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Contents:
Speculations on Antineuronal Antibody-Mediated Neuropsychiatric Disorders of Childhood
Swedo SE, Leonard HL, Kiessling LS: Pediatrics 1994; 93:323-326
Children with an antecedent group-A Beta-hemolytic streptococcal (GABHS) infection develop antibodies to streptococcus A. In some, a cross-reaction to neurons also occurs and results in the production of antineuronal antibodies. Investigators1 suspect that the presence of antineuronal antibodies may, in turn, lead to the onset or exacerbation of tics, TS, or choreiform movements. Evidence suggests that these antineuronal antibodies may not only affect symptoms of movement disorders, but may also induce or exacerbate symptoms of OCD and/or ADHD.
In a test of this hypothesis, three children with recent onset or exacerbation of OCD were evaluated. Throat cultures, antistreptococcal and antineuronal antibodies were strongly positive in each case. Treatment with penicillin or plasmapheresis resulted in dramatic improvement. Furthermore, subsequent relapses and remissions also correlated with antineuronal antibody titers.
The authors cite the case of a 7-1/2 year-old boy who, shortly after developing scarlet fever, also developed abnormal movements and symptoms suggesting ADHD. Throat cultures, antistreptococcal and antineuronal antibodies were positive. Treated with penicillin, his movements and hyperactivity resolved, and his grades improved. The following winter, he again developed a group A Beta-hemolytic streptococcal infection with positive antistreptococcal and antineuronal antibody titers. Again tics, inattention, and overactivity developed. As antibody titers decreased to normal, his symptoms again abated.
Of potentially great importance were a number of additional psychiatric symptoms seemingly associated with GABHS. Swedo and Kiessling systematically evaluated 11 children with Sydenham's chorea, a variant of rheumatic fever. Using structured psychiatric interviews, they found that all the children had had abrupt behavioral changes shortly preceding the development of choreiform symptoms. The most common behavioral change was not symptoms of TS, ADHD or OCD but the exaggeration of normal emotions. These children would suddenly shift from laughter to crying or to angry outbursts within seconds. Seven of the 11 had significant obsessions or compulsions and four met diagnostic criteria for OCD. One third experienced either the onset or exacerbation of symptoms of ADHD. Several experienced the acute onset of separation anxiety.
Note: Matarazzo2 has reported the cases of two boys with TS whose tics were believed to have become exacerbated in the presence of streptococcal infections. Streptococcus was found in ear secretions of Case 1, and was thought to be responsible for chronic tonsillitis in Case 2. Case 1 demonstrated an elevated antistreptolysin-O titer. Treatment with ACTH and prednisone in Case 1 resulted, within five days, in progressive improvement in both aggressive and hostile behavior and in a reduction of tics. Case 1 is further illustrated by samples of handwriting that had become virtually illegible with numerous spelling errors during exacerbation of the behavioral symptoms. Dramatically, the writing samples were legible and without spelling errors after treatment.
Similar treatment in Case 2 brought about a reduction of tics, anxiety, compulsions and excessive speech within one month. Matarazzo believes that, following streptococcal infection in some cases of TS, an autoimmune process emerges and damages brain tissue.
References: 1. Kiessling LS, Marcotte AC, Culpepper L: Antineuronal antibodies in movement disorders. Pediatrics 1993; 92:39-43. 2. Matarazzo EB: Tourette's syndrome treated with ACTH and prednisone: report of two cases. J Child Adolesc Psychopharmacology 1992; 3:215-226.
Swedo SE: JAMA 1994; 272:1788-1791
Conclusion: The nature of the relationship between antineuronal antibodies and neuropsychiatric symptoms is as yet unknown. However, the antibodies appear to recognize cellular components within the basal ganglia, and basal ganglia dysfunction has been implicated in both Sydenham's chorea and OCD. One working hypothesis is that when genetically vulnerable children are exposed to a GABHS infection, antibodies are produced that mistakenly recognize cells within the basal ganglia and cause an inflammatory response. This inflammation is manifest by adventitious movements and psychiatric symptoms. Symptom expression - chorea, tics, and/or obsessions and compulsions - may depend on the epitope recognized by the antineuronal antibody, extent of inflammation, chronicity of the insult, developmental stage of the child's immune system, inherited vulnerability, or a combination of these factors. Sydenham's chorea provides a model for determining the nature and localization of the neuropsychiatric dysfunction because it is a semiacute illness in which subjects can be studied during illness and after recovery. Such examinations not only will increase our understanding of the pathophysiology of this troubling disorder, but also will provide new insight into the etiology of OCD and Gilles de la Tourette's Syndrome.
Dr. Swedo uses the case of a 9 year-old girl to illustrate many of the principles being learned about streptococcal-induced autoimmune neuropsychiatric disorders. Two months after a mild upper respiratory infection without fever, the patient suddenly developed nightmares, separation anxiety, a hand washing compulsion, emotional lability, irritability, fidgetiness, distractibility and inattention. Two weeks later she began to manifest neurologic symptoms including clumsiness, weakness, milk-maid's grip, involuntary writhing movements, choreic jerks and tics. Antistreptolysin-0 titer was strongly positive. She was treated experimentally with six plasmapheresis treatments over a 2-week period and improved dramatically. An exception, even after an additional 6 months of penicillin prophylaxis, was the persistence of cognitive deficits resulting in a decline of her grades from her usual A's and B's to C's. However, after a full year of prophylaxis her cognitive deficits had also resolved.
