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Contents:
by John Walkup, M.D.
A number of articles have been published and reviewed in the TSA/ML regarding the association between Group A β -hemolytic streptococcal infection (GABHS) and the development of tics, Tourette Syndrome (TS) and obsessive compulsive disorder (OCD). Variably referred to as pediatric infection-triggered autoimmune neuropsychiatric disorders (PITANDS) or pediatric autoimmune neuropsychiatric disorders associated with strep infections (PANDAS), this phenomenon is intriguing. This past year a number of papers on the topic have been published and, as is true in most of science, these articles raise more questions than are answered. This editorial will review the work to date on PANDAS/PITANDS, fill in several gaps not addressed in the data-based papers, and answer some of the questions often posed in clinical settings.
Although not broadly accepted, what are the current diagnostic criteria for PANDAS and PITANDS?
The diagnostic criteria for PANDAS (Swedo et al, 1997) are:
The diagnostic criteria for PITANDS (Allen et al, 1995) are similar to those of PANDAS. These criteria define an episode of illness more specifically than those for PANDAS. PITANDS criteria define how symptoms can be associated to an infection and do not require the presence of a neurological abnormality during an episode of illness.
When did the association between GABHS and tics/OCD begin?
In 1989 Susan Swedo and colleagues at the NIMH published the first comprehensive characterization of OCD symptoms in patients with Sydenham’s chorea (SC). The authors speculated that some cases of OCD might have an autoimmune etiology similar to that hypothesized for SC. Louise Kiessling and colleagues at Brown (also in 1989) made the first clinical observation that tic symptoms in some children developed in the con-text of GABHS infections.
What is the etiology of Sydenham’s chorea, and what relevance does this have to tics and OCD?
Sydenham’s chorea is a sequela of an untreated GABHS infection. The pathophysiology of SC is hypothesized to be due to antibodies to GABHS cross-reacting with certain brain regions (specifically the basal ganglia structures of the caudate and putamen) resulting in the characteristic movement and neuropsychiatric problems identified in individuals with SC.
Although antineuronal antibodies have been identified in SC (Husby et al, 1976), only a few reports have identified antineuronal antibodies in cases of tics/OCD (Kiessling et al, 1993, 1994; Tucker et al, 1997). Work is currently underway to replicate and expand these findings to include a characterization of the antineuronal antibodies found in persons with TS. Preliminary findings suggest that antineuronal antibodies are more frequent in subjects with TS than controls. However, there is no correlation between antineuronal antibodies and antistreptococcal antibodies (antistreptolysin O and antiDNAase B) or such clinical features of TS as tic severity, age of onset, presence of comorbid conditions or family history of TS (Singer et al poster presentation, American Academy of Neurology, 1997).
Isn’t streptococcal pharyngitis quite common in children? How can we be sure that the association between GABHS infections and the development of tics is causal?
This is perhaps the most important question facing researchers today. Identifying an association between strep throat and tics/OCD will be difficult. In order to appreciate how difficult a task it will be to confirm an association between GABHS infection and the development of tics/OCD, it is worth reviewing a few issues concerning strep throat. The natural course of strep throat is to go away, on its own and without treatment in approximately three days. The reason we treat acute infections is to decrease the short-term morbidity of this infection and to prevent rheumatic fever (RF). Also, strep throat is a common and communicable infection. Epidemiological studies suggest that 5-20% of children have positive throat cultures at any given time. In the same school, rates of positive throat culture can vary from one classroom to another. In some epidemics, the point prevalence can be as high as 80% of children. On average children have between 1-8 GABHS infections by the time they reach age 13 with the average being three episodes of illness during childhood.
Assessing the relationship between a phenomenon as common as strep throat is even more complicated when we examine the tests used for GABHS antibodies and their relationship to infection. Antistreptolysin O antibody titers peak 3-6 weeks after infection. AntiDNAaSe B anti-body titers peak 6-8 weeks after infection. Although we know a fair amount about the time course of the development of the antibody response, we know very little about the time course for the "back side" of the antibody response curve. With sequential, rising antibody titers we can have some confidence that a patient is developing an antibody response. Unfortunately, with a single value or with declining values, it is difficult to determine when the strep infection occurred.
The development of an antibody response to GABHS has one time course. The time courses for the development of rheumatic fever and SC are different. Studies suggest that often the development of RF occurs within 10-14 days after an acute infection. In contrast, SC can develop months after a GABHS infection. If the development of tics/OCD is related to a previous GABHS infection, then the time course is likely to be more similar to that of SC rather than RF. Given that the time course of infection, antibody response and onset of symptoms are all different, confirming an association will require long term, prospective controlled studies.
What is the B lymphocyte antigen D8/17?
The B lymphocyte antigen D8/17 (D8/17) is a cell surface antigen that is seen more commonly in patients and their family members who have had rheumatic fever than in controls (Khanna et al, 1989). The nature of the relationship between D8/17 and the pathologic process in RF is unknown. At this time D8/17 is hypothesized to be a "marker"for RF that may or may not be involved in RF pathophysiology. Much about D8/17 is unknown, and in many respects this has not been an area of active research focus in immunology or infectious disease for a number of years.
If indeed D8/17 were a marker for rheumatic fever, would it be present in patients considered to have PANDAS/PITANDS?
Two research groups have been actively pursuing this area of research. Swedo et al (1997) and Murphy, Goodman et al (1997) both cited below have assessed the frequency of D8/17 in two different samples of subjects. Murphy and colleagues found that regardless of phenotype, all 31 of their consecutively evaluated childhood onset TS/OCD patients were positive for D8/17. The highly selected sample of tic/OCD subjects recruited by Swedo et al was also positive for the D8/17 antigen. The percent of children whose clinical history was consistent with PANDAS and PITANDS is not clear. Thus, the relationship of D8/17 and PANDAS has yet to be clarified.
A third group has tested subjects with autism for D8/17, and identified that when compared to controls, a high percentage of those subjects were D8/17 positive. In a secondary analysis, ratings of compulsivity and repetitive behaviors were highly correlated with the overall number of D8/17 positive cells (Eric Hollander, U.S. Congress of Psychiatry, December 1997). Again, the subjects were not pre-selected for any specific features of autism. If replicated, the association of D8/17 positive cells with autism suggests that there may be a broad spectrum of clinical features associated with this proposed etiology.
Is PANDAS rare or common?
If the D8/17 antigen is a marker for autoimmune-related cases of tics/OCD, the study of Murphy et al would suggest that the autoimmune etiology is very common. On the other hand, if you define PANDAS as a child who meets all the diagnostic criteria noted above, including documented GABHS infection, the percentage of children with GABHS related tics/OCD is undoubtedly much smaller. Although the Murphy et al estimate may be overly inclusive, to demand that a child have positive lab evidence of infection for a confirmed PANDAS diagnosis ignores the fact that many children who become infected will not have been evaluated adequately or treated.
In the TS Clinic at Johns Hopkins we have been evaluating a consecutive series of tic disorder subjects for the PANDAS diagnostic criteria. Our preliminary findings suggest that 54% (43/80) of subjects have a history of an abrupt onset or exacerbation of tic symptoms. Of those with a history of abrupt onset/exacerbation 35% (15/43) give a history of an infection temporally related to the abrupt onset/exacerbations, and 21% (9/15) of the sample identified a streptococcal infection as the infection temporally related to the abrupt onset/exacerbations. The percentage of subjects who can produce the positive laboratory evidence is likely to be even smaller.
Based on what we know about strep throat, what should clinicians do when they see a youngster with an acute onset of a tic disorder or OCD?
It is prudent to have the patient see a pediatrician and undergo an evaluation for infection (throat culture). Given the duration of strep infections and the time tables for antibody response and subsequent development of post-streptococcal syndromes noted above, it is not at all clear what information a single Antistreptolysin O and AntiDNAase B titer test provides in the evaluation and management of tics/OCD. It is certainly clear that one does not treat a child with antibiotics for an abrupt onset of tics/OCD in the absence of evidence of an acute strep throat. It is also clear that one does not treat elevated strep antibody titers in the absence of an acute infection.
What implication does this proposed autoimmune etiology have for the treatment of TS/OCD?
The implications are significant. If indeed the development of even some cases of TS/OCD is related to an auto-immune etiology, then a whole new group of treatments becomes available—infection fighting agents, immunologicaltreatments and perhaps even vaccines.
To date, what treatments have been used?
A variety have been tried. Glucocorticoids such as prednisone have been used for patients with acute exacerbations of tics/OCD, but without apparent success. In case reports of four patients with TS and/or OCD plasmapheresis, intravenous immunoglobulin (IVIG) and prednisone were used with some apparent success (Allen et al, 1995). There are no other published trials at this time. Swedo and colleagues have completed a blinded crossover prevention trial of penicillin for PANDAS, and they have also con-ducted controlled trials of IVIG and plasmapheresis. The results of these studies are not yet published.
At this point, is the field clear about the advisability of these treatments?
There is no agreement on their use. Although the idea that TS/OCD may have an autoimmune etiology is controversial, for many it is the proposed treatments that raise the most concern. Scientists are quite comfortable studying and debating whether TS/OCD might have an autoimmune etiology. Of greater concern is that these new treatments have been proposed without properly controlled trials, and that many clinicians are employing them without adequate justification. One needs only to review discussions on the Internet to get a sense about how wide-spread several untested treatments have become.
Outside of academic centers or research protocols, it does not appear that there is significant use of IVIG or plasmapheresis. On the other hand, the use of antibiotics prophylactically for children who are deemed vulnerable to future exacerbations appears to be more common. TSA staff report that the practice appears to be fairly common. Families are even calling and questioning the advisability of putting unaffected siblings of TS subjects on penicillin to prevent their "coming down with" TS. The major problem with antibiotic prophylaxis is the absence of either controlled trials, or a clearly developed scientific indication in tics/OCD. Other problems include a lack of information about both antibiotic dosing and the frequency of breakthrough infections. Until we have data showing the effectiveness of antibiotic prophylaxis, dosing and management of breakthrough infections with antibiotic prophylaxis is a dubious intervention. In spite of the lack of information supporting the use of antibiotic prophylaxis, some clinicians and families will still view this intervention as causing little harm. Scientists are concerned about the overuse of antibiotics that can lead to the development of resistant strains of bacteria. Although GABHS does not appear to have mutated or become resistant to penicillin, the overuse of antibiotics for strep could lead to the development of resistant strains of other bacteria.
