Elsevier

The Lancet

Volume 354, Issue 9185, 2 October 1999, Pages 1153-1158
The Lancet

Articles
Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood

https://doi.org/10.1016/S0140-6736(98)12297-3Get rights and content

Summary

Background

In children, exacerbations of tics and obsessive symptoms may occur after infection with group A β-haemolytic streptococci. If post-streptococcal autoimmunity is the cause of the exacerbations, then children might respond to immunomodulatory treatments such as plasma exchange or intravenous immunoglobulin (IVIG). We studied whether plasma exchange or IVIG would be better than placebo (sham IVIG) in reducing severity of neuropsychiatric symptoms.

Methods

Children with severe, infection-triggered exacerbations of obsessive-compulsive disorder (OCD) or tic disorders, including Tourette syndrome, were randomly assigned treatment with plasma exchange (five single-volume exchanges over 2 weeks), IVIG (1 g/kg daily on 2 consecutive days), or placebo (saline solution given in the same manner as IVIG). Symptom severity was rated at baseline, and at 1 month and 12 months after treatment by use of standard assessment scales for OCD, tics, anxiety, depression, and global function.

Findings

30 children entered the study and 29 completed the trial. Ten received plasma exchange, nine IVIG, and ten placebo. At 1 month, the IVIG and plasma-exchange groups showed striking improvements in obsessive-compulsive symptoms (mean improvement on children's Yale-Brown obsessive compulsive scale score of 12 [45%] and 13 [58%], respectively), anxiety (2·1 [31%] and 3·0 [47%] improvement on National Institute of Mental Health anxiety scale), and overall functioning (2·9 [33%] and 2·8 [35%] improvement on National Institute of Mental Health global scale). Tic symptoms were also significantly improved by plasma exchange (mean change on Tourette syndrome unified rating scale of 49%). Treatment gains were maintained at 1 year, with 14 (82%) of 17 children “much” or “very much” improved over baseline (seven of eight for plasma exchange, seven of nine for IVIG).

Interpretation

Plasma exchange and IVIG were both effective in lessening of symptom severity for children with infection-triggered OCD and tic disorders. Further studies are needed to determine the active mechanism of these interventions, and to determine which children with OCD and tic disorders will benefit from immunomodulatory therapies.

Introduction

Obsessive-compulsive disorder (OCD) and tic disorders are common in childhood, affecting 1–2% of school-aged children and adolescents. The obsessional thoughts and compulsive rituals of OCD are generally chronic and disabling, and cause serious psychological distress and lifelong impairment of social and occupational functioning.1 Treatment with serotonin reuptake blocking drugs, behaviour therapy, or both, helps more than 75% of patients, but most show only a partial response, and relapse when medication is discontinued. Tic disorders, including Tourette syndrome, have a more variable course than OCD, since the severity of symptoms waxes and wanes. About two in three of these patients will have complete or partial remission of symptoms during adolescence.2 Medications such as neuroleptics can reduce tic severity, but do not eliminate them.

The cause of OCD and tic disorders is unknown, although the two disorders may have a common cause that is a combination of genetic and environmental factors.3 Post-streptococcal autoimmunity has been postulated as one possible environmental trigger, and Sydenham's chorea, the neurological manifestation of rheumatic fever, has been proposed as a potential model of pathophysiology.4

Molecular mimicry is thought to play a part in the aetiology of Sydenham's chorea, through a process in which antibodies against group A β-haemolytic streptococci crossreact with neuronal cells to produce inflammation in the central nervous system (particularly within the basal ganglia), resulting in chorea, muscle weakness, and emotional lability.5, 6 In some cases, obsessions, compulsions, and tics may also be mediated by post-streptococcal autoimmunity. Several studies have shown crossreactive antistreptococcal antibodies in children with OCD and tic disorders, and a marker of susceptibility to rheumatic fever has been shown in a subgroup of these patients.7, 8, 9 The subgroup shares a unique clinical course and is identified by the acronym PANDAS (paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections).10

The pathophysiology proposed for Sydenham's chorea suggests that treatments that interrupt the autoimmune process might lessen the severity of symptoms. Preliminary results for a controlled trial of plasma exchange and intravenous immunoglobulin (IVIG) in patients with Sydenham's chorea showed efficacy of both treatments.11 We hypothesise that if the aetiology of PANDAS is similar to that in Sydenham's chorea, then immunomodulatory therapies might also be effective treatments for exacerbated neuropsychiatric symptoms.12 Steroid therapy was not a viable treatment option for our study, because tics and OCD may worsen during steroid administration.13 Plasma exchange and IVIG were chosen as the active treatments because of their record of safety and effectiveness in several childhood and adult immune-mediated diseases, as well as anecdotal reports of symptom improvement in patients with infection-triggered exacerbations of OCD.12, 14, 15, 16 We aimed to show whether plasma exchange and IVIG would be better than placebo in decreasing neuropsychiatric symptoms in children with infection-triggered exacerbations of OCD and tic disorders.

Section snippets

Patients

Children aged 5–14 years were recruited nationwide over 4 years via letters to paediatricians, neurologists, and psychiatrists. Referrals were screened by telephone interview to assess study eligibility. Those parents who were interested in the treatment protocol and whose children fitted our criteria were assessed at the National Institute of Mental Health outpatient clinic. Eligibility criteria were: a tic disorder, obsessive compulsive disorder, or both, that met definitions in the

Baseline characteristics

We screened more than 200 children by telephone; 58 underwent face-to-face screening in our clinic. 28 children did not meet eligibility criteria or were unwilling to participate in the randomised trial. 30 children (19 boys, 11 girls) were enrolled in the study (figure 1). One girl (IVIG group) left the study in the first week because of non-compliance; the other 29 completed the ratings at 1 month (ten plasma exchange, ten placebo, nine IVIG). Two children in the plasma-exchange group were

Discussion

Plasma exchange and IVIG were both better than placebo in the treatment of exacerbations of neuropsychiatric symptoms in children with OCD and tic disorders. Both active treatments gave rapid and sustained improvements in global functioning, depression, emotional lability, and obsessive-compulsive symptoms, whereas placebo had little or no effect. The lack of a placebo effect is not surprising, given the number of studies in which placebo has failed to relieve obsessive-compulsive symptoms.27

References (28)

  • G Husby et al.

    Antibodies reacting with cytoplasm of subthalamic and caudate nuclei neurons in chorea and acute rheumatic fever

    J Exp Med

    (1976)
  • LS Kiessling et al.

    Antineuronal antibodies in movement disorders

    Pediatrics

    (1993)
  • HS Singer et al.

    Antibodies against human putamen in children with Tourette syndrome

    Neurology

    (1998)
  • SE Swedo 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)
  • Cited by (477)

    • Role of tonsillectomy and adenoidectomy in parental satisfaction of treatments for PANDAS

      2021, American Journal of Otolaryngology - Head and Neck Medicine and Surgery
    • Current Research Updates on PANDAS and PANS

      2023, Current Developmental Disorders Reports
    • Immune system and obsessive-compulsive disorder: Intervention through immunothera

      2023, Nutrition and Obsessive-Compulsive Disorder: The Interplay
    View all citing articles on Scopus
    View full text