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On Site Link: PANDAS research (pediatric autoimmune
neuropsychiatric disorder associated with streptococcal infection) Dinn
WM, Harris CL, McGonigal KM, Raynard RC.
Obsessive-compulsive disorder
and immunocompetence.
Int J Psychiatry Med. 2001;31(3):311-20.
"OBJECTIVE:
A postinfectious, autoimmune response may be associated with the development of
pediatric obsessive-compulsive disorder (OCD). According to this model, antistreptococcal
antibodies cross-react with basal ganglia neurons following streptococcus infection.
This autoimmune reaction disrupts a basal ganglia-thalamocortical circuit and
generates obsessive-compulsive symptoms. One implication of this model is that
prolonged immunologic stress may be a risk factor for OCD. That is, immunologic
stress may compromise the blood-brain barrier and permit the influx of antistriatal
antibodies into the central nervous system. This article explores one part of
this putative relationship by investigating whether adult OCD patients, compared
to members of other psychiatric groups, demonstrate a higher incidence of recurrent
infections and other conditions suggestive of compromised immune function. METHOD:
To test this hypothesis, we conducted a medical records review of 100 consecutive
patients evaluated at a private psychiatric clinic specializing in the treatment
of anxiety disorders. Sixty-five patients met diagnostic criteria for an Axis-I
syndrome. Primary diagnoses included OCD, posttraumatic stress disorder, social
anxiety disorder, generalized anxiety disorder, panic disorder with agoraphobia,
and dysthymic disorder. Each medical record was reviewed for the presence of target
syndromes or presenting symptoms suggestive of compromised immune function. RESULTS:
Chart review revealed an increased rate of immune-related symptoms and syndromes
among OCD patients in comparison to other anxiety and mood disorder groups. Groups
did not differ significantly in the incidence of non-immune symptoms and syndromes.
CONCLUSION: Adult OCD patients appear to have an increased rate of immune-related
diseases above and beyond that seen in other psychiatric disorders." [Abstract] Kiessling
LS, Marcotte AC, Culpepper L.
Antineuronal antibodies: tics and obsessive-compulsive
symptoms.
J Dev Behav Pediatr. 1994 Dec;15(6):421-5.
"Fluorescent
serum antibody determinations were used to examine whether children with obsessive-compulsive
disorder (OCD) or less pervasive obsessive-compulsive symptoms (OCS) would show
evidence of caudate nucleus involvement. Recent studies of OCD have documented
smaller caudate nucleus volumes in adults with childhood onset than in normal
controls, but not smaller putamen volumes. Thirty-eight cases were recruited from
an ongoing study of childhood neurodevelopmental disorders. Nineteen samples from
clinical cases had existing or previously documented OCS and attention-deficit
hyperactivity disorder (ADHD) with or without concomitant tics. Nineteen additional
clinical controls with ADHD, but without tics or OCS, were identified. The sera
from clinical cases showed antibodies directed against caudate [odds ratio (OR)
2.0; 95% confidence interval (CI) 1.0 to 4.1], putamen (OR 3.0; 95% CI 1.5 to
5.8), or both (OR 2.9; 95% CI 1.58 to 5.7) at a rate significantly higher than
that of clinical controls, providing evidence of basal ganglia involvement in
OCS. These preliminary data do not support a differential effect against caudate
compared to putamen for these children, but suggest a more generalized central
nervous system response." [Abstract] Roy
BF, Benkelfat C, Hill JL, Pierce PF, Dauphin MM, Kelly TM, Sunderland T, Weinberger
DR, Breslin N.
Serum antibody for somatostatin-14 and prodynorphin
209-240 in patients with obsessive-compulsive disorder, schizophrenia, Alzheimer's
disease, multiple sclerosis, and advanced HIV infection.
Biol
Psychiatry. 1994 Mar 1;35(5):335-44.
"Patients with obsessive-compulsive
disorder (OCD) demonstrated significant levels of antibody for somatostatin-28,
its C-terminal fragment somatostatin-14, and prodynorphin. In contrast there were
lower levels of reactivity for somatostatin-28(1-14) (the N-terminal fragment
of somatostatin-28) and negligible reactivity for several other peptides including
beta-endorphin and corticotropin. Healthy volunteers and disease controls [schizophrenia,
Alzheimer's disease, multiple sclerosis, and subjects with advanced human immunodeficiency
virus (HIV) infection] exhibited negligible reactivity. These data raise the consideration
of an autoimmune mechanism for some OCD." [Abstract] Bodner
SM, Morshed SA, Peterson BS.
The question of PANDAS in adults.
Biol
Psychiatry. 2001 May 1;49(9):807-10.
