Encephalitis. HSV Encephalitis. Encephalitis. Viral CNS Infection. WNV Encephalitis GRAY MATTER. Zoran Rumboldt

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1 Encephalitis Viral CNS Infection Hematogenous dissemination ( along peripheral nerves ) Zoran Rumboldt University of Rijeka Medical University of South Carolina Telemedicine Clinic MarinMed Clinic Many have a predilection for GM Imaging reflects infiltration with inflammatory cells, typically as: low CT attenuation low T1 / high T2 signal on MRI Encephalitis WNV Encephalitis CLINICAL PRESENTATION Depressed level of consciousness and seizures Headache, fever, disorientation Majority viral (over 2/3 of infectious agents): Herpes simplex virus (HSV) Varicella-zoster virus (VZV) Arboviruses (WNV, TBE, JE) Enteroviruses Arboviruses - zoonotic diseases transmitted by mosquitoes or ticks GRAY MATTER A common finding is increased T2 signal in bilateral thalami and basal ganglia - Typically Asymmetric Viral infection should always be considered with bilateral deep nuclei lesions in an appropriate clinical setting HSV Encephalitis Diffusion MRI superior for early detection bright DWI low ADC values Enhancement of cauda equina and nerve roots may be present Additional characteristic and specific localization and/or imaging appearance

2 HSV Encephalitis HSV Encephalitis The single most frequent cause of sporadic encephalitis around the world is HSV type 1 PCR in CSF is highly sensitive and specific (> 95%) but the results can be negative during the first 3 days A devastating disease if untreated Specific effective treatment - acyclovir 10 mg/kg/8 h In most cases some concomitant meningeal inflammation - commonly referred to as meningoencephalitis In the tropical countries - southeast Asia and India the viruses are different from those of the Western world Hyperintense lesions involving cortex and adjacent WM on DWI (in appropriate clinical setting) should be considered HSE until proven otherwise The etiology of encephalitis remained unknown in most cases Over 100 different viruses identified as causative agents of CNS infections Topographic viruses may have nonspecific presentation Other infectious and non-infectious processes may simulate characteristic appearances, clinically and on imaging Bacterial (Listeria, Chlamydia, ) parasitic (Malaria) Relevance of infectious agent identified outside of CNS? Location of Imaging Abnormalities in Encephalitis Basal Ganglia TYPICAL EBV HIV (congenital) Measles (SSPE) Many other viruses COMMON Rabies Dengue TBE

3 H1N1 Influenza A Haktanir A. AJNR 2010;31:394 Ormitti F et al. AJNR 2010;31:396 TYPICAL Thalamus Flaviviruses (JE, WNV) EBV Influenza A (H1N1) Many other viruses Brainstem Enteroviruses - dorsal Rabies - dorsal Flaviviruses subst. nigra COMMON Rabies Measles (SSPE) TBE HSV-2 (neonatal) Adenovirus Measles (SSPE) Dengue Poliomyelitis (Enterovirus) ADENOVIRUSES Symmetric bilateral T2 hyperintense lesions: dorsal brain stem & ventral horns of cervical spinal cord (cerebellar dentate nuclei) Ependyma, brainstem, temporal lobes (cerebellum) ADEM Specific antiviral therapy limited: Herpesviruses and HIV Important to distinguish infectious encephalitis from: - Postinfectious/postimmunization encephalitis (ADEM) - Vasculitis - Paraneoplastic syndromes Brain MRI should be performed in all patients Targeted CSF IgM and PCR Brain biopsy rarely indicated WM and GM (Thalamus, Basal Ganglia)

4 Vasculitis Limbic Encephalitis (paraneoplastic) PML HIV NIPAH VIRUS Encephalitis causative agent not identified T2 bright foci in cerebral WM, to a lesser extent GM No edema or mass effect Some enhance & reduce diffusion T2w Viruses - GM FLAIR T2w usually asymmetric

