Genetics of Childhood Disorders: Poststreptococcal Autoimmunity

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J Am Acad Child Adolesc Psychiatry,40:12,1479-1482 December 2001

Genetics of Childhood Disorders:

Autoimmune Disorders

Poststreptococcal Autoimmunity

E. Swedo, M.D.

In the late 1980s, studies of children with Sydenham chorea (SC), the

neurological manifestation of rheumatic fever, suggested that the disorder

might serve as a useful model of pathophysiology for some forms of

childhood-onset obsessive-compulsive disorder (OCD) and tic disorders. The

disorders share anatomic similarities. Both OCD and SC have evidence of

basal ganglia dysfunction, particularly in the caudate nucleus, which is

thought to disrupt signals traveling along the orbitofrontal-striatal

pathways. Furthermore, over 70% of children with SC reported that they had

experienced an abrupt onset of repetitive, unwanted thoughts and behaviors 2

to 4 weeks before the onset of their chorea. These obsessions and

compulsions peaked in intensity concomitantly with the chorea and waned away

slowly over the ensuing months. Because the obsessive-compulsive symptoms

began earlier than the chorea, it seemed possible that poststreptococcal OCD

might occur in the absence of chorea, a hypothesis confirmed by prospective

observations of a large cohort of children with primary OCD.

Among those children, a subgroup was noted to have dramatic symptom

exacerbations following infections with group A b-hemolytic streptococcal

bacteria (GABHS) such as occurs with strep throat and scarlet fever. The

symptom exacerbations were accompanied by a cluster of comorbid symptoms,

including emotional lability, separation anxiety, and attentional

difficulties. The children were young (6–7 years old at symptom onset),

predominantly male, and had frequent comorbid tics. To indicate the

subgroup’s common clinical characteristics and presumed pathophysiology, it

was identified by the acronym PANDAS (pediatric autoimmune neuropsychiatric

disorders associated with streptococcal infections).

The etiology proposed for the PANDAS subgroup is similar to that postulated

for SC. In SC, host susceptibility is thought to play a crucial role in

symptom expression, as fewer than 5% of children are vulnerable to

poststreptococcal sequelae. Familial clustering suggests that genetic

factors are involved in the susceptibility, but is not the sole explanation

as developmental and immunological factors may also play a part.

The constitution of the streptococcal bacteria appears to play an

etiological role in rheumatic fever and other poststreptococcal sequelae.

Although most strains of GABHS produce only acute symptoms, certain

“rheumatogenic” strains incite the production of antibodies that cross-react

with host tissues, producing an “autoimmune”; reaction. Unlike typical

autoimmune disorders, the autoantibodies in rheumatic fever are not directed

primarily against the host tissue, but rather against streptococcal epitopes

that resemble antigens on host cells. In SC, the cross-reactive antibodies

are thought to recognize epitopes on basal ganglia neurons (particularly in

the caudate, putamen, and globus pallidus). The resulting inflammation

disrupts basal ganglia function, causing chorea, emotional lability, and

other neuropsychiatric symptoms. After the streptococcal infection is

eliminated from the nasopharynx, antibody production ceases and circulating

antibodies are cleared over the ensuing weeks to months. The neurological

symptoms also remit—often with no lasting sequelae. However, recrudescences

can occur, particularly when the child is infected again with microbes

resembling the inciting organism.

Although the antineuronal antibody model of SC appears quite convincing, it

has not yet been proven, despite decades of research. Furthermore, recent

studies by a number of research groups have demonstrated several crucial

limitations of the antineuronal antibody model, including its failure to

account for the presence of similar antibodies in the serum of 20% to 40% of

healthy children. Thus, for the PANDAS subgroup, the model has been modified

to indicate that the immune response is not limited to the antineuronal

antibodies. As shown in Figure 1, our working model of pathophysiology

involves a series of factors, including the streptococcus bacteria, host

susceptibility, and abnormal immune responsivity.

The major distinguishing feature of the PANDAS subgroup is the temporal

association between the neuropsychiatric symptom exacerbations and the

infections. Because strep infections are common during childhood,

antistreptococcal titers and throat cultures might be positive during a

symptom exacerbation by chance alone. Thus the PANDAS criteria specify that

GABHS infections must be temporally related to the OCD/tics exacerbations,

that is, positive (or rising) antistreptococcal antibody titers or a

positive throat culture must be present during neuropsychiatric symptom

relapses and there must be evidence of strep negativity during periods of

remission.

