The Journal of P E D I A T R I C S
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Response to intradermal histamine in familial dysautonomia-a diagnostic test The intradermal injection of histamine produces a strikingly different response in the patient with dysautonomia from that in the normal individual or in the supposedly heterozygotic parents and siblings of children with dysautonomia. This observation provides a simple, diagnostic test for the disease and has theoretical implications in understanding the mechanism of the disease.
Alfred A. Smith, M.D.,* and Joseph Dancis, M.D.** NEW
YORK~
N.
Y.
FAMILIAL DYSAUTONOMIA is a rare, inherited disorder limited to Jewish children. I t has a complex symptomatology characterized primarily by absent tearing, hyperhidrosis, postural hypotension, and disturbed vasomotor regulation. ~ Erythematous blotching of the skin commonly occurs with excitement or during eating and can be induced by the intravenous infusion
From the Departments of Psychiatry and Neurology, and the Department of Pediatrics, New York University School of Medicine, New York N. Y. This study was "supported by Grants MH-01434 and GM-04024 from the United States Public Health Service and from the Dysautonomia Association and was done in the Special Clinical Unit of New York University Medical Center. ~Address, Department of Pediatrics, New York University School o] Medicine, 550 First Avenue, New York 16, N. Y. **Dr. Dancls is recipient of a Public Health Service Research Career Award.
of norepinephrine. "~ This last observation prompted the screening of a series of pharmacologic agents for their effect on the cutaneous vessels. The intradermal injection of histamine produced a strikingly different reaction in the dysautonomic individual from that in the notxnal.
PROCEDURE Histamine phosphate 1:1000 (0.03 to 0.05 ml.) was injected intracutaneously, usually into the flexor surface of either forearm, but occasionally into the back ov lower extremities. The site of injection did not affect the response. Twenty-seven children with the clinical diagnosis of dysautonomia were tested as well as 16 unaffected members of their families (14 parents and 2 siblings) and 15 unrelated children of comparable ages. T h e histamine response was evaluated 5 and 10 minutes following the injection. ~Unpublished observation,
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S m i t h and Dances
RESULTS
The reaction to histamine in the normal controls paralleled closely that originally described by Lewis. 2 A wheal appeared at the site of injection, usually about 1 cm. in diameter. Extending from its borders for a distance of 1 to 3 cm. was a zone of e r y thema. The reaction was well developed within 5 minutes and persisted for well over 10 minutes. The response of the unaffected relatives was not distinguishable from the normal. However, the response in patients with dysautonomia differed strikingly. A wheal was also present at the site of injection, similar to the normal response, but the zone of erythema (the "flare" response of Lewis) was missing. Instead, surrounding the wheal was a narrow erythematous areola 1 to 2 mm. wide, deeper in color than the normal flare (Fig. 1 ) . T h e typical dysautonomic response was elicited in twenty-four of the twenty-seven subjects with the clinical diagnosis. In the twenty-fifth and the youngest subject available to us (10 months old), a flare was produced with a 1:1000 dilution of histamine, but the typical dysautonomic response was elicited with a 1:10,000 solution. Following this experience, 6 infants of comparable age were tested with histamine phosphate 1:10,000 and all gave normal and readily distinguishable responses. The twenty-sixth case, that of a 12-yearold boy, shows very mild symptoms of dysautonomia but has evidence (alacrima, absent deep tendon reflexes, a sibling with severe dysautonomia) to make an unequivocal diagnosis. The urinary homovanillic acid --vanillylmandelic acid ratio was typical for dysautonomia? In this patient a flare response was obtained even with a 1:10,000 dilution of histamine. However, the flare was obviously abnormal, as it was eccentric to the injection point extending about 1 cm. proximally and ~ cm. distally. It was irregular, patchy, weak in intensity, and began to fade long before a normal flare was produced in the mother. His histamine response conformed with the impression,of a
dysautonomic type of defect of very mild nature. The twenty-seventh subject is a 3-yearold boy of Jewish parents, an only child. The clinical diagnosis of dysautonomia had been made because of the absence of tearing and slow motor development. His response to histamine is completely normal. Because of this, the patient's record was reviewed criticalIy and the patient examined by us. He was found to have congenital heart disease and a Marcus Gunn phenomenon. ~ Deep tendon reflexes were present and there was no postural hypotension. The urinary homovanillic acid--vanillylmandelie acid ratio was in the normal range? The mother has been advised that the child does not have dysautonomia, a fact of greatest importance to her in family planning. The histamine response was also investigated in several disorders of the central nervous system, including physiologic transection of the cord. Although lesions of the central nervous system have been reported to diminish flare formation 4, 5 a normal response was elicited by histamine 1:10,000 in each case. Chlorpromazine, which is taken by some dysautonomic patients, does not appear to alter the normal response to histamine although antihistaminic drugs can inhibit both wheal and flare formation2 DISCUSSION The symptomatology of familial dysautonomia is distinctive so that the clinical diagnosis is made with relative ease by those familiar with the disease. T h e absence of tears is a striking manifestation which'alerts the clinician. However, as demonstrated by one of our cases, this sign is not restricted to dysautonomia. In many of the children in our group, the diagnosis was delayed for years until the clinical picture became more sharply defined. A simple, reliable objective test should be of value in speeding the diagnosis and in more accurately defining the clinical entity. The response to intradermal * T h e Marcus O u n n phenomonon is a reflex elevation of the eyelid in association with movements of the jaw. The reflex is unilateral a n d occurs in patients who have a partiM ptosis of the eyelld. The cause is unknown.
