HASSANAIN TOMA, MDNEUROLOGY PGY-4

MOVEMBER 2 N D ,2012

Neurology Case of the Week

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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 daysVomiting x 4 days, decreased PO intake.

Admission -1 daycrying episodes.

Admission:Abdominal pain, screaming due to painHe 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/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.

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.

Labs

HEMATOLOGY WBC 9.46HGB 12.4HCT 35.2%Platelet 182% Band 32.9 %

URINALYSIS/FECESColor Ur STRAW

Clarity Ur CLEAR

Specific Gravity Ur 1.030pH Ur 6.0Glucose Ur NEGATIVEKetones Ur 2+ AProtein Ur NEGATIVEBlood Ur NEGATIVEBili Ur NEGATIVEUrobilinogen Ur NORMALNitrite Ur NEGATIVELeukocytes Ur NEGATIVEWBC Ur 1-4RBC Ur 1-4Bacteria Ur NONERenal Epithelial Cells Ur FEW

Casts Ur NONECrystals Ur NONE

CHEMISTRYSodium 137 Potassium 4.0Chloride 101 Carbon Dioxide22 Anion Gap 14 Calcium 9.3Glucose 93 BUN 10 Creatinine 0.31 C Reactive Prot 2.3 H

Protein Total 6.5Alb 3.6Bili, Total 0.6Bili, Direct 0.0Bili, Indirect 0.3AST146 H ALT 138 H AP 143Amylase 70 Lipase 308 H Sed Rate 34H

ENDOCRINOLOGY TSH

3.02 T4 Free

1.5

CSF Clarity CLEARColor COLORLESSRBC 0WBC 2Glucose 79Protein 41

What??

Where??

Differential Diagnosis

MRI - DWI

MRI - FLAIR

MRI - SWI (Susceptibility)

MRI – T2

MRI – T1 Sagital

Labs

INF DIS/ANTIGEN/MOLECULARAdenovirus 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 <1:10 E Equine Enceph IgM CSF <1:10 Calif Enceph IgG CSF <1:10 Calif Enceph IgM CSF <1:10 St. Louis Enceph IgG CSF <1:10 St. Louis Enceph IgM CSF <1:10 W Equine Enceph IgG CSF <1:10 W Equine Enceph IgM CSF <1:10 West Nile Virus IgG CSF Negative West Nile Virus IgM CSF Negative Bart henselae IgG <1:128 Bart henselae IgM <1:20 Bart quintana IgG <1:128 Bart quintana IgM <1:20 Calif (LaCross) IgG <1:10 Calif (LaCross) IgM <1:10 E Equine Enceph IgG <1:10 E Equine Enceph IgM <1:10 St Louis Enceph IgG <1:10 St Louis Enceph IgM <1:10 W Equine Enceph IgG <1:10 W Equine Enceph IgM <1:10 Mycoplasma Ab IgG 0.08 Mycoplasma Ab IgG Interp Negative Mycoplasma Ab IgM 0.12 Mycoplasma Ab IgM Interp Negative

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

MOLECULAR INF DISEASECMV PCR QuantNEGEnterovirus RT-PCR NEGEpstein Barr Virus PCR NEGHerpes Simplex Virus PCR NEGRespiratory 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)

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

abnormalitieshad 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

TreatmentEarly intervention

improves outcome!Often grave

Prognosis

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.