Anti-striatal antibodies in Tourette syndrome cause neuronal dysfunction.

Serologic studies of children with Tourette syndrome (TS) have detected anti-neuronal antibodies but their role in TS has not been explored. Stereotypies and episodic utterances, analogous to involuntary movements seen in TS, were induced in rats by intrastriatal microinfusion of TS sera or gamma immunoglobulins (IgG) under noninflammatory conditions, as found in TS. Immunohistochemical analysis confirmed the presence of IgG selectively bound to striatal neurons. These data support the hypothesis that binding of an anti-neuronal antibody from some children with TS induced striatal dysfunction and suggest a possible cause for the basal ganglia alterations observed in children with TS.

Antibodies against a neuron-like (HTB-10 neuroblastoma) cell in children with Tourette syndrome.

BACKGROUND: Similar to the model for Sydenham's chorea, antineuronal antibodies (ANAb), which develop in response to a preceding streptococcal infection, have been speculated to have a role in the development of Tourette syndrome (TS). METHODS: Serum antibodies against the neuron-like HTB-10 neuroblastoma cell were assayed by ELISA methods and Western blot analysis on 41 children with TS (mean age 11.3 years) and 39 control subjects (mean age 12.1 years). RESULTS: Group comparisons of ELISA assay optical density (OD) showed that mean OD values for serum antibodies were not different [control (mean +/- SEM), .506 +/- .076; and TS, .584 +/- .053 (p = .38)]. In contrast, median values [.353 in control subjects and .477 in TS subjects (p = .012)] were significantly different. Western blots identified numerous bands in all TS and control sera with no difference in identified HTB-10 antigens. There was no relationship between the presence of ANAb and age of tic onset, family history, tic severity, attention deficit hyperactivity disorder, or obsessive compulsive disorder. No relationship existed between positive strep titers (ASO > or = 166 and/or antiDNAaseB > or = 170) and ANAb determinations or the severity of tics. CONCLUSIONS: Children with TS have higher median, but not mean, levels of ANAb, as measured by the HTB-10 neuroblastoma cell membrane assay. This assay system identified antibodies in both control and clinical groups and failed to identify a relationship between antibodies and clinical phenotype or one-time markers for streptococcal infection. Further studies are required to define a possible immune-mediated hypothesis for TS.

Antibodies against human putamen in children with Tourette syndrome.

BACKGROUND: Similar to the model for Sydenham's chorea, antineuronal antibodies, which develop in response to a preceding streptococcal infection, have been speculated to have a role in the development of Tourette syndrome (TS). METHODS: Serum antibodies against human caudate, putamen, and globus pallidus (interna and externa) were assayed by enzyme-linked immunosorbent assay (ELISA) and Western blot techniques and results were correlated with clinical characteristics and markers of streptococcal infection. SUBJECTS: A total of 41 children with TS (mean age, 11.3 years) and 39 controls (mean age, 12.1 years) were included. RESULTS: Compared with controls, TS subjects had a significant increase in the mean (p=0.006) and median (p=0.002) ELISA optical density (OD) levels of serum antibodies against putamen, but not caudate or globus pallidus. Western blots on 20 control and 20 TS serum samples showed that specific antibodies to caudate/putamen occurred more frequently in TS subjects at 83, 67, and 60 kDa; antigens were present in a synaptosomal fraction. TS subjects with a positive family history of tics had higher OD values (p < or = 0.04), but no association was shown with age of tic onset, tic severity, sudden onset of tics, or presence of attention-deficit hyperactivity disorder or obsessive-compulsive disorder. Risk ratio calculations in TS and control groups and in study subjects dichotomized for high and low putamen OD values were similar for titers of antistreptolysin O > or = 166 or antideoxyribonuclease B > or = 170. A subgroup analysis limited to subjects with elevated streptococcal titers, however, showed a significantly (p < or = 0.004) larger number of TS subjects with elevated OD levels. CONCLUSION: Children and adolescents with TS had significantly higher serum levels of antineuronal antibodies against putamen than did controls, but their relation to clinical characteristics and markers for streptococcal infection remains equivocal.

Antiphospholipid antibodies: an epiphenomenon in Tourette syndrome.

