Encephalitis

Encephalitis is a broad term that refers to inflammation of the brain parenchyma.

There are many different aetiologies of encephalitis which characteristically presents with abnormal brain function. This is suggested by altered mental status, motor/sensory deficits, personality change, or even speech alteration.

Encephalitis may be due to a wide variety of pathologies including viral, post-infective, bacterial, autoimmune, or paraneoplastic. It is therefore important to keep an open mind. The most important infective aetiology to exclude is herpes simplex virus (HSV) encephalitis that is usually fatal without treatment.

The true incidence of encephalitis is unknown because many cases are unreported or unrecognised.

The epidemiology of encephalitis depends on the underlying cause. Infectious encephalitis has been estimated at 11.6 cases per 100,000 people with 8.3 cases per 100,000 people due to a viral aetiology. Autoimmune encephalitis is being increasingly recognised with an estimated prevalence of 13.7 per 100,000, which may be higher in certain populations (Dubey, 2018).

Both children and the elderly are more likely to have severe infectious encephalitis, with HSV being particularly devastating. Some causes of encephalitis are more likely to occur in children such as post-infectious encephalitis, also known as acute disseminated encephalomyelitis (ADEM), which has a peak onset between 3-7 years old.

Encephalitis is commonly caused by an infection, although there are a broad range of aetiologies.

There are a large number of causes of encephalitis that can be broadly divided into infectious and non-infectious causes.

• Infectious: secondary to direct infection by a microorganism or virus
• Non-infectious: usually secondary to an immune-mediated mechanism related to cancer, autoimmunity, or following an infection

Infectious

Viral pathogens are commonly implicated in encephalitis. HSV is a common cause of sporadic encephalitis that can be targeted with treatment. Other viral pathogens can include Arboviruses (e.g. West Nile virus), varicella-zoster virus, Epstein-Barr virus, and human immunodeficiency virus (HIV).

Other infectious microorganisms can include bacteria (e.g. Mycoplasma, Tuberculosis, Rickettsial infections), fungi (e.g. Histoplasmosis), and parasites (e.g. Echinococcus). With these types of infections, there may be concurrent inflammation of the meninges leading to meningoencephalitis.

Non-infectious

The non-infectious causes of encephalitis include a broad range of aetiologies with complex underlying mechanisms. Three of the most pertinent causes include:

• Paraneoplastic encephalitis: abnormal immune response against different parts of the brain in the setting of cancer. Thought to be due to shared antigens expressed exclusively by the tumour and nervous system.
• Post-infectious encephalitis: development of encephalopathy (and other neurological signs) following an infection or vaccination. Due to shared antigens between infection and central nervous tissue. Causes generation of autoreactive T cells that react to antigens in the central nervous system leading to inflammation.
• Autoimmune encephalitis: an increasingly recognised condition whereby autoantibodies (antibodies that react against normal tissue) develop against neuronal cell surface/synaptic proteins that lead to characteristic clinical syndromes depending on the autoantibody present.

Herpes simplex virus (HSV) is one of the human herpes viruses that can cause a severe encephalitis.

HSV encephalitis can occur in all ages and may be due to either HSV type 1 or HSV type 2. HSV1 is most commonly seen outside of the neonatal period and causes a clinical syndrome characterised by rapid onset of fever, headache, altered mental status, new-onset seizures, and/or neurological deficits (e.g. dysphasia, hemiparesis). Behavioural changes may also be seen in the condition.

HSV can cause infection of the central nervous system (CNS) by direct invasion via the trigeminal nerve or olfactory tract following primary oropharyngeal infection. Alternatively, invasion into the CNS may occur due to reactivation of the virus that is able to lay dormant within neuronal ganglia after a primary infection that may have been subclinical.

Within the CNS, damage to the brain is thought to be mediated both directly by the virus and indirectly by the immune response to the pathogen. Damage is classically located within the temporal lobes with clinical features reflecting damage to this area of the brain.

Post-infectious encephalitis is an uncommon immune-mediated disorder that is usually seen in children.

