Neuroimmune Dysfunction

Parallels between Sydenham chorea (SC), the neurologic manifestation of rheumatic fever, and childhood-onset OCD suggest that the two disorders may have a shared etiopathogenesis (Garvey et al., 1998). The disorders have similar regional localization, with evidence of dysfunction of the orbitofrontal-striatal circuitry in both OCD and SC. Further, over 70 percent of children with SC report that they have experienced an abrupt onset of repetitive, unwanted thoughts and behaviors 2 to 4 weeks prior to the onset of their chorea (Swedo et al., 1993). The obsessions and compulsions peak in intensity concomitantly with the chorea and wane away slowly over the ensuing months. A subgroup of patients error with childhood-onset OCD was noted to have a similar symptom course. The OCD exacerbations occurred following Group A beta-hemolytic streptococcal (GABHS) infections, accompanied by a cluster of comorbid symptoms, including emotional lability, separation anxiety, and attentional difficulties (Swedo et al., 1998). The children were young (6 to 7 years old at symptom onset), predominantly male, and often had comorbid tics. To indicate their shared clinical features (and presumed etiopathogenesis), the subgroup was identified by the acronym PANDAS —pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (Swedo et al., 1998).

The major distinguishing feature of the PANDAS subgroup is the temporal association between neuropsychiatry symptom exacerbations and GABHS infections—that is, positive (or rising) antistreptococcal antibody titers or a positive throat culture during neuropsychiatric symptom relapses and evidence of GABHS negativity during periods of remission (Perlmutter et al., 1998). This one-to-one correlation is necessary to distinguish GABHS-triggered exacerbations of the PANDAS subgroup from the more typical waxing and waning course seen in Tourette disorder and some cases of childhood-onset OCD. The temporal association between GABHS infections and neu-ropsychiatric symptom exacerbations suggests that prevention of the infections might result in decreased severity of the obsessive-compulsive symptoms. An 8-month long placebo-controlled crossover trial of penicillin prophylaxis was undertaken (4 months of penicillin followed by 4 months of placebo, or the reverse) (Garvey et al., 1999). The penicillin prophylaxis failed to achieve the primary objective of significantly reducing GABHS infections (14 of 35 infections occurred during the penicillin phase), so it was not surprising that there were no between-phase differences in OCD or tic severity. However, poor compliance appeared to contribute to penicillin's lack of effectiveness, as missed doses were frequent.

The role of the immune system in the etiology of OCD and tic disorders is unclear, but clinical observations suggest that symptoms result from a combination of local, regional, and systemic abnormalities (Hamilton et al., 2001). Magnetic resonance imaging (MRI) scans reveal enlargements of the caudate, putamen, and globus pallidus, which points to regional inflammatory changes (Giedd et al., 1996, 2000), while local autoimmune reactions are suggested by the presence of serum antibodies that cross-react with neurons of these same brain regions (Kiessling et al., 1994). Husby and colleagues were the first to describe cross-reactive antibodies in Syden-ham chorea. Although the antibodies were labeled "antineuronal," the investigators postulated that the antibodies must have been raised against epitopes on the GABHS bacteria and then cross-reacted with cells of the caudate nucleus and subthalamus. It was the cross-reactivity that distinguished the antibodies found in the SC patients from antineuronal antibodies found in patients with systemic lupus erythematosus and other neurologic disorders (Husby et al., 1976). Several groups have subsequently reported the presence of antineuronal antibodies in patients with childhood-onset OCD and/or tic disorders (Singer et al., 1998; Morshed et al., 2001).

The striking effectiveness of immunomodulatory therapies, such as therapeutic plasma exchange and intravenous immunoglobulin (IVIG) suggests that there is systemic involvement, at least among severely affected individuals. A randomized, placebo-controlled trial of IVIG and plasma exchange was conducted on 29 children in the PANDAS subgroup at the NIMH (Perlmutter et al., 1999). Both of these immuno-modulatory therapies produced significant improvements in neuropsychiatric symptom severity—placebo administration had no demonstrable effect on obsessive-compulsive symptoms at 1-month follow-up, while IVIG and plasma exchange treatments had produced mean symptom reductions of 45 and 58 percent (respectively). One-year follow-up revealed that 14 of 17 children (82 percent) continued to be "much" or "very much" improved from baseline (Perlmutter et al., 1999). The effectiveness of the immunomodulatory therapies suggests that circulating immune factors play a role in the pathophysiology of the symptoms, but no specific hypotheses can be formulated on the basis of the treatment response because of the broad spectrum of action of both IVIG and plasma exchange.

Anxiety and Depression 101

Anxiety and Depression 101

Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.

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