Antiphospholipids (aPLAs) have been previously identified in children with Tourette syndrome (TS), which has led to the speculation that these antibodies might have a pathophysiologic role in this disorder. Therefore, 21 healthy children and adolescents with TS, whose ages ranged from 7 to 17 years, underwent laboratory studies designed to diagnose the lupus anticoagulant, anticardiolipin (aCL) antibodies [immunoglobulin (Ig) G, IgA, and IgM], and antinuclear antibodies. Although five subjects had at least one value that differed from accepted laboratory standards, the changes were marginal in four of them. Lupus anticoagulant was identified in one patient, based on a minimal requirement of a prolonged dilute Russell viper venom time, clotting studies that did not correct after mixture with normal plasma, and an abnormal platelet neutralization procedure. A prolonged (but correctable) activated partial thromboplastin time was found in one individual, and aCL IgG was marginally increased in three subjects. Two (10%) of a control population of 20 same-age children also had low positive aCL IgG levels. There were no differences in tics (onset, type, frequency, severity, and family history) or comorbid features between children with normal or "abnormal" laboratory study results. Our data suggest that the presence of aPLAs in TS represents an epiphenomenon rather than a pathophysiologic mechanism.

Neuroimmunology of tics and other childhood hyperkinesias.

The etiology of tics and other childhood hyperkinesias is unclear despite attempts to link these movement disorders to neurotransmitter abnormalities and genes. This article will review the studies that suggest that some movement disorders are the result of immunologic factors.

An immunoassay for anti-neuronal antibodies associated with involuntary repetitive movement disorders.

Tourette's syndrome (TS) is a complex neurobehavioral disorder emerging in childhood and is characterized by motor and vocal tics of at least one year in duration. In a portion of patients with TS, environmental (non-genetic) factors may either have an etiologic role or act to modulate the phenotype. One possible environmental factor may be antibodies to central nervous system cells, as sera from several children diagnosed with either TS or Sydenham's chorea contained anti-neuronal antibodies. Using enriched membrane preparations isolated from HTB-10 neuroblastoma cells, a sensitive and specific assay was developed for the determination of human anti-neuronal antibodies associated with involuntary repetitive movement disorders. This assay exhibited between-run and within-run precision of 11.3 percent and 5.9 percent, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of this assay for the diagnosis of TS and TS or chorea are 79.1 percent, 61.2 percent, 61.6 percent, 78.8 percent, and 71.1 percent, 60.9 percent, 68.6 percent, and 63.6 percent, respectively. In addition, there was a significant difference (p < 0.0001) between the mean optical density in the patients with TS and children determined to be clinically "normal".

Antineuronal antibodies: tics and obsessive-compulsive symptoms.

Fluorescent serum antibody determinations were used to examine whether children with obsessive-compulsive disorder (OCD) or less pervasive obsessive-compulsive symptoms (OCS) would show evidence of caudate nucleus involvement. Recent studies of OCD have documented smaller caudate nucleus volumes in adults with childhood onset than in normal controls, but not smaller putamen volumes. Thirty-eight cases were recruited from an ongoing study of childhood neurodevelopmental disorders. Nineteen samples from clinical cases had existing or previously documented OCS and attention-deficit hyperactivity disorder (ADHD) with or without concomitant tics. Nineteen additional clinical controls with ADHD, but without tics or OCS, were identified. The sera from clinical cases showed antibodies directed against caudate [odds ratio (OR) 2.0; 95% confidence interval (CI) 1.0 to 4.1], putamen (OR 3.0; 95% CI 1.5 to 5.8), or both (OR 2.9; 95% CI 1.58 to 5.7) at a rate significantly higher than that of clinical controls, providing evidence of basal ganglia involvement in OCS. These preliminary data do not support a differential effect against caudate compared to putamen for these children, but suggest a more generalized central nervous system response.

Developing a competency-based preventive medicine curriculum for medical schools.

Trends in patient morbidity and mortality, cost-effectiveness, and national recommendations mandate that we practice more preventive medicine. To address this need, we set out to develop a comprehensive curriculum in preventive medicine for medical schools. We constructed a competency-based (i.e., performance-based) curriculum with specific educational objectives defined by outcomes. Subject areas were subdivided by life stages, and learning objectives were created separately for epidemiology, assessment, and intervention. We hope that adoption of such an educational blueprint by medical schools will measurably enhance the attitudes, knowledge, and skills necessary for the incorporation of preventive principles into all aspects of clinical medicine.

