- Email: [email protected]
Allergic, dietary, chemical, stress, and hormonal influences in voice abnormalities
Journal of Voice Vol. 1, No. 4, pp. 378-385 © 1988RavenPress, Ltd., New York
Allergic, Dietary, Chemical, Stress, and Hormonal Influences in Voice Abnormalities Wallace Rubin Department of Otorhinolaryngology and Biocommunication, Louisiana State University School of Medicine, New Orleans, Louisiana, U.S.A.
Summary: Allergic, dietary, chemical, biochemical, stress, and hormonal abnormalities have long been recognized as important factors in both abnormalities of the voice and in the general health of the professional vocalist. In recent years objective methods have become available to evaluate and treat allergic, dietary, and chemical abnormalities and to better understand the effects of stress and hormonal variations. Assessment of allergic disease is efficient and cost effective through the use of in vitro testing techniques combined with skin end point titration. This provides highly specific and objective results and leads to accurate planning of desensitization treatment. This form of treatment can be especially beneficial in the prevention of recurrent laryngitis. An accurate nutritional history provides evidence of food sensitivities that can lead to cyclical allergic-like vocal symptoms that can be prevented with the use of elimination diets and the judicious use of desensitization therapy. An adequate knowledge of the potential effects of chemical sensitivities will assist the patient in the avoidance of provocative chemical exposures. An in depth evaluation of biochemical abnormalities and a specific assessment of the nutritional status must be considered to evaluate the underlying causes of long-standing general health problems that can affect the voice. Likewise, hormonal variations are not only important in their direct effects on the vocal mechanism but in their cyclical effects on the patient's basic biochemical balance. Lastly, stress, which has long been related to problems in professional performance, is only now being fully studied to determine its actual biologic influences and these must be related to the causes of voice disturbances. Understanding all these influences and planning a rational and efficient evaluation of these potential problem areas are imperative in the complete care of the patient with voice abnormalities. Key Words: Allergy--Voice--Desensitization in singers.
relation between these factors and voice problems because they coexisted. Until very recently, it has been necessary to rely solely on the patient's history and skin testing to make an allergic diagnosis and hope that some form of allergic management, either a v o i d a n c e or desensitization, w o u l d solve the patient's problem of hoarseness. For the most part, the biochemical, metabolic, neurotransmitter, autonomic, and hormonal influences as they relate to voice production have been ignored. Do you perform an allergic investigation in all patients with voice p r o b l e m s ? H o w do y o u decide
This monograph describes the author's efforts to correlate vocal s y m p t o m s with objectively confirmed allergic, b i o c h e m i c a l , metabolic, neurotransmitter, autonomic, and hormonal abnormalities. We have in the past assumed an etiologic cor-
The results of this report presented at the Sixteenth Symposium: Care of the Professional Voice, New York, June 1986. Address correspondence and reprint requests to Dr. W. Rubin, at 3434 Houma Blvd., Metairie, LA 70006, U.S.A. 378
I N F L U E N C E S I N VOICE A B N O R M A L I T I E S
379
whom to test and which test to use? Do you test everybody for both inhalants and foods? Do you use in vitro tests such as radioallergosorbent test (RAST)? Is all this cost effective for the patient? Do you perform a biochemical, metabolic, and hormonal screen? Which tests do you use? How do you make these decisions? These are the challenges.
few patients where the allergic history is significant and only the SET tests are positive. Changes in diet and other measures are recommended after a biochemical metabolic screen is performed and evaluated. A similar investigation of hormonal and stress influences is made and correction of significant abnormalities is attempted with the appropriate measures.
PATIENT EXAMINATION
WHY LABORATORY IN VITRO ALLERGY TESTING
All patients evaluated for hoarseness and/or other voice aberrations are examined by mirror examination of the vocal cords and by complete examination of the head and neck. Patients are evaluated for allergic factors that might relate to their voice complaints by the following sequential format. 1. Skin end point titration (SET) is performed for 10 antigens (Alternaria, Candida, Dermatophagoides F a r i n a e - - d u s t mites, giant ragweed, Bermuda grass, June grass, Johnson grass, box elder maple, cat dander, dog dander). 2. A six RAST microscreen panel (grass, tree, weed, dust mites, cat dander, mold) is done on all patients. 3. A 10 RAST panel is performed if any of the SET responses were positive or if the microscreen proved positive. 4. Intradermal provocative food testing and/or IgE, IgG RAST food tests are performed if the history suggests food as a factor. When positive responses are obtained, an attempt is made to neutralize the response and/or symptoms with the proper intradermai neutralizing dose of the antigen and with food elimination or rotation diets. Patients who present with hoarseness are treated pharmacologically while waiting for the in vitro test results. The treatment generally includes voice rest or voice modification procedures and the use of antibiotics, antihistamines, and/or steroids. The steroids used for the short-term acute response are given in small doses by injection. A program of allergic desensitization is begun in those patients with recurrent voice problems and in whom the allergic investigation is significantly positive. This is done only after an in depth procedural explanation to the patient. All allergic treatment for inhalants is carried out using the modified RAST technique as a basis for dosage used except in those
In vitro allergy testing is clinically useful for two reasons. First and foremost, it is the most accurate and objective method for confirming the diagnosis. Second, it is cost effective, especially using the microscreen technique. This is a major consideration in offering modern, efficient, medical care to patients. Studies have shown that there is >95% agreement between the results obtained by microscreen allergy testing as compared with testing with as many as 20 individual allergens. These studies attest to the efficacy of microscreen allergy testing. Intradermal scratch or prick skin testing has a major disadvantage in that it suffers from a lack of specificity. It is unusual for patients to be entirely negative to intradermal skin testing. If a patient happens to have r e s p i r a t o r y or d e r m a t o l o g i c problems due to other causes and also has positive skin reactivity, the physician may attribute the symptoms to the allergen causing the positive skin reactivity. The multiallergen screen serves another useful purpose in that there are patients with upper airway and laryngeal symptoms in whom the history and physical examination may not suggest an allergic diathesis. In such patients a positive microscreen alerts the physician to the possibility of an allergic etiology and can lead to further appropriate testing and treatment (I). CYCLIC CONCEPT OF FOOD SENSITIVITIES Exclusive of IgE-mediated reactions, the majority of food sensitivity develops by repetitive ingestion of a food in a susceptible individual. Symptoms usually begin gradually and may be triggered by an increase in the total allergic 10ad, following an illness, disease, or stress situation. A food may react at any point along the gastrointestinal tract and the usual bowel transit time is 4 days; symptoms in cyclic reactions can be delayed
Journal of Voice, Vol. l, No. 4, 1987
380
W. R U B I N
up to 4 or 5 days. Reactions may be dose related with symptoms occurring only after large feedings or closely spaced feedings over several days. In cyclic food sensitivity a 72 h interval or less is considered "closely spaced," as the masking phenomenon occurs only when the offending food remains in the gastrointestinal tract. Cyclic food sensitivities are not IgE mediated, thus skin tests and in vitro tests measuring IgE antibody to a food are unreliable in diagnosing these responses. Elimination and challenge techniques are used to diagnose cyclic food sensitivities. FOOD HISTORY AND DIET DIARY The food history and diet diary are the key to determining suspected food allergy offenders. Probable food offenders are selected based on a review of the diet and a 2 week diet and symptom diary. Seasonal availability, geographical location, and ethnic preferences are taken into consideration when questioning the patient. The frequency of foods eaten on a daily or weekly basis are noted. A known food offender may suggest another food offender in that particular food family. Specific cravings and/or dislikes may also indicate an offender. Many nutritional supplements such as vitamins are derived from and/or contain food constituents. Diet supplements used for weight control contain foods such as milk, soy, or wheat as major ingredients. With foods eaten once a week or less, it is comparatively easy to establish a cause and effect relationship between ingestion and symptoms. Foods eaten at least every 72 h are subject to masking and therefore are the most appropriate foods for elimination and challenge testing. The eliminated food must be rechallenged before it is returned to the diet on a regular basis. Foods that have been avoided for >2 weeks are best evaluated by eating small amounts three times a day for 3 days along with other foods. If no symptoms occur, tolerance has been achieved and the food can be returned to the diet on a 4 day rotation basis. In unusual situations a cyclic food sensitivity may revert to a fixed type and react with every challenge. If after 2 years of avoidance a food continues to cause reactions, it is best to consider it a fixed allergy and treat it by permanent avoidance. Tolerance can be maintained by rotating the offending food in the diet not more often than every 4 days. Eating the food more frequently will cause
Journal of Voice, Vol. 1, No. 4, 1987
the sensitivity to recur and masking to develop. Sensitivity to a particular food does not necessarily confirm sensitivity to all foods in that particular family. For example a positive reaction to an orange does not necessarily mean that a lemon, lime, tangerine, and kumquat must be avoided (2).