What is the bottom line?
Most new and exciting scientific theories often are accompanied by considerable controversy. Opinions and feelings run strong on both sides of this one. The most serious problem, however, is just how far the field has gone in terms of treatment without evidence from controlled clinical trials, and also without the properly controlled studies confirming the association of GABHS and the development of tics/OCD symptoms. We are hopeful that prospective studies and randomized clinical trials are being developed and will be implemented. In the meantime, rather than rush to treatment, a more skeptical and considered approach is recommended.
References:
Allen AJ, Leonard HL, Swedo SE: Case study: a new infection-triggered, autoimmune subtype of pediatric OCD and Tourette’s syndrome. Journal of the American Academy of Child & Adolescent Psychiatry March 1995; 34(3):307-11.
Dingle J et al, ed: Illness in The Home. Western Reserve Press, Cleveland, 1964.
Husby G, van de Tijn I, Zabriskie J, et al: Antibodies reacting with cytoplasm of subthalamic and caudate nuclei neurons in chorea and acute rheumatic fever. J Exp Med 1976; 144:1094-1110.
Khanna A, Buskirk D, Williams Jr R, et al: Presence of a non-HLA B cell antigen in rheumatic fever patients and their families as defined by a monoclonal antibody. J Clin Invest 1989; 83:1710-16.
Kiessling L: Tic disorders associated with evidence of invasive group A, β -hemolytic streptococcal disease. Developmental Medicine and Child Neurology 1989; 59 suppl:3128.
Murphy T, Goodman W, Fudge M, et al: b lymphocyte antigen D8/17: a peripheral marker for childhood-onset obsessive-compulsive disorder and Tourette’s syndrome. Am J Psychiatry 1997; 402-407.
Singer H, Giuliano J, Hansen B, Hallet J, Laurino J, Benson M, Kiessling L: Antineuronal antibodies, streptococcal infections and Tourette syndrome. Poster presentation, Annual Meeting of the American Academy of Neurology, 1997.
Swedo S, Rapoport J, Cheslow D, et al: High prevalence of obsessive-compulsive symptoms in patients with Sydenham’s chorea. Am J Psychiatry 1989; 146:246-9.
Swedo S, Leonard H, Mittelman B, Allen A, Rapoport J, Dow K, et al: Children with PANDAS (pediatric autoimmune neuropsychiatric disorders associated with strep infections) are identified by a marker associated with rheumatic fever. Am J Psychiatry 1997; 154:110-112.
Tucker D, Leckman J, Scahill L, et al: A putative poststreptococcal case of OCD with chronic tic disorder, not otherwise specified. J Am Acad Child and Adolesc Psychiatry 1997; 35:1684-91.
We are greatly appreciative of Dr. Edward Kaplan’s help with this editorial. Specializing in streptococcal infections, Dr. Kaplan is Professor of Pediatrics at the University of Minnesota Medical School. He provided both a wealth of information about streptococcal infection and just plain common sense about how, in the absence of the properly controlled trials, to think about the association between strep infections and tics/OCD.
Decreased motor inhibition in Tourette’s disorder: Evidence from transcranial magnetic stimulation
Ziemann U, Paulus W, Rothenberger A: Amer J Psychiatry, 1997; 154:1277-1284
Comment: Transcranial magnetic stimulation (TMS) is a non-invasive method of stimulating the cortex. In TMS the power supply produces a magnetic current in a coil that is placed on the scalp. This coil delivers a magnetic current to the brain that excites neurons in a fashion similar to direct electrical stimulation. The strength of the resulting current in the brain depends on the pulse frequency and intensity of the magnetic field produced by the machine. Placement of the coil on the scalp is another important variable because it affects which neurons and subsequent pathways will be stimulated. Using different paradigms, TMS has been used to explore brain function as well as to treat Parkinson’s disease and as an alternative to electroconvulsive therapy in the treatment of depression.
The purpose of this study was to evaluate motor function in TS compared to control subjects. The investigators used a paired pulse technique in which one pulse is followed by another across a range of brief time intervals (e.g., 1 to 30 milliseconds). At shorter intervals (1 to 4 milliseconds) there is an inhibited cortical response to the second pulse. By contrast, longer interstimulus intervals are marked by facilitation. The TS group showed a lower degree of cortical inhibition in the short interstimulus conditions suggesting a failure of inhibition in motor pathways. This study shows that TMS may be a valuable tool for exploring the underlying pathophysiology of TS; whether TMS will have a role in the treatment of TS is less certain.
Elevated cerebrospinal fluid corticotropin-releasing factor in Tourette syndrome: comparison to obsessive compulsive disorder and normal controls
Chappell P, Leckman J, Goodman W, et al: Biological Psychiatry 1996;39:776-783
Abstract: Stress- and anxiety-related fluctuations in tic severity are cardinal features of Tourette’s syndrome (TS), and there is evidence for involvement of noradrenergic mechanisms in the pathophysiology and treatment of the disorder. To examine further the pathobiology of this enhanced vulnerability to stress and anxiety, we measured central activity of corticotropin-releasing factor (CRF) in patients with TS and the related condition, obsessive compulsive disorder (OCD). Lumbar cerebrospinal fluid (CSF) was obtained in a standardized fashion for measurement of CRF from 21 medication-free outpatients with TS, 20 with OCD, and 29 healthy controls. The TS patients had significantly higher levels of CSF CRF than both the normal controls and the OCD patients. However, there was no difference in CSF CRF between the OCD patients and the normal controls. Group differences in CSF CRF were unrelated to current clinical ratings of depression, anxiety, tics, and obsessive compulsive behaviors. Although the functional significance of this finding remains to be elucidated, these results are consistent with the hypothesis that stress-related neurobiological mechanisms may play a role in the pathobiology of TS.
Comment: Corticotropin-releasing factor (CRF) is a stress-sensitive neuropeptide that activates thehypothalamic- pituitary-adrenal axis. Of course, the outcome ofthis activation is the release of adrenal steroids. CRF also plays a role in other neuroendocrine and behavioral aspects of the stress response such as vigilance and arousal. Finally, CRF is known to be involved in reciprocal feed-back systems with other neurotransmitters such as norepinephrine, dopamine and the opioids.1 These findings fit well with the results of a previous report by this same group of investigators 2 that described increased stress-responsivity in TS (see TSA/ML, 1996).
References: 1. Chrousos GP, Gold PW: The concepts of stress and stress system disorders. JAMA, 267:1244-1252. 2. Chappell PB, Riddle MA, Anderson GA, et al: Enhanced stress responsivity of Tourette syndrome patients undergoing lumbar puncture. Biological Psychiatry 1994; 36:35-43.
Asymmetry of basal ganglia perfusion in Tourette’s syndrome shown by Technetium-99m-HMPAO SPECT
Klieger PS, Fett KA, Dimitspoulos T, Kurlan R: J Nuclear Medicine 1997; 38:188-191
Abstract: Our study involved performing brain perfusion SPECT scans on Tourette’s subjects to observe any commonperfusion abnormalities involving the cerebral cortex or subcortical structures.
Method: Six patients with Tourette’s syndrome and nine normal control subjects underwent a brain SPECT study with 99m Tc-HMPAO. Regions of interest were generated over the cerebral cortex, basal ganglia, thalamus and cerebellum to evaluate any relative perfusion abnormalities or asymmetry in the Tourette’s subjects.
Results: Five of the six Tourette’s subjects demonstrated a significant decrease in right basal ganglia activity which was not present in any of the normal control subjects.
Conclusion: Our study suggests an etiology for Tourette’s syndrome involving the right basal ganglia. Further-more, brain SPECT may be useful in the evaluation of these patients if it proves to be sufficiently sensitive and specific in larger study populations.
Comment: Basal ganglia metabolic activity was estimated through perfusion of technetium-99m-HMPAO ina single axial slice. The authors report a decrease in the right to left perfusion ratio in the TS subjects. The authors also found an absolute difference in the activity in the right side of the basal ganglia, but this difference was not significant.
Although previous research has also suggested asymmetryin the basal ganglia, most studies have reported de-creasedmetabolic activity on the left.1 Limitations of thepresent study include the substantial difference in agebetween TS subjects and controls (mean ages were 36 and70 years respectively) and the small sample size. Therefore the claim that SPECT may be useful for assessment seems premature.
References: 1. Moriarty J, Costa DC, Schmitz B, Trimble MR, Ell PJ, Robertson MM: Brain perfusion abnormalities in Gilles de la Tourette’s syndrome. British J Psychiatry 1995; 167:249-254.
The metabolic anatomy of Tourette’s syndrome
Eidelberg D, Moeller JR, Antonini A, et al: Neurology 1997; 48:927-934
Abstract: The functional brain networks underlying the clinicalmanifestations of Gilles de la Tourette’s syndrome (TS) are currently unknown. To identify these networks, we studied TS patients and normal subjects with 18 F-fluorodeoxyglucose (FDG) and PET employing a statistical model of regional metabolic covariation. We studied 10 TS patients (mean age, 41.5 ± 12.7 years) who were either drug naive or medication free for at least 2 years. Ten normal volunteers (mean age, 42.5 ± 11.5) served as controls. We used quantitative FDG/PET to calculate global, regional, and normalized rates of glucose metabolism (GMR, rCMRGlc, and rCMRGlc/GMR) in all subjects. The Scaled Subprofile Model (SSM) was used to identify specific patterns of regional metabolic covariation associated with TS. We found that global and regional metabolic rates were normal in TS. SSM analysis identified two TS-related brain networks. One pattern (15.8% variance accounted for, VAF) was characterized by covariate bilateral metabolic increases in lateral premotor and supplementary motor association cortices and in the mid-brain. Individual patient expression of this pattern (subject score) was abnormally increased in the TS group (p < 0.01). A second pattern (10.5% VAF) was characterized by covariate decreases in caudate and thalamic metabolism associated with smaller reductions in lentiform and hippocampal metabolic activity. Subject scores for this pattern correlated with Tourette Syndrome Global Scale (TSGS) global ratings (r = 0.85, p <0.005). We conclude that the metabolic landscape of TS is characterized by a nonspecific pattern of increased motor cortical activity identified in other hyperkinetic disorders. TS is also associated with a specific brain network characterized by a reduction in the activity of limbic basal ganglia-thalamocortical projection systems.
