PANDAS? Or PAND? Or both? Or neither?

Assessing a (possible?) temporal or pathogenetic relationship with the Group A "streptococcal diseases complex"

By Edward L. Kaplan, MD

Pediatricians increasingly are being asked about PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococci) by parents who read about this entity on the Internet and in the lay press. An association with group A streptococcal infection remains to be confirmed.

Although there have been references to the neuropsychiatric abnormalities in patients with acute rheumatic fever (especially Sydenham's chorea), the 1998 publication by Swedo and colleagues was the first attempt to objectively define PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococci).¹ The authors listed suggested diagnostic criteria for this proposed syndrome in that report (Table 1). As supporting evidence they reported 144 episodes ß of symptomatic exacerbation of either tic disorders or obsessive-compulsive behavior. The authors stated that a large percentage of these patients demonstrated what they considered to be either direct or indirect evidence of a streptococcal infection. Thirty-one percent were described as having documented streptococcal infection, 42% were thought to have had symptoms of pharyngitis or nonspecific upper respiratory tract infection, and 4% had what was described as exposure to group A streptococci.¹

TABLE 1
Criteria for the diagnosis of PANDAS

It has been postulated that even Mozart may have been affected by this syndrome during the second half of the 18th century,² but during the past decade a number of studies have been reported to provide evidence supporting an association of these neuropsychiatric symptoms with group A ß-hemolytic streptococcal infection.^3,4 To date, however, there has been no prospective longitudinal study to statistically or unequivocally confirm a temporal relationship or a pathogenetic association of group A streptococcal infection with these neuropsychiatric signs and symptoms.

One of the most confusing and unresolved issues has been the fact that group A streptococcal infections and the group A streptococcal "carrier" state are very prevalent among the normal pediatric population; it is well appreciated that these organisms are very transmissible from one child to another either at home or at school. Whether it be uncomplicated infections of the upper respiratory tract or as impetiginous lesions of the skin, most individuals experience an early exposure to this organism. For example, in the comprehensive studies published 35 years ago in Cleveland, OH, families were followed for a 10-year period of time for a number of different illnesses.⁵ Dingle and his colleagues reported that by the age of 13 years, the average child had experienced three documented group A streptococcal infections; the range was one to eight infections during the observation period. Similarly, the recent report of age-stratified mean titers and upper limits of normal for antistreptolysin O (ASO) and antideoxyribonuclease B (anti-DNase B) from more than 1,000 American children (ages 2 to 12 years) confirmed that these titers are considerably higher than standards referred to in package inserts; this clearly reflects the high incidence of group A infection in the normal pediatric population.⁶ Further, Cornfeld's studies in Philadelphia in the 1950s indicated prevalence rates of group A streptococci in school children as high as almost 20%; this figure is amazingly similar to that suggested by Wannamaker two decades later.^7,8 Thus, as in the past, group A streptococcal infections remain extremely common. However, their suppurative and nonsuppurative sequelae are uncommon in industrialized countries except in unusual circumstances. These conclusions are supported by comprehensive epidemiologic observations gathered by Hall and colleagues from Monroe County, NY, during 20 years of data collection in the 1960s and 1970s.⁹

In view of a high prevalence of group A streptococci recovered during surveillance studies in the normal population, especially children, and the fact that pharyngitis is one of the most common causes of an office sick-child visit,¹⁰ it is not surprising that a number of illnesses have been mistakenly attributed to an association with group A streptococcal infections. Two of the most frequently cited are Kawasaki disease and Henoch purpura.^11,12 In the latter instance, Hoyer and Ayoub carefully examined patients with this unusual illness and their laboratory values and were unable to convincingly confirm a group A streptococcal etiology.¹²

Because of the absence of appropriately designed prospective studies, the question remains as to whether there is an association of group A streptococcal infections with either onset or exacerbation of tics or obsessive-compulsive behavior. Such reports, along with several laboratory studies, have led some observers to comment about the possibility that these neuropsychiatric abnormalities may represent a variant clinical presentation of the rheumatic fever complex.^13,14 What current evidence can be used in an attempt to more conclusively link these two conditions?

