Intern Seminar 15560170 Int 李俊毅/ VS 謝奇璋

Acute-onset left side weakness Basic information 6Y 6M Boy No underlying history Received vaccine as scheduled Acute-onset left side weakness

Left arm weakness and limping gait Present illness 11/26 LMD Intermittent fever with productive cough Bilateral lower leg pain Drowsiness 12/1 ER Left arm weakness and limping gait No headache, neck stiffness, sore throat, oral ulcer, nor skin rash

Physical examination Consciousness: slow response but oriented HEENT: conjunctiva: not pale sclera: anicteric LAP at left level IIA and right level III Chest: symmetric expansion, clear breathing sound regular heart beat, no murmur Abdomen: soft and flat normoactive bowel sound no tenderness Extremities: freely movable, no pitting edema Skin: no defect

Cranial nerves: no abnormality Neurological examination Cranial nerves: no abnormality Muscle power Deep tendon reflex 5 4 3 4 5 4 3 4

Weak face over left side Spasticity over left side Finger-Nose-Finger: Neurological examination Weak face over left side Spasticity over left side Finger-Nose-Finger: Left upper limb dysmetria Limping gait

Lab data

Sharp CP angle, No active pneumonia patch

Cold agglutinin test : Positive Serologic test 12/1: M. pneumoniae Ab IgM: Positive 12/2: M. pneumoniae Ab 1:160 Cold agglutinin test : Positive HSV1 Ab IgG: negative HSV2 Ab IgG: negative HSV 1&2 Ab IgM: 1:1.255 EBV Ab: negative

12/2 Coxsackie virus Type B3 from throat swab and anus swab Anus swab Nucleic acid detection Enterovirus 71 : negative No virus isolated from CSF CSF Nucleic acid detection HSV-1 negative HSV-2 negative VZV negative

Multifocal lesion on T2 FLAIR Multifocal T2WI/T2FLAIR hyperintense at right midbrain, bilateral dentate nuclei and left hippocampus as well as right insular cortex. Multifocal lesion on T2 FLAIR

Multifocal lesion on T2 FLAIR Multifocal T2WI/T2FLAIR hyperintense at right midbrain, bilateral dentate nuclei and left hippocampus as well as right insular cortex. Multifocal lesion on T2 FLAIR

Multifocal lesion on T2 FLAIR Multifocal T2WI/T2FLAIR hyperintense at right midbrain, bilateral dentate nuclei and left hippocampus as well as right insular cortex. Multifocal lesion on T2 FLAIR

Abnormal awake and sleep EEG 12/2 Abnormal awake and sleep EEG indicates mild cortical dysfunction over posterior hemispheres

Neurologic Image 12/6 Myelitis mixed with meningitis over thoracolumbar spinal cord Interval progression bilateral midbrain with small cystic change at right side IVIG

12/7: M. pneumoniae Ab 1:80 12/11: M. pneumoniae Ab 1:80 Serologic test 12/7: M. pneumoniae Ab 1:80 12/11: M. pneumoniae Ab 1:80 HSV1 Ab IgG: 4.684 HSV2 Ab IgG: 0.802

MBD on 12/16 OPD Follow-up Rehabilitation

Acute Childhood Encephalitis Mycoplasma pneumoniae

Absence of respiratory symptoms Introduction Mycoplasma pneumoniae Extrapulmonary manifestation > 5歲， respiratory 40% community acquired pneumonia 25 % 有Extrapulmonary 3/14 DAY AFTER SYMPTOMS Encephalitis 均出現在 URI 後 9.6天 佔 acute encephalitis 的 8%左右 Enterovirus, herpes virus, and mp 60 %有 long term neurological sequela CV Derma GI Arthritis Mycoplasma: URI, bronchitis pneumonia, Asthma AE Absence of cell wall => pleomorphic, cross filter, parasite, extracellular Absence of respiratory symptoms Mycoplasma pneumoniae—an emerging extra-pulmonary pathogen, Clinical Microbiology and Infection, 2008

+2 Encephalitis Fever >38*c Pleocytosis Seizure Focal Finding EEG Definitions Fever >38*c Encephalitis Pleocytosis Seizure Focal Finding +2 EEG Encephalitis and meningoencephalitis are most common 1-10% child encephalits from MP infection Prodrome 後 2-14 ,9.6天 2/3 long term sequela Enterovirus, herpes virus, and mp Encephalopathy MRI Acute Childhood Encephalitis and Mycoplasma pneumoniae, Clinical Infectious Diseases Volume 32, Issue 12Pp. 1674-1684

Direct Indirect Vascular occlusion Extrapulmonary Manifestation Direct type: locally induced cytokines Classification of Extrapulmonary Manifestation Due to Mycoplasma pneumoniae Infection on the Basis of Possible Pathogenesis, Front. Microbiol., 28 January 2016

on local site through cytokine Extrapulmonary Manifestation Inflammation on local site through cytokine Early –onset encephalitis Direct Genome in CSF Direct type: locally induced cytokines Classification of Extrapulmonary Manifestation Due to Mycoplasma pneumoniae Infection on the Basis of Possible Pathogenesis, Front. Microbiol., 28 January 2016

