PSYCHIATRY ALERTS

CHILD & A DOLESCENT PSYCHIATRY ALERTS Pediatric Autoimmune Neuropsychiatric Disorder (PANDAS) Collection PANDAS: Diagnosis and Treatment A study has found that pediatric autoimmune neuropsychiatric disorder associated with streptococcus is often inappropriately diagnosed in community settings and these patients then receive unwarranted antibiotic and immunosuppressant treatment for obsessive compulsive disorder (OCD) and tics. Background: PANDAS is a controversial diagnosis, and the pathogenesis is unclear. There are no validated diagnostic criteria for PANDAS; however, the authors who described the first cases proposed 5 working criteria for diagnosing the disorder (see below). Antibiotics and immunomodulatory therapies have been studied in PANDAS but results have been mixed, and present guidelines limit their use to treatment of acute infections and research protocols, respectively. Working Criteria for PANDAS diagnosis Presence of DSM-IV OCD and/or tic disorder Onset between age 3 years and puberty Episodic course of symptom severity Temporal association between onset and/or exacerbation with a confirmed group A β-hemolytic streptococcus (GABHS) infection Neurological abnormalities such as tics or choreiform movements (but not chorea) during exacerbation Methods: Study participants were 176 patients aged <21 years who were treated at the Institute for Tourette and Tic Disorders at the New York University Child Study Center. The clinic used the 5 criteria above. Most patients (n=124) were male, and the mean age at intake was 11 years. Patients’ medical records were evaluated to determine the diagnosis for which they were referred to the specialty clinic (i.e., PANDAS, non-PANDAS), any treatment they had received, and laboratory evidence for GABHS infection. Results: Of the 176 patients, 31 had received a diagnosis of PANDAS in a community setting. On evaluation at the clinic, the diagnosis was confirmed in only 12 patients (39%). In the other 19 cases the diagnosis had been made often without laboratory evidence of the temporal association between GABHS and symptoms. Antibiotic treatment had been prescribed for 27 of the 31 patients diagnosed in the community; 22 of these patients did not have laboratory confirmation of GABHS. Two patients were treated with steroids and intravenous immunoglobulin. Conventional pharmacotherapy for tics (e.g., alpha-adrenergic agonists, neuroleptics) and OCD (e.g., SSRIs) were prescribed for 19 of the 31 patients (63%). Patients with confirmed PANDAS at the clinic were significantly more likely to have received these treatments

than those in whom the diagnosis was inappropriate (92% vs 42%). Gabbay V, Coffey B, Babb J, Meyer L, et al: Pediatric autoimmune neuropsychiatric disorders associated with streptococcus: comparison of diagnosis and treatment in the community and at a specialty clinic. Pediatrics 2008;122 (August):273–278. From New York University School of Medicine, New York. From Child & Adolescent Psychiatry Alerts 2008;10 (September). Childhood Disorders and Strep Infection Children with obsessive-compulsive disorder, Tourette's syndrome, or chronic tic disorder were more likely than controls to have had a recent streptococcal infection before onset of these disorders. This finding lends support to the proposition that neuropsychiatric disorders can arise or partly arise as a result of a postinfectious autoimmune phenomenon. Background and Methods: To date, the concept of PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus infection) has been supported by case series. A recent prospective study found that children in the study with symptom exacerbations, were not associated with acute streptococcus infection. The present case-control study was conducted in a large HMO with about 75,000 enrolled children aged 4 to 13. The investigators identified patients with potential onset of OCD, Tourette's syndrome, or chronic tic disorder, excluding those receiving stimulant medication for ADHD. After reviewing the charts to confirm the diagnosis, 144 patients were included in the analysis. Each patient was matched to up to 5 controls for age, sex, and other variables. Past exposure to streptococcal infection was determined from laboratory records. Results: Seventy-one percent of the patients were male. Symptom onset for the neurologic disorder was typically between ages 4 to 6, and diagnosis typically occurred at ages 7 to 10. Patients with the disorders had a 2-fold greater likelihood of streptococcal infection in the 3 months before symptom onset than controls and also a 2-fold higher risk in the past 12 months. Results were also 2-fold higher when the exposure was limited to Group A β-hemolytic strep and when each disorder was examined separately. The authors also examined the effect of multiple recent strep infections. Patients with Tourette's syndrome were 13 times as likely to have more than 1 infection in the past 12 months as controls. Associations of the other disorders with multiple infections were smaller and not statistically significant. Discussion: The hypothesis that streptococcal infection directly leads to neurological disorders in children is unproven. It is supported by the finding of antineuronal antibodies in children with presumed PANDAS and by other immunologic findings. The present study is the first population-based epidemio- logic study of PANDAS. It suggests that the disorders triggered by streptococcal infection have onset relatively quickly, within 3 months of infection. Mell LK, Davis RL, Owens