There are intriguing reports, such as those by Swedo and colleagues, suggesting an association between group A streptococcal infection and these neuropsychiatric symptoms; the conclusions are incompletely supported because the studies are incompletely controlled. A recent report from Italy by Orefici and colleagues describes an association of group A streptococcal infections with tics, but it also was not a prospective longitudinal study.³ Greenberg's report entitled "Systemic exacerbation of focal tics and other symptoms associated with streptococcal pharyngitis in a patient with OCD and tics" represents one example of a number of anecdotal reports that have received publicity in the lay press and on the Web.¹⁵

More credible attempts to associate this symptom spectrum with the rheumatic fever complex include the 1997 report from Swedo and colleagues suggesting that children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection often have a B-cell alloantigen marker (called D8/17) that has been associated with rheumatic fever.¹⁶ These investigators reported that 85% of patients with the PANDAS syndrome, 89% of patients with Sydenham's chorea, but only 17% of 24 healthy children had this non­T lymphocyte marker, which has been reported by Zabriskie and colleagues to be associated with patients with rheumatic fever and rheumatic heart disease. The authors stated that "these results suggest that there may be a sub-group of D8/17 'positive' children who present with clinical symptoms of obsessive-compulsive disease and Tourette syndrome rather than Sydenham's chorea, but who have similar poststreptococcal autoimmunity."¹⁶ In a further attempt to associate these two conditions, it has been pointed out that the latent period for Sydenham's chorea also is considerably longer than the latent period of patients who have more common findings of rheumatic fever, including carditis and arthritis.

This unresolved enigma has practical clinical importance. Were this association definitely proven, the management of patients with tics and obsessive-compulsive disorder (OCD) would dictate long-term antibiotic prophylaxis to prevent recurring group A streptococcal infections just as in patients who have had classic rheumatic fever. Indeed, some investigators have attempted to empirically manage patients with antibiotics in much the way as they would provide secondary prophylaxis for patients with bona fide manifestations of rheumatic fever. The results are inconclusive.¹⁷

One important consideration that must be remembered is that the chronic long-term sequel of acute rheumatic fever is rheumatic valvular heart disease. From 40% to more than 70% of patients with acute rheumatic fever have been reported to develop rheumatic valvular heart disease. Further, an outbreak of rheumatic fever in Utah suggested that there are additional patients who, although not manifesting signs or symptoms of carditis and who do not have audible murmurs, have echocardiographic findings strongly suggestive of mitral valve incompetence.¹⁸ Even patients whose initial clinical presentation is only Sydenham's chorea may ultimately develop valvular heart disease, as has been well documented. If patients with the proposed PANDAS syndrome also represent part of the spectrum of the rheumatic fever complex, should there not be an increased prevalence of rheumatic heart disease in these patients with time? To our knowledge this has not been systematically looked for, even in patients with recent onset or in patients with the Tourette syndrome or OCD who have been followed for many years. Such a simple and relatively inexpensive study could quickly provide this much-needed clinical and pathogenetic information.

Another intriguing unresolved aspect regarding the association of group A streptococcal infections with the PANDAS spectrum relates to the proposed "autoimmunity" mechanism(s). As indicated in the title of this article, one of the most important remaining questions is whether these clinical neuropsychiatric manifestations are related only to group A ß-hemolytic streptococcal infection, or whether they are related nonspecifically to any infection or even to other noninfectious stressful situations. Some years ago, Husby and colleagues reported the presence of a serum antibody in patients with Sydenham's chorea that cross-reacted with caudate nucleus in much the same fashion as "heart reactive" antibodies react with human myocardial sarcolemma in rheumatic heart disease.¹⁹ That report suggested support for the concept of an autoimmune etiology for Sydenham's chorea. More recently, a number of investigators have also reported the presence of other antibodies in the sera of patients with Tourette syndrome. For example, Singer and colleagues looked for serum antibodies against caudate, putamen, and globus pallidus and correlated their presence with clinical evaluations.²⁰ Forty-one patients with Tourette syndrome and 39 "controls" were studied. The authors concluded that "children and adolescents with Tourette syndrome had significantly higher serum levels of anti-neuronal antibodies against putamen than did controls, but their relationship to clinical characteristics and markers for streptococcal infections remains equivocal."²⁰ Other studies have been carried out seeking to confirm an autoimmune etiology for this neuropsychiatric syndrome.²¹

