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Become a member of Movember…Grow a Stache! Ladies are welcome to join Neurology Case of the Week HASSANAIN TOMA, MD NEUROLOGY PGY-4 M O V E M B E R 2 ND, 2 0 1 2 Chief Complaint Altered mental status: Lethargic -> obtunded HPI 5 yo Caucasian boy Admission - 11 days: Fever of 104 -> diagnosed with a sore throat and placed on antibiotics Admission - 8 days: Diarrhea after -> stopped abx -> diarrhea continued. coughing, nasal congestion, and rhinorrhea Admission - 7 days Vomiting x 4 days, decreased PO intake. Admission -1 day crying episodes. Admission: Abdominal pain, screaming due to pain He was transferred here for further evaluation his abdominal pain. Next day became increasingly lethargic, and was intubated for airway protection. GROWTH/DEVELOPMENT: Growth delay and mild development delay. Able to walk, speaks. Attends kindergarten. PAST MEDICAL/SURGICAL/BIRT H HISTORY: Eczema Hypothyroidism milk allergy (has since grown out of this per mom) ADHD. Adverse Reactions/Allergies: FAMILY HISTORY: Asthma, HTN. SOCIAL HISTORY: PAST SURGICAL Milk Products(Rashes) No surgeries. Parents live separately. Preston spends time at each parent's house. Dad smokes outside the home. MEDICATIONS: Levothyroxine Antacid strattera IMMUNIZATIONS: Up to date per mom. Physical Exam General: Intubated, appears of stated age. No spontaneous movement. Head/Neck: Microcephalic. No neck masses. Eyes: PERRL. Erythema of conjunctiva of left eye. ENT: TM's pearly and nonbulging bilaterally. No erythema or exudate of oropharynx. Dry lips. Mental State: Obtunded, not responsive to stimuli. CN II: PERRL slow reacting. CN III & IV: Positve dolls. CN V: Grimaces pain. Corneal reflex preserved in both eyes. CN VI: Unable to access extra ocular movements intact bilaterally. CN VII: Symmetrical face. CN VIII: Unable to assess hearing. CN IX & X: Gag present. Chest: CTAB, no wheezing. CV: RRR, no murmurs, rubs, or gallops. Abdomen: abdomen is soft. Non distended. +BS Lymph: No cervical LAD. Skin: No rashes seen on visible skin. Motor: The tone is hypertonic with rigidity. Sensory: withdraws to pain. Reflexes: 3 diffusely. Upgoing toes. Coordination: could not be tested. Gait: could not be tested. Labs HEMATOLOGY WBC HGB HCT 35.2% Platelet 182 % Band 32.9 % 9.46 12.4 URINALYSIS/FECES Color Ur STRAW Clarity Ur CLEAR Specific Gravity Ur 1.030 pH Ur 6.0 Glucose Ur NEGATIVE Ketones Ur 2+ A Protein Ur NEGATIVE Blood Ur NEGATIVE Bili Ur NEGATIVE Urobilinogen Ur NORMAL Nitrite Ur NEGATIVE Leukocytes Ur NEGATIVE WBC Ur 1-4 RBC Ur 1-4 Bacteria Ur NONE Renal Epithelial Cells Ur FEW Casts Ur NONE Crystals Ur NONE CHEMISTRY Sodium Potassium Chloride Carbon Dioxide Anion Gap Calcium Glucose BUN Creatinine C Reactive Prot Protein Total Alb Bili, Total Bili, Direct Bili, Indirect AST ALT AP Amylase Lipase Sed Rate CSF Clarity Color RBC WBC Glucose Protein 137 4.0 101 22 14 9.3 93 10 0.31 2.3 H 6.5 3.6 0.6 0.0 0.3 146 H 138 H 143 70 308 H 34H ENDOCRINOLOGY TSH 3.02 T4 Free 1.5 CLEAR COLORLESS 0 2 79 41 What?? Where?? Differential Diagnosis MRI - DWI MRI - FLAIR MRI - SWI (Susceptibility) MRI – T2 MRI – T1 Sagital Labs INF DIS/ANTIGEN/MOLECULAR Adenovirus PCR Quant Plasma Not Dete Adenovirus PCR Quant CSF Not Dete West Nile PCR CSF Negative West Nile PCR Blood Negative EBV PCR Quant CSF Not Dete VZV PCR Quant CSF Not Dete SEROLOGY/INF DISEASE E Equine Enceph IgG CSF E Equine Enceph IgM CSF Calif Enceph IgG CSF Calif Enceph IgM CSF St. Louis Enceph IgG CSF St. Louis Enceph IgM CSF W Equine Enceph IgG CSF W Equine Enceph IgM CSF West Nile Virus IgG CSF West Nile Virus IgM CSF Bart henselae IgG Bart henselae IgM Bart quintana IgG Bart quintana IgM Calif (LaCross) IgG Calif (LaCross) IgM E Equine Enceph IgG E Equine Enceph IgM St Louis Enceph IgG St Louis Enceph IgM W Equine Enceph IgG W Equine Enceph IgM Mycoplasma Ab IgG Mycoplasma Ab IgG Interp Mycoplasma Ab IgM Mycoplasma Ab IgM Interp <1:10 <1:10 <1:10 <1:10 <1:10 <1:10 <1:10 <1:10 Negative Negative <1:128 <1:20 <1:128 <1:20 <1:10 <1:10 <1:10 <1:10 <1:10 <1:10 <1:10 <1:10 0.08 Negative 0.12 Negative MOLECULAR INF DISEASE CMV PCR Quant NEG Enterovirus RT-PCR NEG Epstein Barr Virus PCR NEG Herpes Simplex Virus PCR NEG Respiratory Viral Panel PCR Influenza A (subtypes H1, 2009 H1, H3) Influenza B Respiratory Syncytial Virus (RSV) Adenovirus POS Human Metapneumovirus Parainfluenza 1,2,3,4 Rhinovirus/Enterovirus Bordetella pertussis Chlamydophila pneumonia Mycoplasma pneumonia Coronavirus (HKU1, NL63, OC43 and 229E) BIOCHEMICAL GENETICS Phosphoserine 7 Taurine 78 Phosphoethanolamine 0 Aspartic Acid 21 Hydroxy Proline 0 Threonine 304 H Serine 132 Asparagine 73 Glutamic Acid 58 Glutamine 609 Sarcosine 0 Proline 153 Glycine 339 Alanine 464 Citrulline 9 Alpha Amino Butyric Acid 23 Valine 245 Cystine 57 H Methionine 42 Cystathionine 0 Isoleucine 70 Leucine 152 Tyrosine 68 Phenylalanine 87 B-Alanine 0 Homocystine 0 Ornithine 80 Lysine 277 Histidine 74 Arginine 146 H Acute Necrotizing Encephalopathy (ANE) What do we know? Background Establishment as a new disease in 1995 Higher incidence in East Asian countries Handful of cases in Caucasians M=F Peak at 6-18 months old, but can occur in up to 11yo < 5yo 81.8%. Mortality rate 31.8 Neurological sequelae (27.7%) coagulopathy, hepatic dysfunction, and computed tomographic abnormalities had a poor prognosis. Viruses Implicated Acute Presentation Convulsions are 1st sign of brain dysfunction 0.5-3 days after onset of antecedent infections Histology-> encephaloPATHY Necrosis (due to severe edema) in the thalami, tegmentum, and dentate nuclei Florid petechial hemorrhage around small parenchymal vessels Patchy cerebral white matter lesions of ANE are not hemorrhagic Absence of inflammatory cells in brain parenchyma is characteristic, Differentiates ANE from acute disseminated encephalomyelitis & acute hemorrhagic encephalitis Pathogenesis 1- Viral invasion of central nervous system Controversial- via peripheral nerves? positive viral RNA in CSF and brain but lack of inflammation in brain tissue of fatal cases Not dependent on infectious agents. Vascular endothelial cells, astrocytes and neurons -> apoptosis Viral invasion likely a result not a cause of