Post-infectious encephalitis, also known as acute disseminated encephalomyelitis (ADEM), is a demyelinating condition affecting the central nervous system. Demyelination refers to the destruction/loss of myelin that surrounds nerve axons and helps increase the rate of electrical impulses.

Post-infectious encephalitis results in the development of encephalopathy (e.g. confusion, altered mental status, irritability) and other neurological signs (e.g. hemiparesis, cranial nerve palsy, myelopathy) around 4-13 days following an infection or vaccination.

The condition is likely due to the development of antibodies that react against key components of myelin due to its shared structure with antigens found in microorganisms or vaccinations. The condition is usually seen in children and up to 75% of cases have a clear preceding infection or febrile illness.

Autoimmune encephalitis refers to a group of immune-mediated inflammatory disorders of the brain tissue.

In autoimmune encephalitis, an abnormal antibody develops against a specific antigen within the central nervous system such as a synaptic protein. This autoantibody then initiates an immune response that leads to the clinical presentation of encephalitis. There are a number of autoantibodies that may develop that are each associated with a specific clinical syndrome depending on the area the autoantibody attacks.

In NMDA-encephalitis (i.e. autoimmune encephalitis secondary to an autoantibody that targets the NMDA receptor) there is a classic set of symptoms that include (but not limited to) psychiatric manifestations (e.g. agitation, bizarre behaviour, hallucinations, delusions), memory deficits, sleep deficits, seizures, altered mental status and autonomic instability (e.g. hyperthermia, fluctuations in blood pressure).

A paraneoplastic syndrome refers to the non-metastatic manifestations of malignancy.

A paraneoplastic syndrome may develop in a patient with a known malignancy or it may develop before a diagnosis of cancer has been made.

A variety of neurological paraneoplastic syndromes may develop in the presence of malignancy and this is thought to be due to the immune system reacting to antigens expressed exclusively on the tumour and nervous system. The immune system detects these antigens as foreign on the tumour and initiates an immune response against the same antigen in nervous tissue. How exactly this occurs is still unclear.

Paraneoplastic encephalitis may manifest as a range of specific clinical syndromes and may be associated with an underlying autoantibody. Specific cancers have been linked to specific autoantibodies.

• Limbic encephalitis: inflammation localised to areas of the limbic system within the brain that are important in emotion, behaviour, and memory.
• Brainstem encephalitis: inflammation affecting the brainstem. Typical features include gaze palsies, dysphagia, dysarthria, central hypoventilation and vertigo.
• Antibody-related syndromes: a range of neurological symptoms in association with a specific autoantibody (e.g. anti-Hu)

These presentations may be restricted to a specific area (e.g. brainstem) or form part of a wider neurological syndrome involving multiple areas of the central nervous system (e.g. limbic system, temporal lobes, spinal cord).

The classic presentation of acute encephalitis is fever, headache, altered mental status and/or focal neurological deficits.

The presentation of encephalitis is highly variable depending on the underlying cause and the area of the brain that has been affected. A classic triad of new-onset fever, headache, and altered mental status is typical.

Possible features

• Fever
• Headache
• Seizures
• Altered mental status: confusion, agitation, irritability, reduced consciousness
• Behavioural changes: psychotic features (e.g. delusions, hallucinations) and affective features (e.g. anxiety, depression)
• Brainstem dysfunction: dysphagia (abnormal swallowing), dysarthria (abnormal articulation), gaze palsies
• Memory problems: cognitive impairment, memory deficits
• Focal neurological deficits: hemiparesis (unilateral weakness), cranial nerve neuropathies, cerebellar ataxia

Encephalitis versus meningitis

It can be difficult to differentiate between meningitis and encephalitis.

Meningitis refers to inflammation of the meninges and typically presents with headache, photophobia, and neck stiffness. These three features are known as meningism and invariably present with fever.

Brain function should be preserved in meningitis. However, in some cases patients may have features of both meningitis and encephalitis that is known as meningoencephalitis. For more information see our notes on Meningitis.

Neuroimaging, electroencephalography (EEG) and cerebrospinal fluid (CSF) analysis are important in the work-up of encephalitis.

