Toxic encephalopathy associated with use of insect repellant

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Brief clinical and laboratory observations

REFERENCES

1. Witzleben CL, and Chaffey N: Acute ferrous sulfate poisoning, Arch Pathol 82:454, 1966. 2. Brown RJK, and Gray JD: The mechanisms of acute ferrous sulphate poisoning, Can Med Assoc J 73:192, 1955. 3. Covey TJ: Ferrous sulfate poisoning. A review, case summaries and therapeutic regimen, J PEDIATR 64:218, 1964. 4. deCastro FJ, Jaeger R, and Gleason WA: Liver damage and hypoglycemia in acute iron poisoning, Clin Toxicol 10:287, 1977. 5. Rueff B, and Benhamou JP: Progress report: Acute hepatic necrosis and fulminant hepatic failure, Gut 14:805, 1973. 6. Champion HR, Jones RT, Trump BF, et al: A clinicopathologic study of hepatic dysfunction following shock, Surg Gynecol Obstet 142:657, 1976. 7. Ellenberg M, and Osserman KE: Role of shock in the production of central liver cell necrosis, Am J Med 11:170, 1951.

The Journal of Pediatrics July 1979

8. Luongo MA, and Bjornson SS: The liver in ferrous sulfate poisoning, N Engl J Med 251:995, 1954. 9. Whitten CF, Gibson GW, Good MH, et al: Studies in acute iron poisoning. I. Desferrioxamine in the treatment of acute iron poisoning: Clinical observation, experimental studies and theoretical consideration, Pediatrics 36:322, 1965. 10. Barry M, Flynn DM, Letsky EA, et al: Long term chelation therapy in thalassemia major: Effect on liver iron concentration, liver histology and clinical progress, Br Med J 2:16, 1974. 11, Witzleben CL: The pathogenesis of iron hepatotoxicity, Ann NY Acad Sci 165:105, 1969. 12. Cooperstock MS, Tucker RP, and Baublis JV: Possible pathogenetic role of endotoxin in Reye's syndrome, Lancet 1:1272, 1975. 13. Williams R: Fulminant viral hepatitis; Clin Crastroenterol 3:419, 1974.

Toxic ence_pphalo,pathy associated with use of insect repellant Colin M. Zadlkoff, M.B., B. Ch., F.C.P. (S.A.), Johannesburg, South Africa

T w o c A S E S are r e p o r t e d o f toxic e n c e p h a l o p a t h y possibly related to exposure to N , N - D i e t h y l t o l u a m i d e , the chemical c o m p o u n d present in m a n y c o m m e r c i a l available insect repellants in the form o f a spray, liquid, or stick applied to the skin or bedclothes. CASE REPORTS Patient 1. A 5-year-old girl was referred to hospital with a

ten-day history of progressively worsening headaches. Three days prior to admission she was noted to be unduly agitated and mildly disoriented. On the day of admission her speech became slurred, she became severely confused, and she later developed ataxia and had a generalized convulsion. She had been given aspirin on two occasions for headache during the previous ten days. She was afebrile from the onset of the illness and had no rhinitis, pharyngitis, or otitis. There were no rashes. There was no history of measles or other childhood illness, trauma, or allergy. Her development was normal until this episode. Because of the presence of mosquitoeS she had been sprayed with Mylol (Boots Company), an insect repellant containing 10% DET, nightly for almost three months; the parents followed the instructions on the container and ensured that there was no contact with mucous membranes. On admission the child was extremely agitated, restless, and irritable, With constant involuntary movements involving the

From the Ti'ansvaal Memorial Hospital for Children and University of the Witwatersrand. Reprint address: Department of Neurology, Indiana University School of Medicine, 1100 W. Michigan St., Indianapolis, IN 46223.

head, trunk, and all limbs. There was athetosis with wildly thrashing movements, which alternated with short periods of quiet and episodes of marked shaking and crying or screaming. She responded purposefully to noxious stimuli but not to other attempts at communication. There was no focal neurologic deficit and the eyegrounds were normal. Pupils were equal and reactive to light. Deep tendon jerks appeared normal. There was no nystagmus. The respiratory rate was 28/minute, blood pressure 110/65 mm Hg, and pulse 135/minute. Shortly after admission she had a generalized convulsion Which was controlled with intravenous administration of diazepam. Abbreviation used DET: N,N-diethyltolumide A lumbar puncture was performed but the pressure could not be measured because of the child's continued movements. The CSF contained 30 neutrophils and 135 lymphocytes/mm a with protein 18 mg a n d glucose 60 mm/dl. No viruses, bacteria, parasites, or fungi were isolated from the CSF or blood. Hemoglobin was 14 gm/dl, WBC count 13,600/mm ~ with 60% neutrophils, 38% lymphocytes, and 2% monocytes. Ptatelets were normal. Blood urea was 24 mg/dl, sodium 137 mEq/l, potassium 3.9 mEq/l, calcium 5.1 mEq/1 and glucose 72 mg/dl. Blood lead concentration was 19/~g/dl, and copper within normal limits (60 /~g/dl). Thyroid and liver function studies were normal. The child was maintained on intravenous fluids and was treated for meningitis, although this diagnosis was unlikely, with ampicillin 400 mg/kg/day intravenously, but there was no improvement in her condition. She continued to have convul-

