Prospective study of outcome of infants with infantile spasms treated during controlled studies of ACTH and prednisone.

We report the long-term outcome of 64 infants with infantile spasms, followed prospectively, using controlled treatment schedules and objective techniques (24-hour EEG and video monitoring) to determine response. Average age at follow-up was 50 months. Of the 64 infants, three (5%) died; of the others, 41 (67%) had developmental retardation of 50% or more or an IQ of 50 or less. Eight patients (13%) composed our cryptogenic study group and were so classified on the basis of normal CT scan, normal development prior to onset of infantile spasms, and undetermined cause. These patients had the better outcome; 38% had normal development or were only mildly retarded. Both the responders and nonresponders in our symptomatic group had a poor outcome; only 5% had normal development or mild impairment. Outcome was not significantly influenced by short versus long treatment lag or by response to therapy. Other types of seizures occurred in 34 patients (53%). In summary, the overall prognosis for long-term outcome in these 64 patients with infantile spasms was poor.

Computed tomography in infantile spasms: effects of hormonal therapy.

During a prospective double-blind, crossover study of ACTH versus prednisone therapy, serial computed tomography (CT) scans were performed on 16 children with infantile spasms. Pre-treatment scans revealed four findings: normal (6 patients), generalized atrophy (bilaterally enlarged ventricles and/or subarachnoid space) (2 patients), predominantly focal atrophy (3 patients), and congenital anomalies (5 patients). Within 2 weeks of initiating relatively low therapeutic dosages of ACTH or prednisone, a significant number of the infants (63%) had CT findings consistent with decreased cortical volume; in many cases (44%), these findings had not reversed 4 to 6 weeks after discontinuing therapy. Duration of therapy did not correlate significantly with the persistence of CT changes.

The effect of intrauterine malnutrition on the term infant. A 14-year progressive study.

The developmental outcome of 33 newborn infants with clinical intrauterine malnutrition at birth and 13 clinically well nourished infants from a middle to high socio-economic population have been followed from birth to 12-14 years of age. Psychometric studies revealed a lowering of the IQ score in malnourished infants compared to well nourished infants (104 +/- 15 compared to 121 +/- 13, p less than 0.05) and a need for special education (p less than 0.03). Forty-five percent of the malnourished infants' birth weights were above the 10th percentile on the Colorado Intrauterine Growth Grid. The Full Scale IQ of malnourished infants with BW greater and less than 10th percentile on the Colorado Intrauterine Growth Grid were comparable. Malnourished infants with birth weights greater than 10th percentile had lower IQ scores than well nourished infants (101 +/- 13 compared to 121 +/- 13, p less than 0.006). Thirty-nine percent of the infants with handicaps would have been missed if only infants with birth weights less than 10th percentile were considered high risk.

Tics and vocalizations in children treated with carbamazepine.

Three patients are reported who, following the initiation of carbamazepine therapy for seizure control, either experienced the onset of Tourette's syndrome or a worsening of their tics and vocalizations. Blood levels of carbamazepine were within the therapeutic range, and no patient showed clinical signs of intoxication. Tics and vocalizations did not resolve following discontinuation of carbamazepine therapy. Carbamazepine may trigger the onset of Tourette's syndrome in susceptible patients.

Double-blind study of ACTH vs prednisone therapy in infantile spasms.

Twenty-four patients with infantile spasms were entered in a double-blind, placebo-controlled, crossover study to compare the therapeutic effectiveness of ACTH (20 to 30 units/day) with that of prednisone (2 mg/kg/day). Response to therapy was determined by utilizing a comprehensive monitoring system and was defined as a complete cessation of spasms and disappearance of the hypsarrhythmic EEG pattern. A major difference between the effectiveness of ACTH and that of prednisone in stopping the spasms and improving the EEG pattern was not demonstrated. Nine patients responded to ACTH (five initial drug, four crossover), and seven patients responded to prednisone (four initial drug, three crossover). Twelve responded within two weeks of initiation of therapy, and four within six weeks. Therapy was tapered and discontinued immediately after a response was obtained. Five patients had a relapse; four responded rapidly to a second course of therapy. Of the eight patients who failed to respond to hormonal therapy, seven were given clonazepam with no improvement.

Long-term prognosis of patients with infantile spasms following ACTH therapy.

The influence of ACTH on the prognosis of patients with infantile spasms remains controversial. We have examined retrospectively the long-term benefits of initially successful ACTH therapy in patients treated at this institution between 1961 and 1974. Individuals with equivocal or minimal improvement during ACTH therapy were excluded from this study. Eighteen affected infants showed a favorable early response consisting of cessation of seizures for at least 3 weeks during ACTH therapy and concurrent disappearance of the hypsarhythmic EEG pattern. Modal age at last follow-up was 5 years (range, 15 months to 16 years). Infantile spasms recurred in 7 patients (39%), and 8 patients subsequently had other seizure types. All epileptiform (spike) activity disappeared from the EEGs of 8 patients during ACTH therapy, but in 4 of these cases epileptiform activity was present in later tracings. In the remaining 10 patients the hypsarhythmic pattern disappeared in association with ACTH therapy, but the EEG remained epileptiform (often only in sleep). Later EEGs were free of epileptiform activity in 5 of the 10 patients whose tracings contained spike discharges in the early follow-up period. Four patients (22%) were seizure free and without intellectual impairment when last evaluated.

The longitudinal course of congenital rubella encephalitis in nonretarded children.

The neurologic course of congenital rubella syndrome was traced in 29 nonretarded children to 9 to 12 years. During the first two years, manifestations involved abnormal tone and reflexes (69%), motor delays (66%), feeding difficulties (48%), and abnormal clinical behavior (45%). Hearing loss was documented in 76%. From three to seven years, poor balance, motor incoordination (69%), and behavioral disturbances (66%) predominated. Hearing losses increased to 86%. Currently, at 9 to 12 years, 25 have residua which include learning deficits (52%), behavioral disturbances (48%), poor balance (61%), muscle weakness (54%), and deficits in tactile perception (41%). Two additional children now have hearing loss. The encephalitic manifestations of congenital rubella syndrome are diverse. Overriding problems differ at each phase of childhood. Current deficits influence progress in educational and home environments. For these children, adequate intelligence alone does not guarantee academic success.

Use of saliva in therapeutic drug monitoring.

We measured the concentrations of phenobarbital, phenytoin, primidone, ethosuximide, antipyrine, and caffeine in paired samples of saliva and plasma by gas chromatograph-mass spectrometer-computer (GC/MS/COM) and enzyme immunoassay. Mixed saliva was collected for the antipyrine and caffeine studies, parotid saliva for the phenobarbital, primidone, ethosuximide and phenytoin studies. The saliva/plasma (S/P) ratios (by weight) obtained by GC/MS/COM were: phenobarbital, 0.31-0.37; phenytoin, 0.11; ethosuximide, 1.04; antipyrine, 0.83-0.95; caffeine, 0.55. The S/P ratio obtained by enzyme immunoassay were: phenobarbital, 0.32; phenytoin, 0.12; primidone, 0.85. The concentrations of phenytoin, primidone, ethosuximide and antipyrine in saliva correspond to the free fraction of the drug in plasma. When we analyzed samples containing phenobarbital or phenytoin (plasma or saliva) by both techniques, we found that the enzyme immunoassay values were generally higher than GC/MS/COM values, suggesting that the metabolites as well as the parent drug were measured in the immunoassay.