Encephalitis

Encephalitis is inflammation of the brain parenchyma, caused by infection (mainly viral) or an antibody-mediated autoimmune response (autoimmune encephalitis). There are around 2,500 cases of encephalitis are reported annually in England. It has a bimodal age distribution with the highest incidence observed in individuals <1 year old and those >65 years old.

Incidence of autoimmune/immune-mediated encephalitis is increasing (likely due to the increased availability of diagnostic testing and increased awareness doctors).

Pathophysiology

Encephalitis can be caused by infection (viruses and bacteria, and less commonly fungi, parasites and protozoa) or by autoimmune mechanisms.

In viral encephalitis, the virus initially gains entry and replicates in local tissue, such as the GI tract, skin, urogenital system, or respiratory system. Subsequent dissemination to the CNS occurs haematogenously or via retrograde axonal transport (as with the herpes virus, the rabies virus, or certain prion proteins). This then leads to infection and inflammation of brain parenchyma.

With regard to autoimmune encephalitis,  autoantibodies target the neurones expressing the antigens internally or externally → neuronal damage → encephalitis. Given the immune-mediated pathophysiology of autoimmune encephalitis, these conditions are responsive to immunosuppressive therapy.

Let’s discuss some of the causative agents:

Other, rarer, pathogens include:

• Fungal infections:
• Cryptococcus → cryptococcal encephalitis
• Parasitic infections:
• Naegleria fowleri

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Autoimmune encephalitis

Autoimmune encephalitis remains rare and accounts for approximately 1/3rd of cases with identified aetiology.

Autoimmune encephalitis can be associated with:

1. Intracellular neuronal antigens:

An immune response is triggered as a result of paraneoplastic syndromes associated with certain cancers. Autoantibodies are made against these neuronal-specific antigens. Cytotoxic T-cells are activated as well leading to neuronal damage.

The most notable auto-antibodies are:

1. Anti-Hu - associated small cell lung cancer.
2. Anti-Yo - ovarian and breast cancers.
3. Anti-Tr - Hodgkin lymphoma.

2. Surface neuronal antigens:

These auto-antibodies are against antigens on the surface of neurons. They include:

1. ⭐️ Anti-NMDAR antibodies - the most common cause of autoimmune encephalitis.
2. VGKC-complex antibodies → causing limbic encephalitis
3. Anti-AMPA receptor antibodies - also causing limbic encephalitis

🔢 Classification

We can classify encephalitis by either its anatomy or aetiology:

😷 Presentation

The symptoms usually start with the common symptoms of a viral infection:

• Fever
• Headache
• Myalgia
• Fatigue
• Nausea and vomiting

As the infection starts to attack the brain, the following symptoms can occur (quite rapidly over a few hours, or sometimes they can develop over a few days):

🔍 Investigations

💡 Subacute onset of psychiatric symptoms (behavioural changes) in combination with seizures and/or focal neurological deficits should raise clinical suspicion for encephalitis, same for individuals with acute headaches + signs of meningism.

The standard work-up for encephalitis parallels that for meningitis and typically includes:

• Routine bloods
• Blood cultures and viral PCR
• Lumbar puncture, CSF analysis with viral PCR
• CT/MRI head - can provide valuable insight. For instance, HSV typically affects the temporal lobes and bilateral multifocal haemorrhage is typical.
• EEG - may also be useful and can help determine the location in early stages. It shows diffuse slowing with periodic discharges. It can prove more useful than a CT in the first week.
• Serological studies - when there is suspicion of autoimmune encephalitis. CSF and blood samples may show anti-Hu, anti-NMDAR, etc

🧰 Management