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sions once or twice every day, and these proved difficult to control. She was treated with phenobarbital, diazepam, diphenylhydantoin, clonazepam, nitrazepam, and paraldehyde in varying doses and combinations during the 24 days she was in hospital, with little control of either her involuntary movements or the convulsions, which became more severe and regular toward the end of her hospitalization. Haloperidol was also tried in an attempt to control her movements with no success. The child's limbs and her crib had to be padded to prevent injury from the continual thrashing and flailing motions. The child's state of conciousness improved during the first few days in hospital, although she continued to be in an almost constant state of agitation with wild flinging movements of her limbs, episodes of opisthotonos, and crying involuntarily. During brief periods of quiet she was able to indicate with a slurred "yes" or "no" in answer to questions that she wanted to be still but could not do so. Swallowing became a problem; she could not clear saliva spontaneously, and developed right upper lobe pneumonia which cleared with physiotherapy and antimicrobial agents. The child deteriorated steadily and died 24 days after admission, her seizures being more intractable and her agitation worse. At autopsy the brain showed generalized edema with intense congestion of the brain and meninges. There was no evidence of meningitis. Cerebral blood vessels showed swelling of endothelial cells. There was no perivenous or other demyelination and no perivascular infiltrate. Patient 2. An 18-month-old child was admitted to hospital having ingested an unknown, but probably small, amount of Mylol liquid the previous day. She was extremely irritable and lay in an opisthotonic posture, displaying bizarre movements with periods of shaking and crying. She appeared unaware of her surroundings. She had been well except for an upper respiratory infection the week before this episode. Family history was negative. On examination no localizing neurologic deficit could be found and she responded purposefully to noxious stimuli. Head control was poor. Muscle tone was probably normal, but was difficult to assess because of continuous movements. Muscle stretch reflexes were depressed. The remainder of the examination was normal. CSF was abnormal with 25 lymphocytes/mm ~, protein 28 mg/dl, and sugar 62 mg/dl. No bacteria, fungi, or viruses were isolated from the spinal fluid or blood. Blood urea, sodium, potassium, chloride, calcium, magnesium, lead, and sugar values were normal. Urine was normal, with no organisms being isolated and no aminoaciduria. Electroencephalogram, skull radiograph, and brain scan were normal. She improved slowly during the six weeks she was in hospital; her movements becoming more controlled, and she was no longer irritable. Head control was not yet normal but her gait, although ataxic, became progressively steadier. Tendon reflexes remained depressed. She was discharged to a hospital nearer her home for further convalescence. DISCUSSION Insect repellants are commonly used during summer, and complications arising from their use appear to be rare

Brief clinical and laboratory observations

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or of minor degree. D E T , first synthesized in 1954, was found to be an outstanding repellant and therefore an appreciable amount of h u m a n exposure was expected. Extensive testing on animals was carried out and its general safety for h u m a n beings seemed established. 1 The acute LD~o in rats is 2 m g / k g body weight; doses of 75 m g / k g and larger given intravenously are rapidly fatal. There appears to be no cumulative effect with smaller doses, and experimentally five daily injections of 25 mg produced no observable damage. Twenty-four hours o f sustained dermal contact produced rapidly reversible irritation; repeated dermal application to the depilated trunk of rabbits for 13 weeks produced no evidence o f systemic toxicity, only local irritation and desquamation being noted. Prolonged application experimentally has not been attempted in h u m a n beings. Instillation of D E T into the eyes of rabbits produced local reversible irritation but no systemic effects. The systemic signs of toxicity in rats and rabbits given LD~0 were hyperemia of the ears, lacrimation, labored respiration, epileptoid tremors, and convulsions. Those animals that survived recovered completely. Although sensitivity to D E T is probably rare, the first patient reported here m a y be an indication that some examples are missed; the case might well have been labeled an encephalitis, probably of viral origin. Although experimentally there have been no cumulativd effects of subtoxic doses of DET, it is conceivable that in this child there may have been an accumulation of the repellant with deleterious effect. Alternatively, the child may have developed a sensitivity to the insect repellant. The close relationship between the ingestion of D E T and the appearance of clinical disease suggests strongly that the second child had D E T toxicity, and the remarkable similarity of presentation o f the two patients suggests that the first child also had D E T toxicity. One other example of h u m a n toxicity, thought to be on the basis of hypersensitivity, has been reported previously. 2 This 3~A-year-old girl presented with shaking ~and crying spells. She developed movements similar to those described in our two patients, with slurred speech and staggering gait but no seizures. The child had been sprayed with D E T for two weeks prior to admission. With intravenous fluid maintenance and administration of phenobarbital and diphenylhydantoin, her movements were controlled; her ataxia disappeared and her speech was no longer slurred three days after admission. A striking difference between this patient and the t w o children reported in this paper Was the normal CSF; the reason for the difference is unclear. Although these cases suggest a relationship between exposure to the insect repellant D E T and the develop-

