Complicações neurológicas pós infecção por

estreptococos (mitos e verdades)

Silvia Tenembaum

Proposed pathophysiology of immune-mediated disorders

Infection Tumor other

Genetic predisposition

1. Molecular mimicry between infection/tumor and neuronal Ag results in cross-reactive auto-lymphocytes or auto-Ab; or

2. Loss of immune tolerance to self-Ag results in induction and expansion of auto-reactive lymphocytes or auto-Ab; or

3. Non-specific immune activation of cytokines, adhesion molecules, neopterin, etc.

Passage of activated lymphocytes or Ab through intact, or disrupted BBB

Neuronal dysfunction

1. Sydenham chorea

2. PANDAS

3. Encephalitis lethargica

4. Infantile bilateral striatal necrosis

5. NMDA-R encephalitis

6. Immune-mediated chorea

encephalopathy syndrome

Immune- mediated brain disorders where

movement disorders are typical

PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections)

• 1980: A cluster of tic disorders was associated with an outbreak

of streptococcal pharyngitis

• This outbreak + parallels between prodromal period of Sydenham

chorea, and acute onset of OCD/ Tourette Syndrome

Autoimmune brain disease induced by streptococcal infection,

resulting in TIC DISORDER + OCD

• 1998 (Swedo et al) Described 50 patients and coined the term

PANDAS to characterize this association, precipitated by

streptococcal infection

PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections)

Criteria and associated features of PANDAS (Swedo et al, 1998)

Core criteria

• OCD and/or tic disorder (DSM-IV criteria)

• Pediatric prepubertal onset (3 years - puberty)

• Relapsing-remitting course

• Temporal association between symptom onset or exacerbation and group

A streptoc. infection, documented by rapid “strep” test or throat culture

• There should be no evidence of rheumatic carditis or arthritis

Associated factors

• New-onset symptoms in temporal association with core criteria:

hyperactivity, choreiform movements, deterioration in handwriting or

academic decline

• Separation anxiety, irritability, enuresis, frequent urination

• Frequent urinary tract infections and “strep” throat infections, < 7 years

• Behavioural improvement on antibiotic treatment

• Family history of autoimmune disorder

PANDAS HYPOTHESIS= CONTROVERSIAL

• Common neuropsychiatric disorders

• Naturally waxing/waning course

• Very common childhood infection

• Positive streptococcal serology very common

in normal children

ROBUST BIOLOGICAL

MARKER

“At this time, there is no definite pathogenic auto-antibody or specific biomarker for PANDAS”. Brillot et al, 2011

Characteristics of PANDAS (Murphy & Segarra-Brechtel, 2010)

Characteristics Detail

Predisposition Family history of autoimmune or allergic disorders

Family history of rheumatic fever

Clinical onset Preceding infection compatible with group A streptococcus infection

Dramatic onset of tics and/or OC disorder in young child

Rapid alteration in behaviour and personality

Clinical course Spontaneous remission of symptoms or improvement with ATB

Exacerbations with further infections (relapsing course)

Supportive evidence

Culture of group A streptococcus before, or at time of onset

Culture of group A streptococcus at time of relapse

Paired streptococcal serology titres (acute and convalescent)

No place for anti-brain antibodies or immune markers at this time

Treatment Treat symptoms conventionally (tics, obsessive-compulsive disorder)

If group A streptococcus cultured, course of appropriate antibiotic

Consider prophylactic antibiotic if strong association between repeated

infections and relapses

If patient is severely impaired, immune therapies should be considered

Diagnostic criteria for PANS (Pediatric Acute-onet Neuropsychiatric Syndrome)

Core symptoms Detail

I- OCD Abrupt, dramatic onset of OCD or severely restricted

food intake

II- Additional

neuropsychatric

symptoms

(acute onset symptoms)

• Anxiety

• Emotional lability and/or depression

• Irritability, agression, and/or severely oppositional behaviors

• Developmental regression

• Deterioration in school performance (related to ADHD-like

symptoms, memory deficits, cognitive changes

• Sensory or motor abnormalities

• Somatic signs and symptoms, including sleep disturbances,

enuresis, or urinary frequency

III- Symptoms are not better explained by a known neurologic or medical disorder,

such as SC

Swedo et al, 2012

2013 PANS Conference (Stanford University)

Swedo, Leckman, & Rose, 2012; Orefici et al, 2016

PANDAS is clearly a subtype of PANS

Differential diagnosis in children

• Obsessive compulsive disorder

• Anorexia nervosa

• Tourette syndrome

• Transient tic disorder

• Bipolar disorder

• Sydenham chorea

• Autoimmune encephalitis

• Systemic autoimmune disease

• Wilson´s disease

PANS: Pediatric Acute-onset Neuropsychiatric Syndrome

Chang et al, 2015

1- Kovacevic M, Grant P, Swedo SE. Use of intravenous immunoglobulin in the

treatment of twelve patients with PANDAS . J Child Adolesc Psychopharmacol

2015; 25(1):65–69

Retrospective analysis of a small case series demonstrated that despite

heterogeneous duration of illness and recurrence, all patients benefited

from IVIg administration, even when the neuropsychiatric symptoms had

been present for several years prior to treatment.

Nevertheless, the study was limited in its retrospective nature, and patients

were treated with multiple medications, including ATBs and behavioral

therapies

2. Singer HS. PANDAS and immunomodulatory therapy.

Lancet 1999; 354(9185):1137–1138.

He suggested that the lack of observed association

between therapeutic response and the rate of antibody

removal and how antibody-mediated processes in the

periphery can induce neuropsychiatric symptoms remains

difficult to understand

3. Kilbertus S, Brannan R, Sell E, Doja A. No cases of PANDAS on follow-up of

patients referred to a Pediatric Movement Disorder Clinic. Front Pediatr 2014;

25 (2):104

• Over the course of 7 years, only 39/284 patients had acute-onset tics and/or

OCD symptoms.

• None of them evaluated during the acute stage, met full criteria for

PANDAS.

• 38% had no association between their symptoms and streptococcal

infection.

• Only 8% had an acute exacerbation after the initial visit, but tests for GAS (-)

• Conclusion: PANDAS, if it exists, in an exceedingly rare diagnosis encountered

in a pediatric movement disorder clinic. However, some of them met criteria

por PANS, and probably this may be a more appropriate diagnosis

Comprehensive evaluation for children with potential PANS/PANDAS

Comprehensive medical and psychiatric history

Family history Neuro/Psychiatric, Autoimmune

Complete physical examination

Psychiatric evaluation/ mental status Cognition, abnormal movements

General and specific laboratory studies

Complete BCC /liver function tests

ESR

Throat culture

Anti-streptolysin O (ASTO)

Anti-DNAse B

ANA

Antiphospholipid antibody work up

Comprehensive evaluation for children with potential PANS/PANDAS

Infectious disease evaluation • Throat culture sensitive to confirm

streptococcal pharyngitis

• Rapid antigen tests are insufficiently sensitive

Culture-proven GAS infection • Nasal cavity: culture of nasal secretion

• Skin and skin structure,

• (Perianal or vaginal areas)

Hospital Nacional de Pediatría Dr. Juan P. Garrahan

Buenos Aires, Argentina