Complicações neurológicas pós infecção por estreptococos (mitos e verdades) Silvia Tenembaum

Transcription

1 Complicações neurológicas pós infecção por estreptococos (mitos e verdades) Silvia Tenembaum

2 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

3 Immune- mediated brain disorders where movement disorders are typical 1. Sydenham chorea 2. PANDAS 3. Encephalitis lethargica 4. Infantile bilateral striatal necrosis 5. NMDA-R encephalitis 6. Immune-mediated chorea encephalopathy syndrome

4 PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections)

5 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

6 Criteria and associated features of PANDAS (Swedo et al, 1998) Core criteria Associated factors 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 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

7 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

8 Characteristics of PANDAS (Murphy & Segarra-Brechtel, 2010) Characteristics Predisposition Clinical onset Clinical course Detail Family history of autoimmune or allergic disorders Family history of rheumatic fever 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 Spontaneous remission of symptoms or improvement with ATB Exacerbations with further infections (relapsing course) Supportive evidence Treatment 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 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

9 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

10 2013 PANS Conference (Stanford University) PANDAS is clearly a subtype of PANS Swedo, Leckman, & Rose, 2012; Orefici et al, 2016

11 PANS: Pediatric Acute-onset Neuropsychiatric Syndrome 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 Chang et al, 2015

12 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

13 2. Singer HS. PANDAS and immunomodulatory therapy. Lancet 1999; 354(9185): 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

14 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

15 Comprehensive evaluation for children with potential PANS/PANDAS Comprehensive medical and psychiatric history Family history Complete physical examination Psychiatric evaluation/ mental status General and specific laboratory studies Neuro/Psychiatric, Autoimmune Cognition, abnormal movements Complete BCC /liver function tests ESR Throat culture Anti-streptolysin O (ASTO) Anti-DNAse B ANA Antiphospholipid antibody work up

16 Comprehensive evaluation for children with potential PANS/PANDAS Infectious disease evaluation Culture-proven GAS infection Throat culture sensitive to confirm streptococcal pharyngitis Rapid antigen tests are insufficiently sensitive Nasal cavity: culture of nasal secretion Skin and skin structure, (Perianal or vaginal areas)

17 Hospital Nacional de Pediatría Dr. Juan P. Garrahan Buenos Aires, Argentina