Case Study: A New Infection-Triggered, Autoimmune Subtype of Pediatric OCD and Tourette's Syndrome

Case Study: A New Infection-Triggered, Autoimmune Subtype of Pediatric OCD and Tourette's Syndrome ALBERT

J.

ALLEN, M.D., PH.D., HENRIETTA L. LEONARD, M.D.,

AND

SUSAN E. SWEDO, M.D.

ABSTRACT A review of clinical observations and literature reports leads to the hypothesis that, via a process analogous to Sydenham's chorea, infections with group A p-hemolytic streptococci, among others, may trigger autoimmune responses that cause or exacerbate some cases of childhood-onset obsessive-compulsive disorder (OCD) or tic disorders (including Tourette's syndrome). If this hypothesis is correct, then immunological treatments should lead to decreased symptoms in some cases. Four cases with abrupt, severe onset or worsening of OCD or tics are presented from an open treatment study. All were boys aged 10 to 14 years. One had OCD, one had Tourette's syndrome, and two had both OCD and Tourette's syndrome. Clinically and on standardized rating scales, their symptoms were in the moderate to very severe range. Two had evidence of recent group A p-hemolytic streptococci infections, and the others had histories of recent viral illnesses. Two were treated with plasmapheresis, one with intravenous immunoglobulin, and one with immunosuppressive doses of prednisone. All had a clinically significant response immediately after treatment. Diagnostic criteria are provided that describe these cases of pediatric, infection-triggered, autoimmune neuropsychiatric disorders (PITANDs). Suggestions are made regarding the evaluation and management of patients who may have this condition. J. Am.

Acad. Child Ado/esc. Psychiatry, 1995, 34, 3:307-311. Key Words: autoimmune, obsessive-compulsive disorder, tic disorders, streptococcal infections, viral infections, Tourette's syndrome.

An episodic, gradual waxing and waning of symptoms is typical of many cases of obsessive-compulsive disorder (OCD), and a similar symptom course has been associated with Tourette's syndrome ('IS) and other tic disorders (American Psychiatric Association, 1994). In pediatric patients with OCD, we have noted a subgroup whose waxing and waning of symptoms is distinguished by a sudden, dramatic onset of clinically significant symptoms followed by a slow waning over a period

Accepted December 9, 1994. Dr. Allen is a Senior Medical Staff Felloio, Section on Behavioral Pediatrics, Child Psychiatry Branch, NIMH, Bethesda, MD. Dr. Leonard is Head, Unit on Pediatric Neuropsychiatric Disorders, Child Psychiatry Branch, NIMH Dr. Swedo is Head, Section on Behavioral Pediatrics, Child Psychiatry Branch, NIMH The authors flcknow/c·dge till' invaluable CONtributions ofXavier Castellanos,

M.D., Ms. Sara Dow, Susan Leitman, M.D., Gary Mosher, M.D., Collette Parker, M.D., Mr. Daniel Richter, Kenneth Rickler, M.D., Norman Rosenthal, M.D., Mark Schapiro, M.D., lind Gregory j. Swedo, M.D. Reprint requests to Dr. Allen, Section on Behavioral Pediatrics, Child Psychiatry Branch, NIMH, Bldg. 10, Room 6N240, 10 Center Drive MSC 1600, Bethesda, MD 20892-1600; telephone: (301) 496-5323; fax: (301) 402-8497. 0890-8567/95/3403-0307$03.00/0© 1995 by the American Academy of Child and Adolescent Psychiatry.

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of months. This pattern is strikingly rerruruscent of the course of movements in Sydenham's chorea, a variant of rheumatic fever (Swedo, 1994). Indeed, patients with Sydenhams chorea frequently reported a concomitant onset of obsessions and compulsions with their movements (Swedo et al., 1989). In one case series, we subsequently found that about three quarters of the patients had obsessive-compulsive symptoms and one third had frank OCD (Swedo et al., 1993). The obsessive-compulsive symptoms appeared shortly before the onset of choreic movements, and they waxed and waned in severity concomitant with the chorea. It is interesting that approximately one third of children with OCD in one National Institute of Mental Health (NIMH) study had mild choreiform movements (Denckla, 1989). We therefore speculated that Sydenham's chorea might serve as a medical model for OCD (Swedo, 1994). There also appears to be an association between Sydenham's chorea and tic disorders. In addition to the choreic movements, many Sydenharn's patients have tic-like, adventitial movements, an observation that was originally made by Osler (1894) and was recently extended by Kiessling