Comment: This study found no differences in the absolute regional metabolic rates of glucose across the two groups. Using a principal components analytic strategy, the investigators identified two covariance patterns. The first showed an increase in metabolic activity in lateral prefrontal and supplemental motor area for TS patients. The second pattern consisted of lower metabolic activity in the left caudate, both thalami, and both lentiform nuclei. The first pattern is consistent with overactivity in cortical regions that are associated with movement. The second pattern may be even more relevant to the pathophysiology of TS because the underactivity in the caudate, lentiform nucleus and thalami may represent a failure of subcortical inhibitory systems.
Corpus callosum morphology in children with Tourette syndrome and attention deficit hyperactivity disorder
Baumgardner TL, Singer HS, Denckla MB, et al: Neurology 1996; 47:477-482
Abstract: The aim of this study was to investigate the morphology of the corpus callosum (CC) in Tourette syndrome (TS) and attention deficit hyperactivity disorder (ADHD) to determine whether these conditions affect distinct regional differences. Seventy-seven children and adolescents, aged 6 to 16 years, comprised the four research groups—16 patients with TS, 21 patients with TS plus ADHD, 13 patients with ADHD, and 27 unaffected control subjects. A semiautomated, computer-assisted procedure was used to measure the total area, five subregions, centerline length, perimeter, and bending angle of the CC. MRI data were analyzed using several statistical methods, primarily two-tailed analysis of variance to test the effects of TS and ADHD status, while controlling for the influence of age, gender, and total intracranial area (an estimate of brain size). TS was associated with significant increases in the area of four of five subdivisions, the total area, and the perimeter of the CC. ADHD was associated with a significant decrease in the area of the rostral body. There were no interactions between TS and ADHD factors. These findings suggest that the area of the CC is larger in children with TS, and that this difference is independent of age, handedness, intracranial area, and the diagnosis of ADHD. Our findings support hypotheses that the neurobiologic mechanisms in TS and ADHD involve frontal/subcortical circuits.
Comment: The corpus callosum is of interest in TS because abnormalities in morphology provide further evidence of problems of lateralization in TS and related disorders. In contrast to a recent adult study showing a marked reduction in corpus callosum size in TS,1 this study found that children with TS had larger corpus callosal regions than either normal controls or children with ADHD without tics. The TS + ADHD group had slightly smaller corpus collosal areas than those with TS alone. The functional importance of larger corpus callosum areas in TS group is unclear. In a study of healthy adults, Yazgan and colleagues observed that as the corpus callosum area increases, behavioral laterality decreases.2 It is also worth noting that the rostral region of the corpus callosum (which was larger in the TS only group) connects the cerebral hemispheres in the premotor and supplementary motor areas.
References: 1. Peterson BS, Leckman JF, Duncan J, et al: Corpus callosum morphology from magnetic resonance images in Tourette’s syndrome. Psychiatry Research 1994; 55:85-99.
2. Yazgan MY, Wexler BE, Kinsborne M, Peterson B,Leckman JF: Functional significance of individual variations in callosal area. Neuropsychologia 1995; 33:769-779.
Quantitative brain magnetic resonance imaging in attention-deficit hyperactivity disorder
Castellanos FX, Giedd JN, Marsh WL, et al: Archives General Psychiatry 1996; 53:607-616
Abstract: Method: Anatomic brain MRIs for 57 boys with ADHD and 55 healthy matched controls, aged 5 to 18 years, were obtained using a 1.5-T scanner with contiguous 2-mm sections. Volumetric measures of the cerebrum, caudate nucleus, putamen, globus pallidus, amygdala, hippocampus, temporal lobe, cerebellum; a measure of prefrontal cortex; and related right-left asymmetries were examined along with midsagittal area measures of the cerebellum and corpus callosum. Interrater reliabilities were .82 or greater for all MRI measures.
Results: Subjects with ADHD had a 4.7% smaller total cerebral volume (P=.02). Analysis of covariance for total cerebral volume demonstrated a significant loss of normal right>left asymmetry in the caudate (P=.006), smaller right globus pallidus (P=.005), smaller right anterior frontal region (P=.02), smaller cerebellum (P=.05), and reversal of normal lateral ventricular asymmetry (P=.03) in the ADHD group.
Comment: This research is a continuation of earlier work by the same group of investigators.1 The authors compared cerebral and basal ganglia volumes as well as right and left sided structural differences in children with ADHD to controls. A particular strength is that the subjects were well characterized with respect to diagnosis and severity. The MRI acquisition series used thin slices promoting high resolution three-dimensional reconstruction. The most important findings include a decrease in the overall cerebral volume in the ADHD group and the differences noted in brain asymmetries. Normal controls showed right greater than left volumes in the frontal region, caudate, and globus pallidus, but left greater than right volume in the putamen. In the ADHD group—with the exception of the putamen which showed no right-left difference—these asymmetries were reversed. The frontal region, caudate and globus pallidus were smaller on the right in the ADHD group. In contrast to the findings of Baumgartner et al (see above), no differences between the two groups were observed in any region of the corpus callosal area.
References: 1. Castellanos FX, Giedd JN, Eckburg P, et al: Quantitative morphology of the caudate nucleus in attention deficit hyperactivity disorder. American J Psychiatry 1994; 151:1791-1796.
Volumetric MRI analysis comparing subjects having attention-deficit hyperactivity disorder with normal controls
Filipek PA, Semrud-Clikeman M, Steingard RJ, Renshaw PF, Kennedy DN, Biederman J: J Neurology 1997; 48:589-601
Abstract: Participants: Fifteen male subjects with ADHD without comorbid diagnoses (aged 12.4 ± 3.4 years) and 15 male normal controls (aged 14.4 ± 3.4), group-matched for age, IQ and handedness.
Main outcome measures: Global and hemispheric regional volumes (in cm 3 ) of cerebral hemispheres, cortex, white matter, ventricles, caudate, lenticulate, central gray nuclei, insula, amygdala, and hippocampus.
Results: Despite similar hemispheric volumes, ADHD subjects had smaller volumes of (1) left total caudate and caudate head (p < 0.04), with reversed asymmetry (p < 0.03); (2) right anterior-superior (frontal) region en bloc (p < 0.03) and white matter (p < 0.01); (3) bilateral anterior-inferior region en bloc (p < 0.04); and (4) bilateral retrocallosal (parietal occipital) region white matter (p < 0.03). Possible structural correlates of ADHD response to stimulants were noted in an exploratory analysis, with the smallest and symmetric caudate, and smallest left anterior-superior cortex volumes found in the responders, but reversed caudate asymmetry and the smallest retrocallosal white matter volumes noted in the nonresponders.
Conclusions: This study is the first to report localized hemispheric structural anomalies in ADHD, which are concordant with theoretical models of abnormal frontal-striatal and parietal function, and with possible differing morphologic substrates of response to stimulant medication.
Comment: The image acquisition methods were similar to those used by Castellanos et al except that the slice thickness was slightly larger. Consistent with the results of Castellanos et al, this study found smaller mean volume in the right frontal region for the ADHD group. In contrast to the Castellanos study, left caudate volume was smaller in the ADHD group and the left and right side caudate volumes were roughly equal in the ADHD group.
Basal ganglia volumes in children with attention-deficit hyperactivity disorder
Aylward EH, Reiss AL, Reader MJ, Singer HS, Brown JE, Denckla MB: J Child Neurology 1996; 11(2):112-115
Abstract: Previous research has demonstrated volume reduction of the left globus pallidus in children with the codiagnoses of Tourette syndrome and attention-deficit hyperactivity disorder (ADHD), in comparison with children who have Tourette syndrome alone and with normal controls. The purpose of this study was to determine whether children with ADHD alone also had volume reduction of the globus pallidus or other basal ganglia structures. Subjects were 10 boys with ADHD, 16 boys with Tourette syndrome and ADHD, and 11 normal control boys. Groups were matched for age. Boys with ADHD were individually matched for age, handedness, and IQ to 10 of the 16 boys with Tourette syndrome and ADHD. Volumes of caudate, putamen, and globus pallidus were measured and corrected for brain volume. The boys with ADHD had significantly smaller left globus pallidus volume and total globus pallidus volume (corrected for brain volume) than the normal controls. The Tourette syndrome plus ADHD group did not differ from the ADHD group on any of the measures. We conclude that small globus pallidus volume, particularly on the left side, is associated with ADHD.
Comment: On most measures of basal ganglia volume, the TS+ADHD group was intermediate between the ADHD group and controls. The only exception to this pattern was the caudate volume which was largest in the TS+ADHD group. Both the right and left caudate volumes were less in the ADHD group compared to controls, but the difference was not signifcant. When left-right symmetry of the basal ganglia was evaluated, there were no clear differences between the groups.
Brain morphometry in Tourette’s syndrome: the influence of comorbid attention-deficit hyperactivity disorder
Castellanos FX, Giedd JN, Hamburger SD, Marsh WL, Rapoport JL: Neurology 1996; 47:1581-1583
Abstract: Because TS and ADHD are frequently comorbid, we contrasted ADHD boys with and without TS along with control subjects. As expected, we found a significant loss of the normal globus pallidus asymmetry in the patients, but presence or absence of TS did not differentiate the ADHD groups. We conclude that accounting for ADHD comorbidity will be important in future TS morphometric studies.
Comment: This study compared three groups of boys: ADHD only (n=26), TS+ADHD (n=14) and normal controls (n=31). The findings suggest that ADHD alone and TS+ADHD have similar morphological abnormalities especially with respect to asymmetry of the globus pallidus. In this study, controls showed greater right globus pallidi than on the left.
A volumetric MRI study of Gilles de la Tourette’s syndrome
Moriarty J, Varma AR, Stevens J, Fish M, Trimble MR, Roberston MM: Neurology 1997; 49:410-415
Abstract: The neuroanatomic or neuropathologic basis of Gilles de la Tourette’s syndrome (GTS) remains unknown. Recent studies have suggested abnormalities of cerebral asymmetry and basal ganglia volumes. We studied 17 patients with GTS and eight normal controls using volumetric MRI techniques for measuring the caudate nucleus, amygdala, and corpus callosum. One subject with GTS was subsequently excluded because he was left handed. No absolute differences in caudate nucleus volumes between patient and control groups were evident. There was an increase in corpus callosum (CC) cross-sectional area and a loss of the normal asymmetry of the caudate nucleus in the patient group. A loss of the normal correlation between cross-sectional area of the CC and whole brain index (WBI) in the patient group also was found. The amygdala measurements had a poor interrater reliability.