Late–onset encephalitis Multifocal lesion Normal glucose, protein Extrapulmonary Manifestation Inflammation through Auto-immunity Molecular mimicry Late–onset encephalitis Multifocal lesion Normal glucose, protein Indirect Indirect Lymphocytic CSF Pleocytosis, milder than viral etiologies Normal glucose normal protien Multifocal symptoms with or without MRI finding T2 flair signal Abscene of M, pneumoniae Molecular mimicry Auto-antibody in CSF Classification of Extrapulmonary Manifestation Due to Mycoplasma pneumoniae Infection on the Basis of Possible Pathogenesis, Front. Microbiol., 28 January 2016

Vasculitic or thrombotic Extrapulmonary Manifestation Vasculitic or thrombotic Striatal necrosis Stroke Psychologic disorder Vascular occlusion Direct type: locally induced cytokines Classification of Extrapulmonary Manifestation Due to Mycoplasma pneumoniae Infection on the Basis of Possible Pathogenesis, Front. Microbiol., 28 January 2016

Classification of Extrapulmonary Manifestation Due to Mycoplasma pneumoniae Infection on the Basis of Possible Pathogenesis, Front. Microbiol., 28 January 2016

Mechanism Pathogenesis of Neurologic Manifestations of Local damage, cytotoxicity, cyto-adherence, hydrolytioc enzyme Pathogenesis of Neurologic Manifestations of Mycoplasma pneumoniae Infection, Pediatric Neurology 2009

Mechanism Antibody Responses to Mycoplasma pneumoniae: Molecular mimicry, survival within cell Antibody Responses to Mycoplasma pneumoniae: Role in Pathogenesis and Diagnosis of Encephalitis?, PLOS pathogen, 2014

Galactocerebroside Mechanism Molecular mimicry, survival within cell GalC: galactocerebroside Ganglioside quadrosialo Ganglioside monosialo Galactocerebroside Antibody Responses to Mycoplasma pneumoniae: Role in Pathogenesis and Diagnosis of Encephalitis?, PLOS pathogen, 2014

*M. pneumoniae in CSF (PCR, Culture) and/or Groups Probable 11 *M. pneumoniae in CSF (PCR, Culture) and/or *M. pneumoniae in throat specimens (PCR, Culture) and Serologic test (positive) Possible 9 M. pneumoniae in throat specimens (PCR, Culture) or Serologic test (positive) CSF 跟throat 都要做 (從來都沒有兩者都positive 過 Probable 組 有很高的coinfection rate 7/11 Acute Childhood Encephalitis and Mycoplasma pneumoniae, Clinical Infectious Diseases, 2011

2/3 prodromal respiratory symptoms 2/3 focal infiltration Manifestations In both groups 2/3 prodromal respiratory symptoms 2/3 focal infiltration CSF positive, 1/3 have respiratory symptoms Cough, sore throat, hoarseness fever headache myalgia malaise Prodromal illness duration CSF positive < CSF negative Acute Childhood Encephalitis and Mycoplasma pneumoniae, Clinical Infectious Diseases, 2011

EEG and Neuroimaging findings Probable: 85% has EEG and neuroimaging abnormalities 8/11 neurologic deficit: 1.8 years 4/8 need long-term anticonvulsant treatment Possible: 35% has EEG and neuroimaging abnormalities 5/9 neurologic deficit 1/5 need long-term anticonvulsant treatment Mild cognitive impairment in seizure Hemiparesis Dysphagia Dysarthria Truncal ataxia 2/3 Neurologic sequelae Acute Childhood Encephalitis and Mycoplasma pneumoniae, Clinical Infectious Diseases, 2001

History Serologic test PCR and Antibody of CSF PCR of throat sample Diagnosis History Serologic test PCR and Antibody of CSF PCR of throat sample PCR faster than serologic report but can not distinguish between infection or colonization Serologic time consuming, cross reaction with other M Antibody Responses to Mycoplasma pneumoniae: Role in Pathogenesis and Diagnosis of Encephalitis?, PLOS pathogen, 2014

Antibiotics Corticosteroid Immunoglobulins Anticoagulation --- Treatment Antibiotics Corticosteroid Immunoglobulins Anticoagulation --- Plasma exchange Classification of Extrapulmonary Manifestation Due to Mycoplasma pneumoniae Infection on the Basis of Possible Pathogenesis, Front. Microbiol., 28 January 2016

Back to our case URI symptoms before neurological deficit Serologic positive, PCR of CSF: negative M. pneumoniae antibody in CSF? Prognosis: Need long- term rehabilitation

Immunomodulatory combine antibiotics treatment Take home message Extrapulmonary manifestation of M. pneumoniae infection may occur without URI symptoms Serologic test PCR and Culture of CSF and throat samples M. pneumoniae antibody in CSF Immunomodulatory combine antibiotics treatment Intern 李俊毅

Reference Classification of Extrapulmonary Manifestation Due to Mycoplasma pneumoniae Infection on the Basis of Possible Pathogenesis, Front. Microbiol., 28 January 2016 Antibody Responses to Mycoplasma pneumoniae: Role in Pathogenesis and Diagnosis of Encephalitis?, PLOS pathogen, 2014 Mycoplasma pneumoniae—an emerging extra-pulmonary pathogen, Clinical Microbiology and Infection, 2008 Acute Childhood Encephalitis and Mycoplasma pneumoniae, Clinical Infectious Diseases, 2001 Pathogenesis of Neurologic Manifestations of Mycoplasma pneumoniae Infection, Pediatric Neurology 2009