Asthma and Seizures in Children

Symposium on Pediatric Allergy

Asthma and Seizures in Children G. NeUhaus, M.D.,* I. Neuman, M.D.,t E. Ellis, M.D.,t and M. Pirnat, A.B.§

The relationship of asthma to seizures as one of the more obvious manifestations of "cerebral" or "neurologic" allergy is a matter of medical controversy with considerable therapeutic implications. Thus Speer,ZG in a brief historical introduction to Allergy of the Nervous System, cites authors from ancient to modern times who described convulsions, including their own, due to allergic causes, such as eating certain foods, and concludes that "this fact is still little appreciated by most physicians who deal with this great clinical problem." Addressing himself to neurologists who as a group remained ·skeptical of claims made by allergists, Stevens27 quoted Foster Kennedy's observation that cases of allergic epilepsy are "dramatic and rare," and reporting his own patients, Stevens stated that a "re-examination of the role of allergy in epileptogenesis was warranted." Clarification of the relationship between asthma and seizures was sought in this retrospective study for which the impetus came from children with severe asthma receiving care in the Pediatric Unit of the National Jewish Hospital (NJH) of Denver and seen in consultation by the Pediatric Neurology Service of the University of Colorado Medical Center. Particularly looked at was the incidence of abnormal electroencephalograms (EEGs) and of seizures in these asthmatic children and the possible causes of such cerebral dysfunctions.

SUBJECTS AND METHODS The records of 342 children admitted to NJH over a 5-year period from July, 1966, through June, 1971, were reviewed. Intractable perennial asthma was the usual criterion for hospitalization. The patients, ''Departments of Pediatrics and Neurology, University of Colorado Medical Center, Denver tDepartment of Allergy, Hasharon Hospital, Petach-Tikva, Israel !Clinical Research Center, Children's Hospital, Buffalo, New York §San Bernardino County General Hospital, San Bernardino, California Supported in part by NJH Training Grant AI 00407, National Institute of Allergy and Infectious Diseases (I. Neuman, M.D.), and Public Health Training Grant 5 1 N505584 (M. Pirnat, A.B.).

Pediatric Clinics of North America- Vol. 22, No.1, February 1975

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from virtually every state of the Union, ranged in age from 3 to 14 years; sex distribution was about equal. For all 342 children, the chart reviews included the personal and family medical histories, physical and neurologic examinations, estimates of the severity of asthma, the extensive laboratory and radiologic studies, tests of pulmonary function including blood gases, allergy testing by skin and bronchial provocation methods and food "challenges," as well as the hospital course and treatments. Bronchodilator medication consisted of theophylline alone in a dose of 5 to 10 mg per kg by mouth every 6 hours; ephedrine alone in a dose of 0.5 to 1.0 mg per kg every 6 hours; or both drugs together in the same dose in the form of a "combination" preparation. The "combination" tablet also contained 7.5 to 15.0 mg of phenobarbital. In one ephedrine-theophylline "combination," hydroxyzine was substituted for phenobarbital. Many children also received prednisone at some time. This review was begun with the years 1966-69 because during those 3 years, two out of three children admitted, who had no history of seizures, were chosen at random to have EEGs as part of their initial evaluation. Additional EEGs were obtained in many during their stay at NJH. In the last 2 years of this survey, EEGs were performed at Colorado General Hospital (CGH) and were limited to children in whom seizures were observed or suspected. At NJH, 8 channel, monopolar recordings were employed; in many cases, respirations and sometimes also electrocardiograms were monitored simultaneously. For the EEGs at CGH, 16 channels with bipolar leads were used. Photic stimulation and sleep tracings were at least attempted as part of all tracings. Most of the EEGs available showed the children during a drowsy state or evidenced medication-effect; hyperventilation often occurred spontaneously as during the initial phase of an asthmatic attack.

