Neurology Case of the Week

1. Neurology Case of the Week Become a member of Movember…Grow a Stache! Ladies are welcome to join  HassanainToma, MDNeurology PGY-4Movember 2nd,2012

2. Chief Complaint Altered mental status: Lethargic -> obtunded

3. 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.

4. GROWTH/DEVELOPMENT: • Growth delay and mild development delay. • Able to walk, speaks. • Attends kindergarten. PAST MEDICAL/SURGICAL/BIRTH HISTORY: • Eczema • Hypothyroidism • milk allergy (has since grown out of this per mom) • ADHD. PAST SURGICAL • No surgeries. MEDICATIONS: • Levothyroxine • Antacid • strattera Adverse Reactions/Allergies: • Milk Products(Rashes) FAMILY HISTORY: • Asthma, HTN. SOCIAL HISTORY: • Parents live separately. Preston spends time at each parent's house. • Dad smokes outside the home. IMMUNIZATIONS: • Up to date per mom.

5. 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. 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. 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. 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.

6. Labs CSF Clarity CLEAR Color COLORLESS RBC 0 WBC 2 Glucose 79 Protein 41 HEMATOLOGY WBC 9.46 HGB 12.4 HCT 35.2% Platelet 182 % Band 32.9 % 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 137 Potassium 4.0 Chloride 101 Carbon Dioxide 22 Anion Gap 14 Calcium 9.3 Glucose 93 BUN 10 Creatinine 0.31 C Reactive Prot 2.3 H Protein Total 6.5 Alb 3.6 Bili, Total 0.6 Bili, Direct 0.0 Bili, Indirect 0.3 AST 146 H ALT 138 H AP 143 Amylase 70 Lipase 308 H Sed Rate 34H ENDOCRINOLOGY TSH 3.02 T4 Free 1.5

7. What?? Where??

8. Differential Diagnosis

9. MRI - DWI

10. MRI - FLAIR

11. MRI - SWI (Susceptibility)

12. MRI – T2

13. MRI – T1 Sagital

14. 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 EncephIgG CSF <1:10 E Equine EncephIgM CSF <1:10 CalifEncephIgG CSF <1:10 CalifEncephIgM CSF <1:10 St. Louis EncephIgG CSF <1:10 St. Louis EncephIgM CSF <1:10 W Equine EncephIgG CSF <1:10 W Equine EncephIgM CSF <1:10 West Nile Virus IgG CSF Negative West Nile Virus IgM CSF Negative Bart henselaeIgG <1:128 Bart henselaeIgM <1:20 Bart quintanaIgG <1:128 Bart quintanaIgM <1:20 Calif (LaCross) IgG <1:10 Calif (LaCross) IgM <1:10 E Equine EncephIgG <1:10 E Equine EncephIgM <1:10 St Louis EncephIgG <1:10 St Louis EncephIgM <1:10 W Equine EncephIgG <1:10 W Equine EncephIgM <1:10 MycoplasmaAbIgG 0.08 MycoplasmaAbIgGInterp Negative MycoplasmaAbIgM 0.12 MycoplasmaAbIgMInterp 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 Bordetellapertussis Chlamydophila pneumonia Mycoplasma pneumonia Coronavirus (HKU1, NL63, OC43 and 229E) BIOCHEMICAL GENETICS Phosphoserine 7 Taurine 78 Phosphoethanolamine 0 Aspartic Acid 21 HydroxyProline 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

15. Acute Necrotizing Encephalopathy (ANE)

16. What do we know?

17. 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.

18. Viruses Implicated

19. Acute Presentation • Convulsions are 1st sign of brain dysfunction • 0.5-3 days after onset of antecedent infections

20. 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

21. 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

22. Pathogenesis

23. Investigations - Bloods Various abnormal findings Elevation of serum aminotransferases and lactic dehydrogenase indicates liver dysfunction Elevation of creatinekinase, urea nitrogen and amylase indicates concomitant involvement of the muscles, kidneys and pancreas respectively.

24. Labs & Diagnostics

25. 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.

26. 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.

27. 6 Day after 1st MRI

28. 6 Day after 1st MRI

29. Diagnostic Criteria for ANE

30. Treatment Prognosis Early intervention improves outcome! Often grave

31. Treatment

32. BACK TO OUR PATIENT • Methylprednisolone 30mg q24hrs. • Mannitolat 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).

33. Hospital Day 6 Hospital Day 1

34. Nuclear Medicine Scan

35. References 1: Neilson DE. The interplay of infection and genetics in acute necrotizing encephalopathy. CurrOpinPediatr. 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. CurrOpin 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. ActaNeurolScandSuppl. 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.