Rotary diversified diet Rotation of the various food families can be diagnostic, preventive, and therapeutic. Following a rotary diversified diet will prevent the development of new food sensitivities and maintain tolerance to previous food offenders. Rotary means large individual feedings of one to four food families at a single meal. The only ingestion of the food is allowed at 4 day intervals. For example, an orange eaten on Monday may be repeated on Friday. Food family members may be eaten at the same meal and only at 4 day intervals. An alternate plan can be to eat different foods from the same family with a minimum of 2 days between feedings; for example, an orange on Monday and a grapefruit on Wednesday. Diversified means inclusion of foods not ordinarily eaten which ensures proper rotation. CHEMICAL SENSITIVITIES Chemical sensitivities as a result of chemical exposures can result in responses indistinguishable from allergic symptoms. Once an individual is sensitive to a solitary chemical it is apparent that continued exposure results in a spreading phenomenon. This spreading phenomenon results in a person becoming sensitive to other chemicals that he or she was not sensitive to and inhalants and foods that he or she was not previously allergic to. The mechanisms by which symptoms of chemical exposure are produced as well as the spreading effect of chemical exposure can be explained by free radical biochemistry. Free radicals are produced through the metabolism of oxygen and aerobic metabolism. The body has within its chemical environment reducing substances (antioxidants), which neutralize these free radicals. These antioxidants are certain vitamins such as ascorbate acid (vitamin C), [3-carotene (pro-vitamin A), retinol (vitamin A), c~-tocopherol (vitamin E), and some amino acids such as tyrosine, methionine, guanine, cytosine, and histidine. Also needed for this antioxidant
INFLUENCES I N VOICE ABNORMALITIES function are minerals such as magnesium, copper, zinc, selenium, and calcium. The one characteristic that is common to the different classes of chemicals that cause chemical sensitivity is that they are all oxidizing agents or they are chemicals that cause body molecules to become oxidizing agents. They are electron deficient molecules and will therefore take an electron from another molecule that has a lower affinity for its electron. When one of these chemicals enters the body, it can take an electron from an unsaturated fatty acid of the cell wall and thus cause a chain reaction. The cell cannot function well under these damaged conditions and, if enough damage is done to the cell, it dies. If you have enough sick cells or dead cells, the organ will die or malfunction. This malfunction or death produces symptomatology as a direct result of the oxidizing mechanism. One of the cells of the body that is extremely sensitive to free radical damage is the suppressor T-cell. Chemicals enter the body and can cause a decrease in suppressor T-cells and thus allow helper T-cells to be unrestrained in their function. This situation produces an overabundant supply of immunoglobulin of both the E and G type. This oversupply of IgE and/or IgG can cause the patient exposed to chemicals to become allergic and sensitive to substances that previously caused no difficulty. Thus the spreading effect begins. If the body's normal reducing substances necessary for free radical oxidation are used up by a massive exposure to one chemical, there is little or no reducing protection against the presence of other chemicals. Exposure to one chemical that utilizes most of the natural reducing substances allows other chemicals entering the body to cause damage and symptoms that they did not previously produce. Another mechanism by which free radicals can cause disease is by combining with human proteins producing a hapten protein complex. This hapten complex results in the creation of an autoantigen and therefore produces antibodies that can attack body tissues (autoimmune disease). The body uses its normally occurring antioxidants to protect itself against oxidizing agents. When exogenous antioxidants are given to patients that have been exposed to chemicals, there will be a greater antioxidant reserve to neutralize the effect of extraneous oxidizing chemicals. These antioxidant compounds are specific vitamins, amino acids,
381
and trace minerals. They can be given in sufficient quantities to restore the antioxidant capabilities of the body. This approach to the treatment of chemical sensitivities is a current valid treatment modality (3-5).
BIOCHEMICAL ANALYSIS A basic biochemical screen is an integral part of the evaluation of many patients with voice disorders. This is especially true in circumstances of chronic disorders. The biochemical metabolic evaluation should include at least blood serum measurements of the following: cholesterol, triglyceride, thyroid profile, glucose tolerance response, blood urea nitrogen, liver profile (SGOT), complete blood count (CBC), Treponema (FTA-ABS), prolactin level in females, trace minerals (the trace mineral analysis is performed to determine primarily zinc and calcium levels). These tests can be performed for a reasonable cost as part of a SMAC 10 or 20 biochemical study. The percentage of abnormal test results in patient evaluations has been greatest in fat metabolism, sugar metabolism, and the FTA-ABS tests. Abnormality has been found next most commonly in the prolactin and trace mineral tests. Some abnormalities of liver and kidney function and an occasional abnormality in thyroid testing have been found. In the fat metabolism area, triglyceride abnormality has been the most c o m m o n abnormal finding. Management of these abnormalities is based on phenotype, low density lipoproteins, and high density lipoproteins measurements. These tests are performed before treatment and dietary instructions are given to the patient. Dietary control is essential in the treatment of sugar metabolism abnormalities, w h e t h e r the problem is a result of hyper- or hypoglycemia. A great number of patients with poor nutritional habits have been found and confirmed based on flat glucose tolerance curves. These patients respond to a dietary routine that is similar to that prescribed for hypoglycemics, that is, a diet with proper and sufficient complex carbohydrate intake and with little or no refined sugar. The abnormalities found on the CBC studies have been anemias, polycythemias, and an occasional case of leukemia. Abnormalities of liver
Journal of Voice, Vol. 1, No. 4, 1987
382
W. R UB1N
function with the SGOT test have been found primarily in alcoholics. The relationship between prolactin levels in females and neurologic abnormalities has been described by Pinter et al. (6). The most interesting relationship is the fact that a deficiency in tryptophan in people that have poor dietary intake, especially females, causes an elevation of the serum prolactin levels. These patients are easily controlled with change of diet and tryptophan supplementation. Tryptophan is involved in the serotonin cycle and this may well be the neurotransmitter basis of the problem. Trace mineral analysis is a recent addition to our evaluation. The high levels of zinc normally found in the choroid of the eye, the inner ear, and prostate have been described by several authors. The use of zinc and calcium supplementation in our patients who are zinc and/or calcium deficient has been gratifying in terms of hastening recovery.
leased, enter the blood, and join a pool of amino acids (the building blocks of protein) available for transport to the brain. The carrier molecule that transports tryptophan transports eight other neutral amino acids as well. The nine amino acids compete for the carrier. Thus, the more tryptophan in the blood relative to the other competing amino acids the more tryptophan enters the brain and the more serotonin is made. High protein meals alone do not increase brain serotonin because they do not increase the relative amount of tryptophan in the blood. High carbohydrate meals, on the other hand, do increase the relative amount of tryptophan in the blood. After a high carbohydrate meal is eaten, insulin is released and this hormone facilitates the uptake of all the amino acids except tryptophan. The clinical corollary is to supplement a high carbohydrate diet with tryptophan so as to increase the production of serotonin.
