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Encephalitis
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  • Terms combined to give eg meningo-enephalitis, encephalomyelitis
  • Most geographically restricted viruses are arthropod-borne
  • HSV targets brain parenchyma in temporal lobes, sometimes with frontal or parietal involvement
    Mumps can cause acute viral encephalitis or a delayed immune-mediated encephalitis
    Measles causes a post-infectious encephalitis which may have a severe haemorrhagic component (acute haemorrhagic leukoencephalitis)
    Influenza A may give diffuse cerebral oedema
    VZV causes a vasculitis
  • Mollaret’s meningitis is strictly a recurrent meningitis of unknown cause but feeling is that HSV-2 may cause most cases
  • CT head shows brain swelling
    MRI shows temporal high signal esp on left (very well seen on the diffusion-weighted image)
  • EEG: PLEDs (periodic lateralised epileptiform discharges) once thought to be diagnostic of HSE but have now been seen in other conditions
    Brain biopsy used to be gold standard for diagnosis of HSV-1 encephalitis before PCR. May still have a role in undiagnosed pt who is deteriorating.
    FBC: May get raised or low WCC. Atypical lymphocytes in EBV. Eosiniphils in eosinophilic meningitis.
    Low Na due to SIADH common in encephalitis
    Raised serum amylase with mumps infection
    Cold agglutinins present mycoplasma infections, then go on and do serology for atypical resp infections
    Blood cultures should be done if suspect bacterial cause (consider meningococcus PCR on blood)
    CSF and urine bacterial antigen tests
    CXR for pulmonary infiltrates of atypical pneumonia
    HIV testing consider esp if cause of CNS infection uncertain
  • Some debate as to whether positive viral PCR in CSF definitely means infection (some assays are very sensitive)
    If titre of CSF PCR is higher than serum PCR titre then significant
    CSF anti-HSV antibodies not useful as only have sensitivity of 50% by 10 days
    Serum antibody tests: x4 rise in Ab titre between acute and convalescent serum (2-4 weeks apart)
    OCBs positive in CSF suggest inflammation in the CNS (may be useful in differentiating non-infective encephalopathy)
  • Normal glucose ratio said to be 66% but probably not significant until values are below 50%
    Viral CNS infections: early LP may show mainly neutrophils (or no cells)
    Acute bacterial meningitis which has been partly treated with antibiotics may show mostly lymphocytes and cell count may not be very high
    TB meningitis may show polymorphs early on
    Listeria can look like TB but history shorter
  • Aciclovir: nucleoside analogue, highly effective against HSV and some other herpes viruses (VZV, herpes B virus)
    Rare risk of renal failure (and hepatitis, bone marrow failure)
    Oral aciclovir should not be used in HSE as levels achieved in CSF are inadequate
    However, oral valaciclovir may have a role after 10 days iv aciclovir given
    Valaciclovir is converted to aciclovir after absorption and has good oral bioavailability
    Corticosteroids/mannitol may be useful in brain swelling (decompressive hemicraniectomy)
    Recent trial suggests steroids may be beneficial in HSE even if no brain swelling
    VZV encephalitis steroids and aciclovir given as vasculitic component too
    Risk of seizures greatest in those who had seizures during acute period (20% after 5 years) otheriwse risk is 10% after 5 years

Transcript

  • 1. Medical Grand Round Dr. Lucy Strens Consultant Neurologist UHCW Nov 24th 2009
  • 2. Viral encephalitis • Causes • Typical presentation • Investigations • Treatment • Prognosis
  • 3. Terminology • Encephalopathy – Clinical syndrome of reduced consciousness – Many causes, incl. viral encephalitis • Encephalitis – Acute, diffuse, inflammatory process affecting brain parenchyma – Most commonly viral • Meningitis: meningeal inflammation • Myelitis: spinal cord inflammation • Radiculitis: nerve root inflammation
  • 4. Causes of encephalopathy • Hypoxic/ischaemic • Metabolic (liver and renal failure, diabetes) • Toxic (alcohol, drugs) • Vascular (vasculitis, SLE, SAH, SDH, stroke, Behcet’s) • Epileptic (non-convulsive status) • Nutritional deficiency • Systemic infections (malaria) • Traumatic brain injury • Malignant hypertension • Mitochondrial cytopathy (Reye’s and MELAS syndromes) • Hashimoto’s encephalopathy • Paraneoplastic limbic encephalitis • Neuroleptic malignant syndrome…….. (and more!)