In some cases, the dramatic onset of severe OCD and/or tics following a

single, prolonged strep infection is sufficient to warrant inclusion in the

PANDAS subgroup. Usually, however, the temporal relationship can be

established only through prospective documentation of both seropositivity

during symptom exacerbations and seronegativity during periods of remission.

This 1 to 1 correlation is necessary to distinguish strep-triggered

exacerbations of the PANDAS subgroup from the more typical waxing and waning

course seen in Tourette’s syndrome and some cases of childhood-onset OCD.

For rheumatic fever, the etiological role of strep infections was

demonstrated indirectly, through three lines of research: (1)

epidemiological investigations which demonstrated a close temporal

relationship between scarlet fever epidemics and subsequent outbreaks of

rheumatic fever; (2) the prevention of rheumatic fever recrudescences by

penicillin prophylaxis; and (3) demonstration of declining rates of

rheumatic fever following the widespread application of antibiotic treatment

for GABHS pharyngitis. For the PANDAS subgroup, there are no epidemiological

data that yet demonstrate increased rates of OCD and/or tics following strep

epidemics, although a school-based study of the relationship between strep

infections and neuropsychiatric symptoms is currently under way.

The use of penicillin prophylaxis for the prevention of neuropsychiatric

symptom exacerbations was evaluated in a double-blind, placebo-controlled,

8-month-long crossover study by Garvey and colleagues in 1999. Although

individual cases demonstrated between-phase differences, the trial failed to

show overall superiority of penicillin over placebo. This may have been due

to the failure of oral penicillin to prevent strep infections (14 of the 35

infections documented during the study occurred during the penicillin

phase). Ongoing trials are investigating the utility of other antibiotics as

prophylactic agents for the PANDAS subgroup, but at present, there are no

systematic data to support the use of antibiotic prophylaxis for children

with OCD and/or tic disorders. Similarly, the specific strains of strep

bacteria responsible for symptom onset in the PANDAS subgroup remain to be

identified. Knowing which types of bacteria are capable of inducing the

poststreptococcal sequelae may help elucidate the nature of the abnormal

immune response.

As discussed above, host susceptibility is likely to be the result of a

combination of genetic, developmental, and immunological factors.

Developmental vulnerabilities are suggested by the increased rates of

disease among elementary school–age children. Rheumatic fever is rare among

children younger than 3 years of age, peaks in incidence during the

elementary school years, and declines in frequency at adolescence to become

rare again during young adulthood. This pattern might reflect developmental

differences in immune responsivity, or it may be merely the result of

changing risks of exposure to strep infections. These are most common during

the elementary school years, and nearly all children develop protective

immunity by age 12 to 13 years. For the PANDAS subgroup, the peak age at

onset of symptoms is 6 to 7 years, with prepubertal symptom onset serving as

a defining characteristic of the subgroup.

Family history studies have been used to evaluate the role of genetics in

host susceptibility. For rheumatic fever, familial clusters suggested an

autosomal (dominant or recessive, depending on the sample studied) pattern

of inheritance. Preliminary data from 21 patients with SC and 15 children in

the PANDAS subgroup revealed significantly increased rates of rheumatic

fever among the children’s parents and grandparents, in comparison with the

parents and grandparents of 35 healthy controls (5/126 [4.0%], 6/90 [6.7%],

and 3/210 [1.4%], respectively; Swedo et al., unpublished data, 2001). The

between-groups differences were small in this pilot data set, but suggested

that children in the PANDAS subgroup may inherit a susceptibility to

poststreptococcal sequelae similar to that reported for children with SC.

