Comparison of the central nervous system effects produced by six H1-receptor antagonists.

BACKGROUND: A comprehensive comparative study of the central nervous system (CNS) properties of newer H1-receptor antagonist is needed. OBJECTIVE: Our objective was to investigate the central nervous system effects of a single manufacturer's recommended dose of six H1-receptor antagonists, using appropriate controls. METHODS: Fifteen healthy subjects received astemizole 10 mg, cetirizine 10 mg, ketotifen 2 mg, loratadine 10 mg, terfenadine 60 mg, diphenhydramine 50 mg or placebo. Before and 2-2.5 h after dosing, cognitive function was assessed using the P300-event-related potential, somnolence was assessed using a subjective score, and histamine skin tests were performed. RESULTS: In rank order from least to greatest effect on the P300 latency, the medications were: terfenadine, placebo, cetirizine, ketotifen, loratadine, astemizole and diphenhydramine. Only diphenhydramine increased the P300 latency significantly compared with baseline and placebo. Subjective somnolence was significantly greater than baseline and placebo after cetirizine, ketotifen and diphenhydramine. All the H1-receptor antagonists suppressed the histamine induced weal significantly compared with baseline. CONCLUSIONS: The H1-receptor antagonist tested affected cognitive functioning and somnolence to different extents, although all produced satisfactory peripheral H1-blockade.

Adverse central nervous system effects of older antihistamines in children.

Although older, potentially sedating, "first-generation" antihistamines (H1-receptor antagonists) are commonly used in childhood, their central nervous system (CNS) effects have not been well-documented in young subjects. We hypothesized that diphenhydramine and hydroxyzine would affect CNS function adversely in this population. Our objective was to evaluate the effects of these medications on central and peripheral histamine H1-receptors in children. Fifteen subjects with allergic rhinitis were tested before and 2-2.5 h after administration of diphenhydramine, hydroxyzine, or placebo in a double-blind, single-dose, three-way crossover study. Impairment of cognitive processing was assessed objectively by the latency of the P300 event-related potential (P300). Somnolence was assessed subjectively by a visual analog scale. Peripheral H1-blockade was assessed by suppression of the histamine-induced wheals and flares. At the central (Cz) and frontal (Fz) electrodes, diphenhydramine and hydroxyzine increased the P300 latency significantly (P < 0.05) compared to baseline. Hydroxyzine increased somnolence, as recorded on the visual analog scale, significantly compared to baseline (P < 0.05), with a similar trend for diphenhydramine (P = 0.07). Both antihistamines reduced histamine-induced wheals and flares significantly compared to baseline and compared to placebo. In children, diphenhydramine and hydroxyzine are effective H1-receptor antagonists, but both these medications cause CNS dysfunction, as evidenced by increased P300 latency, a measure of cognitive function, and by increased subjective somnolence.

Individual differences in central nervous system response to antihistamines (H1-receptor antagonists).

HYPOTHESIS: We hypothesized that the objectively documented central nervous system response to antihistamines (H1-receptor antagonists) could not be predicted reliably by an individual's subjective perception of somnolence after ingestion of these medications. METHODS: In a double-blind, placebo-controlled, single-dose, four-way crossover study, cetirizine 10 mg, hydroxyzine 50 mg, diphenhydramine 50 mg, or placebo were administered to 20 healthy subjects. Before and two to two and one-half hours after dosing, the latency of the P300 event-related potential (P300) at the central (Cz) and parietal (Pz) scalp electrodes, and the visual analogue scale for somnolence were recorded. Epicutaneous tests with histamine were performed, and serum H1-receptor antagonist concentrations were also measured. RESULTS: Neither cetirizine nor placebo significantly increased the mean P300 latency or somnolence as recorded on the visual analogue scale compared with predose baseline (P > .05), although increases were seen in some subjects after each of these treatments. Hydroxyzine and diphenhydramine increased the mean P300 latency and somnolence significantly (P < .05) compared with baseline; increases were observed in most, but not all subjects. Hydroxyzine increased P300 latency and somnolence significantly compared with placebo and with cetirizine. Diphenhydramine increased somnolence significantly compared with placebo. Overall, correlation between the objective test, P300 latency, and the subjective assessment, somnolence as recorded on the visual analogue scale, was statistically significant but clinically unimportant. Identification of central nervous system adverse effects after one potentially sedating H1-receptor antagonist did not predict central nervous system adverse effects after the others. CONCLUSIONS: Inter-individual objective and subjective central nervous system responses to H1-receptor antagonists are wide-ranging. The subjective responses can be misleading and do not necessarily predict the abnormalities that can be documented objectively after the same H1-receptor antagonist or a different H1-antagonist.

