15 Nov, 2016
Encephalitis
                         Encephalitis: 
 
Encephalitis is defined by the presence of an inflammatory process of the brain in association with clinical evidence of neurologic dysfunction. 
 
It is important to distinguish between infectious encephalitis and post infectious or post immunization encephalitis or encephalomyelitis (e.g., acute disseminated encephalomyelitis [ADEM]), which may be mediated by an immunologic response to an antecedent antigenic stimulus from an infecting microorganism or immunization. Acute Disseminated Encephalomyelitis (ADEM) is an autoimmune disorder that occurs several weeks after a viral illness.  
 
Noninfectious CNS diseases (e.g., vasculitis, lupus cerebritis, collagen vascular disorders, and paraneoplastic syndromes) can have clinical presentations similar to those of infectious causes of encephalitis and should also be considered in the differential diagnosis. 
 
Etiology: 
  1. Infections 
    • Viruses: Most common are HSV, West Nile virus, enterovirus and other herpes viruses. Others include Varicella zoster, influenza , childhood viruses: measles and SSPE, mumps, rubella, EBV, CMV, HHV 6, HIV, arboviruses, West Nile virus, flaviviruses, tick-borne encephalitis virus 
    • Bacteria : Usually S.Pneumo, mycoplasma followed by TB, neurosyphilis, Listeria, coxiella, Lyme 
    • Fungal: Cryptococcus 
    • Protozoans : toxoplasmosis, cerebral malaria, African trypanosomiasis 
    • Prions: e.g. CJD, kuru 
  2. Autoimmune 
    • ADEM 
    • anti-NMDA receptor encephalitis (various other antibodies) 
    • limbic encephalitis 
    • post-viral (e.g. zoster cerebellitis in children) 
 
Mechanism:  
Inflammation of the brain parenchyma results in diffuse and/or focal neuropsychological dysfunction. There may be coexistent involvement of the meninges (meningo-encephalitis). Most cases are viral, but inflammation may result from other infectious (e.g. bacterial, fungal, or protozoan) or autoimmune disorders. 
 