Comment: This study included 16 drug-free, right-handed adults with TS and 8 normal controls. The MRI acquisition used thin slices in the coronal plane (1.5 mm) to make volumetric measurements of the caudate, a mid-sagittal section was used for the corpus callosum. The caudate nucleus showed a right-greater than left asymmetry in the normal control group that was not present in the TS group for whom the right caudate was slightly smaller than the left. There was no difference in the volume of the caudate nuclei between the two groups. The corpus callosal area was greater in the TS group compared to controls which is similar to the results reported by Baumgardner et al (see above) and opposite of the findings by a previous study.1
References: 1. Peterson BS, Leckman JF, Duncan J, et al: Corpus callosum morphology from magnetic resonance images in Tourette’s syndrome. Psychiatry Research 1994; 55:85-99.
Summary
TS morphological studies offer a mixed picture. Abnormalities in basal ganglia asymmetry and volume have been consistently associated with TS across studies. However, the direction of the findings have been inconsistent. These differences become more complex when ADHD is included in the discussion. For example, Filipek et al noted smaller left caudate in ADHD compared to controls and Castellanos et al reported smaller caudate volumes on the right in their sample of boys with ADHD. Finally, the asymmetry results are complicated by the lack of uniform observations among controls across these various investigations. Most studies have found that the right caudate is larger than the left in their control subjects and left larger than right for the putamen, but there is less uniformity concerning the direction of asymmetry for the globus pallidus. The explanation for these differences may be related to source and size of samples and/or methods of image acquisition and measurement. More study with larger, well-characterized subjects is needed.
Fluoxetine has no marked effect on tic symptoms in patients with Tourette syndrome: A double-blind, placebo-controlled study
Scahill L, Riddle MA, King RA, Hardin MT, Rasmusson A, Makuch RW, Leckman JF: J Child Adolescent Psychopharmacol 1997; 7:75-85
The use of fluoxetine in Gilles de la Tourette syndrome and obsessive-compulsive behaviors: preliminary clinical experience
Eapen V, Trimble MR, Robertson MM: Progress Neuro-Psychopharmcol Bio Psychiatry 1996; 20:737-743
Comment: Two recent studies evaluated the efficacy and safety of fluoxetine as monotherapy in the treatment of tics and obsessive-compulsive symptoms. The study by Scahill et al (1997) was a double-blind, placebo-controlled crossover study involving 14 TS subjects ranging in age from 8-33 years. Using a fixed dose of 20 mg per day for eight weeks, these investigators found no effect of fluoxetine on tics as measured by the Yale Global Tic Symptom Severity Scale. In contrast, fluoxetine treatment was associated with a significant reduction in a subgroup of 6 subjects with obsessive-compulsive symptoms. The crossover analysis, which allowed subjects to serve as their own controls, showed similar results. There was a modest decrease in obsessive-compulsive symptoms, but no effect on tics. The most common side effect was transient behavioral activation (insomnia and motor restless-ness) which occurred in over 50% of the subjects who received fluoxetine. The behavioral activation ranged from mild to moderate in severity, tended to emerge early in the trial, and activation was more common in children and adolescents. The study by Eapen, Trimble & Robertson (1996) included 30 subjects with TS (14 children and 16 adults) all of whom had obsessive-compulsive features. Fluoxetine was administered at doses ranging from 20 to 60 mg/day and patients were followed for 12 weeks. By the six-week mark, 5 subjects had dropped out. Three dropped out due to the appearance of depression (one adult) and two children due to emergence of aggressive behavior. Two others dropped out due to lack of benefit. At the 12 week mark, 14 of 25 subjects were rated as at least moderately improved with respect to obsessive-compulsive symptoms. There was little effect on tics. One additional child stopped treatment due the emergence of aggressive behavior. Thus, the results of these two studies are consistent. Fluoxetine appears useful for obsessive-compulsive symptoms in TS, but has little direct effect on tics. Also, children appear to be more susceptible to activating side effects.
Children’s Yale-Brown obsessive compulsive scale: reliability and validity
Scahill L, Riddle MA, McSwiggin-Hardin M, et al: J Am Acad Child Adolesc Psychiatry 1997; 36:844-852
Abstract: Objective: To evaluate the reliability and validity of a semistructured measure of disorder (OCD).
Method: Sixty-five children with OCD (25 girls and 40 boys, aged 8 to 17 years) were assessed with the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Interrater agreement was assessed by four raters in a subsample (n = 24). Discriminant and convergent validity were assessed by comparing CY-BOCS scores to self-ratings of depression, anxiety, and obsessive-compulsive symptoms.
Results: Internal consistency was high, measuring .87 for the 10 items. The intraclass correlations for the CY-BOCS Total, Ob-session, and Compulsion scores were .84, .91, and .66, suggest-ing good to excellent interrater agreement for subscale and total scores. The CY-BOCS Total score showed a significantly higher correlation with a self-report of obsessive-compulsive symptoms (r = .62 for the Leyton survey) compared with the Children’s Depression Inventory (r = .34) and the Children’s Manifest Anxiety Scale (r = .37) (p = .02 and .05 respectively).
Conclusions: The CY-BOCS yields reliable and valid subscale and total scores for obsessive-compulsive symptom severity in children and adolescents with OCD. Reliability and validity appear to be influenced by age of the child and the hazards associated with integrating the data from parental and patient sources.
Comment: The Children’s Yale-Brown Obsessive Com-pulsive Scale (CY-BOCS) is used to evaluate the severity of OCD in children and adolescents. It is a slightly modified version of the original adult instrument, but there are no differences with respect to scoring. The reliability and validity of the adult version is well established.1,2 This study showed that the CY-BOCS has respectable interrater reliability, with better performance in obsessions than compulsions. Results from this study also indicate the importance of acquiring data from multiple sources in the assessment of OCD in children. Then all data, including observation and direct interview with the child, are used to make a rating. To date, the CY-BOCS has been used in treatment studies to measure change over the course of the trial, but this is the first study of its psychometric properties.
References: 1. Goodman WK, Price LH, Rasmussen SA, et al (1989a): The Yale-Brown Obsessive Compulsive Scale: Development, use and reliability. Arch Gen Psychiatry; 46:1006-1011. 2. Goodman WK, Price LH, Rasmussen SA, et al (1989b): The Yale-Brown Obsessive Compulsive Scale: Validity. Arch Gen Psychiatry ; 46:1012-1016.
Controlled stimulant treatment of ADHD and comorbid Tourette’s syndrome: effects of stimulant and dose
Castellanos FX, Giedd JN, Elia J, et al: J Amer Academy Child Psychiatry 1997; 36:589-596
Comment: The use of multiple doses of both methylphenidate and d-amphetamine compared to placebo in three small cohorts of boys was studied. The design used for these three cohorts (n=20 total) was slightly different, but allowed evaluation of both stimulant type and dose level. The study found that a "high" dose of d-amphetamine (0.66 mg/kg/dose) was associated with a 25% increase in tics. Methylphenidate was associated with a 21% increase in tics at the "medium" dose level (0.67 mg/ kg/dose). Individual data were presented graphically for the first ten subjects and showed that five subjects had increased tics on d-amphetamine, 4 on methylphenidate and one on placebo. Three subjects showed decreased tics on "high dose" methylphenidate, and three boys had lower tic scores during the last week of placebo treatment. Mild but consistent increases in tics were observed in ten of thirteen boys followed in the long-term open phase of the study. This study provides additional evidence that some children with TS + ADHD can tolerate treatment with stimulants, though clearly some will show an in-crease in tic symptoms. All available evidence indicates, however, that if tics increase upon exposure to stimulants, they will become reduced when the drug is discontinued.
A controlled trial of deprenyl in children with Tourette’s syndrome and attention deficit hyperactivity disorder
Feigin A, Kurlan R, McDermott MP, et al: Neurology 1996; 46:965-968 A
Abstract: We conducted a double-blind placebo-controlled crossover study to assess the efficacy of deprenyl for attention deficit hyperactivity disorder (ADHD) in children and adolescents with comorbid Tourette’s syndrome (TS). Twenty-four subjects (21 boys, 3 girls; mean age 12 years) were enrolled at two sites (University of Rochester and Baylor College of Medicine). The design included two 8-week treatment periods separated by a 6-week washout period. The primary outcome mea-sures for ADHD and tic severity were total scores on the DuPaul Attention Deficit Hyperactivity Scale (DADHS) and the Yale Global Tic Severity Scale (YGTSS). Fifteen subjects completed the study. The primary analysis revealed no statistically significant beneficial effect of deprenyl on the DADHS (mean improvement 1.3; 95% CI, -2.7 to 5.3; p = 0.50). Further post-hoc analyses revealed, however, that the effect of deprenyl in the first period was substantial (p = 0.02). There was a marginally statistically significant beneficial effect of deprenyl on the YGTSS total score (p = 0.06). Deprenyl may improve both ADHD and tics in children with TS and warrants further study.
Comment: Deprenyl is a selective monoamine oxidase B inhibitor which inhibits the breakdown of dopamine. In addition, deprenyl is metabolized to amphetamine and methamphetamine. In this study, active treatment with deprenyl was started at 5 mg per day and increased to 5 mg bid after one week. Nine subjects dropped out during the first arm of the study. Of these, 6 were randomized to deprenyl and 3 were randomized to placebo. The efficacy of deprenyl was evident in the parallel analysis, but this apparent benefit was not observed in the second treatment period following the six-week washout. Indeed, the group randomly assigned to placebo first showed a small increase in symptoms after crossing over to deprenyl. By contrast the group that received deprenyl first demonstrated a 42% improvement in ADHD symptoms after eight weeks of treatment. The pattern of these results is suggestive of an order effect in that those who received deprenyl first appeared to do better.
