Download - Childhood-onset Obsessive Compulsive Disorder (OCD) and the PANDAS Subgroup Are Contamination Fears Justified?

Childhood-onset Obsessive Compulsive Disorder (OCD) and the PANDAS Subgroup

Are Contamination Fears Justified?

Obsessive Compulsive Disorder in DSM-IV

• Presence of OBSESSIONS – repetitive, intrusive thoughts or concerns; and COMPULSIONS – mental or physical rituals performed repetitively in response to anxiety or compulsive urge

• Symptoms are seen as senseless, excessive, or unreasonable

• Symptoms cause marked distress, are time-consuming, and/or significantly interfere with normal routine, work/school functioning, and/or social relationships

OCD Symptoms in Pediatric Patients

OBSESSIONSConcerns about:

ContaminationSafetyRight/wrong

Intrusive thoughts:CountingNumbers/wordsViolent images

COMPULSIONSOrdering/arrangingSymmetryHoarding/collectingRepeating rituals:

Cleaning/WashingCheckingRe-reading/writing

(Certain # or “just right”)

Neurobiology of OCD

• PET scans demonstrate hypermetabolism of orbital frontal cortex and caudate nucleus; normalizes with response to treatment

• Structural and functional MRI scans demonstrate abnormalities of cortical/basal ganglia function (subtle abnormalities only)

• Neuropsychological deficits, particularly in executive functioning

From: Rapoport & Wise

fMRI scan of the Orbitofrontal-Striatal-Thalamocortical Circuit

Ventral Prefrontal Cortex Basal Ganglia Thalamus Hippocampus

R L

Casey et al. , 2002

Dysfunction in Striatum

Dysfunction in GPi

Basal Ganglia Dysfunction in Childhood-onset OCD

• CT scans demonstrate decreased caudate size in adult males with childhood-onset

• Volumetric changes on structural MRI in caudate, putamen & globus pallidus

• Neuropsychological testing deficits

• Led to the search for a medical modelFrom: Rapoport & others

Pediatric

Autoimmune

Neuropsychiatric

Disorders

Associated with

Streptococcal infections

Background

SYDENHAM CHOREA• Sir William Osler – 1894

“perseverativeness” of behavior in choreic children

• Chapman, Freeman & Grimshaw – increased obsessional neurosis during episode and afterwards

• NIMH: 75% of SC children have OC symptoms

• Sao Paulo (1998): 65% have OCD at initial episode and 100% at recrudescence

OCD/TIC DISORDERS• Post-infectious tics described by

vonEconomo & Sellinger in early 1900’s

• Choreiform movements present in 1/3 of children with OCD

• Episodic course, abrupt onset in some children with OCD

• Kiessling – Tic patients have antineuronal antibodies

• Young children with OCD/tic disorders exacerbate after streptococcal infections

Case Example

C.B.• 10 year old female awoke one morning “a

changed child” • Unable to dress secondary to fears of clothing

being contaminated with blood and AIDS, and simultaneous fear that she would give AIDS to others. Fears quickly generalized to anything red and she began washing excessively

• Abrupt onset of motoric hyperactivity, twitches and tics, as well as handwriting deterioration

• Two days later developed separation anxiety, impulsivity and difficulties with concentration.

Criteria for PANDAS

I. Presence of OCD and/or Tic DisorderII. Prepubertal onsetIII. Episodic course of symptom severityIV. Association with neurological

abnormalitiesV. Temporal relationship between symptom

exacerbations and streptococcal infections

Frequency of Comorbid Symptoms in PANDAS

COMORBID

DIAGNOSES

• ADHD – 40%

• ODD – 40%

• Depression – 36%

• Dysthymia – 12%

• Sep. Anxiety – 20%

• Overanxious – 28%

• Enuresis – 20%

SYMPTOMS DURING EXACERBATIONS

• Choreiform movements - 95%• Emotional lability – 66%• School changes – 60%• Personality change – 54%• Bedtime fears – 50%• Fidgetiness – 50%• Separation fears – 40%• Sensory defensiveness – 40%• Irritability – 40%• Impulsivity /distraction – 38%