The hypothesis regarding possible autoimmunity directed against structures in the human central nervous system gained indirect support from the recent report by Perlmutter and colleagues suggesting that patients with marked neuropsychiatric symptoms were clinically improved after undergoing plasmapheresis.²² The results imply the removal of autoimmune antibodies by the procedure. Using three different study groups—intravenous immunoglobulin (IVIG) vs. plasmapheresis vs. placebo—both IVIG and the plasmapheresis procedure were reported to give better results than in the placebo group; the important question was raised as to how this immunomodulator therapy worked. However, as pointed out in an accompanying invited editorial by Singer,²³ one must be very careful in interpretation of these data and in drawing pathogenetic conclusions.

One is left to ponder the title of this article. Is there a pediatric autoimmune neuropsychiatric disease associated with streptococcal infections (PANDAS) or is there a pediatric autoimmune neuropsychiatric disease either related to other infections or to other stressful situations (only PAND)? Could both hypothesized mechanisms play a role? Does neither have an influence? At the present time it appears that neither of these questions has been satisfactorily addressed. Questions about age of onset, latent period after a hypothesized streptococcal infection, the possibility of exacerbations without streptococcal infections, and seasonal occurrence of either the onset or exacerbations cannot be answered until more comprehensive and prospective studies are completed.

With the persisting and perplexing questions about the epidemiology, etiology, and pathogenesis of this neuropsychiatric syndrome, issues regarding effective medical management can only be controversial. If one knew with certainty that the important factor in initiating either the initial attack or exacerbations is the group A streptococcus and that this clinical entity is a previously unrecognized part of the "streptococcal disease complex" and therefore related to rheumatic fever, without hesitation one would mandate secondary antibiotic prophylaxis for all of these patients just as for individuals with documented rheumatic fever.²⁴ The practical question remains: Since the etiology and pathogenesis remain unknown, is empirical antibiotic prophylaxis warranted? Most authorities believe it is not justifiable and prolonged administration of antibiotics is not indicated. On the other hand, there are physicians who prescribe such management (with or without evidence of a current group A streptococcal infection), in part possibly related to the many very frustrated parents who read the Web and essentially demand this approach. The basis and need for plasmapheresis is even more controversial. It is an invasive procedure with definite risks of both morbidity and mortality. Although the initial study was reported as favorable with respect to relief of symptoms, the data provide no definitive information about etiology.

With our present level of understanding, patients suspected of this clinical entity should be carefully observed and cultured with appropriate indication (such as sore throat). Group A streptococcal infections should be treated as they would in any other patient. Because of the current uncertainty, it might be wise to reculture the throat three to five days after completing oral therapy or one month after intramuscular injection of benzathine penicillin G. This is to document eradication of the organism and reduce confusion. Because of the current controversy about bacteriologic efficacy of shortened courses of oral antibiotic therapy, a full 10 days of oral therapy is warranted.²⁵ While some clinicians are alarmed by the prolonged elevation of streptococcal antibody titers in some patients with this spectrum of neuropsychiatric signs and symptoms, this—by itself—is no indication of a continuing infectious process. In fact, while a considerable amount is known about the rate at which streptococcal antibody titers rise following group A streptococcal infections, comprehensive studies of the rate of decline of serum streptococcal antibodies (for example, ASO or anti-DNase B titers) following uncomplicated streptococcal pharyngitis have yet to be undertaken and reported.

In summary, the so-called PANDAS syndrome still is not adequately defined. With this lack of essential information, clinical management remains imprecise. Some have suggested that if and when a group A streptococcal vaccine becomes available, it will eliminate these concerns. However, it is likely there will be a number of years before a group A streptococcal vaccine is shown to be efficient, is approved, and becomes widely or inexpensively available. Secondly, one cannot make predictions about management and prevention until the etiology of this neuropsychiatric syndrome is more precisely defined.