NUTRITION AND NEUROTRANSMITTERS
PREMENSTRUAL SYNDROME (PMS)
The mechanism of symptom production in patients with allergic, hormonal, and weight loss problems may be as a result of the diminution of the production of the neurotransmitters serotonin, dopamine, and others. The neurotransmitter chemicals (and all other chemicals) ultimately come from our diet. Dietary supplementation of the amino acids tyrosine and tryptophan is logical and has proven beneficial in patient treatment when allergies, hormonal imbalance, stress, and weight loss are involved. Studies of the effects of food intake on brain biochemistry began - 1 0 years ago when Wurtman and his associates initiated animal experiments (7-10). Since then, they and others have firmly established that half a dozen nutrients can alter the synthesis of the neurotransmitters serotonin, dopamine, norepinephrine, acetylcholine, histamine, and glycine. These neurotransmitters are precursor dependent. The rate at which brain enzymes synthesize the transmitters is limited by the availability of the chemical precursors that are derived from food and are transported into the brain by carrier molecules. The most often cited case is that of serotonin and its dependency on tryptophan. Serotonin is made directly from tryptophan and the body's only source of this amino acid is dietary protein. When certain proteins are digested, tryptophan can be re-
Another factor affecting voice problems in professional singers is mediator release in relation to neurotransmitter function. Mediator release causes voice symptoms that occur with PMS and other hormonal problems. The release affects the voice in the same way that it affects the allergic diathesis (11). These hormonal triggers can be operative in premenstrual tension syndromes, during pregnancy, during menopausal syndromes, and while taking oral contraceptives (12). One adverse reaction to oral contraceptives is depression. The control of mood is thought to be related in some way to the function in the brain of serotonin, norepinephrine, and dopamine, which are synthesized from the precursors tryptophan and tyrosine. Preliminary findings indicate that the availability of plasma tyrosine to the brain in females taking oral contraceptives is decreased. This results in a decreased brain concentration of tyrosine and, in turn, a decreased formation of catecholamines. However, the enzyme that converts 5-hydroxytryp' tophan to serotonin is pyridoxal phosphate dependent and it may therefore be sensitive to competitive action from the estrogen conjugates. This also can result in a decreased formation of serotonin. It is not unlikely that catecholamine deficiency plays
Journal of Voice, Vol. l, No. 4, 1987
I N F L U E N C E S I N VOICE A B N O R M A L I T I E S
a major role in the development of depressive symptoms in oral contraceptive users. The symptoms that occur as a result of poor diet and weight loss are also a result of the release of the same chemical mediators. In all three of these circumstances, allergy, PMS, and weight loss, there is a marked decrease of the neurotransmitters dopamine and serotonin. The sequence of events can be a result of poor diet with subsequent lack of precursors tyrosine and tryptophan which causes a decrease of dopamine and serotonin. This drop results both in the symptoms of poor voice and the complaints that are present in PMS. The chemical mediator effects in PMS involve other hormonal relationships. The luteal phase sensitivity and withdrawal of the central effects of the neuropeptides [3-endorphin and o~-melanocyte result in a cascade of neuroendocrine changes within the brain-hypothalamus-pituitary complex. One of the unique features of peptides is that they act as intercellular messengers. An intercellular messenger is defined as a substance released from one cell that is capable of modifying the functional activity of another neighboring or distant cell. Particular brain peptides play a role in regulating anterior pituitary and autonomic nervous system functions. Modulation of neurotransmitter function by these peptides produces alterations in mood and behavior as well as enhancing pituitary release of prolactin and vasopressin. Variable gonadal steroid modulation of these responses from subject to subject accounts for the varieties of clinical manifestations of PMS. The control of PMS based on the relationship between prolactin, dopamine, and other neurotransmitters is just beginning to evolve.
383
years, and in particular during the past 10, there has been serious medical research on this ancient concept (13,14). Scientists have known since the 1950s that the immune systems of laboratory animals can be influenced by behavior. One of the modern pioneers in the field Robert Ader, using the methods of classic conditioning, has shown that rats can be taught to suppress their own immune responses. This was accomplished by associating the taste of a sweetener with the effects of an immunosuppressire drug. Numerous other investigators have demonstrated that when rats and mice are subjected to acute stress by being confined for short periods of time in crowded living quarters they become increasingly susceptible to disease (15). The preliminary results of this investigation show that behavioral therapy improved the immune system's response to disease. Physiologically, the rate at which lymphocytes mobilized to attack foreign bodies accelerated as the numbers of lymphocytes were also increased. The discovery that autonomic nerves interlace lymph tissues has recast our view of the immune system. It seems to resemble an endocrine gland, and, like all endocrine tissue, possesses a direct anatomical link to the brain. There is ample reason to believe that such two-way communication takes place by means of the hypothalamic-pituitaryadrenal axis. Since the substances that exert this influence, adrenocorticotropic hormone and betaendorphin (internally manufactured opiates); lymphokines and cytokines (chemical products of macrophages); and the hormone-like thymosins (synthesized in the thymus) originate within the immune system itself, they might be called immunotransmitters.