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Brief clinical and laboratory observations

The Journal of Pediatrics July 1979

REFERENCES

ment of encephal0pathy, the apparent rarity of the condition does not warrant special precautions in the use of insect repellants at this time. The clinician should be alerted to the fact that such a relationship may exist, and consider D E T exposure in children presenting with a bizarre neurologic illness similar to the one presented in this p a p e r . Other insect repellants such as dimethyl phthalate and dibutyl phthalate als0 appear to cause coma if ingested, and may cause skin irritation. O t h e r neurologic abnormalities have not been described with these agents?

1. Ambrose AN: Pharmacologic and toxicologic studies on N,N-diethyltoluamide, Toxicol Appl Pharmacol 1:97, 1959. 2. Gryboski J, Weinstein D, and Ordway NK: Toxic encephalopathy related to the use of an insect repellant, N Engl J Med 264:289, 1961. 3. Martindale W: The extra pharmacopoeia, ed 26, London, 1972, Pharmaceutical Press, p 931.

Reye-like syndrome associated with valproic acid therapy N. Gerber, R. G. Dickinson, R. C. Harland, R. K. Lynn, D. Houghton, J. I. Antonias, and

J. C. Schimschock, Portland, Ore.

VALPROIC ACID, 2-n-propylpentanoic acid, recently released for the treatment of epilepsy in the United States, is a relatively new anticonvulsant drug with a broad spectrum of activity. VPA appears to be a relatively safe drug with few adverse reactions. The most c o m m o n side effects are nausea, vomiting, a n d abdominal discomfort. Sedation, emotional disturbances, hair loss, skin rashes, and weakness have also occurred.-The drug inhibits the secondary phase of platelet aggregation and may prolong bleeding time. The most serious side effect reported in m a n is potentially fatal hepatic damage. Three deaths caused by liver necrosis in subjects on VPA and other drugs have been reported to the manufacturer. Three other instances (nonlethal) of hepatic damage have also been reported; two of the subjects were receiving VPA alone? A n increase in serum glutamic pyruvic transaminase and serum glutamic oxaloacetic transaminase is observed in a significant n u m b e r of subjects receiving therapeutic doses of VPA. A return to normal levels of these enzymes may occur despite continued therapy with VPA. We describe a child with epilepsy who developed a Reye-like syndrome while receiving VPA. Autopsy revealed fatty infiltration of liver and kidney with bilateral bronchopneumonia. Since a Reye-like syndrome can be From the Epilepsy Center of Oregon, Good Samaritan Hospital, and Department of Pharmacology and Pediatrics, University of Oregon Health Sciences Center. Supported by NS-5-2328. Reprint address: Department of Pharmacology, School of Medicine, University of Oregon Health Sciences Center, 3181 S. IV. Sam Jackson Park Rd., Portland, OR 97201.

produced by a series of 5 carbon-chain fatty acids, ~, 3 the possibility exists that VPA (2-propylpentanoic acid) may have a similar effect. [

Abbreviation used VPA: valproic acid CASE REPORT

This 12-year-old girl was the product of a normal gestation and delivery with the exception of possible rubella during pregnancy. At 4 years, she developed focal motor seizures which progressed to typical grand real epilepsy, treated with phenobarbital and phenytoin. Development was slow, and over the next few years overt mental retardation became apparent. Intractable seizures required frequent hospitalization; she was treated with several drugs, including diazepam, ethosuximide, and clonazepam at one time or another. Numerous tests, including electroencephalogram and carotid arteriograms, were noncontributory; a pneumoencephalogram showed absence of the septum pellucidum. In spite of apparently normal physical development, including the onset of puberty, mental retardation (IQ = 50) and recurrent grand real seizures persisted. At the time of her final illness, she was receiving phenobarbital 60 rag/day, phenytoin 200 rag/day, diamox 125 mg twice a day, and VPA 250 mg three times a day. VPA was well tolerated for two months; serum concentrations were within the expected range and SGOT values were normal. One week prior to her final admission to hospital, the patient developed increasing anorexia, lethargy, occasional vomiting, and a mild fever. A viral respiratory infection was diagnosed and treated with penicillin 250 mg four times a day. She deteriorated steadily, her temperature rose tO 40 ~ C, and she became unconscious and was noted to be hyperventilating. The pupils were large, regular, and reacted to light; she failed to respond to painful stimuli, and had normal

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