"BACKGROUND: Pediatric autoimmune
neuropsychiatric disorders associated with streptococcal infections (PANDAS) are
a well-defined cause of obsessive-compulsive disorder in children. However, they
have not been described or fully investigated in adults newly diagnosed with obsessive-compulsive
disorder. METHODS: We describe an adult with onset of obsessive-compulsive disorder
at 25 years of age after a severe antibiotic-responsive pharyngitis. He was evaluated
with multiple psychiatric rating scales for obsessive-compulsive disorder and
Tourette's syndrome, as well as with serologic assays and radiologic studies.
RESULTS: In all respects except age our patient fulfilled established criteria
for PANDAS. Assays for antibodies to group A beta-hematolytic streptococci, serum
D8,17 lymphocytes, antistriatal (neuronal) antibodies, and anticytoskeletal antibodies
all supported the hypothesis that a poststreptococcal process was active. Magnetic
resonance imaging was abnormal and is described. CONCLUSIONS: The findings suggest
that this patient's illness is similar to PANDAS in presentation and that poststreptococcal
disease may result in adult-onset obsessive-compulsive disorder." [Abstract] Eisen
JL, Leonard HL, Swedo SE, Price LH, Zabriskie JB, Chiang SY, Karitani M, Rasmussen
SA.
The use of antibody D8/17 to identify B cells in adults with
obsessive-compulsive disorder.
Psychiatry Res. 2001 Nov
30;104(3):221-5.
"Compared with healthy control subjects, individuals
with childhood-onset obsessive-compulsive disorder (OCD) have been reported to
have a higher percentage of B cells that react with the monoclonal antibody D8/17,
a marker for rheumatic fever. This study sought to replicate these findings in
adults with OCD. Double-blind analyses of blood samples from 29 consecutive adults
with primary OCD and 26 healthy control subjects were conducted to determine the
percentage of B cells identified by D8/17. Using a standard criterion of >
or =12% labeled B cells to denote positivity, rates of D8/17 positive individuals
did not significantly differ between the OCD (58.6%) and control (42.3%) groups.
Early age of onset was not a predictor of D8/17 positivity in the OCD group. The
percentage of B cells identified by the monoclonal antibody marker D8/17 did not
distinguish adults with OCD from control subjects, nor did it distinguish a sub-group
of adults with OCD who described pre-pubertal onset of their OCD symptoms."
[Abstract] Martino
D, Giovannoni G.
Antibasal ganglia antibodies and their relevance
to movement disorders.
Curr Opin Neurol. 2004 Aug;17(4):425-432.
"PURPOSE
OF REVIEW: Recently, autoaggressive immunological responses were included among
the causative agents of basal ganglia dysfunction. Autoaggressive immune-mediated
illnesses secondary to group A beta-haemolytic streptococcal infections present
with motor and psychiatric symptoms, due to basal ganglia involvement. These disorders
have been associated with serum antineuronal antibodies, relatively specific to
human basal ganglia tissue. This review summarizes the most recent studies concerning
antibasal ganglia antibodies, focusing on the associated phenotypes and the hypotheses
concerning their pathogenicity. RECENT FINDINGS: The spectrum of post-streptococcal
neuropsychiatric disorders associated with antibasal ganglia antibodies seems
broader than previously recognized. Other than chorea, tics and obsessive-compulsive
disorder, which constituted the bulk of previously described disorders associated
with antibasal ganglia antibodies, post-streptococcal neuropsychiatric disturbances
include a wider range of motor and behavioural abnormalities, in keeping with
the multifunctional role of the basal ganglia. An encephalitis lethargica-like
illness following streptococcal infection was reported, and unusual adult-onset
movement disorders associated with antibasal ganglia antibodies were documented.
Moreover, investigators provided preliminary evidence for a pathogenic role of
autoantibodies in Sydenham's chorea, the prototypic post-streptococcal neuropsychiatric
disorder. SUMMARY: Antibasal ganglia antibodies are relatively specific in identifying
post-streptococcal neuropsychiatric disorders, which constitute a wider spectrum
of movement disorders than previously recognized. Although their sensitivity in
diagnosing Sydenham's chorea seems excellent, it is not yet possible to extrapolate
this sensitivity to all the recently identified post-streptococcal neuropsychiatric
disorders. The antigens targeted by these autoantibodies and their pathogenic
importance are currently under investigation. Preliminary evidence suggests that
antibasal ganglia antibodies may be pathogenic." [Abstract]
Murphy TK, Petitto JM, Voeller KK, Goodman WK.
Obsessive
compulsive disorder: is there an association with childhood streptococcal infections
and altered immune function?