  • 5. Causes of acute viral encephalitis Sporadic causes (not geographically restricted) • Herpes viruses – HSV-1, HSV-2, VZV, CMV, EBV, HHV6, HHV7 • Enteroviruses – Coxsackie, echoviruses, enteroviruses 70/71, parechovirus, poliovirus • Paramyxoviruses – Measles, mumps • Others (rarer causes) – Influenza viruses, Adenovirus, parvovirus, lymphocytic choriomeningitis virus, rubella virus, rabies Geographically restricted causes • Arboviruses — Japanese B, St Louis, West Nile, Eastern equine, Western equine, Venezuelan equine, tick borne encephalitis viruses • Bunyaviruses — La Crosse strain of California virus • Reoviruses — Colorado tick fever virus
  • 6. Non-viral causes of infectious encephalopathy Bacterial Mycobacterium tuberculosis Mycoplasma pneumoniae Listeria monocytogenes Borrelia burgdorferi Leptospirosis Brucellosis Legionella Tropheryma whippeli (Whipple’s disease) Nocardia actinomyces Treponema pallidum Salmonella typhi All causes of pyogenic meningitis Rickettsial Rickettsia rickettsia (Rocky Mountain spotted fever) Rickettsia typhi (endemic typhus) Rickettsia prowazeki (epidemic typhus) Coxiella burnetti (Q fever) Ehrlichiosis (Ehrlichia chaffeensis— human monocytic ehrlichiosis) Fungal Cryptococcus Aspergillosis Candidiasis Coccidiomycosis Histoplasmosis North American blastomycosis Parasitic Human African trypanosomiasis (sleeping sickness) Cerebral malaria Toxoplasma gondii Echinococcus granulosus Schistosomiasis
  • 7. Pathogenesis of viral encephalitis • Depends on the virus – direct viral destruction of cells – Para or post-infectious inflammatory or immune- mediated response • Most viruses primarily infect brain parenchyma and neuronal cells • Some cause a vasculitis • Demyelination may follow infection
  • 8. Herpes simplex encephalitis • HSV encephalitis (HSE) most common cause of viral encephalitis in industrialised nations • Annual incidence 1 in 250,000-500,000 • 90% HSV-1 • HSV-2 more common in immuno-compromised, neonates
  • 9. HSV-1 • Primary infection occurs in oral mucosa – 30% people get clinically apparent cold sores – 90% healthy people have been infected with HSV-1 • Virus then travels along trigeminal nerve to ganglion in most (if not all) those infected • 70% cases of HSV-1 encephalitis already have antibody present suggesting reactivation of virus most common mechanism • Why HSV-1 reactivates not known • In children, HSV-1 encephalitis occurs during primary infection
  • 10. HSV-2 • Transmitted via genital mucosa – Genital herpes in adults – USA, 20% of adults sero-positive for HSV-2 • HSV-2 may cause – Meningitis (esp. recurrent meningitis) – Encephalitis (esp in neonates) – Lumbosacral radiculitis • Neonates can be infected during delivery: neonatal herpes (disseminated infection often with CNS involvement)
  • 11. Case example • 57 yr old female • 4 days N&V, severe headache, loss of appetite • Confused, ‘unable to find right word’ • O/E – Temp 39o C, dysphasic, no focal neuro signs (upgoing plantars) – WCC 11.7, CRP 4
  • 12. Case 2 • CSF – WCC 36 (80% lymphocytes), RCC 2 – Normal glucose, protein 0.91g/l – HSV-1 PCR positive
  • 13. Viral encephalitis – clinical presentation • Typical presentation – Acute flu-like prodrome – High fever, severe headache, N&V – Altered consciousness (lethargic, drowsy, confused, coma) – (Seizures) – (Focal neurological signs) • Recent study of HSV-1 encephalitis* – 91% febrile on admission – 76% disorientated – 59% speech disturbances – 41% behavioural change – 33% seizures *Raschilas et al 2002 Clin Infect Dis