Children in the PANDAS subgroup also appear to have increased rates of OCD

and tics among their family members. In a recently completed study by Lougee

of 54 probands in the PANDAS subgroup (24 with a primary diagnosis of OCD

and 30 with a primary diagnosis of a tic disorder), 21 (39%) had at least

one first-degree relative with a history of a motor or vocal tic and 14

(26%) had at least one first-degree relative with OCD. Six mothers (11%), 9

fathers (19%), and 8 siblings (16%) had a motor or vocal tic, while 10

mothers (19%), 5 fathers (11%), and 2 siblings (5%) had OCD. These rates are

substantially higher than those reported for the general population and are

similar to rates previously reported for childhood-onset OCD and tic

disorders. The combination of increased familial rates of OCD/tic disorders

and of increased rates of rheumatic fever suggests that children in the

PANDAS subgroup may have a dual genetic vulnerability—with inherited

susceptibilities to both OCD/tic disorders and poststreptococcal autoimmune

sequelae. Proof of this hypothesis must come from genetic determinations,

rather than family history studies, and awaits future testing.

At present, the role of the immune system in the etiology of OCD and tic

disorders is unknown. Clinical observations suggest that symptoms result

from a combination of local, regional, and systemic abnormalities. The

striking effectiveness of immunomodulatory therapies, such as therapeutic

plasma exchange and intravenous immunoglobulin (IVIG), suggests that there

is systemic involvement, at least in severely affected individuals. Magnetic

resonance imaging (MRI) scans reveal enlargements of the basal ganglia, a

finding which points to regional inflammatory changes, while local

autoimmune reactions are suggested by the presence of serum antibodies that

cross-react with neurons of the caudate, putamen, and globus pallidus.

The effectiveness of both plasma exchange and IVIG in the treatment of

severely affected patients in the PANDAS subgroup suggests that circulating

immune factors play a role in the pathophysiology of the symptoms. Both

treatments have a broad spectrum of potential mechanisms of action, from

clearance of circulating antibodies and cytokines to activation of

subpopulations of T cells and B cells, but the precise mechanism of effect

is unknown. If it could be determined, then it might be possible to

elucidate the nature of the poststreptococcal autoimmune response in the

PANDAS subgroup, as well as to develop targeted therapeutic interventions

suitable for use in less severely ill patients.

Regional inflammation is thought to play a role in the specificity of the

poststreptococcal neuropsychiatric symptomatology. In SC, functional imaging

studies obtained during the acute symptomatic period have demonstrated

increased basal ganglia blood flow, as well as disruptions of the

blood-brain barrier in the caudate nuclei. These abnormalities resolved as

the chorea remitted, suggesting that they were etiologically related to the

neuropsychiatric symptoms. Volumetric MRI scans have revealed bilateral

enlargements of the caudate, putamen, and globus pallidus in a group of

patients with SC, and similar abnormalities have been demonstrated recently

in a group of patients with OCD/tic disorders. In both samples, however,

there was substantial overlap between the patients and control subjects;

thus the volumetric measurements cannot be used as a diagnostic test.

In a small series of PANDAS patients treated with plasma exchange, baseline

caudate enlargements returned to normal after successful treatment. This

result suggests that the enlargement might be a reflection of basal ganglia

inflammation. To evaluate this possibility, all children currently being

treated with plasma exchange at the National Institute of Mental Health are

undergoing a series of MRI scans, in which a variety of specialzed

techniques are used to assess interstitial edema and disruptions of the

blood-brain barrier.

The final area of research interest is the cross-reactive antibodies first

described in SC by Husby and colleagues. The original report describes the

presence of serum antibodies that recognized cells of the caudate nucleus

and subthalamus. The antibodies recognized epitopes on the strep bacteria as

well. It was the cross-reactivity that distinguished the antineuronal

antibodies found in the SC patients from those found in patients with lupus

erythematosus and other neurological disorders.

Several groups have subsequently reported the presence of “antineuronal”

antibodies in the majority of patients with childhood-onset OCD and/or tic

disorders. These antibodies were directed against a variety of tissue

targets including human caudate, neuroblastoma cells, and rat striatum,

among others. Of note, antibodies were noted to be present frequently in the

serum of healthy children (20%–40%), raising the question of whether or not

the antibodies are the cause of the poststreptococcal neuropsychiatric

symptoms. This question might be answered by cross-reactivity studies, such

as those reported by Husby and colleagues, but these have not been done in

the majority of recent studies. Future research should include such

assessments, as well as techniques that will identify specific epitopes

recognized by the antibodies. If the antibodies are interacting with a

specific receptor or a single neuronal cell-type, they might be used to open

doors to better treatments for childhood-onset OCD and tic disorders and

might lead to a greater understanding of the cause and nature of these

troublesome disorders.

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