assumption is untested; the latter is almost certainly incorrect.

A number of workers, failing to find any statistically verifiable advantage of antibiotics for otitis media, have recommended their use only after 3 to 4 days of observation with analgesics and nose drops alone, and only in those cases in which there is convincing evidence of focal bacterial infection, the course of otitis is irregular, or there are complications such as mastoiditis or ear discharge persisting beyond 14 days. [14] [15] [16] [17] [18]

Cantekin used a double-blind, placebo-controlled randomized trial specifically to assess the efficacy of amoxicillin for otitis media with effusion (OME).[19] No benefit was found, and unexpectedly, amoxicillin significantly increased the recurrence rate of OME. Theoretical discussions of possible mechanisms by which antibiotics might increase the incidence of otitis media have focused on their tendency to cause microbes which do not normally colonize the bowel to replace normal antibiotic-sensitive intestinal flora. This might allow absorption of toxic microbial products and/or alter host immunity. As an example, broad spectrum antibiotics, by destroying normal bacteria, allow intestinal proliferation of Candida albicans,[20] a fungus known to induce measurable changes in immune function.[21]

The Developmental Delay Registry, a network of parents of children suffering from a wide spectrum of developmental disorders encompassing hyperactivity and ADD, has reported a survey directly correlating these disorders with antibiotic use. The average number of courses of antibiotic was 12.84 among 449 children diagnosed with developmental delays, compared with 9.71 for 247 normally developing controls.[22] Increased antibiotic use may simply reflect the higher incidence of infections in children with hyperactivity, as reported by Hagerman and Falkenstein. On the other hand, a role for antibiotics in causing hyperactivity would be expected if Cantekin's observation that antibiotics increase recurrence of otitis media, and the assumption that recurrent otitis media causes hyperactivity, are both correct.

While antibiotics may have distanced us from the goal of preventing middle ear infections, yet another clinical strategy is likely to bring us closer; a recent report by Nsouli confirms that elimination diets for food allergy can effectively treat and prevent recurrent otitis media.[23] Elimination diets significantly ameliorated OME in 81 of 104 children (86%) entered in this study, and rechallenge with suspected offending foods provoked a recurrence of OME in 66 out of 70 (94%). As with hyperactivity, the demonstrated benefits of elimination diets for OME are contingent on positive diagnostic oral food challenges, after a successful exclusion diet. In otitis media, cow's milk, wheat, soy, egg white, peanut, and corn are the most frequent provoking foods.[23]

Given the state of this research, further scientific investigation, to determine whether better diagnosis and treatment of food allergies and restraint in the use of antibiotics will reduce the incidence of otitis media and the prevalence of hyperactivity, would be welcome.

IV.  Conclusion

The burgeoning number of children receiving medical treatment for ADD and related conditions is the focus of much public and scientific concern. The current state of knowledge leaves many critical questions unanswered. Clinicians, researchers, medical educators, teachers, parents and those shaping public policy must stay abreast of emerging research, to insure that the course they chart will optimize the healthy development of millions of children.

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1. Swanson JM, et al. (1993). Effect of Stimulant Medication on Children with Attention Deficit Disorder. A "Review of Reviews." Exceptional Children, 60, 154-162.
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2. Levitan H (1977). Food, drug, and cosmetic dyes: Biological effects related to lipid solubility. Proceedings of the National Academy of Sciences, U.S.A., 74, 2914-2918.
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3. Logan WJ, Swanson JM (1979). Erythrosin B Inhibition of Neurotransmitter Accumulation by Rat Brain Homogenate. Science, 206, 363-364.
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4. Augustine GJ, Levitan H (1980). Neurotransmitter Release from a Vertebrate Neuromuscular Synapse Affected by a Food Dye. Science, 207, 1489-1490.
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5. Swanson JM, Kinsbourne M (1980). Food Dyes Impair Performance of Hyperactive Children on a laboratory Learning Test. Science, 207, 1485-1487.
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6. Rowe KS, Rowe KJ (1994). Synthetic food coloring and behavior: A dose response effect in a double-blind, placebo-controlled, repeated-measures study. The Journal of Pediatrics, 125, 691-698.
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7. Egger J, et al. (1985). Controlled Trial of Oligoantigenic Treatment in the Hyperkinetic Syndrome. Lancet, i, 540-545.
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8. Kaplan BJ, et al. (1989). Dietary Replacement in Preschool-Aged Hyperactive Boys. Pediatrics, 83, 7-17.
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9. Carter CM, et al. (1993). Effects of a few food diet in attention deficit disorder. Archives of Disease in Childhood, 69, 564-568.
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10. Boris MD, Mandel FS (1994). Foods and additives are common causes of the attention deficit hyperactive disorder in children. Annals of Allergy, 72, 462-468.
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11. Egger J, Stolla A, and McEwen LM (1992). Controlled trial of hyposensitisation in children with food-induced hyperkinetic syndrome. Lancet, 339, 1150-1153.
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12. Coleman M et al. (1979). A Preliminary Study of the effect of Pyridoxine Administration in a Subgroup of Hyperkinetic Children: A Double-Blind Crossover Comparison with Methylphenidate. Biological Psychiatry), 14, 741-751.
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13. Hagerman RJ, Falkenstein AR (1987). An Association Between Recurrent Otitis Media in Infancy and Later Hyperactivity. Clinical Pediatrics, 26, 253-257.
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14. Van Buchem FL, Dunk JHM, Van't Hof NIA (1981). Therapy of acute otitis media: myringotomy, antibiotics, or neither? Lancet, ii, 883-887.
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15. Van Buchem FL, Peeters MF, Van't Hof MA (1985). Acute otitis media: a new treatment strategy. British Medical Journal, 290, 1033-1037.
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16. Froom J et al. (1990). Diagnosis and antibiotic treatment of acute otitis media. Report from International Primary Care Network. British Medical Journal, 300, 582-586.
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17. Cantekin EI (1990). Antibiotics for secretory otitis media. Archives of Otolaryngology Head and Neck Surgery, 116, 626-628.
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18. Bollag U, Bollag-Albrecht E (1991). Recommendations derived from practice audit for the treatment of acute otitis media. Lancet, 338, 96-99.
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19. Cantekin EI (1991). Antimicrobial Therapy for Otitis Media With Effusion ('Secretory' Otitis Media). Journal of the American Medical Association, 266, 3309-3317.
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20. Stone HH (1973). Alimentary Tract Colonization by Candida Albicans. Journal of Surgical Research, 14, 273-276.
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21. Domer JE and Garner RE (1989). In: The Immunology of Fungal Diseases, Kurstak E (ed.). Marcel Dekker, Inc., New York and Basel, 293-317.
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22. Dorfman K, Lemer P, Nadler J (1995). What puts a child at risk for developmental delays? Results of the Developmental Delay Registry Survey (Unpublished). Full version reproduced in appendix.
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23. Nsouli TM, et al. (1994). Role of food allergy in serous otitis media. Annals of Allergy, 73, 215-219.
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