]. Pediat. Volume 63
Number 5
Smith and Dancis: Histamine test in dysautonomia
Fig. 1. Response to intradermal histamine in a normal (upper) and in his dysautonomic sister. The broad axon flare surrounding the wheal in the normal is replaced by a thin erythematous areola.
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histamine apparently can be used for this purpose. All the 26 dysautonomic subjects tested gave a distinctive reaction. None of the normal subjects, the unaffected relatives of the dysautonomic patients nor individuals with a variety of other neurologic disorders had a similar response. Further experience is needed to better define the accuracy of the test, but it would appear to be highly reliable. We have had the opportunity to test only one dysautonomic infant as young as 10 months of age. Histamine 1:1000 induced a flare response. A 1:10,000 dilution failed to induce a flare, although normal infants of the same age and younger responded with a readily visible flare. A broader experience with infants is obviously desirable for further validation of the test in this group. Production of the flare only after injection of a strong solution of histamine in the infant with dysautonomia indicates a quantitative aberration and suggests deficiency rather than absence of some mediator of this skin reaction. In one mother of a dysautonomic child, there was no wheal or flare response to intradermal histamine 1:1000. Subsequent questioning revealed that she had been taking an antihistaminic medication, cyproheptadine, 6 for migraine. Following withdrawal of the drug, a completely normal response was obtained. Lewis, 2 in his extensive investigations of the histamine response, presents evidence that flaring depends on antidromic transmission (axon reflex) along sensory fibers. The wheal, and probably the areola, results from direct action of histamine on the blood vessels. I t was noted during this investigation that immediately after the injection of histamine 1:1000 into the normal subject intense pain was felt over an area of 2 to 5 cm. roughly the area eventually occupied by the flare. In contrast, the patient with dysautonomia felt pain only in the area immediately surrounding the injection site, possibly 0.25 cm. in diameter. This observation lends support to the concept that sensory nerves play a primary role in the flare re-
Histamine test in [amilial dysautonomia
89 3
sponse and provides objective evidence of involvement of the sensory nervous system in dysautonomia. Riley 1 has noted that m a n y dysautonomic patients will sustain painful injuries, even fractures, without realizing the severity of the injury. The explanation of the relative indifference to pain is unknown. Possibly intense pain requires augmentation of impulses through axon reflexes and the same deficiency that accounts for the absent flare also reduces the recognition of pain. Emotion and food intake often produce in the dysautonomic patient, a symmetrical, sharply demarcated erythema over the face and upper body; in the normal person similar stimuli may initiate blushing. The responses to histamine seem parallel. Normally, a wide zone of homogeneous erythema follows histamine injection but this vascular reaction usually fails in the dysautonomic person, or if present, is weak and the flare irregular. I t is, conceivable, therefore, that blotching may be related to the same abnormality responsible for the missing axon reflex. It has recently been reported from these laboratories that the patient with dysautonomia has an abnormality in the excretion of catecholamine metabolites? This observation emphasized a deficiency in the function of the sympathetic nervous system, which helps explain some of the symptomatology of the disease. However, the abnormal response to histamine suggests a deficiency in the sensory nervous system as well. Sympathetic dysfunction does not account for this deficiency since sympathectomy fails to alter flare formation. 7 Our current concepts of genetic disease suggests that a single defect must still be sought to explain the multiple manifestations of this rare disorder. SUMMARY
1. The intradermal injection of histamine phosphate 1:1000 into normal individuals produces immediate intense pain over an area 2 to 5 cm. in diameter followed by development of a wheal with surrounding erythema occupying roughly the same area as the pain.
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2. T h e response in the p a r e n t s a n d unaffected siblings of the d y s a u t o n o m i c p a tient was the same as in n o r m a l individuals. 3. I n contrast, the d y s a u t o n o m i c p a t i e n t felt p a i n in a very l i m i t e d a r e a ( a b o u t 0.5 cm.) a n d developed a w h e a l w i t h only a 1 to 2 mm. areola of e r y t h e m a . T h e "flare" response was absent. I n one d y s a u t o n o m i c p a t i e n t with very m i l d manifestations, a w e a k a n d a b n o r m a l flare was elicited. 4. I n the only i n f a n t less t h a n 3 years of age available for testing (10 m o n t h s old), h i s t a m i n e 1:1000 p r o d u c e d a slight flare; b u t the response to h i s t a m i n e 1:10,000 r e a d i l y differentiated this infant from others of the same age. 5. I t is concluded t h a t the response to i n t r a d e r m a l histamine, 1:1000, m a y serve as a diagnostic test in familial dysautonomia. I n the occasional case, a dilution of 1:10,000 is preferable.
November 1963
REFERENCES
1. Riley, C. M.: Familial dysautonomia, Adv. Pediat. 9" 157, 1957. 2. Lewis, T.: The blood vessels of the human skin and their responses, London, 1927, Shaw & Sons, pp. 59-71. 3. Smith, A. A., Taylor, T., and Wortis, S. B.: Abnormal cateeholamine metabolism in familial dysautonomia, New England J. Med. 268: 705, 1963. 4. Cooper, I. S.: A neurologic evaluation of the cutaneous histamine reaction, J. Clin. Invest. 29: 465, 1950. 5. Reed, W. B., Pidgeon, J., and Becket, S. W.: Studies on the triple response of Lewis in patients with spinal cord injury, J. Invest. Dermat. 37: 135, 1961. 6. Kalz, F., and Fekete, Z.: Studies on capillary permeability using Coomasie Blue as an indicator, J. Invest. Dermat. 36: 37, 1961. 7. Duner, H., and Pernow, B.: Cutaneous reactions produced by local administration of acetylcholine, acetyl-fi-methyleholine, piperidine and histamine, Acta physiol, scandinav. 25: 38, 1952.