AUTONOMIC DYSFUNCTION (STRESS) The idea that mental states influence the body's susceptibility to and recovery from disease has a long and hallowed history. As early as the 2nd century AD, the Greek physician Galen asserted that cancer struck more frequently in melancholic than in sanguine women. The belief that disease is a consequence of psychic or spiritual imbalance governed the practice of medicine in both Asia and Europe until the rise of modern science and its mechanistic view of physiology. In the 17th century the role of behavior in human disease became a concern to most physicians. Within the past 30
SUMMARY
1. Allergic mechanisms are a significant factor in voice problems in the professional singer. 2. Investigation of allergic causes of recurrent voice problems are warranted and can be cost effective. 3. Desensitization treatment is beneficial in the prevention of recurrent laryngitis in a significant number of professional singers. 4. Dietary, nutritional, chemical, hormonal, and immunologic factors are directly involved in voice
Journal of Voice, Vol. 1, No. 4, 1987
384
W. R UBIN
symptom production and also need to be evaluated and considered in the treatment regime in a positive fashion. 5. Stress is also a factor in the body's immune responses and must be considered especially in relation to a voice professional's performance. APPENDIX
Radioallergosorbent test Radioallergosorbent test is rapidly becoming a standard method for the diagnosis of IgE-mediated hypersensitivity. This assay quantitates the amount of circulating antigen-specific IgE in serum samples by radioimmunoassay (RIA). It is based on the Nobel prize winning RIA procedure developed by Yalow and Berson and possesses two inherent qualities that are essential for reliable allergy diagnosis. 1. Specificity--RAST possesses the specificity of an immunologically mediated antigen antibody reaction. 2. Sensitivity--RAST has sensitivity in the picogram range and is capable of detecting allergen-specific antibody at a concentration of less than a billionth of a gram. No other technique used for clinical allergy diagnosis can match these unique qualities. The RAST technique not only detects the presence of allergen-specific IgE antibody against a particular allergen but also quantitates its serum concentration and the degree of allergen sensitization. Highly sensitive patients, who are potentially at risk for adverse reactions from immunotherapy, are in this way distinguished from lower sensitivity risk-free patients (1,16). Standardization The covalently bound solid phase allergens used in RAST are stable for >1 year, and potency is standardized by testing the allergen-coated disk against a pool of known highly reaginic sera. The stability and biological potency of allergens used for skin testing, on the other hand, are not so standardized and are often of lesser quality than those used in manufacturing the solid phase allergens used in RAST. Reproducibility With properly stored sera, repeat assays weeks, months, or years later yield reproducible test values by either inter- or intralaboratory evalua-
Journal of Voice, Vol. 1, No. 4, 1987
tions with coefficients of variation of 20% or less. Comparable reproducibility is not found in skin testing. Test results in a particular patient are the same even when performed by different physicians in divergent geographical locations. Interpretation of skin test results performed under the same conditions have shown extreme variability sometimes exceeding several thousandfold in test results.
Objective The results are reported in numerical units and are not dependent on subjective assessments of biologically variable skin responses as in skin testing. Precision The immunochemical RAST assay identifies the antigen-specific IgE antibody in question. Results are not altered by drugs, irritants, contaminants, ongoing disease, autonomic nervous system imbalances, and neither highly nor poorly reactive skin. Safety Radioallergosorbent test is an in vitro assay. It poses no risk to the patient. Although uncommon, skin testing may result in anaphylaxis, hepatitis, activation of systemic symptoms, induction of new sensitizations, secondary infections, or the need for ancillary medical care. Cost Although diagnostic RAST may initially be more expensive than skin testing on a test for test basis, it is only moderately so and is justifiable because of its many advantages over skin testing. Moreover, in the management of allergic patients the initially incurred diagnostic expenses are only a small portion of the overall cost of a chronic illness such as allergy. Effective cost containment of allergy diagnosis and treatment could be readily obtained if it were mandatory to demonstrate the presence of clinically relevant allergen-specific IgE antibodies before initiating immunotherapy. Many patients receive allergy injections for years based on a suspected history of allergy coupled with unreliable "false-positive" skin tests. Conversely, some allergic patients are denied specific immunotherapy based on "false-negative" skin test results and repeatedly incur additional unnecessary medical expenses in the quest for relief of their elusive complaints. Other cost containment factors are 1. Fewer individual RASTs are performed than with skin testing because of the knowledge of al-
I N F L U E N C E S I N VOICE A B N O R M A L I T I E S
lergen cross reactivity gleened from RAST inhibition assays. Although almost any substance is available for skin testing, allergens of questionable clinical significance are not available for RAST. The commonly used large battery of screening skin test are time consuming and may be more expensive than selective RAST. 2. Titrated skin testing (multiple serial dilutions of the same allergens) is more expensive than RAST on a test basis and yields less reliable information. These tests yield false-positive results at high allergen concentrations and almost always overestimate the degree of patient sensitivity. 3. F e w e r patients are selected for immunotherapy regimens when the detection of allergenspecific IgE is required prior to initiating such therapy. Allergy injection costs are eliminated in the absence of detectable IgE antibody and other causes responsible for symptoms may be sought once the possibility of IgE-mediated allergy has been eliminated. 4. Only high allergen doses are effective in favorably influencing abnormal immunological and clinical states. By quantitating the IgE antibody titers and thus the risk factors, much larger and effective allergen doses can be safely administered at the onset. This is possible because the majority (85%) of allergic patients have low degrees of sensitization. Wasteful and unneeded arbitrary low doses can be eliminated thus reducing overall costs. This is cost effective because many months or years of injections can be circumvented before evaluating effectiveness of immunotherapy. 5. Highly sensitive risk prone patients are recognized in advance and are treated more cautiously. This prevents arbitrary predetermined dose escalation to maximal levels that may result in serious reactions. 6. The early use of high specific allergen doses accelerates the beneficial immune and clinical responses leading to reversal of tissue pathology and symptoms. This reduces emergency room care, hospitalizations, absenteeism, complicating infections, drug expenses, physical and social limita-
385
tions, while simultaneously improving the quality of life. As with any diagnostic procedure, the use of RAST should be conducted in conjunction with a complete clinical evaluation by an informed physician who is knowledgeable in the management of allergic disorders. Such physicians should be capable of incorporating this information into responsible and cost-effective management of their atopic patients problems.
REFERENCES 1. Fadal RG. Immunoglobulin E and G and the allergic patient. Trans A m Soc Ophthalmol Otolaryngol Allergy 1975; 15:158. 2. Boyles JH Jr. Food allergy diagnosis and treatment. Symposium on immunology and allergy. Otolaryngol Clin North A m 1985;18:775-85. 3. Levine S, Kidd E Antioxidant adaptation--a unified disease theory. J Orthomolec Psychiatry 1985;14:19-37. 4. Levine S, Kidd E Beyond antioxidant adaptation: a free radical-hypoxia-clonal thesis of cancer causation. J Orthomolec Psychiatry 1985;14(3):189-213. 5. Levine S, Kidd E Biochemical pathologies initiated by free radical oxidant compounds in etiology of food hypersensitivity disease. Int Clin Nutr Rev 1985;5:5-14. 6. Pinter E J, Tolls G, Guyda H, Katsarkas A. Hormonal and free fatty acid changes during strenuous flight in novices and trained personnel. Psychoneuroendocrinology 1979;4:79. 7. Wurtman RJ, Fernstrom JD. Nutrition and the brain. Sci A m 1974;230:84-91. 8. Growdon JH, Wurtman RJ. Treatment of brain disease with dietary precursors of neurotransmitters. Ann Intern Med 1977;86:337-9. 9. Growdon JH. Neurotransmitter precursors in the diet: their use in the treatment of brain diseases. In: Wurtman RJ, Wurtman JJ, eds. Disorders o f eating: nutrients in treatment o f brain diseases. New York: Raven Press, 1979:117-70. (Nutrition and the brain; vol 3.) 10. G r o w d o n JH, Wurtman RJ. Nutrients and neurotransmitters, contemporary nutrition. N Y State J M e d 1980; 80(2): 1638. 11. Moiler SE. Tryptophan and tyrosine availability a n d oral contraceptives. Lancet 1979;1:472. 12. Berman RL. Current perspectives in gynecology. Clin Symp 1985;37. 13. Hall NR, Goldstein AL. Thinking well: the chemical links between emotions and health. Science 86 1986;26(2):34-40. 14. Dixon B. Dangerous thoughts. Science 86 1986;26(2):63-6. 15. Darko DE A brief tour of psychoneuroimmunology. Ann Allergy 1986;57:233-8. 16. Fadal RG. The skin t e s t - - h o w good is it? Trans A m Soc Ophthalmol Otolaryngol Allergy 1978;18:74.