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er al. ( 1993) in th eir report of patients w ith increased tics after a com m u nity outb reak of str ep tococcal ph aryn gitis. T he above ob servati on s led us to propose th at , in pedi atri c patients, stre ptococcal infections ("s tre p th roats" and other infect ion s ca use d by gro up A ~-h emolyti c streptococci, GABHS) co uld trig ger th e sudden o nse t or epi sodic wo rsen in g of OCD and/or tic disorders (includ ing TS) via an auto immune p rocess ana logous to Sydenharn's cho rea (Swedo , 199 4 ; Swed o et nl., 1994). This hyp othesis suggests that treatments th at alter immune function might benefit some children expe riencing acute, severe exacerbations of OCD and TS (Swedo, 1994). Furth erm ore, if this is true, th en identifying such children becomes important from both a clinica l and research persp ecti ve as a different ap p roach to assessme nt and trea tme nt wo uld be indicat ed . Fo ur cases treat ed in an o pen NIMH tr ial are presented below; pertinent d ata an d rati ngs a re summarized in Table 1. CASE 1

B.]. was a 14- year-old w ith a 1.5-year histo ry of OCD a nd mild tics, whic h had been stable for severa l m onths wh ile he was tak ing a co m bination of clomipramine and fluo xet ine. T hen, during a sum mer soccer camp, h is OCD sympto ms suddenly wors ened dramat ically. O n his return hom e, h is psychi at rist co ns ulted o ne of us (S.£. S.), who sugges ted a throat culture be don e. The culture was positive and GABH S pharyn gitis was diagnosed, although B.] .'s last sore throat h ad resolved a month earli er. T wo weeks later, he cam e to th e NIMH for evalu ati on . H is obsessions included a fear for his own and hi s father's safety, a need for sym me try , and perfe cti onistic co nc erns. His pred ominate co m pulsions we re checki ng behav iors and exercises (e.g., fingertip pu shups) tha t had to be perform ed perfectly or rep eated until h e was un abl e to co ntinue . At th at time, m or e th an 90% of his waking h ours were occ up ied by ob sessio ns and co m p ulsions. N eurological examination revealed m ororic hyperacti vity and m ild choreiform mo vem ents. Becau se of th e severi ty of B.] .'s OCD , h is suspicio us m ovem ents, and hi s sud den worseni ng du ring a strep to cocca l infection, he was treated wi th a series of six plasm a excha nges over a period of 2 weeks. D uring th is time there was a m ark ed decl ine in his OCD sym p to ms (T able 1). Subjectively, the patient and his

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fam ily rep orted h e was " 80% better." A m agn et ic reson an ce im agin g scan don e after four pl asm a excha nges show ed a 2 5% decrease in the size of th e head of the caudate co m pared to a scan don e befor e treatment (Swed o et al., 1994). After plasm apheresis he began a regime n of pen icillin as prophylaxis aga ins t G ABHS infe cti ons. H e co nti nued to do well at followup several mo nths later. CASE 2

T.]. was a 10-year-old who had no history of psychiatr ic or neurological problem s. The weekend after several family members h ad th e "flu," he had sudden onset of severe ob session s abo ut viruses and chemicals, and he began compulsive h and -washing. After a m onth of co n tin uous illn ess, psych iatri c tr eatm en t was so ugh t an d he started sert raline therapy, with onl y part ial sym pto m relief of his OCD after 2 mo n ths. H e was the n evalua ted at th e NIMH (3 m onths after th e onse t of his illne ss). At th at time hi s fore arms and hands we re cha pped and red , an d co ntam ination fears pr evented him from fully ope n ing his mouth so th at he was un able to eat in th e h ospital or have a throat culture. Because of the abru p t onse t of hi s sym ptoms an d thei r severi ty, T.]. was treated wi th six plasma excha nges over a period of 2 weeks . Pen icillin prophylaxis was not prescrib ed becau se h is epis ode of OCD appeared to have been virally triggered . His sym pto ms declined noticeably during plasm apheresis-after the fourth exchange he could eat at th e hospital and permitted a throat culture. His sym pto ms were so improved 1 mo nth after plasmapheresis th at his sertraline do sage was being tapered, with on ly subclin ical obsessions and co m p ulsions remain ing (Table 1). He was reported to be doing well several m onths lat er. CASE 3

In 19 87 , whe n S.]. was 7 years old, pain ful ulcers developed on h is mouth and lips, and he was no ted to have a po siti ve antinuclear antibo dy titer with spec kled pattern . Shortly after thi s, he h ad the first of m an y GABHS infections, wh ich continue d until 19 89 whe n he had a tonsillectomy. After th e surgery he began to experience mo to r tics (cra n ing of h is neck, eye-bl inking, sho ulde r-sh rugging) and voca l tics (" clicking" so unds), whic h were eventually dia gnose d as TS. His tics declin ed aft er he began to take a low dose of fluphen azine and were stable for ap proxima tely 18 months. Shortly

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NEW SUBTYPE OF PEDIATRIC

or:n

AND TS

TABLE 1 Demographic, Clinical, and Trearmenr Data

Sex, age (years)

Case I (B.].)