Semin Clin Neuropsychiatry.
2001 Oct;6(4):266-76.
"During the last few years, an increased interest
in the possibility of immune mediated pathophysiology of obsessive compulsive
disorder (OCD) and related disorders has been seen. In the late 1980s, the National
Institute of Mental Health reported an increase of obsessive compulsive symptoms
in patients with Sydenham chorea (SC). Subsequently, a precipitating streptococcal
infection in children with sudden onset of OCD symptoms but no chorea led to the
coining of PANDAS (pediatric autoimmune neuropsychiatric disorders associated
with streptococcus).This association has furthered interest in studying immune
parameters in non-PANDAS OCD as well. This article will review the neuropsychiatric
findings in OCD and Tourette syndrome (TS) with emphasis placed on PANDAS, and
its association with SC, and a review of the existing studies that have assessed
immunologic measures in patients with OCD and TS." [Abstract]
Trifiletti RR, Packard AM.
Immune mechanisms
in pediatric neuropsychiatric disorders. Tourette's syndrome, OCD, and PANDAS.
Child
Adolesc Psychiatr Clin N Am. 1999 Oct;8(4):767-75.
"The authors have reviewed
recent data supporting the presence of immune abnormalities in several neuropsychiatric
disorders (TS, OCD, and PANDAS). Several groups agree that there is a subset of
patients with TS and OCD (perhaps about 10%) for whom there is a clear streptococcal
trigger, validating the PANDAS concept. Also, evidence of biochemical markers
for TS and OCD have begun to emerge, namely D8/17 and antibrain antibodies, which
suggest the presence of similar immune abnormalities, even in idiopathic cases.
If this line of research reveals definable, and relatively specific, immune abnormalities
in at least some cases of TS and OCD, it will likely have important implications
for the diagnosis and treatment of these common neuropsychiatric disorders, particularly
in children who respond poorly to conventional therapies. Child psychiatrists
are encouraged to stay tuned." [Abstract] |
Zai G, Bezchlibnyk YB, Richter MA, Arnold P, Burroughs
E, Barr CL, Kennedy JL.
Myelin oligodendrocyte glycoprotein (MOG)
gene is associated with obsessive-compulsive disorder.
Am
J Med Genet. 2004 Aug 15;129B(1):64-8.
"Obsessive-compulsive disorder
(OCD) is a severe neuropsychiatric disorder with a strong genetic component, and
may involve autoimmune processes. Support for this latter hypothesis comes from
the identification of a subgroup of children, described by the term pediatric
autoimmune neuropsychiatric disorder associated with streptococcal infections
(PANDAS), with onset of OCD symptoms following streptococcal infections. Genes
involved in immune response therefore represent possible candidate genes for OCD,
including the myelin oligodendrocyte glycoprotein (MOG) gene, which plays an important
role in mediating the complement cascade in the immune system. Four polymorphisms
in the MOG gene, a dinucleotide CA repeat (MOG2), a tetranucleotide TAAA repeat
(MOG4), and 2 intronic single nucleotide polymorphisms, C1334T and C10991T, were
investigated for the possibility of association with OCD using 160 nuclear families
with an OCD proband. We examined the transmission of alleles of these four polymorphisms
with the transmission disequilibrium test (TDT). A biased transmission of the
459-bp allele (allele 2: chi2 = 5.255, P = 0.022) of MOG4 was detected, while
MOG2, C1334T, and C10991T showed no statistically significant bias in the transmission
of alleles. The transmission of the C1334T.MOG2.C10991T.MOG4 haplotype 1.13.2.2
(chi2 = 6.426, P = 0.011) was also significant. Quantitative analysis using the
family-based association test (FBAT) was significant for MOG4 in total Yale-Brown
Obsessive-Compulsive Scale severity score (allele 2: z = 2.334, P = 0.020). Further
investigations combining genetic, pathological, and pharmacological strategies,
are warranted." [Abstract]
Denys D, Fluitman S, Kavelaars A, Heijnen C, Westenberg
H.
Decreased TNF-alpha and NK activity in obsessive-compulsive disorder.
Psychoneuroendocrinology.
2004 Aug;29(7):945-52.
"BACKGROUND: Accumulating evidence points towards
the involvement of autoimmune mechanisms in the pathophysiology of some subgroups
of obsessive-compulsive disorder (OCD). This study was carried out to investigate
whether obsessive-compulsive disorder is associated with altered activity of the
immune system, and whether these changes are related to particular clinical characteristics.