Allergic, Dietary, Chemical, Stress, and Hormonal Influences in Voice Abnormalities Wallace Rubin Department of Otorhinolaryngology and Biocommunication, Louisiana State University School of Medicine, New Orleans, Louisiana, U.S.A.
Summary: Allergic, dietary, chemical, biochemical, stress, and hormonal abnormalities have long been recognized as important factors in both abnormalities of the voice and in the general health of the professional vocalist. In recent years objective methods have become available to evaluate and treat allergic, dietary, and chemical abnormalities and to better understand the effects of stress and hormonal variations. Assessment of allergic disease is efficient and cost effective through the use of in vitro testing techniques combined with skin end point titration. This provides highly specific and objective results and leads to accurate planning of desensitization treatment. This form of treatment can be especially beneficial in the prevention of recurrent laryngitis. An accurate nutritional history provides evidence of food sensitivities that can lead to cyclical allergic-like vocal symptoms that can be prevented with the use of elimination diets and the judicious use of desensitization therapy. An adequate knowledge of the potential effects of chemical sensitivities will assist the patient in the avoidance of provocative chemical exposures. An in depth evaluation of biochemical abnormalities and a specific assessment of the nutritional status must be considered to evaluate the underlying causes of long-standing general health problems that can affect the voice. Likewise, hormonal variations are not only important in their direct effects on the vocal mechanism but in their cyclical effects on the patient's basic biochemical balance. Lastly, stress, which has long been related to problems in professional performance, is only now being fully studied to determine its actual biologic influences and these must be related to the causes of voice disturbances. Understanding all these influences and planning a rational and efficient evaluation of these potential problem areas are imperative in the complete care of the patient with voice abnormalities. Key Words: Allergy--Voice--Desensitization in singers.
relation between these factors and voice problems because they coexisted. Until very recently, it has been necessary to rely solely on the patient's history and skin testing to make an allergic diagnosis and hope that some form of allergic management, either a v o i d a n c e or desensitization, w o u l d solve the patient's problem of hoarseness. For the most part, the biochemical, metabolic, neurotransmitter, autonomic, and hormonal influences as they relate to voice production have been ignored. Do you perform an allergic investigation in all patients with voice p r o b l e m s ? H o w do y o u decide
This monograph describes the author's efforts to correlate vocal s y m p t o m s with objectively confirmed allergic, b i o c h e m i c a l , metabolic, neurotransmitter, autonomic, and hormonal abnormalities. We have in the past assumed an etiologic cor-
The results of this report presented at the Sixteenth Symposium: Care of the Professional Voice, New York, June 1986. Address correspondence and reprint requests to Dr. W. Rubin, at 3434 Houma Blvd., Metairie, LA 70006, U.S.A. 378
I N F L U E N C E S I N VOICE A B N O R M A L I T I E S
379
whom to test and which test to use? Do you test everybody for both inhalants and foods? Do you use in vitro tests such as radioallergosorbent test (RAST)? Is all this cost effective for the patient? Do you perform a biochemical, metabolic, and hormonal screen? Which tests do you use? How do you make these decisions? These are the challenges.
few patients where the allergic history is significant and only the SET tests are positive. Changes in diet and other measures are recommended after a biochemical metabolic screen is performed and evaluated. A similar investigation of hormonal and stress influences is made and correction of significant abnormalities is attempted with the appropriate measures.
PATIENT EXAMINATION
WHY LABORATORY IN VITRO ALLERGY TESTING
All patients evaluated for hoarseness and/or other voice aberrations are examined by mirror examination of the vocal cords and by complete examination of the head and neck. Patients are evaluated for allergic factors that might relate to their voice complaints by the following sequential format. 1. Skin end point titration (SET) is performed for 10 antigens (Alternaria, Candida, Dermatophagoides F a r i n a e - - d u s t mites, giant ragweed, Bermuda grass, June grass, Johnson grass, box elder maple, cat dander, dog dander). 2. A six RAST microscreen panel (grass, tree, weed, dust mites, cat dander, mold) is done on all patients. 3. A 10 RAST panel is performed if any of the SET responses were positive or if the microscreen proved positive. 4. Intradermal provocative food testing and/or IgE, IgG RAST food tests are performed if the history suggests food as a factor. When positive responses are obtained, an attempt is made to neutralize the response and/or symptoms with the proper intradermai neutralizing dose of the antigen and with food elimination or rotation diets. Patients who present with hoarseness are treated pharmacologically while waiting for the in vitro test results. The treatment generally includes voice rest or voice modification procedures and the use of antibiotics, antihistamines, and/or steroids. The steroids used for the short-term acute response are given in small doses by injection. A program of allergic desensitization is begun in those patients with recurrent voice problems and in whom the allergic investigation is significantly positive. This is done only after an in depth procedural explanation to the patient. All allergic treatment for inhalants is carried out using the modified RAST technique as a basis for dosage used except in those
In vitro allergy testing is clinically useful for two reasons. First and foremost, it is the most accurate and objective method for confirming the diagnosis. Second, it is cost effective, especially using the microscreen technique. This is a major consideration in offering modern, efficient, medical care to patients. Studies have shown that there is >95% agreement between the results obtained by microscreen allergy testing as compared with testing with as many as 20 individual allergens. These studies attest to the efficacy of microscreen allergy testing. Intradermal scratch or prick skin testing has a major disadvantage in that it suffers from a lack of specificity. It is unusual for patients to be entirely negative to intradermal skin testing. If a patient happens to have r e s p i r a t o r y or d e r m a t o l o g i c problems due to other causes and also has positive skin reactivity, the physician may attribute the symptoms to the allergen causing the positive skin reactivity. The multiallergen screen serves another useful purpose in that there are patients with upper airway and laryngeal symptoms in whom the history and physical examination may not suggest an allergic diathesis. In such patients a positive microscreen alerts the physician to the possibility of an allergic etiology and can lead to further appropriate testing and treatment (I). CYCLIC CONCEPT OF FOOD SENSITIVITIES Exclusive of IgE-mediated reactions, the majority of food sensitivity develops by repetitive ingestion of a food in a susceptible individual. Symptoms usually begin gradually and may be triggered by an increase in the total allergic 10ad, following an illness, disease, or stress situation. A food may react at any point along the gastrointestinal tract and the usual bowel transit time is 4 days; symptoms in cyclic reactions can be delayed
Journal of Voice, Vol. l, No. 4, 1987
380
W. R U B I N
up to 4 or 5 days. Reactions may be dose related with symptoms occurring only after large feedings or closely spaced feedings over several days. In cyclic food sensitivity a 72 h interval or less is considered "closely spaced," as the masking phenomenon occurs only when the offending food remains in the gastrointestinal tract. Cyclic food sensitivities are not IgE mediated, thus skin tests and in vitro tests measuring IgE antibody to a food are unreliable in diagnosing these responses. Elimination and challenge techniques are used to diagnose cyclic food sensitivities. FOOD HISTORY AND DIET DIARY The food history and diet diary are the key to determining suspected food allergy offenders. Probable food offenders are selected based on a review of the diet and a 2 week diet and symptom diary. Seasonal availability, geographical location, and ethnic preferences are taken into consideration when questioning the patient. The frequency of foods eaten on a daily or weekly basis are noted. A known food offender may suggest another food offender in that particular food family. Specific cravings and/or dislikes may also indicate an offender. Many nutritional supplements such as vitamins are derived from and/or contain food constituents. Diet supplements used for weight control contain foods such as milk, soy, or wheat as major ingredients. With foods eaten once a week or less, it is comparatively easy to establish a cause and effect relationship between ingestion and symptoms. Foods eaten at least every 72 h are subject to masking and therefore are the most appropriate foods for elimination and challenge testing. The eliminated food must be rechallenged before it is returned to the diet on a regular basis. Foods that have been avoided for >2 weeks are best evaluated by eating small amounts three times a day for 3 days along with other foods. If no symptoms occur, tolerance has been achieved and the food can be returned to the diet on a 4 day rotation basis. In unusual situations a cyclic food sensitivity may revert to a fixed type and react with every challenge. If after 2 years of avoidance a food continues to cause reactions, it is best to consider it a fixed allergy and treat it by permanent avoidance. Tolerance can be maintained by rotating the offending food in the diet not more often than every 4 days. Eating the food more frequently will cause
Journal of Voice, Vol. 1, No. 4, 1987
the sensitivity to recur and masking to develop. Sensitivity to a particular food does not necessarily confirm sensitivity to all foods in that particular family. For example a positive reaction to an orange does not necessarily mean that a lemon, lime, tangerine, and kumquat must be avoided (2).