Inter-observer agreement in the diagnosis of childhood headache.

We prospectively assessed inter-observer agreement in the diagnosis of recurrent headaches in children. Clinical letters containing information on 40 children with headaches (age 4.3 to 17.8 years, median 10.4 years) were given to four Pediatric Neurologists. One or more headache types could be checked off on a data sheet that listed the main types recognized by the International Headache Society and an additional one, "combined migraine and tension-type headache". There were six combinational pairs of neurologists. The six pairs yielded 240 sets of diagnoses. Percentage agreement ranged from 45% to 78%, Kappa values from 0.20 to 0.59, and weighted Kappa from 0.19 to 0.52 within the six pairs. Agreement was 76% when both neurologists in a pair assigned single headache types and 4% when one or both neurologists diagnosed multiple types. The International Headache Society suggests that patients may have multiple types of headache and recommends that all types be classified. We suggest that the option of diagnosing more than one headache type from data in clinical letters may reduce inter-observer agreement.

Benefit/risk ratio of the antihistamines (H1-receptor antagonists) terfenadine and chlorpheniramine in children.

There are few objective studies of the benefit/risk ratio of H1-receptor antagonists in children. We hypothesized that terfenadine would provide as effective peripheral H1 blockade as chlorpheniramine in young patients, but would cause less central nervous system dysfunction. We tested this hypothesis with epicutaneous histamine tests to monitor peripheral H1 blockade, P300-event-related potentials as a measure of cognitive processing, and a visual analog scale for somnolence, in a double-blind, single-dose, placebo-controlled, three-way crossover study in 15 children with allergic rhinitis (mean age, 8.5 +/- 1.4 years). On 3 different days the children received terfenadine, 60 mg, chlorpheniramine, 4 mg, or placebo; the tests were performed before and 2 to 2 1/2 hours after dosing. Both terfenadine and chlorpheniramine suppressed the histamine-induced wheal and flare compared with baseline and with placebo; terfenadine was significantly more effective (p < 0.05). Terfenadine did not increase the latency of P300-event-related potentials at the parietal (Pz) or frontal (Fz) scalp electrodes compared with baseline, in contrast to chlorpheniramine and placebo, which did increase P300 latency. Terfenadine and placebo did not increase somnolence compared with baseline, but chlorpheniramine did. In children, as previously documented in adults, terfenadine has a more favorable benefit/risk ratio than chlorpheniramine, as shown by production of significantly greater peripheral histamine blockade and significantly less central nervous system dysfunction.

International headache society criteria and childhood headache.

The objective of this study was to determine whether the intuitive clinical diagnosis of a headache type made by paediatric neurologists would also have fulfilled International Headache Society (IHS) criteria for that type. Clinical information was recorded on data sheets. The neurologists made clinical diagnoses without referring to a fixed set of criteria. An independent physician then used the information on the data sheets to classify the child's headache by IHS criteria. Complete data sheets were available for 72 children, aged between four and 18 years. The intuitive clinical diagnosis was completely concordant with the criterion diagnosis of the IHS in 61 per cent, partially concordant in 31 per cent and at complete variance in 8 per cent. These data suggest that the IHS criteria can be applied to a majority of children in a referral-based population such as this, but that minor revisions to the criteria are necessary to make them even more applicable to children.

Migraine and complex seizures in children.

A diagnosis of migraine was made in 240 children referred to the Pediatric Neurology Service of the Children's Hospital of Winnipeg, Manitoba, Canada, in a 6-year period from January 1975 to December 1980. Fifty-four of these children had seizures, and in this subgroup 19 (35%) had partial seizures with complex symptomatology. Fourteen of the 19 children had common migraine. Fourteen children had abnormalities in interictal EEGs; EEG findings included focal slow waves, sharp waves, and sharp-and-slow waves. The temporal regions were the sites of abnormality in 13 children. Calculation of the critical ratio and use of the two-sided test approach showed that the probability of seeing 19 children with migraine and complex seizures in our population on the basis of chance was extremely low (p = 0.0096). Our study suggests the presence of an association between migraine and partial seizures with complex symptomatology.