TWO PANDASEdward L. Goodman, MD, FACP, FIDSA,

with the assistance of Susan Swedo, MD NIMH/NIH

July 6, 2005

A Case of PANDAS

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.

2nd Case Presentation

• ZZN 10 year old boy has the acute onset of acute obsessive compulsive disorder– Can’t stop looking at a sore on skin

• Has mother photograph daily

– Intense separation anxiety makes going to school very difficult

– States to mother: “I wish I wasn’t so attached to inaminate objects.”

• Hoards items like candy wrappers

Past History

• Migraine Headaches– Normal MRI head previous year

• Extremely picky eater

• Normal developmental milestones

• Normal weight and height – Recently has lost weight

Presentation

• Physical exam normal

• Psych exam reveals– Mild tic like movements of arms/shoulders and

eye blinking– Normal mental state– Anxiety– Aware that he “feels crazy”

Presentation

• Routine Lab normal

• Anti –streptococcal antibody very high– No history of pharyngitis– Poor oral intake for several days

• Throat culture + for Group A Streptococcus

Management

• Cefadroxil once daily– Did well immediately with resolution of symptoms

– Then mild relapse on 9th day of therapy• Was being given suboptimal dosage of drug

• Strept Screen was negative at the time

• Psychiatry follow up• Whole family (6) had throat cultures: only sister

age 7 had GAS

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

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

0

5

10

15

20

25

1 2 3 4 5 6 7 8 9 10 11Time (Months)

Sym

ptom

Sev

erity

0100200300400500600700800

ASO

Tite

rs

NON-PANDAS

0

5

10

15

20

25

30

1 2 3 4 5 6 7 8 9 10 110

200

400

600

800

AS

O T

iters

Sym

pto

m

Sev

erity

PANDAS

ASO TITER --

Y-BOCS ---

ASO TITER ---Y-BOCS ---

“Prospective Identification and Treatment of Children with PANDAS”

M. Murphy & M. Pichichero

• 12 patients identified over 3 years period• 7 boys & 5 girls presented with neuropsychiatric

symptoms related to GABHS infections– 100% with OCD (3/4’s were germ-related) and

emotional lability

– 58% (7/12) with urinary frequency or enuresis

– 42% (5/12) with acute separation anxiety

– 33% (4/12) with tics or handwriting changes

• Antibiotic treatment of GABHS infections reduced symptom severity in 5 – 21 days

Arch Ped Adolesc Med 2002;156:356-361

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%

Model of Pathogenesis for PANDAS

GABHS

SusceptibleHost

AbnormalImmune Response

CNS & Clinical Manifestations

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

0

2

4

6

8

10

12

NOV DEC J AN FEB MAR APR MAY J UN

Month Observed

TICS

BEHAVIOR

Snider et al, Pediatrics

Postulates of PANDAS Prophylaxis

IF

• OCD/Tics are sequelae of GABHS infections (similar to Sydenham chorea)

THEN• Penicillin prophylaxis should be effective in

reducing exacerbations of OCD/Tics

PCN PCN

4 months 4 months

PLA PLA

Penicillin/Placebo Trial - Results

39 Children completed the 8 months long trial

35 Documented GABHS infections occurred

14 during penicillin, 21 during placebo

Depression & anxiety were significantly better during penicillin phase than placebo phase

But, no difference in OCD or tics severity

M. Garvey et al., Biol Psychiatry

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.

Antibiotics Prophylaxis Trial – Study Design

• Double-blind, parallel-design study of azithromycin (500 mg q week) and penicillin (250 mg po bid)

(Note – All Children receive antibiotics)

• One year long trial with monthly visits for throat culture, titers and symptom ratings

• Comparison of symptom course year prior to study, with course during prophylaxis.

• Assessment of GABHS infections via titers

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

Snider et al., Biol Psych 2005

PCN ZITH

Effectiveness of Antibiotic ProphylaxisYear Prior to Study

Year on Antibiotics

Penicillin Prophylaxis Discontinuation Study

• Currently recruiting 5 – 12 yrs old children who meet criteria for PANDAS subgroup

• 6-months long study, but only two clinic visits are required

• All children receive penicillin prophylaxis and 50% are randomized to continue, and 50% to switch to placebo

• If a child relapses, open-label penicillin is restarted.

Model of Pathogenesis for PANDAS

GABHS

SusceptibleHost

AbnormalImmune Response

Clinical Manifestations

Host Susceptibility

VULNERABLE CHILD

IMMUNOLOGIC

NEUROLOGICGENETICS

TYPES OF EXPOSURES

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 (Lougee et al, 2000)

• 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

• D8/17 prevalence significantly greater among patients with OCD/tics or rheumatic fever than controls

Model of Pathogenesis for PANDAS

GABHS

SusceptibleHost

AbnormalImmune Response

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; appears to affect cell signaling

Immunomodulatory Treatment TrialPlasma Exchange vs. IVIG vs. Placebo

Pla sm a Excha ngeN = 10

IV IGN = 9

SH AM IV IGN = 10

RANDOMIZATION

Perlmutter et al., Lancet

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

0

5

10

15

20

25

30

35

40

45

Baseline 1 Month Baseline 1 Month Baseline 1 Month IVIG Placebo Plasma Exchange

YBO

CS

Rating

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

0

20

40

60

80

Sum

YB

OC

S+

TS

UR

S

IVIGPlasma Exchange

Baseline 1 mo 1 yr 1 yr Baseline 1 mo

Caudate Size in 14 y.o. Patient with OCD

Summary - Future Directions

GABHS

Vulnerable Host

Altered Immune

Response

PANDAS

• Identify pathogenic factors • Prevent symptom onset/worsening

• Identify susceptible hosts• Protect at-risk individuals

• Determine nature of local, regional and systemic autoimmunity

• Develop new immunologic therapies

• Identify unique clinical characteristics• Identify CNS basis of OCD/tics

Implications:

• Is this only the first of many to be discovered biologic bases of behavioral disorders?

Thanks to the following

• Susan Swedo, MD NIMH/NIH who provided references and many slides

• Beverly Dickson, MD, who authorized the follow up throat cultures

• Sharon Williamson, MT(ASCP), who assisted with the throat cultures

Bibliography

Thanks to Susan Swedo, MD of the NIMH, Beverly Dickson, MD and Sharon Williamson, MT (ASCP) for their help in preparing this presentation.