Approach

Encephalitis is a medical emergency.[33] An acute or subacute onset of a febrile illness, altered mental status, focal neurological abnormalities, and seizures raises suspicion for this condition.​[13][48]​​​​ The main differential to distinguish is encephalopathy secondary to metabolic or toxic disturbances, which is more associated with systemic, generalised symptoms (such as myoclonus or asterixis) and typically lacks focal findings seen with encephalitis. Once a primary central nervous system disease is suspected, the diagnostic approach is geared towards determining the aetiology and appropriate therapy (i.e., finding the appropriate antiviral or antibacterial agents vs. immunotherapy).

Clinical evaluation

History may provide differentiation factors. Age (extremes of age), chronicity of disease, and immune status (HIV, organ transplantation, immunosuppressive medication) are important aspects to review. The time of year (summer), geographical location, travel history, and other exposure history (including occupational, vector, animal, ill contacts, water, sexual) are additional considerations.[26]​ Other factors to consider are a recent viral illness or vaccination, or a history of autoimmune disorders or malignancies.

General examination features such as skin rashes and/or bites, parotitis, or upper respiratory tract involvement may suggest a specific aetiological agent. Altered mental state, ranging from subtle alterations in level of arousal and behavioural abnormalities to coma, is typical. Lethargy, drowsiness, confusion, disorientation may be seen.[13]​ Focal neurological findings are common and include hemiparesis, ataxia, pyramidal signs (brisk tendon reflexes, extensor plantar responses), cranial nerve deficits, involuntary movements (myoclonus and tremors) may occur.

Cognitive behavioural issues frequently occur, and these include: altered personality, withdrawal, akinetic mutism, bizarre behaviour, memory problems, and an amnesic state. Seizures of all varieties occur; complex partial seizures are most commonly seen. Signs of meningoencephalitis (e.g., headache, photophobia, neck stiffness) are present in patients with meningeal inflammation. Symptoms and signs of a systemic illness, such as fever or upper respiratory or gastrointestinal symptoms, may precede or occur concurrently with the other presenting features. Other less common signs and symptoms include autonomic and hypothalamic disturbances, pericarditis/myocarditis, arthritis, retinitis, and acute flaccid paralysis, depending on the causative pathogen.[13]

Autoimmune encephalitis associated with surface antibodies targeting neuronal surface or synaptic antigens presents with a broad range of features, but well-recognised clinical syndromes do occur. Limbic encephalitis associated with leucine-rich glioma-inactivated 1 (LGI1) antibodies usually affects older patients, and is associated with faciobrachial dystonic seizures (e.g., rapid jerks of the face and/or ipsilateral arm and shoulder) before the development of frank seizures, behavioural changes, and cognitive impairment.[49][50]​ Limbic encephalitis associated with contactin-associated protein-like 2 (CASPR2) antibodies is associated with peripheral nervous system involvement, including neuromyotonia and neuropathic pain syndromes. Anti-N-methyl-D-aspartate receptor (Anti-NMDA-R) encephalitis is marked by rapid onset (less than three months) and primarily affects young patients, with a female predominance.[31] Its features include early abnormal behaviour and cognition, memory deficit, speech disorder, seizures, abnormal movements (e.g., orofacial, limb, or trunk dyskinesias), reduced consciousness level, and autonomic dysfunction or central hypoventilation.[51] Psychiatric symptoms including agitation, hallucinations, delusions, and catatonia are common presenting symptoms.[52]

Investigations required for all patients

A lumbar puncture is recommended for patients with suspected encephalitis, as long as there is no contraindication.[13]​ Contraindications to lumbar puncture include mass effect causing potential herniation, coagulopathy, concern for lumbar spine abscess, or open skin lesion at the site of entry. Usually three or four tubes of cerebrospinal fluid (CSF) are collected by lumbar puncture for diagnostic studies. The first tube has the highest potential for contamination with skin flora and should not be sent to the microbiology laboratory for direct smears, culture, or molecular studies.[26]​ A minimum of 0.5 to 1.0 mL of CSF should be sent immediately after collection to the microbiology laboratory in a sterile container for bacterial testing.[26] Larger volumes (5-10 mL) increase the sensitivity of culture and are required for optimal identification of mycobacteria, fungi, or malignancy.[26]​ ​CSF should not be refrigerated.[26]

Routine investigations in all patients should include:​[26][33]

  • Cerebrospinal fluid (CSF):

    • Opening pressure

    • Cell count

    • Protein

    • Glucose

    • Gram stain

    • Bacterial culture

    • Herpes simplex virus-1/2 polymerase chain reaction (PCR)

    • Enterovirus PCR

    • Measles, mumps (if unvaccinated)

    • Erythrovirus B19

    • Influenza (depending on the season)

    • Hold residual sample for further testing.