Encephalitis is a broad term with many aetiologies. A formal diagnosis depends on the exact cause. For example, HSV encephalitis requires identification of the virus within the CSF whereas autoimmune encephalitis requires the appropriate clinical context with supportive investigations such as identification of a specific autoantibody.

We discuss some of the broad investigations that are used in the work-up for all cases of encephalitis.

Basic investigations

As patients may present with a variety of symptoms, investigations are important to exclude alternative diagnoses (e.g. urinary tract infection, space-occupying lesion) before moving on to more specialist tests. For example, it is critical to exclude infection in patients presenting with fever. Typical basic tests may include:

• Bedside: observations, urinalysis, ECG, sputum cultures
• Bloods: full blood count, urea & electrolytes, bone profile, liver function tests, CRP, blood cultures, coagulation
• Imaging: chest x-ray, CT head

Neuroimaging

Imaging of the brain is useful to exclude an alternative diagnosis such as cerebrovascular event (i.e. stroke) or space-occupying lesion (e.g. tumour). A CT may be completed initially because it is relatively easy to access and produces a quick result. However, MRI can provide more detail and some features on MRI may be supportive of encephalitis.

EEG

An electroencephalogram is a non-invasive method of assessing and recording the electrical activity of the brain. In a patient with altered mental status of unknown cause is important to exclude non-convulsive status epilepticus. This refers to ongoing seizure activity without obvious tonic-clonic activity. Certain electrical activity on an EEG may be suggestive of encephalitis.

CSF analysis

Performing a lumbar puncture and taking a sample of cerebrospinal fluid is often completed as part of the work-up for encephalitis. This is particularly important for infective causes when analysis of the CSF can directly identify the causative pathogen (e.g. HSV).

A variety of tests may be performed on CSF samples:

• CSF protein: a rise in the protein content is typical with encephalitis. May be normal.
• CSF viral PCR: involves amplification of viral genetic material within the CSF. Can be used to confirm the diagnosis of HSV encephalitis or other viral pathogens that can be tested.
• CSF microscopy, culture and sensitivity: provides a white cell count that may be elevated in encephalitis. HSV1 and autoimmune encephalitis typically cause an elevation in lymphocytes. Microscopy and culture are completed to exclude a bacterial pathogen.
• CSF glucose: typically normal in viral encephalitis
• CSF serology: antibody tests can be performed on the CSF. Particularly important for paraneoplastic and autoimmune aetiologies.

Serological testing

This involves performing a blood test and checking the serum for the presence of antibodies associated with paraneoplastic or autoimmune encephalitis.

The principal treatment of HSV encephalitis is intravenous aciclovir.

The management of encephalitis should be directed towards the underlying cause. Antimicrobials or antivirals should be directed towards infectious causes. Immunosuppressive therapies (e.g. steroids) can be used to treat paraneoplastic, autoimmune, and post-infective causes but it is essential an infection is excluded before these are initiated.

Here, we specifically discuss the treatment of HSV encephalitis.

HSV encephalitis

The primary antiviral treatment available for HSV encephalitis is aciclovir that works by competitively inhibiting the viral DNA polymerase, which prevents replication. Given that HSV encephalitis is associated with significant morbidity and mortality, intravenous aciclovir should be started empirically in anyone with suspected encephalitis.

The HSV PCR result from the CSF can then be used to help exclude the diagnosis and enable aciclovir to be discontinued. Occasionally, patients with a high probability of HSV encephalitis may need to continue treatment even with a negative PCR, although the likelihood reduces to 5%. If the HSV PCR is positive, or the disease is highly suspected, a full course of treatment is given over 14-21 days.

Untreated, HSV encephalitis is associated with a high mortality.

The prognosis of encephalitis is specific to the underlying condition.

The mortality associated with HSV encephalitis can be as high as 30% even in patients who receive appropriate treatment. Furthermore, residual neurological deficits may remain such as amnesia, impaired new learning, or behavioral abnormalities.

Interestingly, HSV encephalitis has been linked with the development of autoimmune encephalitis due to the formation of NMDA receptor antibodies. Therefore, patients who develop recurrent neurological symptoms after treatment for HSV encephalitis should be investigated for a possible autoimmune cause.

Last updated: May 2022