RESULTS Electroencephalographic Findings "Evaluation" EEGs were performed during 1966-69 in 115 out of 177 children without a history of seizures admitted to NJH. As indicated in Table 1, only 13 or 11.3 per cent of these 115 EEGs were considered abnormal. Epileptiform focal spiking, slowing, or paroxysmal discharges were seen in five, and diffusely disorganized or dysrhythmic patterns in eight; four of the latter (including the EEGs of twins) or only 3.5 per cent of the 115 "evaluation" EEGs exhibited occipital dominant slowing. Noteworthy was that in the 32 children with seizures considered related to severe asthma and its complications, nine (36 per cent) of the 25 initial EEGs were normal. Among the 4 7 children with seizures under various circumstances during the 5-year survey, no EEGs were obtained in 12, as detailed in the last column of Table 1; however, in nine of the patients, their first

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Table 1. Seizures and Initial Electroencephalograms in Children with Intractable Asthma

(") PATIENTS

Seizure Situation

NORMAL

No.

PerCent

First EEG

No.

PerCent

ABNORMAL

No.

PerCent

TYPES OF ABNORMALITY

Epileptiform

Dysrhythmic

NoEEG

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1>0

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No seizures Asthma-related seizures Febrile convulsions Symptomatic seizures Idiopathic seizures TOTAL

295 32 8 4 3 342

86.3 9.4 2.3 1.2 0.8 100.0

115* 25 5 4

102 9 3 0 0

*EEG study 1966-69 in asthmatic children without seizures. tFour EEGs showed occipital dominant slowing.

88.7 36.0 60.0 0.0 0.0

13 16 2 4

11.3 64.0 40.0 100.0 100.0

5 13 1 3 1

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180 7 3 2

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seizures had occurred prior to admission to NJH, six out of seven in association with acute asthma attacks and three with febrile illnesses. Incidence and Etiology of Seizures No seizures were recorded, as seen in Table 1, in 295 or 86.3 per cent of the 342 children covered by this study, or conversely, 4 7 or 13.7 per cent had one or more epileptic spells. These children fell readily into two cohorts, depending on whether their seizures were considered to be related to asthma or not. The latter, much smaller group, whose initial seizures often preceded the onset of asthma, was made up of eight children (2.3 per cent) with febrile convulsions due to nonneurologic illnesses, four (1.2 per cent) with seizures symptomatic of cerebral insults, and 3 (0.8 per cent) with idiopathic seizures. The causes of the four "symptomatic" epilepsies, all of which preceded admission to NJH, were: (I) spastic "cerebral palsy" with mental retardation; (2) measles encephalitis; (3) aseptic meningoencephalitis with no virus identified; and (4) postoperative hypoglycemia (18 mg per 100 ml) following extraction of a congenital cataract. Though these children with recurrent seizures were on anticonvulsant medications, breakthroughs with generalized and partial seizures could not be linked to asthmatic attacks. The much larger group comprised 32 patients (9.4 per cent), the relationship of whose seizures to their asthmatic state is the main subject of this inquiry. Review of the charts, particularly for other pertinent neurologic data, provided largely negative findings. In only five children, four with abnormal EEGs and two with seizures, was there a family history of epilepsy, a figure so low as to suggest either parental denial or fragmentary inquiries. Marked coughing was a chief symptom of asthmatic attacks, yet no case of syncope within seconds of coughing as described in the literature20 was noted. Headache was a common complaint, but only one case of "pseudotumor cerebri" was seen by one of the authors (E.F.E.) in a child who had been on triamcinolone, a drug no longer in use at NJH. While most of the children admitted had histories of food allergies, positive skin tests, and bronchial challenges, no correlation with seizures could be established. During the 1966-69 EEG study, many children, especially those over 6 years of age, had bronchial challenge with an allergen at the time of the EEG recording, but no alterations were noted. This review, therefore, implicated recurrent cyanotic attacks, i.e., repeated episodes of hypoxemia, as playing a predominant role in the occurrence of asthma-related seizures (Table 2). From the histories it was also evident that seizures related to cyanotic attacks did not recur in most of the children as their asthma came under control, while a few patients showed progressive neurologic involvement with seizure and personality disorders in consequence of their severe asthma. The histories below, two illustrated by serial EEGs, are cited as cases in point.

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Table 2. Asthma and Correlated Seizures PATIENTS

Related Seizures

SEVERITY OF ASTHMATIC STATE

Intractable asthma Attacks with cyanosis Attacks with cyanosis and loss of consciousness TOTALS

30 32

No.