5 Anti-NMDAR California Encephalitis Project - from 2007 anti-n-methyl-d-aspartate receptor (anti-nmdar) encephalitis Autoantibodies to synaptic proteins LIMBIC ENCEPHALITIS First described in thought to be paraneoplastic >4 times as frequent as HSV-1, WNV, or VZV The leading entity in young females Seizures, psychosis, autonomic instability Stiff neck unusual, less cells and protein in CSF ½ MRI findings 14% temporal lobe involvement da Rocha AJ, et al. AJNR 2015; 36: Gable MS, et al. Clinical Infectious Diseases 2012;54: N-Methyl-D-Aspartate Receptor Antibodies A viral-like prodrome followed by severe psychiatric features, amnesia and seizures may develop. After a few days to weeks, a movement disorder appears (often dyskinesia of the mouth and face) followed by a decreased level of consciousness and dysautonomia, requiring intensive care support. MRI findings are neither sensitive nor specific FDG-PET/CT often abnormal before the initial EEG, MRI, CSF studies most frequently brain hypometabolism Autoimmune Encephalitis Limbic encephalitis is far more common than previously thought, not always associated with cancer, and treatable. differentiated by the specific antibody subtype antibody-mediated attack on neuronal structures results in a localized inflammatory response at a specific location, leading to substantial variability limbic dysfunction the single most consistent finding Diagnosing AE is complicated by: availability, sensitivity, and specificity of antibody testing, new antibodies being rapidly identified; nonspecific diagnostic tests; competing differential diagnoses. AE remains a diagnosis of exclusion some types consistently lack imaging manifestations, others characteristically demonstrate extralimbic lesions

6 Autoimmune Encephalitis PARANEOPLASTIC NONPARANEOPLASTIC Group I antibodies target intracellular antigens Group II antibodies to antigens on the cell surface Kelley AB et al. AJNR Group I more commonly paraneoplastic, poor outcome/response to Tx less specific for encephalitis (also found in other cancer patients) Anti-Hu (small cell lung ca) Anti-Ma (testicular tumors in young men) Anti-CV2 (striatum CJD DWI!) Anti-GAD (Glutamic acid decarboxylase non paraneoplastic) Group II less frequently paraneoplastic, better outcome/response to Tx more specific marker for encephalitis serum titers possible underlying systemic AI disorder / after a viral infection NMDAr (ovarian teratoma older women, MRI frequently normal) VGKC (Voltage-gated potassium channel - epilepsy MTS) VGCC (Voltage-gated calcium channel - migratory MRI lesions) GABA (A - extralimbic lesions; B - small cell lung ca) Kelley AB et al. AJNR Anti-Hu Anti-CV2 striatum CJD Anti VGKC MTS DWI Kotsenas AL, et al. AJNR 2014;35:84 89

7 VGKC Anti-VGCC MTS migratory lesions Thyroid dysfunction with antithyroid antibodies Hashimoto Encephalopathy Graves disease or Hashimoto thyroiditis migratory pattern of cortical lesions in different regions Hashimoto encephalopathy more prominent WM lesions Anti-glutamate receptor 3 (GluR3) antibodies associated with Rasmussen encephalitis, SLE, other AI migratory lesions Anti-NMDAr antibodies found in patients with Rasmussen encephalitis and HSV encephalitis Rasmussen Encephalitis viral encephalitis can trigger an autoimmune reaction, particularly anti NMDAr encephalitis - prolonged or atypical neurologic symptoms recur after successful treatment a few weeks after recovery from HSV encephalitis, abnormal movement and/or behavioral changes without new MRI lesions or response to antiviral therapy Recurrent/new neurologic/psychiatric symptoms after treated HSV encephalitis - secondary AE?

8 Postictal Changes GBM also overlap with demyelination (anti-mog) HSE vs AE BL asymmetric limbic system involvement sparing BG - concern for HSE (and Neurosyphilis) also hemorrhagic foci and gyriform enhancement Psychiatric symptoms - unique for AE Mesial temporal involvement only -AE Insular and diffuse temporal involvement -HSE Acute onset with fever & intact basal ganglia -HSE Autoimmune Encephalitis Imaging is important as it can support the clinical diagnosis, particularly in the absence of antibodies. Structural imaging findings may be subtle, usually best seen on FLAIR. A progressive as well as a relapsing-remitting course can be observed. Demaerel P, et al. Neuroradiology 2011;53: Kelley AB et al. AJNR Bright DWI lesions of cortex and adjacent WM - bilateral asymmetric - should be considered HSE until proven otherwise acute onset with fever and absence of BG involvement Encephalitis Diff Dg: ADEM & Vasculitis postictal changes, Gliomas Autoimmune Encephalitis Psychiatric Symptoms Diagnosis of Exclusion Mesial Temporal and beyond (Non)paraneoplastic, 2 Groups Anti-NMDAR encephalitis frequently without MRI findings