Pediatric Autoimmune Neuropsychiatric Disorders Associated with

Streptococcal infection (PANDAS)

Dr Prashant Makhija

INTRODUCTION Group of neuropsychiatric disorders that are proposed to have an

autoimmune basis and to be related to infection with group A beta-hemolytic streptococci (GAS)

Neuropsychiatric disorders- obsessive–compulsive disorder (OCD) and tic disorder or Tourette’s syndrome

Susan E. Swedo et.al - Clinical Description of the 50 Cases Epidemiology- true incidence/prevalance not known, rare

disorder, 10 cases were identified among 30,000 throat cultures positive for GAS

1.http://www.uptodate.com/contents/pandas-pediatric-autoimmune-neuropsychiatric-disorder-associated-with-group-a-streptococci

2. Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections: Clinical Description of the First 50 Cases. Susan E. Swedo et.al. Am J Psychiatry 1998; 155:264–271

3. Perrin EM. Et.al. Arch Pediatr Adolesc Med 2004; 158:848

PATHOGENESIS

EVIDENCE Presence of antineuronal antibodies among patients with

childhood-onset OCD and/or tic disorders

Animal studies suggest these antineuronal antibodies may play an etiologic role in these neuropsychiatric disorders

Striking effectiveness of immunomodulatory therapies, such as therapeutic plasma exchange and intravenous immunoglobulin (IVIG) in the PANDAS subgroup

LA Snider and SE Swedo. PANDAS: current status and directions for research. Molecular Psychiatry (2004) 9, 900–907

Genetic predisposition- rates of tic disorders and OCD in first-degree relatives of children in the PANDAS subgroup are higher than those in the general population

MRI scans- enlargements of the caudate, putamen, and globus pallidus, which points to regional inflammatory changes

LA Snider and SE Swedo. PANDAS: current status and directions for research. Molecular Psychiatry (2004) 9, 900–907

CLINICAL FEATURES

Clinical Description of the 50 Cases[Susan E. Swedo.et.al(1998) ]

Age Prepubertal (3-11), 6.3 years for tics and 7.4 years for obsessive-

compulsive symptoms, 3 years younger than that from other childhood-onset OCD and tic disorders

Sex M:F= 2.6:1

Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections: Clinical Description of the First 50 Cases. Susan E. Swedo et.al. Am J Psychiatry 1998; 155:264–271

Symptoms primary diagnosis of OCD (N=24, 48%) and those with primary

tic disorder(N=26, 52%)

43 (86%) of the children reported obsessive-compulsive symptoms, and 40 (80%) of the children were found to have motor tics

severity of the obsessive-compulsive symptoms as well as motor and vocal tics was moderate, on average

Symptoms of OCD varied by primary diagnosis - Children with primary OCD reported more washing and checking behaviors than did children with a primary diagnosis of tic disorder

Psychiatric comorbidity was common for the children with PANDAS- ADHD, affective disorders, and anxiety disorders were most prevalent (40%,42%, and 32%, respectively)

Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections: Clinical Description of the First 50 Cases. Susan E. Swedo et.al. Am J Psychiatry 1998; 155:264–271

COMORBID DIAGNOSES

Symptoms Associated With Exacerbations of PANDAS

DIAGNOSTIC CRITERIA Presence of OCD and/or a tic disorder

Pediatric onset: Symptoms of the disorder first become evident between 3 years of age and the beginning of puberty

Episodic course of symptom severity: Clinical course is characterized by the abrupt onset of symptoms or by dramatic symptom exacerbations

Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections: Clinical Description of the First 50 Cases. Susan E. Swedo et.al. Am J Psychiatry 1998; 155:264–271

DIAGNOSTIC CRITERIA(contd..)

Association with GABHS infection: Symptom exacerbations must be temporally related to GABHS infection, i.e., associated with positive throat culture and/or elevated anti-GABHS antibody titers

Association with neurological abnormalities- During symptom exacerbations, patients will have abnormal results on neurological examination. Motoric hyperactivity and adventitious movements (including choreiform movements or tics) are particularly common

Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections: Clinical Description of the First 50 Cases. Susan E. Swedo et.al. Am J Psychiatry 1998; 155:264–271

Sydenham Chorea Versus PANDASFeature Sydenham chorea PANDAS

Age at onset (yr) 5–15 6–9 years

Male:female Close to 1:1 most studies 2.6:1

Typical duration 1–6 mths Relapsing-remitting course

Time lag between inciting infection/symptom

Longer Shorter

Association with rheumatic fever Characteristic. A ‘‘major’’ Jones criterion

Rare

Association with carditis Common (25–80%) Rare

Association with arthritis Common Rare

Presence of chorea Obligatory Rare; mild if present

Presence of tics Uncommon Characteristic

Presence of OCD Frequent Characteristic

Clinical signs of motor impairment (milkmaid’sgrisp, darting tongue)

Present Present in 30–40% of cases

Antineuronal antibodies Common; usually anti–basal ganglia

Common; usually anti–basal ganglia

Putative GABHS M-protein subtypes involved

M6, lesser extent M5, M19 M12, lesser extent M3, 13, 11, 1

Evidence against negative reports from investigators who were not able to induce

behavioral changes through an infusion

isolated group A b-hemolytic streptococcal infection is common in children-GAS accounts for 15 to 30 percent of all cases of pharyngitis in children between the ages of 5 and 15 years Prospective surveillance identified GAS carriage in 2.5 percent of well children and 4.4 percent of children with URI (including a sore throat)