Per Cent

180 96 66 342

52.6 28.1 19.3 100.0

CAsE 1. R. W. was a 4 1/2-year-old girl on admission to NJH. Her asthma had its onset before 1 year of age and had resulted in many hospitalizations in another state. Shortly before she was 4 years old, a recurrent hypoxic crisis resulted in loss of consciousness but no definite convulsive movements. An EEG was interpreted as "epileptiform" and she was placed on diphenylhydantoin prophylactically. Despite this she sustained several brief seizures associated with cyanotic attacks, which occurred frequently. On admission to NJH, her neurologic evaluation was unremarkable. Her EEG during the waking state was within the range of normal, but during hyperventilation and sleep, it showed bursts of generalized paroxysmal activity. As her asthma came under control, primarily with adjustment of steroid therapy, she experienced no further episodes of unconsciousness or seizures, and diphenylhydantoin was slowly withdrawn. Prior to discharge from NJH 3 years after admission, a repeat EEG at CGH showed, similar to her tracing at NJH, normal activity during wakefulness, rare spike and paroxysmal slow wave discharges during hyperventilation, and generalized paroxysmal discharges with photic stimulation, suggestive of increased cerebral excitability. CASE 2. S. D., one of twin boys, developed asthmatic symptoms when 3 years old and between 4 and 6 years of age, he had at first numerous asthmatic attacks with cyanosis and then recurrent tonic-clonic seizures of 3 to 4 minutes' duration, all of them with cyanotic attacks. After age 6, coincident with less severe asthma, with no cyanotic attacks, he had no further seizures. His EEG at NJH was normal. CASE 3. M. A. McC. was 2 112 years old when first admitted to NJH. Asthmatic attacks, frequently with severe cyanosis, had begun in infancy and had required many hospitalizations. She was reported to have "passed out several times" when she was blue. Her initial EEG at NJH at age 4 showed a great deal of slowing and assymmetry with hyperventilation (Fig. 1). Despite a vigorous anti-asthmatic regimen, she progressed to have many severe asthmatic attacks, often with brief loss of consciousness. Although at times an outpatient, she was admitted repeatedly at NJH for residential treatment. An EEG at 6 years 7 months of age showed occasional right hemisphere sharp and slow wave complexes. Shortly before she turned 7 years old, she suffered a generalized seizure of about 30 minutes duration without asthmatic symptoms at the time. Neurologic examination was normal but an EEG showed bursts of high voltage paroxysmal slowing in all leads. Anticonvulsants were added. When her asthma was under good control, with no further seizures nor severe attacks of asthma, her EEG, taken at CGH at age 8, was interpreted as within normal limits. After discharge from NJH to her home in Pennsylvania, there were limited records as to her course until notification of her death at 10 years of age. CAsE 4. L. De M. was admitted to NJH at age 7 years3 months because of lifethreatening asthma which had its onset towards the end of her second year of life. Close relatives had asthma but no seizures. She had been on special diets, hyposensitization injections, and a variety of anti-asthmatic drugs, including steroids. By age 6, she was repeatedly hospitalized in her home state for severe attacks of bronchospasm with cyanosis and "syncope." Tonic-clonic movements had not been observed with these brief spells of unconsciousness, but loss of bowel and

Figure 1. EEG changes from diffusely slow to show first sharp and slow wave complexes in all right-sided leads, then high voltage paroxysmal slowing as patient's asthma worsens and a generalized seizure independent of an asthmatic crisis ensues. With asthma under control and on anticonvulsants, EEG becomes normal.

Figure 2. EEG changes from normal to epileptiform as asthma progresses to recurrent cyanotic attacks and loss of consciousness to a brief cardiorespiratory arrest and eventually generalized and psychomotor seizures independent of asthmatic crises.