Antineuronal antibodies in movement disorders.

OBJECTIVE: To determine whether children with recent onset of movement disorders (Tourette syndrome, motor and/or vocal tics, chorea, choreiform movements) show evidence of serological antibodies directed against the human central nervous system as previously documented in research on Sydenham's chorea. METHODS: Serum antibodies against previously frozen human caudate nucleus sections were analyzed using a blinded design and immunofluorescent staining methods. The sera of one group of 50 children referred for evaluation of attention deficit hyperactivity disorder, behavior disorders, and learning disabilities (24 with an associated movement disorder) seen between June 1989 and June 1990 were analyzed. The study was replicated in 33 children (21 with an associated movement disorder) seen between June 1990 and November 1990. RESULTS: In the original sample of 50 children, those with movement disorders were significantly more likely to have evidence of antineuronal antibodies than were those without movement disorders (odds ratio [OR] 4.80, 95% confidence interval [CI] 2.58 to 8.93). Results of the replication were similar (OR 6.00, 95% CI 2.56 to 14.03). For the total group, the OR was 5.50, (95% CI 3.54 to 8.99), which is highly significant. The percentage of children with a movement disorder whose sera were strongly positive for antineuronal antibodies (44%) was very similar to that previously found in children with Sydenham's chorea (46%). Children with movement disorders were also more likely than children without movement disorders to have at least one antistreptococcal titer elevated. CONCLUSIONS: The data strongly suggest an association between antecedent group A beta-hemolytic streptococcal infection as inferred from elevated antistreptococcal titers and the presence of serum antineuronal antibodies, which may, in turn, be linked to childhood movement disorders.

What is measured by the Conners' Teacher Behavior Rating Scale? Replication of factor analysis.

The revised 28-item Conners' Teacher Behavior Rating Scale (TBRS) is subjected to factor analysis replication, with a referral sample of 354 children. The factor structure is more clearly defined than in the original normative study, and a primary factor of hyperactivity emerged, accounting for 39% of the variance. Six factors that emerged, all with eigenvalues of 1.00 or more, accounted for 69% of the variance. Hyperactivity and conduct factors, which are consistent over multiple studies, emerged. Items consistent with inattentive, unsociable, and passive behavior also separated into discrete factors. This suggests that using a mixed clinical population produces a clearer delineation of factors, which may provide the basis for subtyping a clinical population. Use of the TBRS as the diagnostic measure in medication studies, and its relationship with the abbreviated Teacher Rating Scale (ATRS), are explored.

Evidence for differential hemispheric function in children with hemiplegic cerebral palsy.

Eight children with right infantile hemiplegia and eight with left infantile hemiplegia were compared with each other and with 13 sibling controls on a test of manual dexterity, an extended neurological examination and a battery of neuropsychological tests. Right-hemiplegic children performed significantly less well than left-hemiplegic children and the controls on measures of syntactical awareness and the repetition of semantically coherent materials, despite similar verbal IQs. Both hemiplegic groups tended to perform less well than the controls, although not significantly so, on the short-term memory task, repetition of digits, and on a task of confrontation naming. There was also a strong correlation between left-hand impairment and poor arithmetical computation skill in both hemiplegic groups, which conforms with present views as to right-lateralization of certain mathematical functions. The results as a whole support the premise that there is innate hemispheric organization for some language tasks.

Dyslexia: automated diagnosis by computerized classification of brain electrical activity.

We describe a method for the diagnosis of dyslexia based upon a study of electroencephalographic and evoked potential data recorded from 13 normal and 11 dyslexic boys. Measurements were made from topographic maps of brain electrical activity recorded during resting and activated testing conditions. Using a statistically based technique, we developed rules for classification that successfully diagnosed 80 to 90% of subjects not used in the initial rule development. The nature of the most useful measurements suggests that aberrant neurophysiology in dyslexia involves both hemispheres and is present at rest as well as during complex testing. The method has promise for future diagnosis and research.