D: Association between streptococcal infection and obsessive-compulsive disorder, Tourette's Syndrome, and tic disorder. Pediatrics 2005;116 (July):56-60. From the Pritzker School of Medicine, University of Chicago, Chicago, Ill., and other institutions. Funded by the Group Health Cooperative. From Child & Adolescent Psychiatry Alerts 2005;7 (October). PANDAS Symptoms in Pediatric Practice Children with confirmed group A β-hemolytic streptococcal infection did not appear to be at increased risk for development of symptoms of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection.1 Methods: This study was conducted to determine whether a hypothetical mild variant of PANDAS could be detected in pediatric practice. Patients, aged 4–11 years, had throat cultures obtained during a single group A strep season. The sample included 411 symptomatic children who had strep infection, 207 with non-streptococcal acute respiratory illness ("presumed viral" etiology), and 196 patients seen for well- child care. Children with strep, confirmed by rapid testing, were prescribed antibiotics at the time of the initial examination. All patients were assessed for neuropsychiatric symptoms at the baseline visit and at 2 and 12 weeks. The study authors developed a parent questionnaire about the recent onset of 20

unusual child behaviors and a child questionnaire, administered either orally or in writing, about inter- nalizing or anxious thoughts and obsessive-compulsive symptoms. The authors defined a mild PANDAS variant as 2 or more symptoms on either the parent or child questionnaire. Results: Questionnaires were completed by 84% of parents at 2 weeks and 78% of parents at 12 weeks and by somewhat smaller proportions of children. At baseline, parents of children with strep reported the recent onset of several neuropsychiatric symptoms (i.e., inattentiveness; fidgetiness; clinginess; unusual noises) more often than parents of well children. However, there were no significant differences in these symptoms between children with confirmed strep infection and those with presumed viral illness. Also according to parent reports, rates of obsessive-compulsive symptoms and tics were not elevated in either group of ill children. Symptom rates indicated by child reports did not differ significantly between groups. The 3 groups did not differ in rates of symptom onset over time. Children with strep infection were not at increased risk for onset of a mild PANDAS variant compared with well children, and parents of children with symptomatic strep did not report higher rates of transient, lasting, or worsening behavior problems than other groups. Discussion: The observation of increased behavioral symptoms in ill children, regardless of the etiology, is consistent with previous reports. The study has a sufficient sample size to detect a 10% higher rate of mild PANDAS in children with strep than in those without. The study may have failed to detect an increased rate because treatment of all children with strep with antibiotics may have prevented the emer- gence of PANDAS symptoms. Alternatively, the variant may not exist or may be too rare to detect in a sample of this size. Yet another explanation for the negative results is the suggestion, supported by previous research, that PANDAS is associated with asymptomatic strep infection.2 Editorial:3 PANDAS is uncommon enough in general pediatric practice that use of the questionnaires in children with strep would identify more false positives than children with the disorder. The questionnaires might be more useful in children with a higher a priori risk of PANDAS: those seen in a psychiatric or neurological practice that specializes in obsessive-compulsive disorder or tic disorders. 1Perrin E, Murphy M, Casey J, Pichichero M, et al: Does group A β-hemolytic streptococcal infection increase risk for behavioral and neuropsychiatric symptoms in children? Archives of Pediatric and Adolescent Medicine 2004;158 (September):848–856. From the University of North Carolina, Chapel Hill; and other institutions. Funded by the Robert Wood Johnson Clinical Scholars Program; and the NIH. 2Murphy M, et al: PANDAS in primary care practice: presenting complaints, clinical and lab findings of 25 patients with new onset PANDAS [abstract]. Pediatric Research 2002;51:277A. 3March J: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS): implications for clinical practice (editorial). Archives of Pediatric and Adolescent Medicine 2004;158 (September):927–929. From Duke University Child and Family Study Center, Durham, N.C. From Child & Adolescent Psychiatry Alerts 2004;6 (November). New Strep Infections and Symptom Exacerbations In most children with Tourette's syndrome or obsessive-compulsive disorder (OCD), acute streptococcal infections were not found to be associated with symptom exacerbations. Methods: The relationship between neuropsychiatric symptom exacerbation and new group A β- hemolytic streptococcal (GABHS) infection was followed in 30 patients (aged 7–17 years) with OCD and/or Tourette's syndrome. At baseline, 8 of the patients met criteria for probable PANDAS. Repeated serologic testing for newly-acquired GABHS infection was performed in the 30 patients and in 19 healthy comparison subjects. Nonspecific markers of acute inflammation and D8/17 reactive B-lymphocytes (a marker of rheumatic fever) were also measured. Tic and OCD symptoms were evaluated monthly using the Yale Global Tic Severity Scale and the Yale-Brown Obsessive-Compulsive Scale. Results: At baseline, antistreptococcal antibody levels were not elevated in subjects compared with controls but patients with OCD or tics had higher levels of nonspecific markers of immune activation and D8/17-expressing cells. However, there was no relationship between these immunologic findings and