Rotary diversified diet Rotation of the various food families can be diagnostic, preventive, and therapeutic. Following a rotary diversified diet will prevent the development of new food sensitivities and maintain tolerance to previous food offenders. Rotary means large individual feedings of one to four food families at a single meal. The only ingestion of the food is allowed at 4 day intervals. For example, an orange eaten on Monday may be repeated on Friday. Food family members may be eaten at the same meal and only at 4 day intervals. An alternate plan can be to eat different foods from the same family with a minimum of 2 days between feedings; for example, an orange on Monday and a grapefruit on Wednesday. Diversified means inclusion of foods not ordinarily eaten which ensures proper rotation. CHEMICAL SENSITIVITIES Chemical sensitivities as a result of chemical exposures can result in responses indistinguishable from allergic symptoms. Once an individual is sensitive to a solitary chemical it is apparent that continued exposure results in a spreading phenomenon. This spreading phenomenon results in a person becoming sensitive to other chemicals that he or she was not sensitive to and inhalants and foods that he or she was not previously allergic to. The mechanisms by which symptoms of chemical exposure are produced as well as the spreading effect of chemical exposure can be explained by free radical biochemistry. Free radicals are produced through the metabolism of oxygen and aerobic metabolism. The body has within its chemical environment reducing substances (antioxidants), which neutralize these free radicals. These antioxidants are certain vitamins such as ascorbate acid (vitamin C), [3-carotene (pro-vitamin A), retinol (vitamin A), c~-tocopherol (vitamin E), and some amino acids such as tyrosine, methionine, guanine, cytosine, and histidine. Also needed for this antioxidant
INFLUENCES I N VOICE ABNORMALITIES function are minerals such as magnesium, copper, zinc, selenium, and calcium. The one characteristic that is common to the different classes of chemicals that cause chemical sensitivity is that they are all oxidizing agents or they are chemicals that cause body molecules to become oxidizing agents. They are electron deficient molecules and will therefore take an electron from another molecule that has a lower affinity for its electron. When one of these chemicals enters the body, it can take an electron from an unsaturated fatty acid of the cell wall and thus cause a chain reaction. The cell cannot function well under these damaged conditions and, if enough damage is done to the cell, it dies. If you have enough sick cells or dead cells, the organ will die or malfunction. This malfunction or death produces symptomatology as a direct result of the oxidizing mechanism. One of the cells of the body that is extremely sensitive to free radical damage is the suppressor T-cell. Chemicals enter the body and can cause a decrease in suppressor T-cells and thus allow helper T-cells to be unrestrained in their function. This situation produces an overabundant supply of immunoglobulin of both the E and G type. This oversupply of IgE and/or IgG can cause the patient exposed to chemicals to become allergic and sensitive to substances that previously caused no difficulty. Thus the spreading effect begins. If the body's normal reducing substances necessary for free radical oxidation are used up by a massive exposure to one chemical, there is little or no reducing protection against the presence of other chemicals. Exposure to one chemical that utilizes most of the natural reducing substances allows other chemicals entering the body to cause damage and symptoms that they did not previously produce. Another mechanism by which free radicals can cause disease is by combining with human proteins producing a hapten protein complex. This hapten complex results in the creation of an autoantigen and therefore produces antibodies that can attack body tissues (autoimmune disease). The body uses its normally occurring antioxidants to protect itself against oxidizing agents. When exogenous antioxidants are given to patients that have been exposed to chemicals, there will be a greater antioxidant reserve to neutralize the effect of extraneous oxidizing chemicals. These antioxidant compounds are specific vitamins, amino acids,
381
and trace minerals. They can be given in sufficient quantities to restore the antioxidant capabilities of the body. This approach to the treatment of chemical sensitivities is a current valid treatment modality (3-5).
BIOCHEMICAL ANALYSIS A basic biochemical screen is an integral part of the evaluation of many patients with voice disorders. This is especially true in circumstances of chronic disorders. The biochemical metabolic evaluation should include at least blood serum measurements of the following: cholesterol, triglyceride, thyroid profile, glucose tolerance response, blood urea nitrogen, liver profile (SGOT), complete blood count (CBC), Treponema (FTA-ABS), prolactin level in females, trace minerals (the trace mineral analysis is performed to determine primarily zinc and calcium levels). These tests can be performed for a reasonable cost as part of a SMAC 10 or 20 biochemical study. The percentage of abnormal test results in patient evaluations has been greatest in fat metabolism, sugar metabolism, and the FTA-ABS tests. Abnormality has been found next most commonly in the prolactin and trace mineral tests. Some abnormalities of liver and kidney function and an occasional abnormality in thyroid testing have been found. In the fat metabolism area, triglyceride abnormality has been the most c o m m o n abnormal finding. Management of these abnormalities is based on phenotype, low density lipoproteins, and high density lipoproteins measurements. These tests are performed before treatment and dietary instructions are given to the patient. Dietary control is essential in the treatment of sugar metabolism abnormalities, w h e t h e r the problem is a result of hyper- or hypoglycemia. A great number of patients with poor nutritional habits have been found and confirmed based on flat glucose tolerance curves. These patients respond to a dietary routine that is similar to that prescribed for hypoglycemics, that is, a diet with proper and sufficient complex carbohydrate intake and with little or no refined sugar. The abnormalities found on the CBC studies have been anemias, polycythemias, and an occasional case of leukemia. Abnormalities of liver
Journal of Voice, Vol. 1, No. 4, 1987
382
W. R UB1N
function with the SGOT test have been found primarily in alcoholics. The relationship between prolactin levels in females and neurologic abnormalities has been described by Pinter et al. (6). The most interesting relationship is the fact that a deficiency in tryptophan in people that have poor dietary intake, especially females, causes an elevation of the serum prolactin levels. These patients are easily controlled with change of diet and tryptophan supplementation. Tryptophan is involved in the serotonin cycle and this may well be the neurotransmitter basis of the problem. Trace mineral analysis is a recent addition to our evaluation. The high levels of zinc normally found in the choroid of the eye, the inner ear, and prostate have been described by several authors. The use of zinc and calcium supplementation in our patients who are zinc and/or calcium deficient has been gratifying in terms of hastening recovery.
leased, enter the blood, and join a pool of amino acids (the building blocks of protein) available for transport to the brain. The carrier molecule that transports tryptophan transports eight other neutral amino acids as well. The nine amino acids compete for the carrier. Thus, the more tryptophan in the blood relative to the other competing amino acids the more tryptophan enters the brain and the more serotonin is made. High protein meals alone do not increase brain serotonin because they do not increase the relative amount of tryptophan in the blood. High carbohydrate meals, on the other hand, do increase the relative amount of tryptophan in the blood. After a high carbohydrate meal is eaten, insulin is released and this hormone facilitates the uptake of all the amino acids except tryptophan. The clinical corollary is to supplement a high carbohydrate diet with tryptophan so as to increase the production of serotonin.