REFERENCES

1. Swedo SE, Leonard HL, Garvey M, et al: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: Clinical description of the first 50 cases. Am J Psychiatry 1998;155:264

2. Simkin B: Was PANDAS associated with Mozart's personality idiosyncrasies? In Medical Problems of Performing Artists. Philadelphia, PA, Hanley and Belfus, 1999, p 113

3. Cardona F, Orefici G: Group A streptococcal infections and tic disorders in an Italian population, in Martin DR, Tagg JR (eds): Streptococci and Streptococcal Diseases: Entering the New Millennium: Proceedings of the XIV Lancefield Symposium on Streptococci and Streptococcal Disease (in press)

4. Trifiletti RR, Packard AM: Immune mechanisms in pediatric neuropsychiatric disorders. Child Adolesc Psychiatr Clin N Am 1999;8:767

5. Dingle JH, Badger GF, Jordan WS Jr: Illness in the Home. Cleveland, OH, The Press of Western Reserve University, 1964

6. Kaplan EL, Rothermel CD, Johnson DR: Antistreptolysin 0 and Anti-Deoxyribonuclease B titers: Normal values for children ages 2­12 in the United States. Pediatrics 1998; 101:86

7. Cornfeld D, Werner G, Weaver R, et al: Streptococcal infections in a school population: Preliminary report. Ann Int Med 1958;49:1305

8. Wannamaker LW: Perplexity and precision in the diagnosis of streptococcal pharyngitis. Am J. Dis Child 1972;124:352

9. Gray BM: Streptococcal infections, in Evans AS, Brachman PS (eds): Bacterial Infections of Humans, ed 3. New York, Plenum Medical Book Company, 1998, p 692

10. Schwartz RH, Quinnell RK: Throat cultures in the office. Am Fam Physician 1980;21(6):72

11. Leung DY, Meissner C, Fulton DE, et al: The potential role of bacterial superantigens in the pathogenesis of Kawasaki syndrome. J Clin Immunol 1995;15:11s

12. Ayoub EM, Hoyer J: Anaphylactoid purpura: Streptococcal antibody titers and b 1c-globulin levels. J Pediatr 1969;75:193

13. Kurlan R: Tourette's syndrome and "PANDAS": Will the relation bear out? Neurology 1998;50:1618

14. Shulman ST: Pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS). Ped Infect Dis J 1999;18:28

15. Greenberg BD, Murphy DL, Swedo SE: Symptom exacerbation of vocal tics and other symptoms associated with streptococcal pharyngitis in a patient with obsessive- compulsive disorder and tics (Letter). Am Journ Psychiatry 1998;155:1459

16. Swedo SE, Leonard HL, Mittleman BB, et al: Identification of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with rheumatic fever. Am J Psychiatry 1997;54:110

17. Garvey MA, Perlmutter SJ, Allen AJ, et al: A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections. Biol Psychiatry 1999;45:1564

18. Veasy LG, Wiedmeier SE, Orsmond GS, et al: Resurgence of acute rheumatic fever in the intermountain area of the United States. N Engl J Med 1987;316(8):421

19. Husby G, v de Rign I, Zabriskie JB, et al: Anti-neuronal antibody in Sydenham's chorea (Letter). Lancet 1977;1:1208

20. Singer HS, Giuliano JD, Hansen BH, et al: Antibodies against human putamen in children with Tourette syndrome. Neurology 1998;50:1618

21. Laurino JP, Hallett J, Kiessling LS, et al: An immunoassay for anti-neuronal antibodies associated with involuntary repetitive movement disorders. Ann Clin Lab Sci 1997;27:230

22. Perlmutter SJ, Leittman SF, Garvey MA, et al: Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet 1999;354:1153

23. Singer HS: PANDAS and immunomodulatory therapy. Lancet 1999;354:1137

24. Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association: Treatment of acute streptococcal pharyngitis and prevention of rheumatic fever: A statement for health professionals. Pediatrics 1995;96:758

25. Bisno AL, Gerber MA, Gwaltney JM Jr, et al: Diagnosis and management of group A streptococcal pharyngitis: A practice guideline. Clin Infect Dis 1997; 25:574

THE AUTHOR is Professor of Pediatrics, University of Minnesota Medical School, Minneapolis.

 

Edward Kaplan. PANDAS? Or PAND? Or both? Or neither?. Contemporary Pediatrics 2000;8:81.