Clinical Features: 
Abnormal brain function (diffuse or focal): 
  • altered mental status (confused, agitated, obtunded, somnolescent) 
  • motor and sensory deficits 
  • altered behavior 
  • personality changes 
  • speech disorders 
  • movement disorders 
  • seizures 
  • hemiparesis 
  • cranial nerve palsies 
  • exaggerated deep tendon reflexes 
Associated features: 
  • may be co-existent meningism (meningo-encephalitis) 
  • vesicles may be present or absent in herpes encephalitis 
Laboratory tests 
  • CBC, CRP, CMP, glucose 
  • LP 
    1. lymphocytic pleocytosis 
    2. viral: WCC elevated, lymphocytes less than 250, elevated protein, normal or moderately low glucose 
    3. viral culture 
    4. herpes/ enterovirus PCR on CSF 
    5. VDRL 
    6. Ziehl-Nelsen stain and TB culture 
    7. cytology 
    8. cryptococcal antigen or India Ink 
  • Serology: viruses (e.g. arbovirsuses), HIV, syphilis, toxoplasmosis, EBV, CMV, Rickettsia IgM, Lyme serology etc. 
  • Other body fluids should also be cultures if it is suspected to be the source. For example, in patients with varicella or herpes zoster, the etiology may be determined by scrapings from the base of active vesicles and testing by direct fluorescent antibody to identify viral antigen. However, a positive result for a vesicular fluid sample does not necessarily indicate that this is the etiology of encephalitis, because varicella zoster virus may be reactivated in the context of CNS disease caused by other agents; 
  • Herpes simplex PCR should be performed on all CSF specimens in patients with encephalitis (A-III). In patients with encephalitis who have a negative herpes simplex PCR result, consideration should be given to repeating the test 3–7 days later in those with a compatible clinical syndrome or temporal lobe localization on neuroimaging.  
  • For certain viral agents, the presence of virus-specific IgM in CSF specimens may be indicative of CNS disease caused by that pathogen
  • Malaria screen 
  • Suspected autoimmune cause: 
    1. Anti-NMDA, LG1, CASPR2, AMPA, GABA-B, Anti-Hu/ Ma2, VGKC, GAD, DPPX, mGluR5 antibodies 
    2. Vasculitis screen 
    3. Paraneoplastic screen and imaging for underlying tumour 
Imaging 
  • MRI: Needs to be done in all patients. 
    • Temporal localization of lesions in HSV encephalitis 
    • Enhancing multifocal white matter changes (demyelination) 
    • West Nile: basal ganglia, thalamic, mesial temporal involvement 
    • Normal MRI does not exclude encephalitis 
  • FDG-PET scanning usually shows hyper metabolism, although there can also be areas of hypo metabolism 
  • CT head with and without iv contrast, if MRI can’t be done. 
    • before LP in older patients, if signs of raised ICP or focal neurology 
    • only 1/3 HSV encephalitis patients have abnormal CT heads 
Special tests 
  • EEG : Paroxysmal lateralizing epileptiform discharges may occur before imaging changes in HSV encephalitis (sensitive, not specific) 
  • Brain biopsy (last resort; generally not required due to the availability of PCR) 
  • CSF cultures are generally of limited value in the determination of the viral causes of encephalitis but are very important in the diagnosis of bacterial and fungal infections. 
  • In patients with viral encephalitis, CSF analysis typically reveals a mild mononuclear pleocytosis, although a polymorphonuclear cell predominance may initially be seen if the sample is obtained early in the course of illness; persistent neutrophilic pleocytosis has been observed in patients with West Nile virus encephalitis. CSF protein concentration is generally mildly or moderately elevated. Patients may have significant numbers of RBCs in the CSF, as a result of the development of hemorrhagic encephalitis. Up to 10% of patients with viral encephalitis can have completely normal CSF findings. 
  • The presence of virus-specific IgM in CSF is usually indicative of CNS disease, because IgM antibodies do not readily diffuse across the blood-brain barrier. 
  • An initially negative CSF PCR result for herpes simplex virus may become positive if the test is repeated 1–3 days after the initiation of treatment, and the presence of <10 WBCs/mm3 in CSF has been associated with a higher likelihood of a negative CSF PCR result. Therefore, in undiagnosed cases in which patients have clinical features of herpes simplex encephalitis or temporal lobe lesions on neuroimages, consideration should be given to repeating the PCR for herpes simplex virus 3–7 days later on a second CSF specimen. In this instance, a negative CSF PCR result may allow discontinuation of acyclovir therapy.  
 
Treatment 
  • Resuscitation: attend to ABCs and treat seizures 
  • Acyclovir treatment should be initiated in all patients with suspected encephalitis, pending results of diagnostic studies. Intravenous Acyclovir should be initiated as soon as the diagnosis of HSE is suspected rather than delayed until the diagnosis is confirmed; delayed initiation of Acyclovir treatment for more than 2 days after hospital admission is associated with poor outcomes . 
  • Specific treatment 
    • Acyclovir 10mg/kg Q8hrly until definitive imaging done 
    • Empiric antibiotics to cover for bacterial meningitis is often required 
    • Other specific agents where indicated (e.g. anti-malarials, immunosuppressants for autoimmune causes) 
    • In patients with clinical clues suggestive of rickettsial or ehrlichial infection during the appropriate season, doxycycline should be added to empirical treatment regimens. 
    • Lyme meningitis/encephalitis is treated with ceftriaxone and not doxycycline. 
    • Varicella-zoster virus: acyclovir is recommended; ganciclovir can be considered an alternative; adjunctive corticosteroids can be considered 
    • EBV or HHV 6 can be treated with ganciclovir. 
PEARLS: 
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Neurology