NUTRITION AND NEUROTRANSMITTERS
PREMENSTRUAL SYNDROME (PMS)
The mechanism of symptom production in patients with allergic, hormonal, and weight loss problems may be as a result of the diminution of the production of the neurotransmitters serotonin, dopamine, and others. The neurotransmitter chemicals (and all other chemicals) ultimately come from our diet. Dietary supplementation of the amino acids tyrosine and tryptophan is logical and has proven beneficial in patient treatment when allergies, hormonal imbalance, stress, and weight loss are involved. Studies of the effects of food intake on brain biochemistry began - 1 0 years ago when Wurtman and his associates initiated animal experiments (7-10). Since then, they and others have firmly established that half a dozen nutrients can alter the synthesis of the neurotransmitters serotonin, dopamine, norepinephrine, acetylcholine, histamine, and glycine. These neurotransmitters are precursor dependent. The rate at which brain enzymes synthesize the transmitters is limited by the availability of the chemical precursors that are derived from food and are transported into the brain by carrier molecules. The most often cited case is that of serotonin and its dependency on tryptophan. Serotonin is made directly from tryptophan and the body's only source of this amino acid is dietary protein. When certain proteins are digested, tryptophan can be re-
Another factor affecting voice problems in professional singers is mediator release in relation to neurotransmitter function. Mediator release causes voice symptoms that occur with PMS and other hormonal problems. The release affects the voice in the same way that it affects the allergic diathesis (11). These hormonal triggers can be operative in premenstrual tension syndromes, during pregnancy, during menopausal syndromes, and while taking oral contraceptives (12). One adverse reaction to oral contraceptives is depression. The control of mood is thought to be related in some way to the function in the brain of serotonin, norepinephrine, and dopamine, which are synthesized from the precursors tryptophan and tyrosine. Preliminary findings indicate that the availability of plasma tyrosine to the brain in females taking oral contraceptives is decreased. This results in a decreased brain concentration of tyrosine and, in turn, a decreased formation of catecholamines. However, the enzyme that converts 5-hydroxytryp' tophan to serotonin is pyridoxal phosphate dependent and it may therefore be sensitive to competitive action from the estrogen conjugates. This also can result in a decreased formation of serotonin. It is not unlikely that catecholamine deficiency plays
Journal of Voice, Vol. l, No. 4, 1987
I N F L U E N C E S I N VOICE A B N O R M A L I T I E S
a major role in the development of depressive symptoms in oral contraceptive users. The symptoms that occur as a result of poor diet and weight loss are also a result of the release of the same chemical mediators. In all three of these circumstances, allergy, PMS, and weight loss, there is a marked decrease of the neurotransmitters dopamine and serotonin. The sequence of events can be a result of poor diet with subsequent lack of precursors tyrosine and tryptophan which causes a decrease of dopamine and serotonin. This drop results both in the symptoms of poor voice and the complaints that are present in PMS. The chemical mediator effects in PMS involve other hormonal relationships. The luteal phase sensitivity and withdrawal of the central effects of the neuropeptides [3-endorphin and o~-melanocyte result in a cascade of neuroendocrine changes within the brain-hypothalamus-pituitary complex. One of the unique features of peptides is that they act as intercellular messengers. An intercellular messenger is defined as a substance released from one cell that is capable of modifying the functional activity of another neighboring or distant cell. Particular brain peptides play a role in regulating anterior pituitary and autonomic nervous system functions. Modulation of neurotransmitter function by these peptides produces alterations in mood and behavior as well as enhancing pituitary release of prolactin and vasopressin. Variable gonadal steroid modulation of these responses from subject to subject accounts for the varieties of clinical manifestations of PMS. The control of PMS based on the relationship between prolactin, dopamine, and other neurotransmitters is just beginning to evolve.
383
years, and in particular during the past 10, there has been serious medical research on this ancient concept (13,14). Scientists have known since the 1950s that the immune systems of laboratory animals can be influenced by behavior. One of the modern pioneers in the field Robert Ader, using the methods of classic conditioning, has shown that rats can be taught to suppress their own immune responses. This was accomplished by associating the taste of a sweetener with the effects of an immunosuppressire drug. Numerous other investigators have demonstrated that when rats and mice are subjected to acute stress by being confined for short periods of time in crowded living quarters they become increasingly susceptible to disease (15). The preliminary results of this investigation show that behavioral therapy improved the immune system's response to disease. Physiologically, the rate at which lymphocytes mobilized to attack foreign bodies accelerated as the numbers of lymphocytes were also increased. The discovery that autonomic nerves interlace lymph tissues has recast our view of the immune system. It seems to resemble an endocrine gland, and, like all endocrine tissue, possesses a direct anatomical link to the brain. There is ample reason to believe that such two-way communication takes place by means of the hypothalamic-pituitaryadrenal axis. Since the substances that exert this influence, adrenocorticotropic hormone and betaendorphin (internally manufactured opiates); lymphokines and cytokines (chemical products of macrophages); and the hormone-like thymosins (synthesized in the thymus) originate within the immune system itself, they might be called immunotransmitters.