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bladder control suggests that some may have been seizures. The EEG obtained 1 month after admission to NJH was considered normal (Fig. 2). Following an asthmatic crisis, a second tracing suggested paroxysmal activity, but an EEG a month later was again normal. Her family moved to Denver so that she could be followed at NJH, primarily as an outpatient. Despite vigorous treatment, lifethreatening attacks continued, some now associated with "jerking." One morning at home, she had a respiratory arrest, received immediate mouth-to-mouth breathing and a subcutaneous injection of Adrenalin with good response. Four months later, at about age 9, generalized seizures not coupled with asthmatic attacks began. She was placed on phenobarbital and diphenylhydantoin. An EEG at CGH showed sharp transient activity excessive for age, but possibly due to medications. Severe hypoxic attacks with loss of consciousness increased. Resistant to lsuprel and Adrenalin, she became severely steroid-dependent with consequent growth retardation. At age 10, despite anticonvulsants, and not linked to a cyanotic spell, she suffered status epilepticus, stopped by intravenously administered diazepam. Subsequently seizures, independent of asthmatic attacks, were often preceded by auras of "dizziness" or vague visual phenomena. EEGs now were epileptiform. By age 12, auras of "smelling burning leaves" ushered in what were now clearly temporal lobe seizures. Primidone was added to her anticonvulsant medications. With one asthmatic crisis, bringing her in to CGH, she required respiratory assistance. Soon thereafter, she also had left-sided Jacksonian as well as nocturnal seizures. Concurrent with this progression of her illness, she became dull, anxious, depressed, and paranoid, often threatening to have an "arrest" to get her way. Psychiatric therapy instituted on an outpatient basis culminated shortly after her 13th birthday in adinission to Colorado Psychiatric Hospital. On neurologic examination, she responded slowly and showed slight tremor of her hands. She refused to cooperate in a formal mental examination. Depressed and withdrawn, she was demanding with respect to medications. Wheezing was noted nightly and treated as prescribed by the consultant from NJH. Angry with her family and anxious about the question of going home over Christmas, she developed an acute asthmatic attack with respiratory and cardiac arrest. She was resuscitated within seconds by closed-chest massage. Transferred to CGH a block away, another arrest, necessitating open-heart massage, was followed by death 3 hours later. Pulmonary pathology was that of perennial asthma. Neuropathologic examination showed neuronal loss and reactive gliosis in both hippocampi, but particularly marked cerebellar atrophy, consistent with profound hypoxemic damage.

DISCUSSION The relationship of allergy to neurologic disorders has been much debated. This retrospective study, the collaborative effort of pediatricians specializing in these disciplines, sought answers to the fairly specific issue of the relationship of asthma to seizures. The finding of an incidence of 11.3 per cent of abnormal EEGs among 115 children with severe perennial asthma but without seizures at any time is comparable to the data of Swedish investigators who "despite rigorous criteria for selection of normal subjects (recorded) some form of paroxysmal activity-exclusive of 14/6 second positive spikes-in resting EEGs and/or upon some form of provocation ... in 99" -or about 10 per cent-out of 1000 children 1 to 15 years of age. 22 In studies on EEG abnormalities in normal children reviewed by the Swedish group, 5 considerable variations exist, depending on the age groups studied and criteria, especially for normality, employed. Comparison of our findings in asthmatic children with related studies, with particular regard to EEG abnormalities and seizures, is