disease 2- Predisposition Mutations in the gene Ran-binding 2 (RANBP2) associated with familial or recurrent viral ANE. Autosomal-dominant ANE due to missense mutations in RANBP2 Hepatic and/or renal dysfunction 3- cytokine storm proinflammatory cytokines interleukin (IL)-6, IL-1b, tumor necrosis factor (TNF)-a, soluble TNF receptor IL-6 level was correlated with worse prognosis IL-6 and TNF-a -> apoptosis & injury of vascular endothelium, glial cells, and neurons, -> vascular lesions and breakdown of the blood–brain barrier (BBB) -> induce brain edema and damage, CNS disorders, and/or systemic symptoms Other cytokines/chemokines CXCL8/IL-8, CCL2/MCP-1, and CXCL10/IP-10 Pathogenesis Investigations - Bloods Various abnormal findings Elevation of serum aminotransferases and lactic dehydrogenase indicates liver dysfunction Elevation of creatine kinase, urea nitrogen and amylase indicates concomitant involvement of the muscles, kidneys and pancreas respectively. Labs & Diagnostics Investigations - Imaging Bilaterally symmetric lesions of the thalami ± lateral putamin & external capsule, tegmentum, cerebellar nuclei The lesions are often necrotic and hemorrhagic. Diffusion-weighted imaging (DWI) -> cytotoxic edema. Axial T2-weighted image showing bilaterally symmetric hyperintensity in the thalami. Note the target appearance of the lesions. Axial T2-weighted image showing bilaterally symmetric hyperintensity in the dorsal pons. Coronal FLAIR images showing bilaterally symmetric hyperintensity in the thalami and dorsal columns. 6 Day after 1st MRI 6 Day after 1st MRI Diagnostic Criteria for ANE Treatment Early intervention improves outcome! Prognosis Often grave Treatment BACK TO OUR PATIENT Methylprednisolone 30mg q24hrs. Mannitol at a 0.5g/kg q6 hour Serum osm goal ~ 320. 3% hypertonic saline Na goal high 140 and low 150 range. NO HYPOTHERMIA PROTOCOL Patient died on Hospital day 8 (diffuse cerebral edema) Autopsy: Diffuse brain edema, simplified broad gyri and friable brain parenchyma consistent with multifocal bilateral hemorrhagic and ischemic strokes (pending examination after fixation). Hospital Day 6 Hospital Day 1 Nuclear Medicine Scan References 1: Neilson DE. The interplay of infection and genetics in acute necrotizing encephalopathy. Curr Opin Pediatr. 2010 Dec;22(6):751-7. Review. PubMed PMID: 21610332. 2: Wang GF, Li W, Li K. Acute encephalopathy and encephalitis caused by influenza virus infection. Curr Opin Neurol. 2010 Jun;23(3):305-11. Review. PubMed PMID: 20455276. 3: Mizuguchi M, Yamanouchi H, Ichiyama T, Shiomi M. Acute encephalopathy associated with influenza and other viral infections. Acta Neurol Scand Suppl. 2007;186:45-56. Review. PubMed PMID: 17784537. 4: Mastroyianni SD, Gionnis D, Voudris K, Skardoutsou A, Mizuguchi M. Acute necrotizing encephalopathy of childhood in non-Asian patients: report of three cases and literature review. J Child Neurol. 2006 Oct;21(10):872-9. Review. PubMed PMID: 17005104. 5: Mizuguchi M. Acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in Japan and Taiwan. Brain Dev. 1997 Mar;19(2):81-92. Review. PubMed PMID: 9105653.