METHODS: Ex vivo production of TNF-alpha, IL-4, IL-6, IL-10, and IFN-gamma in
whole blood cultures, and NK-cell activity and peripheral blood NK cell-, monocytes-,
T-cell-, and B-cell- percentages were measured in 50 medication-free outpatients
with OCD and 25 controls. RESULTS: In OCD patients, we found a significant decrease
in production of TNF-alpha (p < 0.0001) and NK-activity (p = 0.002) in comparison
with controls. No significant differences were observed in the other immune variables.
Patients with first-degree relatives with OCD had significant lower NK-activity
than patients who had no relatives with OCD (p = 0.02), and patients with a childhood
onset of OCD had significantly lower number of NK-cells than patients with a late
onset (p= 0.003). CONCLUSIONS: Changes in TNF-alpha and NK activity suggest a
potential role of altered immune function in the pathophysiology of obsessive-compulsive
disorder." [Abstract] Monteleone
P, Catapano F, Fabrazzo M, Tortorella A, Maj M.
Decreased blood levels
of tumor necrosis factor-alpha in patients with obsessive-compulsive disorder.
Neuropsychobiology.
1998;37(4):182-5.
"To investigate immune system function in obsessive-compulsive
disorder (OCD) we measured plasma levels of tumor necrosis factor-alpha (TNF-alpha),
interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) in 14 drug-free obsessive-compulsive
patients and 14 matched healthy controls. No significant differences were observed
between patients and controls in plasma levels of IL-1 beta and IL-6, whereas
plasma levels of TNF-alpha were significantly lower (p = 0.001) in the former.
Blood levels of prolactin did not differ between the two groups, whereas plasma
cortisol concentrations were significantly higher in patients than in healthy
subjects (p = 0.02). No significant correlation was found between immune parameters,
on the one hand, and endocrine or psychopathological measures on the other. These
results suggest that OCD is associated with a decreased production in TNF-alpha,
but normal synthesis of IL-1 beta and IL-6." [Abstract]
Brambilla
F, Perna G, Bellodi L, Arancio C, Bertani A, Perini G, Carraro C, Gava F.
Plasma
interleukin-1 beta and tumor necrosis factor concentrations in obsessive-compulsive
disorders.
Biol Psychiatry. 1997 Dec 1;42(11):976-81.
"Plasma
interleukin-1 beta (Il-1 beta) and tumor necrosis factor-alpha (TNF-alpha) concentrations
were measured twice, at a 48-hour interval, in 27 drug-free obsessive-compulsive
patients (12 women and 15 men) and in 27 sex-age-matched healthy controls. Il-1
beta and TNF-alpha concentrations were significantly lower in patients than in
controls, whereas there were no differences in either group between men and women,
between the samples of the two days, or, in the patients, between those who had
and those who had not been previously treated with psychopharmacologic drugs."
[Abstract] Ravindran
AV, Griffiths J, Merali Z, Anisman H.
Circulating lymphocyte subsets
in obsessive compulsive disorder, major depression and normal controls.
J
Affect Disord. 1999 Jan-Mar;52(1-3):1-10.
"BACKGROUND: Obsessive compulsive
disorder (OCD) shares several features with depressive illness (e.g., comorbidity,
early escape from dexamethasone suppression, effectiveness of serotonergic pharmacotherapy).
It was of interest to establish whether OCD, like major depression, was also associated
with immune alterations, notably elevations of circulating natural killer (NK)
cells. METHOD: Circulating lymphocytes were determined from morning blood samples
taken from OCD and major depressive patients, as well as from age- and sex-matched
controls. Stress perception and coping styles were evaluated in order to assess
whether such variables accompanied the NK alterations. Finally, in a subset of
patients, symptoms of the illness, stress/coping, and circulating lymphocytes,
were also evaluated following 12 weeks of antidepressant medication (serotonergic
reuptake inhibitor). RESULTS: The major depressive and OCD patients reported increased
perception of day-to-day stresses, coupled with reliance on emotion focused coping
styles. Moreover, circulating NK cells were elevated among male OCD and major
depressive patients, whereas only a modest increase of NK cells was seen in female
major depressives. Twelve weeks of medication alleviated depressive and OCD symptoms,
and resulted in normalization of NK cells in the major depressives. However, in
OCD patients the reduction of symptoms was not accompanied by significant variations
of circulating NK cells. CONCLUSIONS: Although major depression and OCD are both
accompanied by elevated circulating NK cells, at least in males, normalization
of NK cells following treatment was only evident in depression. The persistent
elevations of NK cells among male OCD patients may reflect either a trait characteristic
of the illness, or symptom reduction and not true remission. LIMITATIONS: Although
elevations of lymphocyte subsets in major depressive and OCD patients were observed,
conclusions concerning immune status in OCD ought to be held in abeyance pending
assessment of other indices of immune and cytokine functioning." [Abstract] Maes
M, Meltzer HY, Bosmans E.