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limited by the wide variability in the groups studied, the criteria for EEG abnormalities, as well as the allergic manifestations of the patients. Remarkably higher incidences of abnormal EEGs and seizures in allergic patients have been reported in some series.3· 4 • 7 • 21 On the other hand, Fein and Kamin" found in 9000 patients with allergy only 0.2 per cent with seizures, an incidence close to the "allergy-related convulsions" cited in a recent review by CampbelU Occipital dysrhythmia, orginally stressed by Dees and Lowenback4 as a characteristic EEG finding in asthmatic children, was not observed to any significant extent in our group, amounting to only 3.5 per cent of 115 "evaluation" EEGs. The children here reported were extensively studied for the presence of inhalant and food factors. In none was there any seasonal history of seizures suggestive of seasonal allergic factors. In those above 6 years of age, bronchial challenges and skin tests to positive allergens were done routinely. No adverse central nervous system effects, or EEG changes when monitored, were seen following bronchial challenges. While many of the asthmatic patients were alleged to have "food allergies" on admission to NJH, with the exception of clear-cut IgE mediated anaphylactic-type reactions (in which cases provocation feeding was omitted), food challenges only rarely were able to corroborate the "food allergy" histories. In no instance in the latter circumstance was an adverse reaction to a food manifested by central nervous system signs or symptoms. What role may be played by the psychologic factors accompanying asthma cannot be stated from our data. Leigh and Pond/ 5 comparing adults with bronchial asthma and using nonepileptic patients with psychiatric disorders as their controls, found an equal incidence of about 40 per cent of EEG abnormalities, but a high proportion of these constituted diffuse theta rhythms, 14 and 6 per sec positive spikes and "alpha variants." Fowler and co-workers/ who also failed to evoke seizures or significant EEG changes by allergic challenges, stressed the importance of the similarities of EEG abnormalities between children with allergies and with behavioral disorders. Possibly the fact that the incidence of abnormal EEGs in children with severe asthma but no seizures observed during 1966-69 was about one-third that found by most other authors may be related to the emphasis placed on helping them to lead as normal a life as possible at NJH. Hypoxia may have been, as with seizures, the most important factor in the development of abnormal EEGs in many of the asthmatic children. The review of the EEGs obtained during the study years 1966-69, however, offered no evidence of their usefulness in prognosis for seizures. There were at least five children with intractable asthma but normal EEGs initially who went on to develop seizures with and even without asthmatic attacks. In a couple of children i"epeat EEGs obtained after a brief seizure linked to an asthmatic crisis were still normal. But with recurrent cyanotic attacks, EEGs often became abnormal. Conversely, control of asthma in children who did not appear to have sustained irreversible cerebral damage could be correlated at times with reversal of abnormal to normal EEGs.

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Thus, Holmgren and Kraepelien found EEGs obtained during asthmatic attacks definitely more abnormal than those while the children were relatively free of asthma. 10 These authors concluded that the "EEG changes seem to have a certain correlation to the degree of severity of asthma." Panzani et al./ 1 while finding EEG abnormalities unchanged during attacks of asthma and during remissions, found also that many of the patients "had an increased number of fits at periods when their asthma was troublesome," and that "in some cases the EEG abnormalities (were) the result of repeated asthmatic (or migraine) attacks." That EEG changes might·even occur as a delayed reaction to acute cerebral hypoxia has recently also been reported. 1" The rarity of cough syncope in children with asthma, noted by Katz, 1 " was reinforced by finding no such case in our survey. Seizures, irrespective of cause, were recorded in the histories of 4 7 or 13.7 per cent of the total group of ~42asthmatic children. This is nearly twice the incidence of seizures in children generally reported.t. 9 • 17 • 2 H Among this cohort of asthmatic children, 2.3 per cent had a history of febrile convulsions only, virtually identical with the incidence of 2 per cent calculated from 51 reports by Millichap 18 and found in 18,500 young children by van den Berg and Yerushalmy. 2 " There were only three children, less than 1 per cent of the total, in whom asthma was relatively uncomplicated and whose seizures were of undetermined cause. This incidence is compatible with minimal estimates of recurrent idiopathic seizures in the population at large, as is the 1.2 per cent of children with symptomatic seizures. 24 In 32 children, or 9.4 per cent, seizures were labeled as "asthmarelated." But in all of these, with one exception, seizures occurred in direct relationship to cyanotic asthmatic attacks, often only after there had been many such episodes, resulting in hypoxemia. In four of these children, convulsions were the sequel to cardiorespiratory arrests. Progressively worsening epilepsy and mental and emotional deterioration were described in detail in one girl whose neuropathologic findings confirmed the concept that seizures in asthmatics were primarily due to cerebral hypoxia. The pathophysiology, treatment, and some of the complications, especially seizures, of status asthmaticus are the subject of the article by Cotton and Parry in this symposium, while for a succinct discussion of clinical and neuropathologic aspects of cerebral hypoxia, both acute and severe as well as repeated and milder, reference is made to a recent summary by Schneck.25 Still many factors pertaining to hypoxemic brain damage remain to be studied, e.g., the threshold, the points of reversibility or irreversibility, or the proportion of damaged or dead cells to viable, normal neurons before neurologic or behavioral manifestations become manifest. The role of the drugs used in the treatment of asthma in the pathogenesis of seizures is unclear. Both ephedrine and theophylline are analeptic drugs and their seizure potential in overdosage is well known. Theophylline toxicity has received particular attention. 16 • 19 Cerebral hypoxia resulting from a striking decrease in cerebral blood flow due to a highly significant increase in cerebrovascular resistance, following the