symptom severity either at baseline or longitudinally. During follow-up, serologic evidence of new GABHS infection was not found to be correlated with symptom exacerbation. A total of 16 patients had an exacerbation of neuropsychiatric symptoms. These occurred 1–5 months after either a GABHS infection or an increase in immune activation in 6 of the patients (all males). Among these patients, 3 had been identified with probable PANDAS at baseline. Although a small number of exacerbations were preceded by GABHS infections, most were not. Therefore, the infection does not appear to be an important factor in the onset or course of tics or OCD in most patients with these disorders. These results do not rule out a possible relationship between infection and exacerbation in a subset of children with neuropsychiatric disorders. This is the first larger scale prospective study that has systematically followed GABHS infections and symptom exacerbations. Luo F, Leckman J, Katsovich L, Findley D, et al: Prospective longitudinal study of children with tic disorders and/or obsessive- compulsive disorder: relationship of symptom exacerbations to newly acquired streptococcal infections. Pediatrics 2004;113 (June):578–585. From Yale University, New Haven, Conn.; and New York Medical College, Valhalla, N.Y. Funded by the Tourette Syndrome Association; and other sources. From Child & Adolescent Psychiatry Alerts 2004;6 (August). PANDAS Remains Controversial The validity of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection as a clinical diagnosis was the subject of a recent debate. The 5 proposed NIMH diagnostic criteria for PANDAS (see box below) were reviewed by 1 group who concluded the PANDAS hypothesis remains unproven.1 A second group who had reported the first 50 cases of PANDAS responded to the criticisms and presented recommendations for diagnosis and treatment.2 NIMH Diagnostic Criteria for PANDAS According to Group I, the clinical boundaries of the syndrome have not been scientifically validated. Although originally 1. Presence of OCD or a tic disorder. proposed to describe tics or obsessive-compulsive disorder 2. Onset between 3 years of age and the (OCD) associated with streptococcal infection, some research beginning of puberty. has suggested PANDAS should include poststreptococcal ADHD, anorexia nervosa, and other neuropsychiatric 3. Abrupt onset or a course characterized syndromes. In addition, symptom severity necessary to make by dramatic exacerbations. a diagnosis has not been established. Neither a specific clinical course nor a temporal association with streptococcal infection 4. Onset or exacerbation is temporally has been adequately documented. Also, the proposed range of related to infections with GABHS. age for onset, 3–12 years, includes the peak risk periods for both group A strep infections and tic/OCD onset. Given the 5. Abnormal results of neurologic examina- high incidence of strep infections and prevalence of carrier tion (hyperactivity, choreiform move- status in school-aged children as well as the lack of established ments, and/or tics) during exacerbation. time boundaries for the association, the symptoms can not definitively be attributed to PANDAS. Finally, the requirement for children with PANDAS to have demonstrable neurologic abnormalities is a difficult diagnostic problem and may result in including some children with Sydenham's chorea, another strep-related illness. Faced with these diagnostic uncertainties, the Group I authors do not recommend laboratory testing to confirm PANDAS. They suggest only the tics and OCD symptoms be addressed and treated with appropriate pharmacotherapy or cognitive behavioral therapy. The benefit of antibiotics in suspected PANDAS is unproven and immunomodulating therapies should be reserved for participants in clinical trials. The Group II authors, who reported the first cases of PANDAS, argue that the diagnostic criteria have functioned effectively to identify homogeneous groups of patients who respond to novel preventive and treatment strategies. The abrupt symptom course of PANDAS, for which the characteristics and severity required for diagnosis are defined in the DSM, is clearly distinct from the undulating course of non- PANDAS tics and OCD and clearly correlated with antibody titers. In addition, choreiform movements,

which are present in 95% of children with PANDAS, are distinctly different from the choreatic movements associated with Sydenham's chorea; moreover, cases of PANDAS are not merely missed cases of Sydenham's chorea. Because historical data show poststreptococcal sequelae are uncommon before age 3 years and after age 12 years, they feel the PANDAS age range is biologically relevant. Group II recom- mends obtaining throat cultures or antibody titers in children with abrupt onset or exacerbation of tics/OCD and serial antistreptococcal antibody titers as needed. Antibiotics are indicated only to treat acute infection, but clinical trials of prophylactic use are underway. They also recommend tics and OCD be treated with standard therapies. A controlled clinical trial found immunomodulating therapies (IV immunoglobulin and therapeutic plasma exchange) effective in 29 children with severe PANDAS and immunomodulators are now considered acceptable as second-line or adjunctive treatment in acutely and severely affected children. 