Observations on the responsiveness of human subjects to human growth hormone. Effects of endogenous growth hormone deficiency and myotinic dystrophy.

The effect of human growth hormone (HGH) on the N, P, Na, and K balance, and on the body weight (BW) of three groups of subjects was measured. In group I were nine cases (age 6-69) with HGH deficiency; in group II, eight cases (age 9-79) with normal endogenous HGH; in group III, four cases with myotonic dystrophy (age 45-51). After a 7 day control period, the hormone was administered for 7 days. Each subject was tested with three doses of HGH: dose A, 0.0168 U/kg BW(3/4) per day; dose B, 0.0532 U/kg BW(3/4) per day; dose C, 0.168 U/kg BW(3/4) per day. In group I, the responsiveness to HGH declined with age. Two subjects aged 6 yr responded to all three doses of HGH with positive balances in N, P, Na, and K and increases in BW. At ages 15-17, responses were obtained only to doses B and C in three cases, and only to dose C in two cases. Two subjects, aged 42 and 69, responded only to dose C. Not only did the threshold dose increase with age in group I, but the magnitude of the responses declined with age as well.Patients of group II were less responsive to all doses of HGH than were patients of group I at comparable age. None responded to dose A or dose B. All responded to dose C, but the increments in balances and in BW stimulated by this dose were only one-third to one-half as great as in HGH-deficient subjects of similar age. Three patients of group III responded to all three doses of HGH, and one responded to doses B and C. The responses were similar in magnitude to those in the 6-yr old HGH-deficient children, and greater than those in all other subjects studied. These data show that responsiveness to exogenous HGH rises with deficiency of endogenous HGH, and that individuals with myotonic dystrophy are hyperresponsive to exogenous HGH.

Tiagabine for complex partial seizures: a randomized, add-on, dose-response trial.

OBJECTIVE: To determine the efficacy and tolerability of tiagabine, a new antiepileptic drug (AED) that inhibits gamma-aminobutyric acid (GABA) uptake, at 3 dose levels vs placebo as adjunctive therapy in patients with intractable complex partial seizures (CPS). DESIGN: Randomized, double-blind, placebo-controlled study with a parallel-group, add-on design, starting with a 12-week unblinded baseline phase followed by a 20-week double-blind treatment phase. SETTING: Twenty-one US medical centers. PATIENTS: Patients (N = 297) aged 12 to 77 years, previously diagnosed as having CPS and receiving stable regimens of 1 to 3 hepatic enzyme-inducing AEDs; divalproex sodium or valproic acid was allowed in combination with any of these drugs. INTERVENTIONS: Placebo or tiagabine 4 times a day at 16, 32, or 56 mg daily. MAIN OUTCOME MEASURES: Median change in 4-week CPS frequency and adverse events. RESULTS: Median decreases in 4-week CPS frequency for the 32-mg (-2.2) and 56-mg (-2.8) tiagabine groups were significantly greater than for the placebo (-0.7) group (P = .03 and P < .03, respectively); 20% and 29% of patients in the 32- and 56-mg groups had a 50% or greater reduction in the frequency of CPS vs 4% in the placebo group (P = .002 and P < .001, respectively). Adverse effects were similar for placebo and tiagabine except for a significantly greater incidence of dizziness in the 32-mg tiagabine group, tremor in the 32- and 56-mg groups, abnormal thinking (usually mental lethargy or difficulty concentrating) in the 56-mg group, and depressed mood in the 16- and 56-mg groups. CONCLUSIONS: Tiagabine is efficacious and well tolerated as adjunctive therapy for CPS; there is a clear dose-response relationship.

Prognosis of photoparoxysmal response in nonepileptic patients.

Photoparoxysmal response (PPR) is sometimes incidentally encountered in EEGs performed for evaluation of nonepileptic symptoms. We conducted the first long-term study of a cohort of nonepileptic patients to determine their risk of having seizures subsequent to incidental recording of PPR. After 6 to 12 years (mean, 9 years), none of the 33 patients had had epileptic seizures. To identify prognostic factors associated with PPR, we performed a case-control study comparing the cohort with 33 age-matched patients who had had epileptic seizures prior to PPR recording. There was no statistically significant difference between the two groups with respect to the clinical or EEG data. Morphology of the PPR discharge was not different between the two groups. Contrary to what is widely believed, persistence of PPR discharges beyond stimulation was not associated with a high risk of developing seizures. Prognosis of PPR is age-dependent and seems favorable in adults without previous epileptic seizures.