Pindolol and methylphenidate in children with attention-deficit hyperactivity disorder: clinical efficacy and side effects
Buitelaar JK, van der Gaag RJ, Swaab-Barneveld H, Kuiper M: J Child Psychology Psychiatry 1996; 37:587-595
Abstract: The purpose of this study was to examine the efficacy and side-effects of pindolol, a β -blocker, in children with attention-deficit hyperactivity disorder (ADHD). Fifty-two ADHD children, 7-13 years old, participated in a prospective double-blind placebo-controlled comparison of pindolol and methylphenidate (MPH). Active treatment was pindolol and MPH: pindolol 20 mg b.i.d. or MPH 10 mg b.i.d. for 4 weeks. The outcome was assessed on the basis of the Abbreviated Conners Rating Scales (ACRS) completed by parents, teachers, and by a psychologist during psychological testing. Pindolol treatment was associated with a higher incidence of paraesthesias and with more intense nightmares and hallucinations than MPH or pla-cebo treatment. These side-effects led to an interim change in design by ending pindolol treatment after 32 participants. Pindolol proved to be just as effective as MPH in decreasing hyperactivity and conduct problems at home, and hyperactivity problems at school. Pindolol, however, had less therapeutic effects than MPH during psychological testing, and failed to affect conduct problems in school. In sum, pindolol was modestly effective in the treatment of ADHD. Safety concerns on troubling side-effects clearly limit the use of it.
Comment: Interest in developing non-stimulant pharmacotherapeutic approaches for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) prompted this comparison of the beta-blocker, pindolol with methylphenidate. As indicated in the abstract, the original design was aborted due to the emergence of hallucinations and nightmares on pindolol in 10% of the first 32 sub-jects. Despite the promising results on the primary symptoms of ADHD, there appear to be limitations to the use of pindolol. Because this study used only a single dose of pindolol, it is unclear whether lower doses would retain the beneficial effects and avoid the adverse side effects.
Dopamine agonist treatment of Tourette disorder in children: results of an open-label trial of pergolide
Lipinski JF, Sallee FR, Jackson C, Sethuraman G: Movement Disorders 1997; 12:402-407
Abstract: This exploratory study was meant to determine the effect of the dopamine (DA) agonist pergolide on Gilles de la Tourette syndrome (GTS) in children and adolescents and to ascertain correlates of pergolide response. Thirty-two outpatients, aged 7-19 years, were systematically assessed in a neuropsychiatric clinic for the presence of GTS and comorbid disorders. After a 6-week open-label, fixed-flexible dosing schedule, response to pergolide on standard GTS severity outcome measures was assessed. Overall, 75% of patients (24/32) had a >50% drop in their tic severity rating from baseline with a mean treatment dosage of 177 ± 61 micrograms/day. Highly signifi-cant (p = 0.0001) baseline to week 6 differences were demonstrated in all tic symptom measures. The presence of restless legs syndrome (RLS) comorbidity (59%) was highly associated with a positive response. These results suggest DA agonism as a strategy, and pergolide in particular, may be a practical form of therapy for GTS. Response predictors of patient comorbid RLS argue for its further study with regard to GTS.
Comment: At low doses, pergolide acts as a selective agonist at dopamine D2 autoreceptors. This effect may reduce dopamine activity in the brain. Based on this rationale, the authors conducted an open trial of pergolide (100 to 300 micrograms per day in three divided doses) in 32 patients with TS and observed that 75% (n=24) had a greater than 50% improvement. The observation that positive clinical response was associated with RLS is of interest as dopamine agonists have been used in the treatment of this condition. The beneficial results of pergolide reported by Lipinski et al stand in contrast to other investigations. Goetz et al,1 evaluated the efficacy of the dopamine agonist, talipexole, in a double-blind, crossover study in 13 adults with TS and reported little benefit (see TSA/ML, 1996). Also, in a recent review, Chappell et al 2 cited results of a pilot study with pergolide in 12 TS patients. Of these, only one patient showed a positive response. Clearly, more study is needed to confirm the findings of this study.
References: 1. Goetz CG, Stebbins GT, Thelen JA: Talipexole and adult Gilles de la Tourette’s syndrome: Double-blind, placebo-controlled clinical trial. Movement Disorders 1994; 9:315-317. 2. Chappell PB, Scahill L, Leckman JF: Future therapies of Tourette syndrome. Neurologic Clinics 1997; 15:429-450.
Neuropsychological correlates of learning disability subtypes in children with Tourette’s syndrome
Yeates KO, Bornstein RA: J International Neuropsychological Society 1996; 2:375-382
Comment: Seventy subjects with TS (6 to 18 years) who were divided into four subgroups: a reading disabled group (n=10); an arithmetic disabled group (n=14); a group with reading and arithmetic disability (n=20); and a non-learning disabled group (n=26). Learning disability of any type was associated with higher level of obsessive-compulsive symptoms. Those in the reading disability or the combined reading and arithmetic disability groups were more likely to have comorbid ADHD. The group with only arithmetic disability showed the least cognitive impairment. Those with both reading and arithmetic disabilities showed the greatest cognitive deficits. The authors propose that reading disability is not more common in TS and is not etiologically related to TS. Arithmetic disabilities, however, may be more common in TS, and thus might be etiologically linked to this disorder.
Neuropsychological status of children with Tourette’s syndrome with and without attention deficit hyperactivity disorder
Schuerholz LJ, Baumgardner TL, Singer HS, Reiss AL, Denckla MB: Neurology 1996; 46:958-965
Abstract: To determine the frequency of learning disabilities (LD) and describe the neuropsychological profile of children with Tourette’s syndrome (TS) with and without attention deficit hyperactivity disorder (ADHD), we analyzed psychosocial, psychoeducational, and neuropsychological data from 65 children between the ages of 6 and 14 years selected from a larger study of LD. Three groups were formed: TS only, TS + ADHD, and TS +/- ADHD. The third group was composed of children whose ADHD status was not as strongly confirmed by the three different instruments used for ADHD diagnosis. From other (non-TS) research projects in the Center, a comparison group of 27 unaffected siblings who had no diagnosis of ADHD was formed. All children were unmedicated at the time of assessment and had the full set of data available for analysis. LDs were present in 23% of the total TS sample, but LD was not present in the TS-only group. All TS groups had scores at or below 1 SD from the mean on measures of choice reaction time, but the TS-only group was significantly poorer on a measure of executive function (letter word fluency).
Comment: This study differed from the research con-ducted by Yeates and Bornstein (see above) in that the comparison groups were defined according to the presence or absence of comorbid ADHD rather than by learn- ing disability status. Nonetheless, the findings are similar. TS alone does not appear to be associated with learning disability. Put another way, the presence of a learning disability is associated with psychiatric comorbidity— especially ADHD. This observation is consistent with a recent report from a clinical series of TS cases which showed that comorbid ADHD was the best prediction of school difficulties.1
References: 1. Abwender DA, Como PG, Kurlan R, et al: School problems in Tourette’s syndrome. Arch Neurology 1996; 53:509-511.
Right hemisphere dysfunction in subjects with attention-deficit disorder with and without hyperactivity
Garcia-Sanchez C, Estevez-Gonzalez A, Suarez-Romero E, Junque C: J Child Neurology 1997; 12:107-115
Abstract: In the present study, we investigate possible right hemisphere dysfunctions in attention-deficit disorder with hyperactivity and attention-deficit disorder without hyperactivity. The right hemisphere performance of 60 teenagers, 16 having attention-deficit disorder with hyperactivity, 9 having attention-deficit disorder without hyperactivity, and 35 controls, selected clinically (DSM-III) and experimentally (through Continuous Performance Test and Paced Auditory Addition Task), with normal IQ were assessed using a wide-ranging battery of visuospatial, visuoperceptive, and visuconstructive functions (Benton’s Line Orientation, Benton’s Visual Retention, Raven’s Progressive Matrices, Wechsler Adult Intelligence Scale [WAIS] Block-Design, Rey’s Complex Figure). Teenagers with attention-deficit disorder with and without hyperactivity per-formed significantly worse than controls. Greater differences were found between subjects with attention-deficit disorder without hyperactivity and controls than between subjects with attention-deficit disorder with hyperactivity and control subjects. Our results seem to be consistent with right-hemisphere dysfunction, especially in subjects with attention-deficit disorder without hyperactivity. Additionally, WAIS Block-Design and Benton’s Line Orientation are the visuospatial tests with the highest discriminant power to differentiate between controls, subjects with attention-deficit disorder without hyperactivity, and subjects with attention-deficit disorder with hyperactivity.
Comment: These results are consistent with the studies by Yeates, Bornstein, Schuerholz, et al. ADHD appears to be associated with visuospatial deficits and poor performance on tests of attention. These deficits are presumed to indicate right-hemisphere dysfunction. Putting together the results of these three studies, it appears that TS alone may be associated with mild right-hemisphere deficits. If the deficit is more severe, the child is more likely to show behavioral signs of ADHD as well.
The Great Smokey Mountains study of youth: goals, design, methods, and the prevalence of DSM-III-R disorders
Costello EJ, Angold A, Burns BJ, et al: Arch Gen Psychiatry 1996; 53:1129-1136
Comment: This study consisted of separate, face-to-face interviews with a parent and the child. Those interviewed were part of a second stage sample that included approximately 800 screen positives and 200 screen negatives from the first stage. The inclusion of screen negatives protects against missing cases of psychiatric disorder and allows a fair estimation of the prevalence of psychiatric disorders in a community sample of children. This study differs from several previous studies in that it provides estimates for three-month prevalence as opposed to life-time prevalence. Depending on the chronicity and course of a given disorder, the difference between lifetime prevalence and three-month prevalence could be substantial. The prevalence of all tic disorders combined was esti-mated at 4.2%, with an approximately 2 to 1 ratio for boys. Although not completely clear from the report, it appears that this estimate of 4.2% included Transient Tic Disorder, Chronic Tic Disorders and TS. Fewer than 5 cases of TS were identified in the sample for a three-month prevalence of 0.1 (± 0.06)% or roughly 1 case per 1000 to 2000. An unexpected finding is this study was a 2% prevalence for ADHD which is considerably lower than most previous studies. No explanation was offered for the lower estimate of ADHD.