1Kurlan R, Kaplan E: The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) etiology for tics and obsessive-compulsive symptoms: hypothesis or entity? Practical considerations for the clinician. Pediatrics 2004;113 (April):883–886. From the University of Rochester School of Medicine, Rochester, N.Y.; and the University of Minnesota School of Medicine, Minneapolis. Funded by the NIH; and the National Institute of Neurological Disorders and Stroke. 2Swedo S, Leonard H, Rapoport J: The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) subgroup: separating fact from fiction (commentary). Pediatrics 2004;113 (April):907–911. From the NIMH, Bethesda, Md.; and Brown University, Providence, R.I. From Child & Adolescent Psychiatry Alerts 2004;6 (June). Detecting PANDAS in Patients with OCD In children with obsessive compulsive disorder, symptom fluctuations were associated with changes in group A streptococcal antibody titers. This finding adds support to the existence of pediatric autoimmune neuropsychiatric disorders associated with streptococcus. Methods: The 25 study subjects presented to a specialty clinic with both OCD and tics (n=21), OCD only (n=3), or tics only (n=1). Neuro-psychiatric symptoms were assessed at 6-week intervals (on at least 6 occasions) using the Children's Yale-Brown Obsessive Compulsive Scale (C-YBOCS) and the Yale Global Tic Severity Score (YGTSS). The clinical course of OCD/tics was categorized as episodic (remitting fully between episodes); sawtooth (remitting partially between episodes); stable (regardless of severity); or remitted or remitting. At each clinic visit, blood was drawn to measure group A streptococcal antibody titers. At study entry, antibody titers were elevated in 11 of 15 children who were later characterized as having an episodic or sawtooth course and in 3 of 10 with a stable or remitting course. Patients with episodic/sawtooth symptoms were mostly male (10 of the 15), three-fourths had comorbid ADHD, and the average duration of OCD symptoms was shorter than in children with a stable/remitting clinical course. Results: During follow-up, 15 patients experienced 30 clinically important exacerbations of OCD or tics. All 15 patients had been classified as having an episodic or sawtooth course. Antibody titer increases were detected at 30 follow-up visits in 18 patients. Significantly more of the increases occurred in patients with a fluctuating symptom course than in children with chronic or remitted disease. Increases in titer were correlated with worsened symptoms at the following visit. OCD symptoms were more strongly associated with antibody fluctuations than were tics. Murphy T, Sajid M, Soto O, Shapira N, et al: Detecting pediatric autoimmune neuropsychiatric disorders associated with streptococcus in children with obsessive-compulsive disorder and tics. Biological Psychiatry 2004;55 (January 1):61–68. From the University of Florida, Gainesville. Funded by the NIMH. From Child & Adolescent Psychiatry Alerts 2004;6 (March). Overview of Anxiety Disorders The spectrum of anxiety disorders includes separation anxiety disorder; specific phobias; generalized anxiety disorder; social phobia; panic disorder; posttraumatic stress disorder; obsessive-compulsive disorder; and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection

(PANDAS). Each has distinct diagnostic features and requires specific treatment. Separation anxiety disorder typically has onset between the ages of 4 and 8 years and may be developmentally continuous with panic disorder in adulthood. School refusal is common in children with separation anxiety disorder. In a controlled trial, cognitive-behavioral treatment (CBT) reduced fear, anxiety, depression, and coping scores and improved school attendance. SSRIs also have demonstrated efficacy in a controlled trial. Specific phobias have onset between the ages of 5 and 8 years and research has not determined whether they are learned or "hard-wired." Pharmacotherapy is not recommended for children with specific phobias. Treatment consists of CBT and psychoeducation focused on exposure and management and self- control strategies. Generalized anxiety disorder often develops between the ages of 6 and 10 years and is often comorbid with depression, possibly reflecting shared genetic susceptibility to the 2 conditions. Patients should be monitored for development of depression. Both CBT and SSRIs are effective in treating generalized anxiety disorder and early intervention could reduce later morbidity from depression. Worry-related symptoms (e.g., intolerance of uncertainty, cognitive avoidance) of generalized anxiety disorder improved in a series of 7 patients who received CBT, and treatment with sertraline was effective and well tolerated in a small controlled trial. Studies of extended-release venlafaxine and buspirone are currently underway. Social phobia onset usually occurs at age 11–13 years and evidence exists that behavioral inhibition observed earlier in life may predispose individuals to social phobia. Individual CBT has not been studied in children with social phobia and results with group CBT have been mixed. In small open-label studies, sertraline reduce social phobia symptoms in 65% of patients, and the combination of citalopram and psychoeducation produced improvement in 83% of patients. Preliminary reports suggest efficacy for paroxetine and extended-release venlafaxine. Panic disorder is rare in children and relatively