Spinal cord infarction due to minor trauma in children.

In two children, ages 22 months and 4 years, after slight trauma, flaccid weakness of both arms developed, followed by flaccid quadriplegia with sphincter involvement. No vertebral fracture or dislocation was found, myelograms were negative, and diagnosis was made only after the full clinical syndrome developed. Pathologic studies revealed ischemic infarction involving the cervical cord and low medulla in one patient, and central gray matter of low cervical cord in the other, without hematomyelia or external compressive lesions. The pattern of infarction may be related to spasm of distal branches of the central sulcal arteries in a terminal arterial bed.

Clinical predictability of intraventricular hemorrhage in preterm infants.

Ninety-eight infants of less than 35 weeks' gestation, consecutively admitted to a regional neonatal intensive care unit, were followed prior to computerized tomography (CT) scan for clinical signs of subependymal and/or intraventricular hemorrhage. The presence or absence of intracerebral hemorrhage was confirmed by CT scan in all patients, and the severity of hemorrhage was quantitated as mild, moderate, or marked. Thirty-seven out of 98 infants (38%) demonstrated intracerebral hemorrhage on CT scan; 20 of 37 (54%) were predicted clinically. Clinical predictability was related to severity of hemorrhage as quantitated by CT scan. Clinical signs that were found helpful in predicting subependymal and/or intraventricular hemorrhage were fall in hematocrit, failure of rise in hematocrit with transfusion of packed red blood cells, tight fontanel, decrease in spontaneous activity, decreased tone, abnormal eye signs, and seizures.

Comparison of lumbar puncture with computed tomography scan as an indicator of intracerebral hemorrhage in the preterm infant.

Computed tomography (CT) scan is the most accurate method for diagnosing intracerebral hemorrhage in the high-risk preterm infant. The present study was undertaken to evaluate lumbar puncture (LP) as a reliable means of diagnosing such hemorrhages. Forty eight infants less than 35 weeks gestation, requiring intensive care, were evaluated by CT scan at 48 to 96 hours of life, and serial LPs were performed. The initial LP preceded the CT scan by one to four hours and repeat LPs were done three and five days later if the initial CT scan revealed intracerebral hemorrhage. The initial LP was successfully performed in 28 of 48 infants. Of these 48 infants, 15 had hemorrhage by CT scan. The initial LP was consistent with the diagnosis on scan in eight of these 15. In the other seven infants, initial LP was normal in three, traumatic in one, and unsuccessful in three. The second LP was consistent with hemorrhage in four of the latter seven. Thus, in only eight of 15 infants, in whom CT scans revealed intracerebral hemorrhage, was the initial LP useful in confirming the diagnosis. Furthermore, LPs showed bloody cerebrospinal fluid in 10 of 18 infants whose CT scans were normal. At the present time LP cannot be considered a reliable means of identifying infants with subependymal-intraventricular hemorrhage.

Reliability of ultrasound in diagnosis of intracerebral hemorrhage and posthemorrhagic hydrocephalus: comparison with computed tomography.

Subependymal and intraventricular hemorrhage are frequent complications of the high risk preterm infant. It has been stated recently that ultrasound may be used to diagnose intraventricular hemorrhage. A comparative prospective study of ultrasound scan (US) with a commercially available B-mode real time linear array US machine and the computed tomography (CT) scan was undertaken to determine the accuracy of US in diagnosing the presence and quantity of subependymal and intraventricular hemorrhage and in following infants with hemorrhage for the development of progressive hydrocephalus. There were 101 patients followed with serial US examination for evidence of subependymal and/or intraventricular hemorrhage. CT correlation was obtained on each patient. The US examination correlated with the CT scan in 77 of these 101 patients. The demonstration of hydrocephalus by US in eight infants with postthemorrhagic hydrocephalus was reliable, and the correlation with CT scan was excellent.