Gilles de la Tourette’s syndrome in special education schools: a United Kingdom study
Eapen V, Robertson MM, Zeitlin H, Kurlan R: Neurology 1996; 244:378-382
Abstract: In order to determine the prevalence of tic disorders in children with severe school problems requiring a residential facility and comparison groups of children in regular day schools, we performed direct clinical examinations for the pres-ence of tics and Gilles de la Tourette’s syndrome (GTS) in 20 children from a residential school for emotional and behavioral difficulties (EBD); 25 children from a residential school for learning disabilities: 17 "problem"children (PC) (identified by teachers as having academic or behaviour problems) and 19 normal children (NC) selected at random (using random numbers) from a regular school. Of the EBD students, 65% were judged to have definite tics as compared with 24% of students with learning difficulties (P < 0.05), 6% of PC (P < 0.003) and none of the NC (P < 0.0006) group. Most of the affected students met diagnostic criteria for GTS. Our findings suggest that GTS is commonly associated with the need for special education and that this association is particularly robust for children with severe school problems. In these children, the presence of tics may be an indicator of an underlying dysfunction of neurological development.
Comment: The frequency of tics and TS in this sample of children drawn from a residential school is strikingly different than that observed in the large community survey by Costello, et al (see above). This difference suggests that children with TS are at higher risk for behavioral disorders and learning disabilities. Furthermore, it may have been their behavioral and learn-ing difficulties that prompted referral to specialized treatment settings and not their tics. Indeed, only 1 in 20 subjects diagnosed as having a tic disorder in the study had been previously diagnosed.
Comment: Thirty researchers from eleven centers located in five countries are cooperating in a TSA-funded effort to identify the gene(s) that cause TS. To date, careful clinical assessment of 100 affected sibling pairs and their parents has been completed, and genotyping of family DNA is underway. In anticipation of the need to verify future findings from this first group, TSA is already sup-porting the collection of a second set of 100 sibpairs.
No evidence for a major gene effect of the dopamine D4 receptor gene in the susceptibility to Gilles de la Tourette syndrome in five Canadian families
Barr CL, Wigg KG, Zovko E, Sandor P, Tsui LC: American Journal of Medical Genetics 1996; 67:301-305
Abstract: Gilles de la Tourette Syndrome (TS) is a neuropsychiatric disorder characterized by both motor and vocal tics affecting approximately 1/10,000 females and 1/2000 males. Because of the success of neuroleptics and other agents interact-ing with the dopaminergic system in the suppression of tics, a defect in the dopamine system has been hypothesized in the etiology of TS. In this paper we test the hypothesis that the dopamine D4 receptor (DRD4) is linked to the genetic susceptibility to TS in five families. We tested three polymorphisms in the DRD4 gene and a polymorphism in the closely linked locus, tyrosine hydroxylase (TH). We found no evidence for linkage of DRD4 or TH to TS using an autosomal dominant model with reduced penetrance or using non-parametric methods. The presence of a mutation that results in a truncated non-functional D4 receptor protein was also tested for, but was not observed in these families.
Linkage study of the dopamine D5 receptor gene and Gilles de la Tourette syndrome
Barr CL, Wigg KG, Zovko E, Sandor P, Tsui L C: American Journal of Medical Genetics 1997; 74:58-61
Abstract: A defect in the dopamine system has been hypothesized as the etiological defect in Gilles de la Tourette syndrome (TS). In this report, we test the hypothesis that the dopamine D5 receptor locus (DRD5) is linked to the genetic susceptibility to TS in five families studied in Canada. We tested for linkage to the dopamine D5 receptor gene using a microsatellite polymorphism located in the same cosmid clone. Using an autosomal dominant model with reduced penetrance, we were able to exclude linkage in four of the five families for the TS and chronic multiple tics (CMT) phenotype. Also, no evidence for linkage was found using nonparametric methods in all five families.
Polygenic inheritance of Tourette syndrome, stuttering, attention deficit hyperactivity, conduct, and oppositional defiant disorder: the additive and subtractive effect of the three dopaminergic genes—DRD2, D beta H, and DAT1
Comings DE, Wu S, Chiu C, Ring RH, Gade R, Ahn C, MacMurray JP, Dietz G, Muhleman D: American Journal of Medical Genetics 1996b; 67:264-288
Abstract: Polymorphisms of three different dopaminergic genes, dopamine D2 receptor (DRD2), dopamine beta-hydroxy-lase (D beta H), and dopamine transporter (DAT1), were examined in Tourette syndrome (TS) probands, their relatives, and controls. Each gene individually showed a significant correlation with various behavioral variables in these subjects. The additive and subtractive effects of the three genes were examined by genotyping all three genes in the same set of subjects. For 9 of 20 TS associated comorbid behaviors there was a significant linear association between the degree of loading for markers of three genes and the mean behavior scores. The behavior variables showing the significant associations were, in order, attention deficit hyperactivity disorder (ADHD), stuttering, oppositional defiant, tics, conduct, obsessive-compulsive, mania, alcohol abuse and general anxiety-behaviors that constitute the most overt clinical aspects of TS. For 16 of the 20 behavior scores there was a linear progressive decrease in the mean score with progressively lesser loading for the three gene markers. These results suggest that TS, ADHD, stuttering, oppositional defiant and conduct disorder, and other behaviors associated with TS, are polygenic, due in part to these three dopaminergic genes, and that the genetics of other polygenic psychiatric disorders may be deciphered using this technique.
Studies of the c-Harvey-Ras gene in psychiatric disorders
Comings DE, Wu S, Chiu C, Muhleman D, Sverd J: Psychiatry Research 1996; 63:25-32
Abstract: Herault et al (1993) previously reported a significant association between autism and the larger fragments of the c-Harvey- Ras (HRAS) Bam H1 polymorphism. We have sought to verify this finding and determine if there was any evidence for an association with other psychiatric disorders. Because of its greater sensitivity, we have examined the HRAS Msp 1 polymorphism. We found a just significant increase in the prevalence of the > 2.1 kb alleles in 48 subjects with autism versus 50 control subjects. There was no increase in the preva-lence of the > 2.1 kb alleles in 164 probands with Tourette’s syndrome. Examination of 16 preselected symptom clusters, however, showed a significant trend toward higher scores for obsessive-compulsive and phobic symptoms in > 2.1 kb homo-zygotes. While this locus requires further study, in conjunction with the results of Herault et al., the present findings suggest that genetic defects in HRAS, and possibly other components of the G protein secondary messenger system, may play a role in some psychiatric disorders.
Increased prevalence of the seven-repeat variant of the dopamine D4 receptor gene in patients with obsessive-compulsive disorder with tics
Cruz C, Camarena B, King N, Paez F, Sidenberg D, de la Fuente JR, Nicolini H: Neuroscience Letters 1997/August 1; 231(1):1-4
Abstract: The polymorphism characterized by a varying number of 48 bp repeats (VNTR) in the dopamine D4 receptor (DRD4) gene was examined in 61 obsessive-compulsive disorder (OCD) probands with and without tics. Most of the OCD patients with tics showed at least one copy of the 7-fold variant compared to those affected subjects without tics (91 vs. 48%, respectively, Yates corrected chi2 = 5.54, P = 0.018). Similarly, a higher number of copies of this common variant were detected in the group of probands displaying tics compared to those OCD’s without tics (Yates corrected chi2 = 4.66, P = 0.03). Our study suggests that the seven-repeat allele of the DRD4 gene could be a factor in the phenotypic variance of tics among OCD individuals.
Linkage disequilibrium between an allele at the dopamine D4 receptor locus and Tourette syndrome, by the transmission-disequilibrium test
Grice DE, Leckman JF, Pauls DL, Kurlan R, Kidd KK, Pakstis AJ, Chang FM, Buxbaum JD, Cohen DJ, Gelernter J: American Journal of Human Genetics 1996; 59:644-652
Abstract: Dopaminergic abnormalities are implicated in the pathogenesis of Tourette syndrome (TS) and chronic multiple tics. We used the transmission-disequilibrium test (TDT) method to test for linkage disequilibrium between a specific allele (the seven-repeat allele (DRD4*7R) of the exon 3 VNTR polymorphic site) at the D4 dopamine receptor locus (DRD4) and expression of chronic multiple tics and TS. This particular allele had been shown in functional studies to have different binding properties compared with the other common alleles in this DRD4 polymorphic system. We studied 64 family trios (consisting of an affected person and two parents, at least one heterozygous for DRD4*7R), including 12 nuclear family trios and 52 trios from four large TS kindreds. The DRD4*7R allele was transmitted significantly more frequently than expected (chi 2 TDT ranging from 8.47 [P < .004] to 10.80 [P = .001], depending on breadth of disease definition and inclusion or exclusion of inferred genotypes). Confirmation of this finding will depend on either replication in other samples or the identification of a transmitted functional mutation within this sample.
Comment: Linkage studies of large TS pedigrees have not been successful in identifying the TS gene(s). As a result investigators are resorting to other methods of identifying gene(s) that may be involved in the pathogenesis of TS. Investigators in the few studies cited above have used known genes that may have a role in TS and at-tempted to identify an association between those genes and persons affected with TS. As we see more and more TS genetic studies published, we will likely have many positive studies, negative studies and even studies with contradictory results. We should not be dismayed. Sorting out TS genetics will require many studies. Until we find the TS gene(s) it is probably better to focus on the methodology and the strengths and limitations of each study, rather than focus on the findings per se. None of these investigations cited above is perfect. The studies are included not because they are definitive, but rather because they are part of an expanding database that, cumulatively, will contribute to finding the TS gene(s). The two studies by Barr et al did not identify an associa-tion between D4 and D5 receptor loci in their subject population. Even though Barr et al did not find an association with D4DR loci, Grice and colleagues identified an association between TS and a specific allele of the D4 receptor loci. Nonetheless, the negative finding of Barr et al is not contradicted by Grice et al, but should be seen as complementary. The Grice et al study is important for two reasons. First, it shows a positive association between TS and a gene considered to be a good candidate for TS involvement. The second is somewhat less obvious. For a number of years, investigators have been attempting to find the single gene responsible for TS. Grice et al sug-gest that the D4DR*7R allele may play a role in the development of TS in some individuals with TS. The study does not suggest that the D4DR*7 is the TS gene, but rather it is one among a possible number of other genetic factors associated with the development of TS. The study by Cruz et al is an extension of Grice et al in a population of subjects with OCD. It is especially intriguing that the DRD4*7R allele appears to be associated with subjects with OCD/tics. These two studies support a growing trend away from the idea of a single TS gene to a more complex pattern of inheritance that includes mul-tiple genes and the influence of environmental factors. Comings has hypothesized that TS and its comorbid conditions are caused by multiple genetic defects in serotonin and dopamine metabolism. He has advocated that the only way the TS gene(s) will be identified is by genetic association studies. The two studies cited above reflect his research ideas. The results of these investigations provide preliminary evidence of associations between certain known genetic sites and psychiatric disorders including TS. Comings’ critics most often cite his unique approach to characterizing the clinical features of TS by including a wide range of other conditions as part of the TS pheno-type. This approach to defining the TS phenotype makes it difficult for others to replicate his findings.