AUTONOMIC DYSFUNCTION (STRESS) The idea that mental states influence the body's susceptibility to and recovery from disease has a long and hallowed history. As early as the 2nd century AD, the Greek physician Galen asserted that cancer struck more frequently in melancholic than in sanguine women. The belief that disease is a consequence of psychic or spiritual imbalance governed the practice of medicine in both Asia and Europe until the rise of modern science and its mechanistic view of physiology. In the 17th century the role of behavior in human disease became a concern to most physicians. Within the past 30
SUMMARY
1. Allergic mechanisms are a significant factor in voice problems in the professional singer. 2. Investigation of allergic causes of recurrent voice problems are warranted and can be cost effective. 3. Desensitization treatment is beneficial in the prevention of recurrent laryngitis in a significant number of professional singers. 4. Dietary, nutritional, chemical, hormonal, and immunologic factors are directly involved in voice
Journal of Voice, Vol. 1, No. 4, 1987
384
W. R UBIN
symptom production and also need to be evaluated and considered in the treatment regime in a positive fashion. 5. Stress is also a factor in the body's immune responses and must be considered especially in relation to a voice professional's performance. APPENDIX
Radioallergosorbent test Radioallergosorbent test is rapidly becoming a standard method for the diagnosis of IgE-mediated hypersensitivity. This assay quantitates the amount of circulating antigen-specific IgE in serum samples by radioimmunoassay (RIA). It is based on the Nobel prize winning RIA procedure developed by Yalow and Berson and possesses two inherent qualities that are essential for reliable allergy diagnosis. 1. Specificity--RAST possesses the specificity of an immunologically mediated antigen antibody reaction. 2. Sensitivity--RAST has sensitivity in the picogram range and is capable of detecting allergen-specific antibody at a concentration of less than a billionth of a gram. No other technique used for clinical allergy diagnosis can match these unique qualities. The RAST technique not only detects the presence of allergen-specific IgE antibody against a particular allergen but also quantitates its serum concentration and the degree of allergen sensitization. Highly sensitive patients, who are potentially at risk for adverse reactions from immunotherapy, are in this way distinguished from lower sensitivity risk-free patients (1,16). Standardization The covalently bound solid phase allergens used in RAST are stable for >1 year, and potency is standardized by testing the allergen-coated disk against a pool of known highly reaginic sera. The stability and biological potency of allergens used for skin testing, on the other hand, are not so standardized and are often of lesser quality than those used in manufacturing the solid phase allergens used in RAST. Reproducibility With properly stored sera, repeat assays weeks, months, or years later yield reproducible test values by either inter- or intralaboratory evalua-
Journal of Voice, Vol. 1, No. 4, 1987
tions with coefficients of variation of 20% or less. Comparable reproducibility is not found in skin testing. Test results in a particular patient are the same even when performed by different physicians in divergent geographical locations. Interpretation of skin test results performed under the same conditions have shown extreme variability sometimes exceeding several thousandfold in test results.
Objective The results are reported in numerical units and are not dependent on subjective assessments of biologically variable skin responses as in skin testing. Precision The immunochemical RAST assay identifies the antigen-specific IgE antibody in question. Results are not altered by drugs, irritants, contaminants, ongoing disease, autonomic nervous system imbalances, and neither highly nor poorly reactive skin. Safety Radioallergosorbent test is an in vitro assay. It poses no risk to the patient. Although uncommon, skin testing may result in anaphylaxis, hepatitis, activation of systemic symptoms, induction of new sensitizations, secondary infections, or the need for ancillary medical care. Cost Although diagnostic RAST may initially be more expensive than skin testing on a test for test basis, it is only moderately so and is justifiable because of its many advantages over skin testing. Moreover, in the management of allergic patients the initially incurred diagnostic expenses are only a small portion of the overall cost of a chronic illness such as allergy. Effective cost containment of allergy diagnosis and treatment could be readily obtained if it were mandatory to demonstrate the presence of clinically relevant allergen-specific IgE antibodies before initiating immunotherapy. Many patients receive allergy injections for years based on a suspected history of allergy coupled with unreliable "false-positive" skin tests. Conversely, some allergic patients are denied specific immunotherapy based on "false-negative" skin test results and repeatedly incur additional unnecessary medical expenses in the quest for relief of their elusive complaints. Other cost containment factors are 1. Fewer individual RASTs are performed than with skin testing because of the knowledge of al-
I N F L U E N C E S I N VOICE A B N O R M A L I T I E S
lergen cross reactivity gleened from RAST inhibition assays. Although almost any substance is available for skin testing, allergens of questionable clinical significance are not available for RAST. The commonly used large battery of screening skin test are time consuming and may be more expensive than selective RAST. 2. Titrated skin testing (multiple serial dilutions of the same allergens) is more expensive than RAST on a test basis and yields less reliable information. These tests yield false-positive results at high allergen concentrations and almost always overestimate the degree of patient sensitivity. 3. F e w e r patients are selected for immunotherapy regimens when the detection of allergenspecific IgE is required prior to initiating such therapy. Allergy injection costs are eliminated in the absence of detectable IgE antibody and other causes responsible for symptoms may be sought once the possibility of IgE-mediated allergy has been eliminated. 4. Only high allergen doses are effective in favorably influencing abnormal immunological and clinical states. By quantitating the IgE antibody titers and thus the risk factors, much larger and effective allergen doses can be safely administered at the onset. This is possible because the majority (85%) of allergic patients have low degrees of sensitization. Wasteful and unneeded arbitrary low doses can be eliminated thus reducing overall costs. This is cost effective because many months or years of injections can be circumvented before evaluating effectiveness of immunotherapy. 5. Highly sensitive risk prone patients are recognized in advance and are treated more cautiously. This prevents arbitrary predetermined dose escalation to maximal levels that may result in serious reactions. 6. The early use of high specific allergen doses accelerates the beneficial immune and clinical responses leading to reversal of tissue pathology and symptoms. This reduces emergency room care, hospitalizations, absenteeism, complicating infections, drug expenses, physical and social limita-
385
tions, while simultaneously improving the quality of life. As with any diagnostic procedure, the use of RAST should be conducted in conjunction with a complete clinical evaluation by an informed physician who is knowledgeable in the management of allergic disorders. Such physicians should be capable of incorporating this information into responsible and cost-effective management of their atopic patients problems.
REFERENCES 1. Fadal RG. Immunoglobulin E and G and the allergic patient. Trans A m Soc Ophthalmol Otolaryngol Allergy 1975; 15:158. 2. Boyles JH Jr. Food allergy diagnosis and treatment. Symposium on immunology and allergy. Otolaryngol Clin North A m 1985;18:775-85. 3. Levine S, Kidd E Antioxidant adaptation--a unified disease theory. J Orthomolec Psychiatry 1985;14:19-37. 4. Levine S, Kidd E Beyond antioxidant adaptation: a free radical-hypoxia-clonal thesis of cancer causation. J Orthomolec Psychiatry 1985;14(3):189-213. 5. Levine S, Kidd E Biochemical pathologies initiated by free radical oxidant compounds in etiology of food hypersensitivity disease. Int Clin Nutr Rev 1985;5:5-14. 6. Pinter E J, Tolls G, Guyda H, Katsarkas A. Hormonal and free fatty acid changes during strenuous flight in novices and trained personnel. Psychoneuroendocrinology 1979;4:79. 7. Wurtman RJ, Fernstrom JD. Nutrition and the brain. Sci A m 1974;230:84-91. 8. Growdon JH, Wurtman RJ. Treatment of brain disease with dietary precursors of neurotransmitters. Ann Intern Med 1977;86:337-9. 9. Growdon JH. Neurotransmitter precursors in the diet: their use in the treatment of brain diseases. In: Wurtman RJ, Wurtman JJ, eds. Disorders o f eating: nutrients in treatment o f brain diseases. New York: Raven Press, 1979:117-70. (Nutrition and the brain; vol 3.) 10. G r o w d o n JH, Wurtman RJ. Nutrients and neurotransmitters, contemporary nutrition. N Y State J M e d 1980; 80(2): 1638. 11. Moiler SE. Tryptophan and tyrosine availability a n d oral contraceptives. Lancet 1979;1:472. 12. Berman RL. Current perspectives in gynecology. Clin Symp 1985;37. 13. Hall NR, Goldstein AL. Thinking well: the chemical links between emotions and health. Science 86 1986;26(2):34-40. 14. Dixon B. Dangerous thoughts. Science 86 1986;26(2):63-6. 15. Darko DE A brief tour of psychoneuroimmunology. Ann Allergy 1986;57:233-8. 16. Fadal RG. The skin t e s t - - h o w good is it? Trans A m Soc Ophthalmol Otolaryngol Allergy 1978;18:74.