  • 14. Clinical presentation • More subtle presentations now recognised – Low grade fever – Speech disturbances (dysphasia, aphasia) – Behavioural changes • Subacute and chronic presentations can be caused by CMV, VZV, HSV (immuno- compromised) • Any adult with seizure + fever or seizure from which they do not recover must be investigated for possible CNS infection
  • 15. Encephalopathy vs encephalitis? Encephalopathy Encephalitis Clinical features Fever Uncommon Common Headache Uncommon Common Depressed mental status Steady deterioration May fluctuate Focal neurological signs Uncommon Common Type of seizure Generalised Generalised or focal Laboratory findings Blood Leucocytosis uncommon Leucocytosis common CSF Pleocytosis uncommon Pleocytosis common EEG Diffuse slowing Diffuse slowing and focal abnormalities MRI Often normal Focal abnormalities
  • 16. Clues in history • Recent rashes • Vaccination history • Travel history • Recent animal/insect bites, contact with sick animals • Immunosuppression (HIV, transplant) • Drugs, alcohol
  • 17. Clues on examination • Skin rashes, bites, injection sites • Examine chest, abdo, ears, genitals, urine for infection • Meningism, subtle motor seizures, focal neuro signs • NB ‘cold sores’ not diagnostic!
  • 18. Investigations • General – Haematological and biochemical blood screen – Serology, blood cultures, HIV – Drug screen, urine analysis – CXR • Neurological – CT head, MRI brain – LP (if not contraindicated on cranial imaging) – EEG – ((brain biopsy))
  • 19. MRI brain (T2W image): right temporal lobe high signal in a patient with herpes encephalitis
  • 20. Axial DWI: restricted diffusion in the left medial temporal lobe consistent with herpes encephalitis.
  • 21. CSF examination • Opening pressure • Send samples for – Cell count and differential – Protein, glucose (plasma glucose) – Gram stain and culture – Viral PCRs (HSV 1*, HSV2, VZV, EBV, CMV, enteroviruses) – Other tests as appropriate (discuss with micro!) *HSV-1 CSF PCR still positive in 80% pts after one week of treatment (may be negative in first few days) PCR tests for HSV have overall sensitivity and specificity >95%
  • 22. Typical CSF findings in CNS infections Viral Bacterial TB Fungal Normal Opening pressure Normal/high High High High/v. high 10-20 cm Colour Clear Cloudy Cloudy/yellow Clear/cloudy Clear Cells/mm3 Sl. increase 5-1000 High/v. high 100-50,000 Sl. increase 25-500 Normal/high 0-1000 < 5 Differential Lymphocytes Neutrophils Lymphocytes Lymphocytes Lymphocytes CSF/plasma glc ratio Normal Low Low/v. low (<30%) Normal/low 66% Protein (g/l) Normal/high 0.5-1 High >1 High/v. high 1-5 Normal/high 0.2-5 <0.45 Bloody tap: subtract 1 WBC for every 700 RBCs subtract 0.1g/l protein for every 1000 RBCs
  • 23. Management of viral encephalitis • O2, fluids, NG feed?, ITU? • Aciclovir – Start as soon as suspect viral encephalitis – iv aciclovir 10mg/kg tds – 14-21 day course in confirmed HSE – Monitor renal function – Only stop if definite other diagnosis made • Antibiotics too if delay in getting CSF/imaging • Management of complications (brain swelling, seizures)
  • 24. Prognosis in HSE • Mortality > 70% if untreated (20% with Rx) • Poor prognostic factors – Age > 60 yrs – GCS < 7 – Delay in starting aciclovir (esp > 2 days) • 2/3 rds pts have neuropsychiatric sequelae – 69% memory impairment – 45% personality/behaviour change – 41% dysphasia – 25% epilepsy www.encephalitis.info