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intravenous administration of 0.5 gm theophylline in adults (doses calculated to have amounted to about 7 mg per kg intravenously) was originally reported by Wechsler, Kleiss, and Kety. 30 Though this finding has been confirmed by others, cited by Lang, Zimmer, and Oberdorster, 14 these investigators, reporting their contrary observation of theophyllineinduced vasodilation in dogs, discuss various mechanisms, including the possible role of cyclic AMP, by which theophylline is thought to affect cerebral circulation. It should also be noted that Gardner and coworkers8 reported that ephedrine potentiated the complications of theophylline and increased the mortality in experiments with mice. Similarly, Weinberger and Bronsky at NJH recently showed that in the theophylline-ephedrine "combination," theophylline alone was largely responsible for the bronchodilator activity, with little increment therein by the addition of ephedrine, whereas the latter greatly increased central nervous system side effects. 31 While it is also known that seizures occur as a result of antihistamine overdosage, and that an occasional child has a paradoxical reaction manifested by central nervous system excitation to even usual doses of antihistamines, the data in our study do not permit conclusions on any of the above points. At most, it may be said that theophylline was suspect in one patient with a level slightly higher than the upper therapeutic range and though he had had cyanotic attacks but no prior seizures, there was a positive family history for epilepsy. Thus one might speculate on his "seizure-susceptibility," both genetic and due to his many previous hypoxic attacks, made manifest at theophylline levels tolerated by other patients under other circumstances. The usefulness of theophylline in the management of status asthmaticus has been well demonstrated,23 however, and these comments are made to reinforce the need for further understanding of the mechanism of action of this and other agents used in the treatment of asthma.

SUMMARY A retrospective study of 342 children with perennial intractable asthma admitted to NJH between 1966 and 1971 was undertaken to assess the relationship of asthma to seizures. A 3-year study of the EEGs in children without seizures showed the incidence of abnormal EEGs to be similar to that of healthy "normal" children. Development of abnormal EEGs and the high incidence of asthma-related seizures was correlated best with cyanotic asthmatic attacks to the point of loss of consciousness. Since this study was undertaken, several more children have been seen with histories of progressing from severe asthmatic attacks to cyanotic, then syncopal, spells and eventually to both asthmarelated seizures and convulsions occurring independently of asthmatic attacks. The findings of this study lead to the conclusion that vigorous antiasthmatic therapy by forestalling hypoxemic brain damage will best prevent seizures in asthma.

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REFERENCES I. Abernathy, R. S.: A survey of 156 seizure patients in a general pediatric clinic. Lancet, 1:115-120, 1966. 2. Campbell, M. B.: Neurological manifestations of allergic disease. Ann. Allerg., 31:485498, 1973. 3. Chobot, R., Dundy, H. D., and Pacella, B. L.: The incidence of abnormal electroencephalographic patterns in allergic children. J. Allerg., 21:334-338, 1950. 4. Dees, S.C., and Lowenbach, H.: Allergic epilepsy. Ann. Allerg., 9:446-458, 1951.