1.http://www.uptodate.com/contents/pandas-pediatric-autoimmune-neuropsychiatric-disorder-associated-with-group-a-streptococci

2. Piero Pavone et.al. J Child Neurol 2006;21:727–736

OCD occurs in 1 to 2 percent of school-age children and transient motor tics in as many as 25 percent

Occurrence of OCD/Tics with GAS- coincidental

1.http://www.uptodate.com/contents/pandas-pediatric-autoimmune-neuropsychiatric-disorder-associated-with-group-a-streptococci

2. Piero Pavone et.al. J Child Neurol 2006;21:727–736

MANAGEMENT Therapy for GAS infection

Therapy for OCD/Tic disorder

Immunomodulatory therapy ?

Prophylactic therapy ?

GAS infection Children with positive culture or rapid antigen detection test for

GAS - antistreptococcal therapy ↓ incidence suppurative complications, ↓ nonsuppurative complications, ↓ the risk of transmission

no randomized controlled trials of antibiotic treatment of children suspected of having PANDAS syndrome

http://www.uptodate.com/contents/pandas-pediatric-autoimmune-neuropsychiatric-disorder-associated-with-group-a-streptococci

Prospective study(Murphy. et.al., 2002) Children with abrupt onset of neuropsychiatric symptoms and

evidence of recent GAS infection, antistreptococcal (penicillin or cephalosporin) therapy was associated with prompt symptom resolution in all cases

Antistreptococcal therapy also was associated with prompt resolution of symptoms in patients who developed recurrent symptoms associated with GAS infection

mean time to resolution of symptoms was shorter among children treated with cephalosporin than with penicillin (14 versus 5 to 6 days)

Murphy ML et.al. Prospective identification and treatment of children with pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal infection (PANDAS). Arch Pediatr Adolesc Med 2002; 156:356.

Neuropsychiatric therapy Manifestations respond to treatment with standard

pharmacologic and behaviour therapies

Evidence-based treatment for OCD Pharmacological- SSRIs first-line pharmacological treatment, Nonpharmacological interventions - cognitive behavioral

therapy (ie, exposure and response prevention) is considered first- line nonpharmacological treatment

1.http://www.uptodate.com/contents/pandas-pediatric-autoimmune-neuropsychiatric-disorder-associated-with-group-a-streptococci

2. Vilma Gabbay et.al . Pediatrics 2008;122;273

Treatment of Tic disorder/Tourette’s syndrome α adrenergic agonists - clonidine and guanfacine atypical neuroleptic agents - risperidone typical neuroleptic agents- haloperidol or pimozide

1.http://www.uptodate.com/contents/pandas-pediatric-autoimmune-neuropsychiatric-disorder-associated-with-group-a-streptococci

2. Vilma Gabbay et.al . Pediatrics 2008;122;273

Immune modulating therapy Glucocorticoids, plasma exchange, and intravenous

immunoglobulin (IVIG) Treatment of PANDAS with immune modulating therapies-not

recommended outside of the research setting May be considered an alternative for severely ill patients who

have not responded to standard therapies

1.http://www.uptodate.com/contents/pandas-pediatric-autoimmune-neuropsychiatric-disorder-associated-with-group-a-streptococci

Prophylactic therapy Prophylactic antibiotics to prevent recurrences of PANDAS- not

recommended Prospective case-control study (Shulman ST et.al, 2009) -

continuous prophylaxis against GAS might prevent an average of 0.06 exacerbations per patient-year

Shulman ST et. al. Pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS): update. Curr Opin Pediatr 2009; 21:127

PROGNOSIS

Long-term outcome of children who meet criteria for PANDAS is not known

Unrecognized PANDAS and untreated PANDAS may result in an increased risk of progression to lifelong OCD and tic disorders

1. Dale RC, Heyman I, Giovannoni G, Church AW. Incidence of anti-brain antibodies in children with obsessive-compulsive disorder. Br J Psychiatry 2005; 187:314

2. http://www.uptodate.com/contents/pandas-pediatric-autoimmune-neuropsychiatric-disorder-associated-with-group-a-streptococci

SUMMARY AND CONCLUSION

Subset of children whose symptoms of obsessive compulsive disorder (OCD) or tic disorders are exacerbated by group A streptococcal (GAS) infection- hypothesized association between PANDAS and GAS is controversial

PANDAS, five working criteria OCD and/or tic disorder Pediatric onset (between three years and onset of puberty) Abrupt onset and episodic course of symptoms Temporal relation between GAS infection and onset and/or

exacerbation Neurologic abnormalities or tics during exacerbations

Children who present with abrupt onset of OCD/tic disorder be evaluated for GAS infection

Children with abrupt onset OCD and/or tic disorders and evidence of GAS infection - be treated with antistreptococcal therapy along with standard neuropsychiatric treatment for OCD/tic disorder

Treatment with immune-modulating therapies outside of the research setting not recommended

Use of prophylactic antibiotics to prevent recurrences of PANDAS not recommended

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