uncommon in adolescents. Panic disorder may be associated with negative outcomes including other anxiety disorders, mood disorders, substance abuse, and suicidality. Although widely used, there are no published studies supporting CBT or SSRI therapy in pediatric panic disorder. Benzodiazepines may be useful for relief of acute episodes. Post-traumatic stress disorder developed in about one-third of a group of children under observation after a specific trauma. However, little is known about its prevelance in unselected populations. CBT is generally accepted as first-line treatment for post-traumatic stress disorder and SSRIs are widely used. Obsessive-compulsive disorder in children may represent a subtype distinct from the adult disorder, with a high rate of accompanying tic disorders, "aggressive" obsessions, and a chronically disabling course. PANDAS may cause obsessive-compulsive symptoms in children, perhaps interacting with genetic susceptibility. CBT focused on exposure and response prevention is effective in pediatric obsessive- compulsive disorder, but many patients require concomitant pharmacotherapy. Consensus guidelines recommend SSRIs be used initially and if there is no improvement with ≥2 agents, a trial of clomipramine is warranted. Controlled trials in adults and an open-label study in children suggest augmentation strategies with atypical antipsychotics may provide some benefit. Antibiotic prophylaxis is not recommended for children with PANDAS, and plasma exchange and IV immunoglobulin, while effective, are not routinely used because of their invasive nature. Parents of children with PANDAS should be advised to monitor their children for signs of streptococcal infection. Discussion: There is general consensus that CBT is the psychotherapeutic treatment of choice for anxiety disorders in children and in adolescents. Response rates range from 60–90% and gains appear to persist for up to 6 years. Most CBT protocols are targeted to middle childhood, and there is a need to develop treatments more developmentally sensitive for younger children and for adolescents. While SSRIs are the first-line pharmacotherapy for most childhood anxiety disorders, studies supporting their use are gener-

ally short term (8–12 weeks) and the agents are often prescribed for at least a year. The few long-term studies indicate prolonged use is safe and well tolerated, but there has been some preliminary evidence suggesting risk for growth suppression. Arnold P, Banerjee S, Bhandari R, Lorch E, et al: Childhood anxiety disorders and developmental issues in anxiety. Current Psychiatry Reports 2003;5 (August):252–265. From the Center for Addiction and Mental Health; and the University of Toronto, Ont., Canada. Funded by the Ontario Mental Health Foundation; and other sources. Drug Trade Names: buspirone—BuSpar; citalopram—Celexa; clomipramine—Anafranil; paroxetine—Paxil; sertraline—Zoloft; venlafaxine—Effexor From Child & Adolescent Psychiatry Alerts 2003;5 (October). PANDAS and Tourette's Syndrome Cross-reactive antibodies induced by group A streptococcal infection binding to basal ganglia antigens is a proposed mechanism for pediatric autoimmune neuropsychiatric disorders and Sydenham’s chorea. A study was undertaken to explore an association between antibasal ganglia antibodies and a history of streptococcal infection in children and adults with Tourette's syndrome. Methods: Participants with Tourette's syndrome (n=100; 56 children) were evaluated for recent streptococcal infection using antistreptolysin O titers and for the presence of antibasal ganglia antibodies. Control groups included children and adults with neurological disease, otherwise healthy children who had a recent streptococcal infection, and healthy adults. Results: Antistreptococcal antibodies were elevated in 80% of healthy children with a recent infection. Titers also showed significantly increased levels in 64% of the children with Tourette's syndrome, compared with 18% of children with neurological disease (p<0.0001). Results were similar in the analysis of adult patients: 68% of patients with Tourette's syndrome, 12% with neurological disease, and 8% of comparison subjects had elevated levels. Antibasal ganglia antibodies were detected in 12 children (20%) and in 12 adults (27%) with Tourette's syndrome, compared with 2–4% of the comparison groups (p<0.05 in children and p<0.005 in adults). The same pattern of IgG binding to large basal ganglia neurones was found in the 10 patients (5 children) with Tourette's syndrome who were positive for antibasal ganglia antibodies. Church A, Dale R, Lees A, Giovannoni G, et al: Tourette's syndrome: a cross sectional study to examine the PANDAS hypothesis. Journal of Neurology, Neurosurgery, and Psychiatry 2003;74 (May):602–607. From the Institute of Neurology, London, U.K.; and other institutions. From Child & Adolescent Psychiatry Alerts 2003;5 (August). ADHD Associated with Streptococcal Infection Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are typically associated with OCD and motor tics. Two recent cases report affected children presenting with symptoms of ADHD. A 9-year-old boy had a 4-year history of disruptive behavior that was not alleviated by methylphenidate. He had no tics or OCD, but his behaviors were found to be associated with episodes of upper respiratory tract infection. Throat culture and antibody titers were positive for GABHS. A 10-day course of penicillin resulted in marked improvement, and residual symptoms were controlled with continued methylphenidate. A 7-year-old girl had sudden onset of ADHD without tics or OCD that was treated with pemoline. At age 13, she presented with severely increased inattention. Her medical history included several episodes of upper respiratory tract illness, including past GABHS infections. Throat culture for GABHS was positive. Treatment with penicillin resulted in immediate improvement, and a recurrence was also treated success- fully with an antibiotic. Waldrep D: Two cases of ADHD following GABHS infection: a PANDAS subgroup (letter)? Journal of the American Academy of Child