5. Eeg-Olofsson, 0., Petersen, I., and Sellden, U.: The development of the electroencephalogram in normal children from the age of 1 through 15 years. Neuropaediatrie, 2:375404, 1971. 6. Fein, B. T., and Kamin, P. B.: Allergy, convulsive disorders, and epilepsy. Ann. Allerg., 26:241-247, 1968. 7. Fowler, W. M., Heimlich, E. M., Walter, R. D., eta!.: Electroencephalographic patterns in children with allergic convulsive and behavior disorders. Ann. Allerg., 20:1-14, 1962. 8. Gardner, R. A., Hansen, A. E., Ewing, P. L., eta!.: Unexpected fatality in a child from accidental consumption of antiasthmatic preparation containing ephedrine, theophylline, and phenobarbital. Texas State J. Med., 46:516-520, 1950. 9. Graham, P., and Rutter, M.: Organic brain dysfunction and child psychiatric disorders. Br. Med. ]., 3:695-700, 1968. 10. Holmgren, B., and Kraepelien, S.: Electroencephalographic studies of asthmatic children. Acta Paediatr. Scand., 42:432-441, 1953. U. Jenne,]. W., Wyze, E., Rood, F. S., eta!.: Pharmacokinetics of theophylline. Clin. Pharmacal. Ther., 13:349-360, 1972. 12. Katz, R. M.: Cough syncope in children with asthma. J. Pediatr., 77:48-51, 1970. 13. Lagergren,]., and Stensman, R.: Acute cerebral anoxia in childhood followed by delayed EEG-reaction in spite of clinical improvement. Neuropaediatrie, 2:226-234, 1970. 14. Lang, R., Zimmer, R., and Oberdi:irster, G.: Impairment of cerebrovascular autoregulation by theophylline. Exp. Neurol.. 40:661-674. 1973. 15. Leigh, D., and Pond, D. A.: The electroencephalogram in cases of bronchial asthma. J, Psychosom. Res., 1:120-127, 1956. 16. McKee, M., and Haggerty, R. ].: Aminophylline poisoning. N. Eng.]. Med., 256:956-957, 1957. 17. Miller, F.]. W., Court, S.D. M., Walton, W. S., eta!.: Growing up in Newcastle-uponTyne. London, Oxford University Press, 1960, p. 164. 18. Millichap, ]. G.: Definition and statistics. In Febrile Convulsions. New York, The Macmillan Company, 1968, pp. 9-11. 19. Nolke, A. C.: Severe toxic effects from aminophylline and theophylline suppositories in children. ].A.M.A., 161:693-697, 1956. 20. O'Doherty, D. S.: Tussive syncope and its relation to epilepsy. Neurology, 3:16-21, 1953. 21. Panzani, R., Boyer, R., and Turner, M.: The electroencephalogram in migraine and asthma. Ann. Allerg., 18:491-509, 1960. 22. Petersen, 1., Eeg-Oiofsson, 0., and Sellden, U.: Paroxysmal activity in EEG of normal children. In Kellaway, P., and Petersen, I. (eds.): Clinical Electroencephalography of Children. New York, Grune & Stratton, 1968, pp. 167-187. 23. Pierson, W. E., Bierman, C. W., Stamm, S. ]., eta!.: Double-blind trial of aminophylline in status asthmaticus. Pediatrics, 48:642-648, 1971. 24. Robb, P.: Epilepsy: a review of basic and clinical research. NINDB Monograph No. 1, U.S. Dept. HEW, 1965, pp. 1-3. 25. Schneck, S. A.: Cerebral anoxia. In Baker, A. B. (ed.): Clinical Neurology. New York, Harper and Row, 1972, Vol. I. 26. Speer, F.: The history of allergy of the nervous system. In Speer, F. (ed.): Allergy of the Nervous System. Springfield, Ill., Charles C Thomas, 1970, pp. 3-13. 27. Stevens, H.: Allergy and epilepsy. Epilepsia, 6:205-216, 1965. 28. Thorn, D. A.: Convulsions of early life and their relation to the chronic convulsive disorders and mental defect. Am.]. Psychiat., 98:574-580, 1941-42. 29. van den Berg, B. ]., and Yerushalmy, ].: Studies on convulsive disorders in young children. I. Incidence of febrile and nonfebrile convulsions by age and other factors. Pediatr. Res., 3:298-304, 1969. 30. Wechsler, R. L., Kleiss, L. M., and Kety, S. S.: The effects of intravenously administered aminophylline on cerebral circulation and metabolism in man.]. Clin. Invest., 29:2830, 1950. 31. Weinberger, M. M., and Bronsky, E. A.: Evaluation of oral bronchodilator therapy in asthmatic children. J. Pediatr., 84:421-427, 1974. G. Nellhaus, M.D. University of Colorado Medical Center 4200 East Ninth Avenue Denver, Colorado 80220