Psychoimmune investigation in obsessive-compulsive
disorder: assays of plasma transferrin, IL-2 and IL-6 receptor, and IL-1 beta
and IL-6 concentrations.
Neuropsychobiology. 1994;30(2-3):57-60.
"This
study was carried out to investigate the immune function in obsessive-compulsive
disorder (OCD). Plasma levels of interleukin (IL)-1 beta, IL-6, soluble IL-6 receptor
(sIL-6R), sIL-2R, and transferrin receptor (TfR), and baseline plasma cortisol
levels were measured in 19 OCD patients and 19 normal controls. No significant
differences in any of the above immune variables were found between subjects with
OCD and normal controls. There was a significant positive correlation between
IL-6 or sIL-6R concentrations and severity of compulsive--but not obsessive--symptoms.
In subjects with OCD, there was a significant negative relationship between sIL-2R
concentrations and plasma cortisol values. In subjects with OCD and in the study
group as a whole, there were significant positive relationships between sIL-2R
and TfR concentrations." [Abstract]
Carpenter
LL, Heninger GR, McDougle CJ, Tyrka AR, Epperson CN, Price LH.
Cerebrospinal
fluid interleukin-6 in obsessive-compulsive disorder and trichotillomania.
Psychiatry
Res. 2002 Nov 15;112(3):257-62.
"Recent studies have suggested that neuroimmune
abnormalities may play an important role in the pathogenesis of obsessive-compulsive
disorder (OCD) and related disorders. This study was undertaken to determine whether
cerebrospinal fluid (CSF) concentrations of the proinflammatory cytokine interleukin
(IL)-6 differ between OCD and trichotillomania patients and healthy control subjects.
Lumbar puncture with a standardized procedure was performed on 26 patients with
OCD and 9 with trichotillomania. All patients were drug-free and met DSM-IV criteria.
Twenty-six age- and sex-matched healthy volunteers underwent the same procedure.
CSF was assayed for IL-6 using a quantitative 'sandwich' enzyme immunoassay technique.
Mean+/-S.D. CSF IL-6 levels did not differ between OCD patients (n=26) (2.4+/-1.1
pg/ml) and controls (n=26) (2.4+/-1.9 pg/ml) or between trichotillomania patients
(n=9) (2.3+/-0.8 pg/ml) and their matched controls (n=14) (1.9+/-0.5 pg/ml). These
findings fail to support speculation that ongoing immune activation may be causally
involved in the pathogenesis of OCD or trichotillomania." [Abstract] Black
JL, Lamke GT, Walikonis JE.
Serologic survey of adult patients with
obsessive-compulsive disorder for neuron-specific and other autoantibodies.
Psychiatry
Res. 1998 Dec 14;81(3):371-80.
"A subset of patients with pediatric onset
obsessive-compulsive disorder (OCD) and tic syndromes (e.g. Tourette's syndrome)
have symptom onset or exacerbation associated with infection. Some of these patients
have been demonstrated to have antineuronal antibodies reactive with nuclei of
the basal ganglion. It has been hypothesized that these patients have an immune
process initiated by infection that affects the basal ganglion and causes obsessive-compulsive
symptoms. The term pediatric autoimmune neuropsychiatric disorders associated
with streptococcal infections (PANDAS) has been coined to describe those patients
with evidence of recent group A beta hemolytic streptococcal infection. We tested
the serum from 13 adult patients with obsessive-compulsive disorder for panels
of autoantibodies that serve as markers of autoimmunity in the practice of neurology
and internal medicine. We investigated the frequency of neuron-specific autoantibodies
[N-type and P/Q-type voltage-gated calcium channel antibodies, type 1 Purkinje
cell antibodies, types 1 and 2 antineuronal nuclear antibodies, amphiphysin antibodies,
and glutamic acid decarboxylase (65 kDa) antibodies], other organ-specific autoantibodies
(muscle acetylcholine receptor-binding antibodies, striated muscle antibodies,
thyroid microsomal and thyroglobulin antibodies), and non-organ-specific autoantibodies
(antinuclear antibodies, antimitochondrial antibodies, and smooth muscle antibodies)
to determine if any of these antibodies might serve as a serological marker for
adult OCD or yield evidence of an autoimmune diathesis. Although most of our subjects
had onset of OCD before 19 years of age (N=8) or before puberty (N=4), the study
revealed no humoral evidence of autoimmunity involving the neuron-, organ-, and
non-organ-specific antibodies that we assayed." [Abstract] |