and Adolescent Psychiatry 2002;41 (November):1273–1274. From Walter Reed Army Medical Center, Washington, D.C. Drug Trade Names: methylphenidate—Ritalin; pemoline—Cylert From Child & Adolescent Psychiatry Alerts 2003;5 (January). Prospective Study of PANDAS in Primary Care A temporal association between Group A β-hemolytic streptococcal (GABHS) tonsillopharyngitis and pediatric autoimmune neuropsychiatric disorder has been confirmed in a prospective study.1 Background: A recent news report in JAMA2 highlighted the unpublished results of the first prospective study of children with PANDAS. The complete results of the study have since been published. Methods: Children with PANDAS from a single pediatric practice (n=12; mean age, 7 years) were identified during the index episode of the disorder. All children presented with the abrupt, explosive onset of new behavioral problems such as obsessive-compulsive disorder (OCD), tic disorder, age-inappropriate separation anxiety disorder, or attention-deficit/hyperactivity disorder; the onset of neuropsychiatric symptoms could be pinpointed to a single day in 7 patients. Diagnosis of PANDAS was confirmed by a current or recent throat culture positive for GABHS, and all children received antibiotic treatment. Results: Most children had positive throat cultures for GABHS, and those who did not had elevated antistreptococcal antibody titers. The recent episode of tonsillopharyngitis was typically mild and not associated with fever. Ten of the children had negative cultures or antibody tests within 3 months before the index episode, indicating they were not carriers. However, 11 of the patients had an episode of GABHS illness before the episode associated with onset of PANDAS. Symptoms of PANDAS in this group were similar to those of OCD, but appeared at a much younger age than is typical of OCD. Most of the obsessions in this sample were germ- or illness-related, and although 3 boys experienced tics, they appear to be less common than previously reported. Urinary compulsions were more common in this sample than in traditional OCD. Antibiotic therapy led to marked improvement in behavioral symptoms within about 1–3 weeks. Half of the patients had recurrent episodes of PANDAS; 1 patient had 6 recurrent episodes. The 2 children with the most frequent recurrences also had numerous episodes of streptococcal illnesses before onset of PANDAS. After the index episode, recurrent Group A strep infections and OCD symptoms recurred only concurrently. Treatment of recurrent episodes led to resolution of neuropsychiatric symptoms and to negative throat cultures in all cases. Discussion: Although the design of this study did not permit estimation of the incidence of PANDAS, the authors suggest it is more common than rheumatic fever or poststreptococcal glomerulonephritis. Community-based pediatricians may see an average of 1–3 cases/year. 1Murphy M, Pichichero M: Prospective identification and treatment of children with pediatric autoimmune neuropsychiatric disorder associated with Group A streptococcal infection (PANDAS). Archives of Pediatric and Adolescent Medicine 2002;156 (April):356–361. From the University of Rochester Medical Center, Rochester, N.Y. 2Stephenson J: Strep A, neuropsychiatric disorders tie found (news report). JAMA 2002;287 (February 20):828. See Child & Adolescent Psychiatry Alerts 2002;4 (April):19. From Child & Adolescent Psychiatry Alerts 2002;4 (June). Antibiotics for Early PANDAS Treatment with antibiotics resulted in resolution of obsessive compulsive symptoms in a group of children with a first episode of strep-related pediatric autoimmune neuropsychiatric disorder.1 Previous research has shown a lack of response to antibiotics in children with longstanding PANDAS.2 The 12 children, aged 5–11 years, with abrupt onset of neuropsychiatric symptoms and OCD that had a temporal association with a Group A β−hemolytic streptococcal infection, received a diagnosis of PANDAS. More than half of the patients had urinary symptoms, including frequent need to urinate, ritu- alistic urinary hygiene, and fear of germs; many were initially evaluated for urinary tract infection. Most obsessive thoughts involved fear—of infection, injury, illness, or death of the patient or a loved one. The