Dysfunction in Striatum

Dysfunction in GPi

Neuropsychological Tests of Executive Function

BJ Casey et al, 2002

Structural MRI

Giedd et al, 2000

Model of Pathogenesis for PANDAS

GABHS

SusceptibleHost

AbnormalImmune Response

CNS & Clinical Manifestations

Documentation of Etiologic Role for GABHS in Rheumatic Fever

• Direct Evidence– GABHS infection prior to rheumatic fever symptoms

– Identification of “rheumatogenic” strains of GABHS

• Indirect Evidence– Epidemiologic studies showed temporal relationship

– Penicillin prophylaxis prevents recrudescences

– Rheumatic fever rates declined after antibiotic treatment of GABHS pharyngitis became routine

Epidemiological Evidence of a Relationship Between GABHS and Rheumatic Fever

Point Prevalences for Tics & Behavioral Problems in a Virginia Elementary School Population

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BEHAVIOR

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0100200300400500600700800

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Azithromycin & Penicillin Prophylaxis Trial

GOAL OF THE INVESTIGATION:

To establish that azithromycin and penicillin provide effective prophylaxis against GABHS infections for the PANDAS subgroup.

HYPOTHESIS OF THE INVESTIGATION:

If antibiotics prophylaxis prevents GABHS infections, then neuropsychiatric symptom exacerbations will be decreased.

Penicillin (PCN) vs. Azithromycin (Zith)

• Streptococcal Infections*– Year Prior to Study 2.0/ subject– Study Year 0.0/ subject

• Exacerbations*– Year Prior to Study 2.0/ subject– Study Year .74/ subject

*T >5.25; p< 0.01 for both

N = 22

PENICILLIN AZITHROMYCIN


GABHS

SusceptibleHost


Clinical Manifestations

PANDAS – Host Susceptibility

• Increased familial rates of OCD & tics– 36/50 (67%) of PANDAS probands had an affected 1o relative

– 15% of relatives had OCD

– 15% of relatives had tic disorder

• Increased familial rates of rheumatic fever– 5/126 (4%) PANDAS parents/grandparents affected

– 6/90 (7%) of Sydenham parents/grandparents affected

– 3/210 (1.4%) of controls parents/grandparents affected(Lougee et

al, 2000)

Host Susceptibility

VULNERABLE CHILD

IMMUNOLOGIC

NEUROLOGICGENETICS

TYPES OF EXPOSURES


GABHS

SusceptibleHost


Clinical Manifestations

PANDAS – Abnormal Immune Response

• Local– Identification of antineuronal antibodies

• Regional– Pathological reports from Sydenham chorea– Volumetric changes in basal ganglia

• Systemic– Cytokine abnormalities– Effectiveness of immunomodulatory therapies

Antineuronal Antibodies in OCD/Tics

• Kiessling et al. – Serum antibodies recognize human caudate and neuroblastoma cell line

• Singer et al. – Antibodies against human caudate & putamen; but also present in 40% controls.

• Hallett et al. – Serum from patients induces stereotypies in rats infused in basal ganglia

• Morshed et al. – Antibodies against striatum among patients; sera also induces stereotypies

• Cunningham et al. – Cross-reactive antibodies present in sera of acutely ill SC patients; affects cell signaling

• Kirvan et al – Cross-reactive antibodies in PANDAS sera are comparable to those in SC, but lower concentrations.

Reactivity with Neurons and Caudate/Putamen

PANDAS

PANDAS

Controls

SC

SC

Control

PANDAS

Controls

Induced CaM kinase II Activity

SC PANDAS Non-PANDAS 405060708090

100110120130140150160170180190200210220230240250

CaM

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ase

II a

ctiv

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% a

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asal

rat

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Immunomodulatory Treatment TrialPlasma Exchange vs. IVIG vs. Placebo

Pla sm a Excha ngeN = 10

IV IGN = 9

SH AM IV IGN = 10

RANDOMIZATION

Change in OCD Severity 1 Month Following Treatment With IVIG, Placebo, or Plasma Exchange

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YBO

CS

Rating

Response to Immunomodulatory Therapy with IVIG (n=9) or Plasmapheresis (n=8)

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YB

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IVIGPlasma Exchange

Baseline 1 mo 1 yr 1 yr Baseline 1 mo

Caudate Size in 14 y.o. Patient with OCD

Childhood-onset Obsessive Compulsive Disorder (OCD) and PANDAS

Are Contamination Fears Justified?