Case 2 (T.].)

Case 3 (S.].)

Case 4 G.].)

Male, 14

Male, 10 OCD (conramination)

Male, 13 TS

No

Yes

Male, 13 ADHD, 1'S, OCD (contamination, rereading, need for perfection) Yes

GABHS pharyngitis (positive culture)

Viral, possibly influenza

Viral, possibly influenza

Diagnosis (including predominate obsessions and compulsions) Prodromal symptoms or prior episodes Suspected infectious trigger for treatmenr episode Duration of episode before treatment

Mild motor and vocal tics, OCD (exercise, need for perfection) Yes

2 weeks

3 months

5 months

Laboratory results before treatment

ASO = 340 Anti-DNAse B = 1:340 ANA negative C-YBOCS = 40 (maximum possible score)

ASO, ANA negative

ASO = 240 ANA positive, 1:320, speckled Ex MTR = 13 Ex VTR = 2 Hx MTR = 18 Hx VTR = 5

Plasmapheresis C-YBOCS = 19.5 (-51%)

Plasmapheresis Prednisone 8 (-38%) C-YBOCS = 10 (-60%) Ex MTR Ex VTR = 2 (0%) Hx MTR = 10 (-44%) Hx VTR = 0 (-100%)

Pretreatment ratings"

Treatment Posttreatment ratings" (% change from pretreatment)

C-YBOCS = 25

GABHS pharyngitis (positive culture) month ASO, ANA negative

C-YBOCS = 28 Ex MTR = 9 Ex VTR 12 Hx MTR 16 Hx VTR 19 IVIG C-YBOCS = 26 (-7%) Ex MTR 4 (-56%) Ex VTR = 4 (-67%) Hx MTR 6 (-62%) Hx VTR = 12 (-37%)

Note: OCD = obsessive-compulsive disorder; TS = Touretre's syndrome; ADHD = attention-deficit hyperactivity disorder; GABHS = group A ~-hemolytic streptococci; ASO = anti-streptolysin 0; Anti-DNAse B = anti-streptococcal DNAse B; ANA = antinuclear antibodies; C-YBOCS = Children's Yale-Brown Obsessive Compulsive Scale (Goodman and Price, 1992) (a score of 20 reflects OCD symptoms of moderate severity; scores range from 0 to 40); Ex MTR = examiner's motor tic ratings on the Shapiro tic rating scale (Shapiro et al., 1978) (a score of 12 reflects tics of moderate severiry; scores range from 0 to 20); Ex VTR = examiner's vocal tic ratings on the Shapiro tic rating scale (Shapiro et al., 1978); Hx MTR = historical (from parent/child) motor tic ratings on the Shapiro tic rating scale (Shapiro et al., 1978) (a score of 15 reflects tics of moderate severity; scores range from 0 to 25); Hx VTR = historical (from parent/child) vocal tic ratings on the Shapiro tic rating scale (Shapiro er al., 1978); IVIG = intravenous immunoglobulin. "All ratings shown are the means from two physicians with training in mental health research. b Posttreatment ratings are within a month of completing tteatment.

after a bout of the "flu," his tics escalated dramatically. Of particular concern were new, violent tics of his head and neck that were so extreme that 5.]. had physical discomfort. Now 13 years old, he was referred to the NIMH for evaluation. He was found to have an antinuclear antibody titer of 1:320 (speckled patterri}, and subsequently a transient rash developed. A rheumatologist concluded he did not have lupus, however. Six months after his viral illness,S.]. was treated with immunosuppressive doses of prednisone. A clinically significant improvement in his tics was evident 2 weeks later (Table 0, although residual movements remained. His tics again worsened suddenly a few weeks later,

]. AM. ACAD. CHILD ADOLESC. PSYCHIATRY. 34:3. MARCH 1995

after a viral respiratory infection and an allergic reaction to an influenza immunization. A retrial of prednisone at that time was unsuccessful (no change in tic ratings, data not shown). CASE 4

].]. was a 13-year-old with a long history of asthma, hyperactivity, TS, and oeD. He had previously been enrolled in several protocols at the National Institutes of Health (NIH) for these illnesses. His neuropsychiatric symptoms were believed to be episodic but had been relatively well controlled for about 6 months while he was taking a combination of methylphenidate and clomipramine. After a documented case of GABHS

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pharyngitis, he experienced rapid, severe worsening of both his TS and OCD. This occurred during a family trip to Thailand and Arizona, during which the family had to alter their travel plans because of ].].'s obsessive fears that the plane would crash. ].]. also had severe vocal tics (spitting and nearly continuous screaming) during the trans-Pacific flights, and he was unable to finish any reading material because he felt the need to reread every sentence many times. Approximately 2.5 months after his infection and a month after his symptoms increased, he was treated with intravenous immunoglobulin (l mg/kg per day for 2 days). His parents reported that his tics began to improve within a week of the intravenous immunoglobulin treatment. At 1 month follow-up (Table 1), there was a clinically significant improvement in his tics, but his OCD was essentially unchanged. His parents reported that ].]. was doing well several months later, at which time he entered a protocol (NIH protocol 93-M-OI22) comparing penicillin with placebo as prophylaxis against neuropsychiatric episodes triggered by GABHS infections.