children received antibiotic treatment, and obsessive-compulsive symptoms resolved within an average of 14 days. Half of the children had at least 1 recurrence of OCD associated with group A β-hemolytic strep infection, with a seasonal peak in the fall and winter. These episodes also resolved with antibiotic treatment. The NIMH is recruiting participants for 2 treatment trials for PANDAS. Information on the trials is available at: www.nimh.nih.gov/studies/3anxdisocdtourette.cfm. 1Stephenson J: Strep A, neuropsychiatric disorders tie found (news report). JAMA 2002;287 (February 20):828. 2Perlmutter S, et al: A case of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. American Journal of Psychiatry 1998;155 (November):1592–1598. From Child & Adolescent Psychiatry Alerts 2002;4 (April). Plasma Exchange for Childhood-Onset OCD In a recent study, 9 of 10 patients with OCD and PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) had significant improvement of OCD symptoms following plasma-exchange treatment.1 In another recent open trial, 5 children (mean age, 15 years) with OCD who had failed several medication and behavioral therapy trials and had no clinical or laboratory evidence of PANDAS, underwent 5 plasma exchange procedures over a 2-week period.2 Patients’ regular medications were continued, and each child underwent standardized behavioral ratings (e.g., Clinical Global Impression scale, Yale-Brown Obsessive Compulsive Scale) weekly for 4 weeks. None of the patients showed significant improvements on any of the standardized behavioral rating scales, and all continued to be profoundly impaired by their symptoms. The efficacy of plasma exchange in OCD appears to be limited to a subgroup of children with PANDAS. 1Perlmutter S, et al: Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet 1999;354:1153–1158. 2Nicolson R, et al: An open trial of plasma exchange in childhood-onset obsessive compulsive disorder without poststreptococcal exacerbations. Journal of the American Academy of Child and Adolescent Psychiatry 2000;39 (October):1313–1315. From the NIMH, Bethesda, Md. From Child & Adolescent Psychiatry Alerts 2000;2 (November). Anorexia Nervosa Triggered by Infection A series of 4 cases of infection-associated anorexia nervosa (AN) at The Menninger Clinic Eating Disorders Program have been described. All 4 patients showed improvement when treated with antibiotics. The authors suggest that AN may be part of the spectrum of PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus). According to the hypothesis, antibodies to group A β-hemolytic streptococcus may cross-react with neurons in the basal ganglia as part of a postinfectious process, possibly altering emotions and behavior. Other PANDAS disorders are tics and OCD. Anorexia nervosa is rare in children under age 13 years. The 4 patients (3 girls) with possible PANDAS AN had onset at ages 10 and 11 years. Two also had OCD. Anorexia first developed following an upper respiratory infection (URI) in 1 patient and a flu-like illness in another. One patient had frequent antibiotic-treated URIs throughout childhood, developed anorexia at 11 years, and had some improvement when treated with antibiotics for strep throat. The fourth patient, a boy, had acute onset of anorexia at age 10 and an exacerbation following an untreated severe URI. All patients had sinusitis at their initial evaluation in the clinic. When antibiotics were prescribed for sinusitis, the patients abruptly began to eat and gain weight. Obsessive-compulsive symptoms also improved in the 2 patients with OCD. The patients remained well after resolution of these episodes. The evidence that anorexia was strep-related is sugges- tive but not conclusive. Cultures were not obtained for streptococcal disease at illness onset. All patients had positive serologic tests (both anti-DNase B and anti-streptolysin O), but these antibodies are common in children. The role of antibiotics is uncertain, particularly since the children received other treatments. Abrupt improvements are uncommon in anorexia nervosa but have been observed following antibiotic or immunologic therapy in possible PANDAS tics and OCD. Sokol M: Infection-triggered anorexia nervosa in children: clinical description of four cases. Journal of Child and Adolescent Psychopharmacology 2000;10 (Summer):133–145. From The Menninger Clinic, Topeka, Kans. From Child & Adolescent Psychiatry Alerts 2000;2 (September).

PANDAS Update There is additional support for the hypothesis that tics or obsessive-compulsive symptoms may develop in a subgroup of children following infection with group A β-hemolytic streptococci. The mechanism of these disorders, called PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection), is believed to be antibacterial antibodies that cross-react with brain structures. Methods: Study subjects included a nationwide sample of 34 children in whom a streptococcal infection was associated with the onset or exacerbation of tics (n=16) or obsessive-compulsive symptoms (n=18). MRI scans of the brain were compared with those of 82 healthy controls participating in an ongoing NIMH study of brain development. Results: All brain scans were judged clinically unremarkable by a neuroradiologist. However, compared with the control group, the PANDAS group had a larger caudate nucleus (8%), putamen (5%), and globus pallidus (7%). All increases in the volume of basal ganglia structures were statistically significant (p=0.02–0.004). Thalamic area or total brain volume did not differ significantly between the groups. Basal ganglia size in the PANDAS group was not correlated with the duration or severity of symptoms or with the presence of OCD or tics. The study authors concluded that MRI scans are not sufficiently accurate to be useful in the diagnosis or clinical monitoring of children with post-streptococcal OCD or tics. Giedd J, et al: MRI assessment of children with obsessive-compulsive disorder or tics associated with streptococcal infection. American Journal of Psychiatry 2000;157 (February):281–283. From the NIMH, Rockville, Md. From Child & Adolescent Psychiatry Alerts 2000;2 (April). Etiology of PANDAS Although evidence indicates that pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) is