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Does managing encephalitis makes your head hurt?!

29/5/2015

 
Picture
A 79 year old lady, who had been previously fit and well, presented with fever, acute confusion and aggression after a seizure. Her family said she had been her normal happy self the day before but she had been complaining of a headache. The doctors admitting her made a clinical diagnosis of encephalitis. A CT scan of the patients head was done to rule out raised intracranial pressure, and showed no abnormality. Cerebrospinal fluid (CSF) from a lumbar puncture showed raised lymphocytes, high protein and normal glucose compared to serum glucose.  

What are the clinical features of encephalitis?
Encephalitis is acute inflammation of the brain. It can present with a mixture of symptoms and signs including:
  • Fever
  • Headache
  • Neck stiffness
  • Decreased conscious level
  • Confusion
  • Seizures
  • Focal neurological signs
  • Personality change, hallucinations, aphasia (with HSV)
  • Ophthalmic shingles (with VZV)
  • Rash (with Enterovirus and Measles Virus)

The patient was started on empirical treatment with IV Amoxicillin, IV Cefotaxime and IV Aciclovir. The following day she had not improved, so the team rang the Microbiologist with a list of extra tests they wanted performing on the CSF sample. The problem is doctors take very little CSF (even though they send 4 tubes) and often have an extensive list of tests they want to be performed. The thing is each tube contains only around 4 drops, equivalent to 0.2ml...that just doesn’t go very far, especially if one tube goes to biochemistry for protein and another to cytology to look for abnormal cells and immune mediated causes. Microbiology is greedy, we take two tubes but this is still only 8 drops (0.4mls).

What causes encephalitis?
There are many causes of encephalitis which can be broadly grouped into:
  1. Infectious - 42% of cases (investigated by microbiology)
  2. Immune mediated – 21% of cases (investigated by cytology and blood sciences)
  3. Unknown – 37% of cases (where no cause is ever found)
 
So what do we do with our 8 drops to ensure we use it as efficiently as possible?
  • 1 drop from each bottle for cell count (to compare the number or red blood cells in each bottle to identify patients with a subarachnoid haemorrhage and to give a total white blood cell count)
  • 1 drop for Gram film (to look for bacteria)
  • 1 drop for Culture (to grow any bacteria such as Streptococcus pneumoniae, Neisseria meningitidis and Listeria monocytogenes)

This leaves only 4 drops or 0.2ml left to do any other tests! What is done with these precious drops?

Up to 90% of infectious encephalitis is caused by just 3 viruses HSV, VZV and Enterovirus. Identifying these infectious causes is important as they have specific treatments (e.g. IV Aciclovir for HSV and VZV). So normally virology is given the remaining 4 drops for PCR.

So now there are no more drops for that long list of exotic and rare causes that the team have phoned the Microbiologist about and the results from any further CSF sample taken may be altered as the patient is now on antibiotics. 

There are some rare causes of infectious encephalitis in the UK, which are more commonly related to underlying immunodeficiency or incomplete vaccinations, including:
  • Mycobacterium tuberculosis (if unvaccinated)
  • Mumps Virus (if unvaccinated)
  • Measles Virus (if unvaccinated)
  • Influenza A & B
  • Adenovirus
  • Parechovirus
  • Cytomegalovirus
  • Epstein-Barr Virus
  • Human Herpes Virus types 6 & 7
  • JC Virus
  • Lymphocytic choriomeningitis Virus
  • Human Immunodeficiency Virus

It is important to remember that 1 in 5 encephalitis presentations are non-infectious; instead they are immune-mediated so your differential diagnosis should also include:
  • Acute disseminated encephalomyelitis (ADEM)
  • NMDA (N-methyl-D-aspartate) receptor antibodies
  • VGKC (voltage-gated potassium channel) antibodies
  • Vasculitis
  • Multiple sclerosis (MS)
  • Paraneoplastic

But hold on! Before you try excluding all these possible causes think about the probability of these diagnoses first. Having said this, it is still important to try and identify the cause of the patient’s encephalitis because immunomodulation may be beneficial in immune-mediated encephalitis (e.g. steroids, intravenous immunoglobulin, plasma exchange or removal of underlying tumour). It is also important that investigation and treatment of immune-mediated causes is not unduly delayed by attempts to diagnose a possible infectious cause.

I think my patient may have encephalitis, what investigations should I do?
Any patient who is suspected as having encephalitis based on their clinical presentation should be managed as a medical emergency. Whilst it is important to investigate these patients for an underlying cause it is essential not to delay antibiotic treatment, as delays longer than 6 hours can result in long-term neurological damage.

All patients with suspected encephalitis should have a lumbar puncture as soon as it is safe to do so. As much CSF as possible (within reason!) should be sent to the laboratory and a peripheral blood glucose should be taken at the same time to compare to CSF glucose (see previous blog). A suggested investigation strategy is shown in the flow chart below.
Encephalitis Investigations Flowchart
Click for larger image
It is important to remember that lymphocytic CSF with a high protein occurs in immune-mediated encephalitis as well as infectious encephalitis, so don’t narrow down the differential diagnosis without further investigation for viruses by PCR.

Magnetic Resonance Imaging (MRI) is abnormal in 90% of patients on admission, and is very helpful in the diagnosis of encephalitis, if available. The principal abnormalities include changes in the cingulate gyrus and medial temporal lobe.

If no common infectious cause can be found, it is then worth testing for VGKC and NMDA antibodies in both CSF and serum. All patients with immune-mediated encephalitis should be investigated for an underlying tumour. Up to 10% of VGKC antibody encephalitis patients have a thymoma or small cell lung cancer, and up to 50% of NMDA antibody encephalitis patients have teratomas.

Will my patient recover or should I warn them about potential long-term effects?
Despite appropriate treatment up to 80% of patients have ongoing neurological symptoms, such as headaches and weakness, after HSV encephalitis. These are more common in the elderly and in those in whom treatment with IV Aciclovir is delayed.

The patient above was diagnosed by PCR as having HSV encephalitis. Her Amoxicillin and Cefotaxime were stopped and the IV Aciclovir was continued for 3 weeks without a repeat lumbar puncture as the patient refused to have this done. Although her fever and confusion resolved she did continue to get headaches.

Acute encephalitis can be difficult to manage; the main reason for this difficulty is the large number of potential causes and the small amount of CSF available for investigations. Look for common causes first before considering the rarer ones, and remember to identify and treat any non-infectious causes too. 

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    Blog Author:

    David Garner
    Consultant Microbiologist
    Surrey, UK

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