DISCUSSION

We report these cases because our preliminary evidence suggests that immunomodulatory treatments may improve symptoms for some OCD and TS patients with severe illness due to a postulated autoimmune etiology. Further research is needed to establish the efficacy of these interventions as the novelty of this approach, the economic costs, and the potential medical risks demand scientific proof rather than anecdotal evidence. A treatment protocol with a double-blind, placebo-controlled component has been approved by the NIMH institutional review board and is under way. (To refer patients, contact the authors.) Although our preliminary results promise great treatment benefit to some individuals with this subtype of pediatric OCD and/or tic disorders, ultimately such research may be more important because of information it provides about the etiology of some OCD and TS cases. In turn, this may lead to the development of new, more specific treatment and prevention regimens. The essential features of these cases are summarized by the phrase: pediatric, infection-triggered, autoimmune neuropsychiatric disorders (PITANDs). Some of these cases may be triggered by viruses rather than

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GABHS, as in cases 2 and 3 presented here. At this time, no laboratory measure appears to be both sensitive and specific for PITAND cases. Thus, identification of cases currently depends on the patients' clinical histories. The following criteria appear to accurately identify this subgroup of patients: 1. Pediatric onset: symptoms of the disorder first become evident between 3 years of age and the beginning of puberty. 2. At some time in his or her life, the patient must have met diagnostic criteria for OCD and/or a tic disorder. 3. The onset of clinically significant symptoms must be sudden (with or without a subclinical prodrome), and/or there must be a pattern of sudden, recurrent, clinically significant symptom exacerbations and remissions. Onset of a specific episode typically can be assigned to a particular day or week, at which time symptoms seemed to "explode" in severity. 4. Increased symptoms should not occur exclusively during stress or illness, should be pervasive, should be of sufficient severity to suggest the need for treatment modifications, and (if untreated) should last at least 4 weeks before improvement is noted. 5. During OCD and/or tic exacerbations, the majority of patients will have an abnormal neurological examination, frequently with adventitious movements (c.g., mild chorea).

6. There must be evidence ofan antecedent or concomitant infection. Such evidence might include a positive throat culture, positive streptococcal serological findings (e.g., anti-streptolysin 0 or anti-streptococcal DNAse B), or a history of illness (e.g., pharyngitis, sinusitis, or flu-like symptoms). 7. Patients mayor may not continue to have clinically significant symptoms between episodes of their OCD and/or tic disorder. By design, these criteria permit patients with both very severe and relatively mild symptoms to be diagnosed with PITANDs. This is important because infectious and autoimmune processes may be amenable to preventive interventions, and thus recognition of early, less affected cases may be desirable. At present, identification of PITAND cases may be important for two reasons. First, patients with this syndrome may be candidates for experimental treatment protocols that could directly benefit the patients

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NEW SUBTYPE OF PEDIATRIC OCD AND TS

and increase our knowledge about this condition. Second, it is our clinical impression that some of these patients may benefit from careful monitoring by physicians for GABHS infections. This is based, in part, on the fact that, before the onset of routine penicillin prophylaxis, rheumatic fever episodes were reduced merely by surveillance throat cultures and aggressive treatment of GABHS (for a review, see Foggo, 1985). Early treatment of streptococcal infections could theoretically limit the immune response (Berrios et al., 1985) and potentially blunt increases in obsessions, compulsions, or tics. Thus, on initial presentation, we would suggest inquiring about recent illnesses and obtaining a throat culture and streptococcal serological studies (anti-streptolysin 0 and/or anti-streptococcal DNAse B). Subsequent preventive care might include periodic throat cultures for asymptomatic GABHS infections (as was found in case 1) and treatment of positive cultures. As research in this area proceeds, these patients may also benefit from new diagnostic tests, treatments, or prophylactic measures. Indeed, we are currently engaged in a double-blind, placebocontrolled trial of penicillin for the prevention of oeD or tic disorder exacerbations.

J.

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93:323-326 Swedo SE, Leonard HL, Schapiro MB er al. (1993), Sydcnham's chorea: physical and psychological symptoms of St Virus dance. Pediatrics

91:706-713 Swedo SE, Rapoport ]L, Cheslow DL cr al. (1989), High prevalence of obsessive-compulsive symptoms in patients with Sydenharn's chorea. Am 1 Psychiatry 146:246-249

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