triggered by streptococcal infection, many uncertainties remain regarding this proposed etiology. Children with PANDAS have repeated episodes of tics and/or obsessive compulsive disorder (OCD). Many of the clinical features in patients with PANDAS are also seen in those with Syndenham's chorea, which is a variant of rheumatic fever. In both conditions, these features are attributed to basal ganglia abnormalities that may result from cross reactivity of antibodies to group A β-hemolytic streptococcal bacteria. Lessons From Rheumatic Fever: It is instructive to review how evidence was obtained to prove that rheumatic fever results from streptococcal infection. The strongest evidence came from studies demonstrating that prophylactic penicillin therapy reduced the incidence of rheumatic fever in patients who had streptococcal infections. The debate regarding streptococcal infection as an etiologic agent lasted nearly a century. The natural history and epidemiology of pediatric OCD must be studied in order to further understand the role of group A β-hemolytic streptococcal infections in the etiology of OCD and tic disorders. Longitudinal studies must be undertaken to assess the PANDAS attack rate and to determine which strains of group A β-hemolytic streptococcus produce neuropsychiatric symptoms. Also, to prove that penicillin would be effective for preventing episodes of symptoms in patients with PANDAS would require an extensive effort. Previous studies of this nature required large numbers of patients and long follow-up periods. Since data showing the effectiveness of prophylactic penicillin for patients with PANDAS has not been acquired, this therapy is not yet warranted. Garvey M, et al: PANDAS: the search for environmental triggers of pediatric neuropsychiatric disorders: lessons from rheumatic fever. Journal of Child Neurology 1998;13 (September):413–423. From the NIMH, Bethesda, Md. From Child & Adolescent Psychiatry Alerts 1999 (April). OCD and Tics Associated with Streptococcal Infection Pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) was reported in a 5-year-old girl with recurrent exacerbations of tics and OCD symptoms. PANDAS is an

acronym designating a subgroup of children with OCD and tic disorders whose symptoms seem to be triggered by streptococcal infections. To include children in the PANDAS subgroup, an association between streptococcal infections and exacerbations of tic and OCD symptoms must be established. Other features include acute onset of symptoms, episodic relapsing-remitting course (vs a waxing-waning symptom pattern), a younger average age of onset (7.4 years for OCD, 6.3 years for tics,) that is nearly 3 years younger than previously reported in childhood-onset OCD and tic disorders This patient presented to the National Institutes of Mental Health (NIMH) with sudden onset of motor and vocal tics and OCD symptoms. Over the prior 2 months, she had become hypersensitive to her clothes, changing them frequently. She had rapid onset of nearly constant eye-blinking, head-jerking, and nose-rubbing tics, as well as the abrupt onset of obsessions and compulsions. These involved ordering and arranging, counting, contamination, and hoarding; separation anxiety, insomnia, nightmares, clumsi- ness, irritability, and restlessness developed also. Her past medical, psychiatric, social, and developmental histories were essentially unremarkable. The patient’s mother had a 1-month history of transient trichotillomania, and her father had a history of vocal tics. For 3 months before the onset of tics and OCD symptoms, she had been ill with recurrent fevers and was thought to have had a chronic viral infection. Several weeks after the onset of her tics, she had a positive throat culture for group A β- hemolytic streptococcal infection. She was started on oral amoxicillin. Within several days, her tics almost disappeared, but her OCD did not improve. Within 2 days of stopping amoxicillin, she had a high fever and the tics returned. The tics improved again 2 days after amoxicillin was restarted. The child was admitted to the pediatric medical unit at the NIMH. At the time of her initial evaluation, her throat culture was negative, but she had elevated antistreptococcal antibody titers. Her EEG, ECG, and brain MRI studies were unremarkable. She was enrolled in an NIMH PANDAS therapeutic trial and received 1 g/kg/day of IV immunoglobulin for 2 days; afterwards, she was started on prophylactic amoxicillin (250 mg orally b.i.d.). She had been free of OCD symptoms and had only mild tics for 3 months after receiving the immunoglobulin when an upper respiratory infection developed. This was followed by a rapid relapse of her tics, separation anxiety, contamination obsessions, and emotionally lability. A throat culture was again negative, but her antistreptococcal antibody titer was elevated. Amoxicillin was restarted, and her symptoms improved after a dosage increase several weeks later. During the following several months, she had 2 exacerbations of her neuropsychiatric symptoms associated with acute pharyngitis. Neither episode responded to amoxicillin. However, 1 month following a second 2-day immunoglobulin IV infusion, her neuropsychiatric symptoms were 70–90% improved. Perlmutter S, et al: A case of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. American Journal of Psychiatry 1998;155 (November):1592–1598. From the NIMH, Reston, Va. From Child & Adolescent Psychiatry Alerts 1999;1 (March)

PSYCHIATRY ALERTS

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