Intraventricular hemorrhage: a prospective evaluation of etiopathogenesis.

In a study population of 151 newborn infants less than 35 weeks gestation, who required intensive care for more than 24 hours, clinical and biochemical factors associated with the presence of intraventricular hemorrhage (IVH) were prospectively evaluated. The diagnosis of IVH was confirmed by computed tomography, ventricular tap, or autopsy. Alveolar rupture was highly correlated with the presence of IVH. Other factors associated with IVH were: hypoxemia, hypercarbia, mechanical ventilation, peak inflation presser > 25 cm H2O, inspiratory to expiratory ratio > 1:1, patent ductus arteriosus, bicarbonate administration after the first day of life, volume expansion in the first day of life, hypotension, stages III and IV hyaline membrane disease, and intrauterine growth retardation. Early bicarbonate administration (first day), sodium administration > 8 mEq/kg/day, acidosis and birth weight less than or equal to 1,200 gm were associated with IVH only in the infants who died with IVH. Factors not associated with IVH were Apgar less than or equal to 5 at one and five minutes, birth weight, gestational age, male sex, osmolality greater than or equal to 300, serum sodium greater than or equal to 150, hypothermia, continuous distending pressure > 6 cm H2O, positive end-expiratory pressure > 5 cm H2O, outborn birth, obstetric trauma, or coagulopathy. Certain therapeutic interventions may lead to an increase incidence of intracerebral hemorrhage in the high-risk preterm infant.

Hypercatecholaminemia in Reye's syndrome.

To evaluate the role of catecholamines in Reye's syndrome, a specific and sensitive radioenzymatic assay was used to study plasma and CSF concentration of dopamine, norepinephrine, and epinephrine in 14 patients with liver-biopsy-proven Reye's syndrome. The results (median and range) revealed significant (P less than .04, P less than .0024, and P less than .030, respectively) elevation in plasma dopamine (131, 0 to 1,193 pg/mL), norepinephrine (1,455, 20 to 5,271 pg/mL), and epinephrine (345, 7.6 to 2,504 pg/mL) at the onset of the disease when compared with the level of these neurotransmitters in a group of hospitalized patients without hepatic disorders. There was a positive correlation between plasma catecholamines and stage of coma on admission (r = .54 to .86; P less than .001 to .024). Furthermore, the concentration of dopamine, norepinephrine, and epinephrine in the CSF increased significantly during the development of cerebral edema in all patients with Reye's syndrome as compared with concentrations in a control population. Hypercatecholaminemia may contribute to the encephalopathy of Reye's syndrome.

Evidence for hypertyraminemia in Reye's syndrome.

Utilizing a specific and sensitive radioimmunoassay, palsma and urine tyramine were measured in 14 consecutive patients with liver biopsy-proven Reye's syndrome. Plasma tyrosine was measured in 11 of these patients. The results revealed significant (P less than .003) elevation in plasma (3.4 +/- .52 ng/ml) (mean +/- SEM) and urine (1.00 +/- .26 mg/24 hr) tyramine as well as plasma tyrosine (204 +/- 52.5 mumole/liter) at the onset of the disease when compared to the levels of tyramine and tyrosine in a group of hospitalized patients without hepatic disorders. Furthermore, there was a positive correlation between plasma tyramine and days in coma (r = .86; P less than .001), and between plasma tyramine and tyrosine (r = 0.80; P less than .001). These data suggest that there is s substantial disturbance of tyrosine metabolism in Reye's syndrome and that the accumulation of this amino acid and its metabolite, tyramine, may contribute to the encephalopathy of this disease.

Placebo-controlled evaluation of Ritalin side effects.