Tourette syndrome in a pedigree with a 7;18 translocation: identification of a YAC spanning the translocation breakpoint at 18q22.3
Boghosian-Sell L, Comings DE, Overhauser J: American Journal of Human Genetics 1996; 59:999-1005
Abstract: Tourette syndrome is a neuropsychiatric disorder characterized by the presence of multiple, involuntary motor and vocal tics. Associated pathologies include attention deficit disor-der and obsessive-compulsive disorder (OCD). Extensive linkage analysis based on an autosomal dominant mode of transmission with reduced penetrance has failed to show linkage with polymorphic markers, suggesting either locus heterogeneity or a polygenic origin for Tourette syndrome. An individual diagnosed with Tourette syndrome has been described carrying a constitutional (7;18) chromosome translocation (Comings et al 1986). Other family members carrying the translocation exhibit features seen in Tourette syndrome including motor tics, vocal tics, and OCD. Since the disruption of specific genes by a chromosomal rearrangement can elicit a particular phenotype, we have undertaken the physical mapping of the 7;18 translocation such that genes mapping at the site of the breakpoint can be identified and evaluated for a possible involvement in Tourette syndrome. Using somatic cell hybrids retaining either the der(7) or the der(18), a more precise localization of the breakpoints on chromosomes 7 and 18 have been determined. Furthermore, physical mapping has identified two YAC clones that span the translocation breakpoint on chromosome 18 as determined by FISH. These YAC clones will be useful for the eventual identification of genes that map to chromosomes 7 and 18 at the site of the translocation.
Linkage analysis and exclusion of regions of chromosomes 3 and 8 in Gilles de la Tourette syndrome following the identification of a balanced reciprocal translocation 46 XY, t(3:8)(p21.3q24.1) in a case of Tourette syndrome
Brett PM, Curtis D, Robertson MM, Dahlitz M, Gurling HM: Psychiatric Genetics 1996; 6:99-105
Abstract: Gilles de la Tourette syndrome (GTS) and related disorders such as chronic multiple tics and obsessive compulsive behavior are likely to be genetically transmitted with a Mendelian autosomal dominant mode of transmission. Following our discovery of a patient with GTS who also carried a balanced translocation 46 XY, t(3:8) (p21.3 q24.1), a linkage study of several families was performed covering the areas on chromosomes 3 and 8 implicated by the cytogenetic abnormality in this unique GTS patient. A positive multipoint lod score of 2.9 was obtained on chromosome 3 with markers at the loci RAF1, THRB and D3S11. Subsequently, the genetic map of this region was improved and new polymorphic markers close to our original three markers were identified. With the new map the maxi-mum two-point lod with any marker was reduced to 1.77 at RAF1, and the FASTMAP approximate multipoint lod excluded the likely region of the breakpoint. After constructing a somatic cell hybrid, the original three markers were mapped relative to the break point of the translocation and to other new markers. It was confirmed that the original markers were at least 20 cM away from the position of the break point. In addition, we traced further family members of our translocation GTS proband, and identified affected individuals who did not possess the translocation. We concluded that the translocation was not responsible for the GTS symptoms in our affected proband.
A serotonin receptor gene (5HT1A) variant found in a Tourette’s syndrome patient
Lam S, Shen Y, Nguyen T, Messier TL, Brann M, Comings D, George SR, O’Dowd BF: Biochemical & Biophysical Research Communications 1996; 219:853-858
Abstract: Serotonergic pathway disturbances have been impli-cated in neuropsychiatric disorders such as Tourette’s syndrome (TS), substance abuse, and depression. In order to search for the presence of an association between these neuropsychiatric disorders and particular serotonin receptors isolated from these patients, we have started to analyze the structure of these receptor genes. We now report that a missense nucleotide change in the 5HT1A receptor gene produces a variant form of the 5HT1A receptor (Arg(219) to Leu) identified in DNA extracted from a TS patient. Also, in several DNA samples examined, both in controls and in the patients, we found a second missense nucleotide change which resulted in an amino acid change (Asn(417) to Lys) located in the carboxyl tail of the receptor. Several other polymorphic changes have been reported previously in the hu-man 5HT1A receptor and we have also confirmed these findings in our samples.
Comment: Another approach to locating the TS gene is to find persons with TS who have readily identifiable genetic abnormalities and then assess whether the genetic abnormality appears to cosegregate with TS in other fam-ily members. The study of Brett et al did not find an asso-ciation between TS and a balanced reciprocal transloca-tion. The study of Boghosian-Sell et al did identify an association between a 7;18 translocation and TS in one family and describes efforts to do a comprehensive physi-cal map of the area of the translocation. Using a somewhat different approach, Lam et al specu-lated that abnormalities in serotonin metabolism may be important in TS. In the process of analyzing the structure of serotonin receptor genes in affected individuals, the authors identified abnormalities in these receptors and confirmed the findings of others. Although this study presents preliminary evidence for an association between serotonin receptor abnormalities in some subjects with TS, it has not demonstrated that those abnormalities are part of the underlying pathology of TS.
Sex of parent transmission effect in Tourette’s syndrome: evidence for earlier age of onset in maternally transmitted cases suggests a genomic imprinting effect
Eapen V, O’Neill J, Gurling HM, Robertson MM: Neurology 1997; 48:934-937
Abstract: Parent of origin effects caused by genomic imprinting may influence the phenotypic expression of a number of herit-able human disorders. To test this phenomenon in Tourette’s syndrome (TS), we studied 437 first degree relatives systematically ascertained through 57 probands. We compared age at onset, age at diagnosis, and phenotypic expressions as observed in the diagnosis of TS, chronic motor tics, and obsessive com-pulsive behavior in the offspring of affected males with the offspring of affected females. Of the 437 subjects, 16.7% had matrilineal inheritance and 13.9% had patrilineal inheritance, as determined by family history methodology. Chi-square analysis of the different phenotypic expressions and sex of the transmit-ting parent failed to provide evidence of significant group differences. We found no significant differences in the age at diagno-sis either. However, the maternally transmitted offspring showed a significantly earlier age at onset. This points to a parent of origin effect on the putative TS gene that could be explained by meiotic events or even intrauterine environmental influences. These findings may help explain the hitherto conflicting reports about the nature of genetic transmission in TS, and suggest a need to re-examine family data separately for maternally and paternally transmitted cases, taking into account the possible role of imprinting.
Bilineal transmission and phenotypic variation of Tourette’s disorder in a large pedigree
McMahon WM, van de Wetering BJ, Filloux F, Betit K, Coon H, Leppert M: Journal of the American Academy of Child & Ado-lescent Psychiatry 1996, 35:672-680
Abstract: Objective: Variability in the clinical phenotype of Tourette’s disorder (TD) was assessed in a single large family, with a focus on the influence of bilineal transmission.
Method: Tics, obsessive-compulsive symptoms, and attention-deficit symptoms were evaluated through interview and standardized checklists for 175 descendants and 16 spouses who married into a single four-generation pedigree.
Results: Some form of tic disorder was diagnosed in 67% of descendants and 44% of married- in spouses. TD was found in 36% of descendants and in 31% of married-in spouses. Impairment was minimal in most cases, but age at onset and location and number of tics were typical of TD described in clinic samples. Obsessive-compulsive symptoms were found in 38% of descendants and 62% of those with current TD, but obsessive- compulsive disorder was found in only four individuals. Attention- deficit hyperactivity disorder occurred in 25% of children. Multivariate analysis indicated that offspring of two parents with tic disorders manifested significantly more lifetime tics, more severe categories of tic disorders, and an earlier age at onset for TD compared with offspring of one or no affected parents.
Conclusions: TD in this family is most often a mild disorder but otherwise similar to published clinical cases. Increased morbidity is significantly associated with bilineality. The frequency and impact of bilineality raise questions about possible assortative mating, the prevalence of TD, and assumed mechanisms of transmission and etiology.
Family study and segregation analysis of Tourette syndrome: evidence for a mixed model of inheritance
Walkup JT, LaBuda MC, Singer HS, Brown J, Riddle MA, Hurko O: American Journal of Human Genetics 1996, 59:684- 693
Abstract: To investigate the transmission of Tourette syndrome (TS) and associated disorders within families, complex segregation analysis was performed on family study data obtained from 53 independently ascertained children and adolescents with TS and their 154 first-degree relatives. The results suggest that the susceptibility for TS is conveyed by a major locus in combination with a multifactorial background. Other models of inheritance were definitively rejected, including strictly polygenic models, all single major locus models, and mixed models with dominant and recessive major loci. The frequency of the TS susceptibility allele was estimated to be .01. The major locus accounts for over half of the phenotypic variance for TS, whereas the multifactorial background accounts for approximately 40% of phenotypic variance. Penetrance estimates suggest that all individuals homozygous for the susceptibility allele at the major locus are affected, whereas only 2.2% of males and 0.3% of females heterozygous at the major locus are affected. Of individuals affected with TS, approximately 62% are heterozygous and approximately 38% are homozygous at the major lo-cus. While none of the families had two parents affected with TS, 19% of families had two parents affected with the broader phenotype, which includes TS, chronic tic disorder, or obsessive- compulsive disorder.