The paper provides a review of rheumatic fever. The diagnosis requires evidence of an antecedent group A streptococcal infection. The full syndrome involves carditis, polyarthritis, chorea, and the rarer subcutaneous nodules and erythema marginatum. The 1992 modification of the Jones criteria permits the diagnosis of rheumatic fever in some patients (with evidence of an antecedent streptococcal infection) with carditis or Sydenham's chorea alone without other features of the Jones criteria.
Rheumatic chorea is characterized by muscular weakness (e.g. milk-maid's grip) and the presence of chorea, including clumsiness, and Sydenham's speech (explosive bursts of dysarthric speech). Dr. Swedo emphasizes that psychiatric symptoms, though often undiagnosed, are prominent in Sydenham's chorea and typically precede the appearance of chorea. The most common psychiatric symptom is emotional lability. Nightmares, inattention and separation anxiety disorder also occur. Obsessive-compulsive symptoms (present in 70% of children with Sydenham's chorea) are indistinguishable from those of classic OCD. The psychiatric symptoms typically precede chorea by 2 to 4 weeks, peak along with the severity of motor symptoms, and disappear shortly after the chorea subsides.
Sydenham's chorea typically occurs in 10 to 20 percent of acute rheumatic fever cases. It can appear 1 to 6 months after the etiologic streptococcal infection (when antistreptococcal antibody titers may no longer be elevated). Dr. Swedo recommends considering rheumatic fever in "any child presenting with an acute onset of hyperkinesis, adventitial movements or behavioral change."
Kiessling1 suggests that studies to evaluate for prior streptococcal infections may include Streptozyme, antistreptolysin 0 (ASO), and antideoxyribonuclease B (Anti- DNAase B). The latter may have the longest time course and be the most likely to remain elevated by the time symptoms appear.
Note 1: Dr. Swedo includes autoimmune TS and autoimmune OCD among the autoimmune neuropsychiatric disorders - all secondary to antecedent streptococcal infection. (Swedo et al2 have elsewhere proposed the term, antineuronal antibody-mediated neuropsychiatric disorders, which includes these autoimmune neuropsychiatric disorders: Sydenham's chorea, some cases of OCD and TS.) Her paper describes autoimmune OCD as including contamination fears, fear of harm to a loved one, and washing and checking compulsions. The symptoms of autoimmune OCD thus appear to resemble those of classic OCD. However, obsessive-compulsive symptoms of OCD that are comorbid with TS have been found to differ from those of classic OCD. Specifically, symmetry and "just-right" phenomena are more characteristic of OCD comorbid with TS. Therefore an unanswered question is whether the symptoms of autoimmune OCD differ phenomenologically from those of non-autoimmune OCD when the latter is comorbid with TS.
Note 2: Many of us who treat TS are psychiatrists or neurologists who have forgotten and/or are unfamiliar with current issues in the diagnosis and treatment of group A B-hemolytic streptococcal infections (GABHS). Therefore, we offer the following review:3
Penicillin is still the drug of choice for GABHS pharyngitis. Cephalosporins are not superior, but are equally effective. Bacteriologic failure rates after a ten-day course of oral penicillin range from 12% to 15%.
Streptococcal carriers continue to harbor GABHS in the upper respiratory tract following appropriate antibiotic therapy. The major concern about such cases is the risk of rheumatic fever. The carrier state may be eradicated with oral rifampin 20 mg/kg every 24 hours for 4 doses during the last four days of a ten-day course of oral penicillin. Alternatively, oral rifampin 10 mg/kg can be given every 12 hours for eight doses with one dose of IM benzathine penicillin G. Oral clindamycin 20 mg/kg/day in three doses for ten days is another alternative.
GABHS pharyngitis cannot be ruled out by a rapid strep test because its sensitivity is too low. It should be combined with a throat culture. Identifying GABHS pharyngitis is important, but non-GABHS streptococcal pharyngitis is generally not necessary to identify. (A positive ASO titer is not specific for GABHS and could indicate a group G B-hemolytic streptococcal infection.4
Barring the development of a GABHS vaccine, prevention of rheumatic fever outbreaks is not possible since in about 75% of cases the preceding GABHS infection is either completely asymptomatic or too mild to come to medical attention. The best prevention is accurately identifying the etiology of acute pharyngitis and treating GABHS infections.
References: 1. Kiessling LS, Marcotte AC, Culpepper L: Antineuronal antibodies in movement disorders. Pediatrics 1993; 92:39-43. 2. Swedo SE, Leonard HL, Allen AJ: New developments in childhood affective and anxiety disorders. Curr Probl Pediatr 1994; 24:12-38. 3. Gerber MA, Markowitz M: Streptococcal pharyngitis:clearing up the controversies. Contemporary Pediatrics 1992; April: 118-129. 4. Gerber MA, Randolph MF, Martin NJ, Rizkallah MF, Cleary P, Kaplan EL, Ayoub EM: Community-wide outbreak of group G streptococcal pharyngitis. Pediatrics 1991; 87:598-603.
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