OBJECTIVE: To address the frequency of side effects of Ritalin therapy in children with attention deficit hyperactivity disorder (ADHD) using the Barkeley Side Effects Questionnaire (BSEQ) in a clinical setting. DESIGN: Randomized double-blind placebo-controlled cross-over trial. SETTING: A large rural tertiary care clinic. PATIENTS: 234 consecutive children aged 5 through 15 years who met the Diagnostic and Statistical Manual of Mental Disorders (3rd ed, revised) criteria for ADHD were enrolled. Of these children, 206 had sufficient side effects data for analysis. INTERVENTIONS: 0.3 mg/kg per dose and 0.5 mg/kg per dose Ritalin compared to placebo in separate 2-week trials. Each treatment was given three times a day for 7 consecutive days. MEASUREMENTS AND MAIN RESULTS: Parents, blinded to the treatment assignment, assessed side effects via the BSEQ at baseline and at the end of each of the 4 treatment weeks. Univariate odds ratios (OR) were used to describe the magnitude of differences in observed side effects between Ritalin and placebo weeks of the trial for each of the items on the BSEQ. The frequency of the following side effects significantly increased with Ritalin therapy: insomnia (OR = 3.13, 95% confidence interval [CI] = (1.80,5.42)), appetite disturbance (OR = 19.00, 95% CI = (9.18,39.31)), stomachache (OR = 7.00, 95% CI = (3.29, 14.89)), headache (OR = 5.29, 95% CI = (2.51,11.15)), and dizziness (OR = 7.50, 95% CI = (1.93,29.13)). The frequency of the following side effects significantly decreased with Ritalin therapy: staring and daydreaming (OR = 0.47, 95% CI = (0.27,0.84)), irritability (OR = 0.33, 95% CI = (0.18,0.61)), anxiety (OR = 0.42, 95% CI = (0.23,0.76)), and nailbiting (OR = 0.19, 95% CI = (0.07, 0.53)). The incidence rates of the remaining BSEQ items did not differ significantly between the Ritalin and placebo weeks of the trial. CONCLUSION: The BSEQ proved to be clinically effective in tracking Ritalin side effects and should be incorporated into the routine evaluation and monitoring of ADHD patients for whom stimulants are prescribed.

Relationship between pressure passivity and subependymal/intraventricular hemorrhage as assessed by pulsed Doppler ultrasound.

A prospective study was undertaken using a range-gated, pulsed Doppler velocimeter to study flowpressure relationships in the anterior cerebral artery. Serial velocity and pressure studies were performed with each infant serving as his or her own control. The hypothesis tested was that ill preterm infants sustaining subependymal/intraventricular hemorrhage would have absent autoregulation. The hypothesis has been tested in 88 studies on 32 infants. Of 32 infants studied, 15 were judged to be pressure passive; nine of these children bled. The other 17 infants were not pressure passive; eight of these children bled (P greater than .05). From these studies, it may be concluded that the pressure passive state is not the final common link in the genesis of subependymal/intravertricular hemorrhage. Pulsed Doppler ultrasound may provide an extremely useful noninvasive technique for studying both the arterial and venous sides of the cerebral circulation.

MR of Leigh's disease (subacute necrotizing encephalomyelopathy).

MR images of three patients with Leigh's disease (subacute necrotizing encephalomyelopathy) were compared with CT findings. In all patients typical lesions in the basal ganglia were identified with both MR and CT. In two patients MR permitted identification of additional lesions not detected with CT. In one patient progression of MR abnormalities over a 4-month period correlated well with clinical deterioration in neurologic status. T2-weighted images with a repetition time (TR) greater than 1950 msec and an echo time (TE) greater than or equal to 60 msec or inversion-recovery images with a 50-msec TE, 1213-msec inversion time, and 3000-msec TR were advantageous in identifying multiple necrotic lesions in the brainstem, deep gray matter, periventricular white matter, and cerebral cortex. In this series MR was more sensitive in detecting and localizing multifocal necrotic lesions of Leigh's disease than CT was, and thus may be a useful diagnostic tool for patients with the appropriate clinical and laboratory abnormalities.

Yield of sphenoidal recording in sleep-deprived outpatients.