Comment: A number of studies published this past year have focused on the clinical phenotype and models of inheritance for TS. Eapen et al suggest that some of the controversy surrounding the model of inheritance for TS may be related to whether the parent passing on the gene was the subject’s mother or the father. Rarely have family studies differentially analyzed their data depending on whether the father or the mother was affected. One of the problems with the published family studies is that they have small sample sizes that make it difficult to do such analyses. McMahon et al raise the issue of assortative mating in TS. In most TS genetic studies it is presumed that spouses married randomly. In McMahon’s large mulitgenerational pedigree 16 spouses who married into the pedigree were also affected with TS or related conditions. In this report McMahon noted that having two parents affected with TS is associated with more severe symptoms and earlier age of onset. In the largest published family study and segregation analysis, Walkup et al identified a complex model of inheritance for TS. The model includes the contribution of a major gene as well as other genes and environmental factors. This model is substantially different from the prevailing autosomal dominant model of inheritance for TS. The major gene for TS identified here is more common and functions as an intermediate between dominant and recessive—persons with one copy of the gene are at some risk for developing TS, but those with two copies of the gene are at much greater risk for TS. This model predicts that the majority of individuals with one copy of the gene are unaffected, and that a substantial portion of the TS population actually has two copies of the gene—one from each parent. Also, the model is consistent with observations of two affected parents in some TS families, and is also consistent with some subjects with TS having no affected parents.
Group A streptococcal infections and childhood neuropsychiatric disorders: relationships and therapeutic implications
Allen A: CNS Drugs 1997; 8:267-275
Summary: Recently an hypothesis concerning the pathophysiology of some cases of pediatric-onset obsessive compulsive disorder (OCD) and/or tic disorders has been proposed. Infections with group A β -hemolytic streptococci, and perhaps other agents, are believed to trigger an immune response that cross reacts with neurons in the basal ganglia, disrupting their function and resulting in neuropsychiatric symptoms. Therapeutic possibilities derived from this model have been proposed in terms of four sequential events that are hypothesized to occur: (i) infection; (ii) generation of an immune response; (iii)reversible injury to the basal ganglia; (iv) irreversible injury to the basal ganglia. However, at the present time, research supporting any specific therapeutic approach is extremely limited or nonexistent. Comment: This overview of the association among infectious agents, autoimmune processes and childhood onset neuropsychiatric disorders covers a wide range of issues not usually addressed in data-based papers on these subjects. Of particular interestis the discussion of the potential for treatment interventions based on a comprehensive understanding of immunology. Dr. Allen is a clinician who is knowledgeable about this issue and he is familiar with the treatment trials that have been undertaken to date. His assertion that there are no data supporting any treatment intervention at this time needs to be taken seriously by clinicians who are considering immunological interventions in children with TS or OCD.
B lymphocyte antigen D8/17: a peripheral marker for childhood-onset obsessive-compulsive disorder and Tourette’s syndrome
Murphy T, Goodman W, Fudge M, et al: Am J Psychiatry 1997; 402-407
Abstract: Objective: It has been hypothesized that Sydenham’s chorea, a major manifestation of rheumatic fever, may provide a medical model for obsessive-compulsive disorder and associated conditions, such as Tourette’s syndrome. Monoclonal antibody D8/17 identifies a B lymphocyte antigen with expanded expression in nearly all patients with rheumatic fever and is thought to be a trait marker for susceptibility to this complication of group A streptococcal infection. The authors investigated whether D8/ 17 expression is greater than normal in some forms of obsessive-compulsive disorder and Tourette’s syndrome.
Method: By immunofluorescence techniques, 31 patients with childhood-onset obsessive-compulsive disorder and/or Tourette’s syndrome or chronic tic disorder and 21 healthy comparison subjects were evaluated for percentage of D8/17-positive B cells. None had rheumatic fever or Sydenham’s chorea. Levels of antineuronal antibodies and streptococcal antibodies were also determined.
Results: The average percentage of B cells expressing the D8/17 antigen was significantly higher in the patients (mean = 22%, SD = 5%) than in the comparison subjects (mean = 9%, SD = 2%). When classified categorically, all patients but only one comparison subject were D8/17 positive. No difference between groups in the presence of antineuronal antibodies or high streptococcal titers was found.
Conclusions: Patients with childhood-onset obsessive-compulsive disorder or Tourette’s syndrome had significantly greater B cell D8/17 expression than comparison subjects despite the absence of documented Sydenham’s chorea or rheumatic fever. These findings suggest that D8/17 may serve as a marker for susceptibility among some forms of childhood-onset obsessive-compulsive disorder and Tourette’s syndrome, as well as rheumatic fever or Sydenham’s chorea.
Comment: The investigators studied a consecutive series of childhood onset TS/OCD subjects for the presence of the D8/17 cell surface antigen. The B lymphocyte cell surface antigen D8/17 is a putative marker for rheumatic fever. The results of the study are intriguing; 97% of subjects were positive for D8/17 compared to 5% of controls. This percentage of D8/17 positives is similar to that seen in subjects with rheumatic fever. To date, no other clinical populations have shown such a high frequency of D8/17 positives that would suggest a similarity between persons who have had rheumatic fever and subjects with childhood onset TS/OCD. Clearly these results require replication and suggest that more research is needed concerning the potential importance of the D8/17 antigen as a marker for TS/OCD.
Children with PANDAS (pediatric autoimmune neuropsychiatric disorders associated with strep infections) are identified by a marker associated with rheumatic fever
Swedo S, Leonard H, Mittelman B, Allen A, Rapoport J, Dow K, et al: Am J Psychiatry 1997; 154:110-112
Abstract: Objective: The authors’ goal was to determine whether a trait marker of rheumatic fever susceptibility (labeled D8/17) could identify children with pediatric autoimmune neuropsychiatry disorders (obsessive-compulsive disorder and tic disorders) associated with streptococcal infections (PANDAS).
Method: Blood samples obtained from 27 children with PAN-DAS, nine children with Sydenham’s chorea, and 24 healthy children were evaluated for D8/17 reactivity. Individuals were defined as D8/17 positive if they had 12% or more D8/17+ cells.
Results: The frequency of D8/17-positive individuals was significantly higher in both patient groups than it was among the healthy volunteers: 85% of the children with PANDAS and 89% of the children with Sydenham’s chorea, compared with 17% of the healthy children, were D8/17 positive. Further, the mean number of D8/17+ cells was similar in the two patient groups and was significantly higher in these groups than in the group of healthy children.
Conclusions: These results suggest that there may be a subgroup of D8/17-positive children who present with clinical symptoms of obsessive-compulsive disorder and Tourette’s syndrome, rather than Sydenham’s chorea, but who have similar poststreptococcal autoimmunity.
Comment: Swedo and colleagues were first in the modern era to make the connection between Sydenham’s chorea and neuropsychiatric symptoms—specifically obsessive compulsive symptoms. Their more recent efforts have focused on children who develop tic and obsessive compulsive symptoms in the context of a recent streptococcal infection, so called PANDAS. Children with PANDAS appear to be a subgroup of a larger population of children with TS/OCD. A group of children who met their diagnostic criteria (see editorial) for PANDAS and controls were assessed for the presence of the D8/17 cell surface antigen. The majority of children characterized with PANDAS were positive for the D8/17 antigen compared to about 20% of controls which suggests an association between PAN-DAS and the D8/17 marker.
Alternative Therapies and Tourette Syndrome
Alternative therapies involve a wide range of treatments and have become a growing movement in health care that not only involve specific treatments, but bespeak a significant change in the attitude of the general public toward medical care. Increasingly, practitioners are being asked about the safety and efficacy of homeopathic remedies, herbal preparations, mineral supplements and specific dietary programs—whether tried in combination with more traditional pharmacotherapy or taken alone. While some may argue that forays into such alternative remedies should be primarily "results" driven, the attitude of the medical professionals may also be an important element in the therapeutic equation. In the absence of clear guidance from research data on the safety and efficacy of alternative treatments, clinicians must find ways to discuss these treatments with patients and their families. Too often queries about such treatments are met with "there are no data about the safety or efficacy of this substance." In a recent issue of a newsletter de-voted to alternative therapies (Latitudes, Vol. 3 No. 1), I appealed for more collaborative studies, and pointed out that such investigations take time and considerable resources. Clearly, this response is of little help to today’s physician endeavoring to respond to patients’ questions about these therapies. Regularly, I am struck by the intensity of my patients’ feelings when such questions are raised. Typically they have experienced multiple failures of traditional medications, or they have endured intolerable levels of side effects from these interventions. It should be noted that those who are doing well with minimal or no side effects rarely request significant changes in their medical care.) These individuals need to be heard, their discouraging experience needs to be validated, and above all, they need to find relief for their symptoms. A righteous or dismissive attitude by physicians is likely to be counterproductive. Rather, we should be forthcoming about the limitations of our knowledge, and offer our patients choices based on the best information available to us at the present time. This approach allows us to work with our patients in a mutual quest for symptom relief. By being open minded we are not necessarily undermining patient’s perceptions of our level of expertise, but rather we are indicating a willingness to provide them with choices to help focus on the probabilities of success and/or complications related to a particular intervention. There are those who regard the environmental ecology movement as one that takes an extreme position. Actually, collected data on potential treatments that include the influence of environmental factors should be welcomed. This information will serve as a better basis for discussions with our patients about a variety of treatment options.
— K. Rickler, M.D. A member of TSA’s Medical Advisory Board, neurolo-gist Kenneth Rickler, M.D. serves as liaison to the TSA for guidance on issues of alternative and complementary therapies.
Cohen DJ, Leckman JF, Pauls D: "Neuropsychiatric disorders of childhood: Tourette’s syndrome as a model," Acta Paediatrica Supplement July 1997, 422:106-11
Leckman JF, Peterson BS, Anderson GM, Arnsten AF, Pauls DL, Cohen DJ, "Pathogenesis of Tourette’s syndrome," Journal of Child Psychology & Psychiatry & Allied Disciplines 1997, 38:119-142
Palumbo D, Maughan A, Kurlan R, "Hypothesis III: Tourette syndrome is only one of several causes of a developmental basal ganglia syndrome," Archives of Neurology April 1997,54(4):475-83
Robertson MM, Stern JS, "The Gilles de la Tourette syndrome," Critical Reviews in Neurobiology 1997, 11(1):1-19
Comment: A number of reviews articles have been published this year. All provide comprehensive overviews of TS. The article by Palumbo, Maughan and Kurlan is the third in a series reflecting Dr. Kurlan and colleagues’ view of TS. This series is more conceptual than most other review articles on TS, and provides insights into the theoretical mindset of one of the premiere research groups focusing on TS.
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