  • Serum:

    • FBC

    • Serum electrolytes/liver function test

    • Blood cultures (two sets)

    • Hold for further testing

  • Imaging:

    • Chest x-ray

    • Neuroimaging (MRI with contrast is the study of choice; however, CT may be more readily available and produce better quality imaging in an uncooperative patient)

  • Electroencephalogram may be indicated to investigate seizures, status epilepticus, and altered behaviour or consciousness.​[13][48]

Further investigations required for specific groups

Adults

  • CSF

    • Varicella zoster virus (VZV) PCR, VZV IgG/IgM

    • Cryptococcal antigen and/or India ink staining

    • Oligoclonal bands and IgG Index

    • Venereal Disease Research Laboratory (VDRL), fluorescent treponemal antibody absorption (FTA-ABS) test

    • West Nile virus testing (West Nile IgM)

  • Serum

    • HIV serology (consider RNA)

    • Non-treponemal testing (VDRL, rapid plasma reagin, ICE Syphilis recombinant antigen test), with treponemal testing for positive/equivocal results (FTA-ABS, enzyme immunoassay, or microhaemagglutination assay)

Throat

  • Antigen detection tests and PCR are performed on throat swabs to detect enterovirus, poliovirus, cytomegalovirus, adenovirus, mumps, measles, influenza, and parainfluenza[13]

Children

  • CSF

    • Rotavirus (if unvaccinated)

    Serum

    • Epstein-Barr virus (EBV) serology (viral-capsid antigen IgG and IgM and EBV nuclear antigen IgG)

    • Mycoplasma pneumoniae IgM and IgG

  • Nasopharyngeal/respiratory tract aspirate

    • Influenza/adenovirus PCR

Immunosuppressed patients

  • CSF

    • Cytomegalovirus PCR

    • Epstein-Barr virus PCR

    • Human herpesvirus-6/7 PCR

    • HIV PCR

    • JC virus PCR

  • Toxoplasma gondii serology and/or PCR

  • Mycobacterium tuberculosis testing (TB PCR and AFB culture)

  • Fungal testing

Other tests to consider

  • CSF viral-specific IgG/IgM antibodies and serum PCR (if a viral aetiology is suspected).[26]​​

  • Serum 16S ribosomal RNA gene (rRNA) sequencing for bacteria, acid-fast bacilli, fungus.

  • Serum for LGI1 or CASPR2 antibodies and NMDA receptor antibodies. Voltage-gated potassium channel positivity, in the absence of LGI1 or CASPR2 antibodies, may not be a true marker of disease.[1][53]

  • CSF and serum paraneoplastic antibody testing if there is a clinical suspicion.[54]​ Up to 14% of patients with anti-NMDA-R encephalitis have antibodies in the CSF, but not serum. The clinical course seems to correlate better with CSF antibodies than serum antibodies.[55] 

  • CSF analysis for NMDA receptor antibodies may be useful in patients with relapsing symptoms after herpes simplex encephalitis (HSE), if clinical suspicion for autoimmune encephalitis supports this. In 20% of patients with HSE, antibodies may be triggered against the NMDA receptor.[56][57][58] These patients may respond to immunotherapy.[59]

  • Stool culture (obtained more frequently in children when gastrointestinal symptoms precede encephalitis, or when enterovirus is suspected).

  • Sputum culture (for Mycoplasma, tuberculosis [acid-fast stain], and fungal infections).

  • Sputum PCR (in children, for Mycoplasma pneumoniae and enterovirus).

  • Arbovirus testing: if an arbovirus infection is suspected, specific guidance on testing, such as that outlined by the Centers for Disease Control and Prevention, should be sought. CDC: Division of vector-borne diseases (DVBD) Opens in new window

  • CSF real-time quaking-induced conversion assay (RT-QuIC) if prion disease is suspected. See Prion disease.

  • Brain biopsy: although it is the most specific diagnostic test, brain biopsy is not performed routinely due to its invasive nature, lack of widespread availability, and because DNA amplification techniques are now widely available to identify virological causes. Where diagnosis is uncertain and prognosis remains poor, brain biopsy may be essential. Important for diagnosis and treatment, the brain biopsy may also provide an aetiological clue.[60]​ UK guidelines recommend to consider stereotactic biopsy in patients with suspected encephalitis in whom no diagnosis has been made after the first week, especially if there are focal abnormalities on imaging and no clinical improvement.[13]

  • Whole-body CT and whole-body PET scans (performed if an underlying cancer is suspected).

  • Abdominal/pelvic ultrasound may be useful if anti-NMDA-R encephalitis is suspected; up to 58% of affected young female patients have an ovarian teratoma.[52]

  • If malignancy screening is negative, repeating the assessment 3 to 6 months later should be considered in cases where the autoantibody found is strongly associated with malignancy.[1][52]

Additional tests (typically restricted to academic centres)

Magnetic resonance spectroscopy

  • Advanced imaging techniques provide metabolic data that can be used to clarify abnormal brain areas and identify the aetiology. They are obtained in patients with a clinical diagnosis of encephalitis but in whom aetiology is unknown, or if diagnosis of encephalitis is suspected but cannot be differentiated from brain tumours (e.g., by first-line tests).

Next-generation sequencing of CSF

  • As opposed to directed PCR amplification of a selected number of targets, technology is now available to detect organisms in an unbiased manner. Genetic material is isolated from organisms, and select DNA and RNA sequences can be amplified with universal primers. The sequence is then compared with publicly available sequences to identify the organism. Furthermore, unbiased next-generation sequencing will provide a powerful tool to potentially identify new and/or potentially treatable infectious agents.

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