We retrospectively reviewed the results of sphenoidal recordings performed after sleep deprivation in 101 consecutive outpatients whose prior scalp EEGs failed to show epileptiform discharges (EDs). These patients were suspected of having seizures of temporal lobe origin. Blinded reviews of the recordings by two electroencephalographers showed a tendency for sphenoidal recording to detect EDs at a higher rate than scalp recording, but the difference did not reach statistical significance (p = 0.06). However, EDs appeared exclusively at sphenoidal electrodes in 11 patients and exclusively at scalp electrodes in 3. The probability of detecting EDs with combined scalp and sphenoidal recordings was greater when spells were characterized by focal symptoms or signs. Except in three patients, initial EDs occurred during the first 30 min of recording. We recommend that post-sleep-deprivation recording be performed initially with scalp and other noninvasive electrodes (such as anterior temporal, ear, or cheek electrodes). If no EDs occur after 30 min, sphenoidal electrode insertion and recording may then be considered, especially in patients with spells characterized by focal signs or symptoms.

Stimulant use and the potential for abuse in Wisconsin as reported by school administrators and longitudinally followed children.

The purpose of this study was to describe stimulant use and abuse as reported by school administrators and children diagnosed with attention deficit/hyperactivity disorder or attention deficit disorder inattentive. Five years after being identified as Ritalin responders, 161 children were surveyed regarding stimulant use and abuse. School principals in central Wisconsin were also surveyed regarding stimulant use and policies. No child believed stimulants as prescribed could lead to abuse. Sixteen percent of the children had been approached to sell, give, or trade their medication. During school hours, 44% of children and 37% of schools reported stimulants were stored unlocked. Not all schools had written policies regarding prescription drugs, and 10% permitted students to carry their own medication. Monitoring prescription usage, periodic reassessment of efficacy, and continuing education of family and teaching staff should be part of the multimodal treatment for this disorder. School policies should be developmentally sensitive.

Neurologic outcome following pediatric resuscitation.

This study reports the survival rate and short-term neurologic outcome of children who sustained cardiac arrests at Henrietta Egleston Hospital for Children, a pediatric teaching hospital. A commonly held belief in pediatric centers has been that children tolerate the insult of cardiac arrest better than adults. Cardiac arrest was defined as the need for external or internal cardiac compressions. Critical care nurses specially trained for this project collected the arrest data and performed the serial neurological exams. Results showed that despite a low overall survival rate, neurological outcome appears to be good after the arrest even in patients who expire prior to discharge. Major neurologic deficits, such as hemiplegia and severe developmental delay, do not occur. Nursing implications of the study, which is in its second year, are discussed.

Posthemorrhagic hydrocephalus in high-risk preterm infants: natural history, management, and long-term outcome.

The natural history, medical management, and outcome in infants with progressive posthemorrhagic hydrocephalus after intraventricular hemorrhage were studied prospectively. Infants with asymptomatic severe posthemorrhagic hydrocephalus were managed with a predetermined protocol. Outcome between groups at 1 to 2 years and at more than 3 years was compared. The natural history study, restricted to the inborn population, revealed that posthemorrhagic hydrocephalus developed in 53 of 409 infants with intraventricular hemorrhage. The progression of hydrocephalus either was arrested or regressed in 35 of 53 infants; progression to severe hydrocephalus occurred in 18 of 53 infants. The severe posthemorrhagic hydrocephalus was asymptomatic in 16 of 18 infants. The management and outcome study included both inborn and outborn infants. Of 50 infants, 12 had symptomatic severe hydrocephalus and 38 had asymptomatic severe hydrocephalus. The 16 infants managed with close observation were as likely to remain shunt free as the 22 infants managed with serial lumbar punctures. Of 38 infants, 20 were managed without shunts. At 3 to 6 years, the outcome of infants in the close observation group did not differ from that in the lumbar puncture group. Long-term outcome of infants with progression to asymptomatic severe hydrocephalus did not differ from that of infants in whom disease progression was arrested. Poor outcome in infants with intraventricular hemorrhage and subsequent posthemorrhagic hydrocephalus was related to severity of hemorrhage and gestational age at birth less than 30 weeks. Because long-term outcome of infants with severe hydrocephalus did not differ from that of infants in whom the progression of hydrocephalus was arrested or whose condition improved before hydrocephalus became severe, we currently attempt medical management of these infants.