Intracranial Infections

• Background – clarification of terms and a brief overview
• Main session – 3x 10-15 minute cases covering 3 different intracranial cases
• Advance session – 1x 10-15 minute case on more complex elements of case 1
• Quix – 5 minutes
• Summary – 5 minutes

LP interpretation – https://www.rch.org.au/clinicalguide/guideline_index/csf/
Use this to refresh yourself on LP interpretation (1 min)

Common organisms – https://www.ebmedicine.net/topics/infectious-disease/pediatric-bacterial-meningitis look at Table 1 for a summary of common bacterial causes of meningitis in different age groups. (1 min)

UK clinical pathway for non-neonatal paediatric meningitis and interactive e-learning
module https://bsac.org.uk/paediatricpathways/meningitis.php (2 mins)

Neonatal HSV – https://em3.org.uk/s/Editable-version-of-Neonatal-Herpes-Simplex-Virus-HSV-Infection-by-EM3-A1-poster.pdf (2-3 mins)

Complications of meningitis – https://cks.nice.org.uk/topics/meningitis-bacterial-meningitis-meningococcal-disease/background-information/complications/ (1 min)

For reference: NICE guideline on meningitis in children – March 2024
https://www.nice.org.uk/guidance/ng240

CNS infections encompass a range of clinical syndromes and have a variety
of aetiologies. They can be broadly categorised as:

• Meningitis
• Encephalitis
• Intracranial infections (extradural/epidural, subdural and intraparenchymal)

Often their signs and symptoms are vague and non-specific, thus requiring a
degree of clinical suspicion to investigate further. In most cases, a headache
accompanied with a fever should lead one to think about the presence of a CNS
infection. When there is a fever alongside focal neurology one must consider
whether there is a space-occupying lesion with an infective origin, i.e., an abscess.
Complicating matters further, a fever may not always be present.

All CNS infections can lead to significant lifelong complications and can also be
fatal if untreated or detected late. The nature of complications depends on the
site of infection and inflammation, coupled with host and pathogen factors such
as whether there may be an underlying immunodeficiency or a particular strain
of virus or bacteria. For example, streptococcal infections can be particularly
purulent and have a higher tendency for auditory impairment and the development
of hydrocephalus. In children, post-infective damage can result in cerebral palsy
and developmental delay.

Meningitis is inflammation of the meninges, and encephalitis is infection of
the brain tissue. Viral meningitis is the most common cause and in most cases
is self-limiting. However particular viruses in particular cohorts can be more
concerning. For example, enterovirus infections in neonates are usually more
critical than those in older children. HSV encephalitis is concerning in all ages.
Bacterial meningitis requires antibiotic treatment. Because we cannot clinically
distinguish between bacterial and non-bacterial causes of meningitis, if meningitis
is suspected, antibiotic therapy should be empirically commenced to cover for
potential bacterial infection. Fungal CNS infections can occur too, but are not
commonly seen in immunocompetent hosts.

The epidemiology of bacterial meningitis has dramatically changed in the last
few decades with thanks to the immunisation programme. Historically very common
causes of meningitis included Neisseria meningitidis (‘meningococcus’), Streptococcus pneumoniae (‘pneumococcus’) and Haemophilius influenzae. Cases of these have now fallen as infants have been vaccinated against multiple strains of
these bacteria. Meningitis remains a public health concern, and is a notifiable
condition to help trace contacts who could benefit from chemoprophylaxis.

Diagnosis can be challenging. The gold standard for detecting meningitis and
encephalitis is from CSF samples provided there are no signs of raised intracranial
pressure, and imaging is of limited utility. Brain abscesses, however, can be diagnosed following cranial imaging, with microbiological samples being obtained following neurosurgical intervention.

6 year old boy is brought to emergency department by his parents who are worried he has become increasingly withdrawn and lethargic. He has had a fever for 3 days, accompanied with reduced appetite. His parents have been giving antipyretics which brings the fever down but it does not change his withdrawn disposition as it usually does when he’s febrile. This worries them. On examination his cardio-respiratory, abdominal and ENT examinations are normal however he does appear drowsy and you note he flex his neck. His neurological examination is otherwise normal. He is able to ambulate with a lot of encouragement from his parents. There are no rashes or lymphadenopathy. He is previously fit and well and has no medical history.

What are your differentials?

What investigations would you perform?

What is would be your empirical treatment and its duration?

Your differential here should include a CNS infection, principally meningitis.
However, the source behind his fevers is not entirely clear and his symptoms are
overall non-specific. Accordingly, one should also consider less obvious sources of
infection, which could include an uncomplicated sinusitis. With common things
being common, do not forget to that a case like this could be a viral infection
such as influenza. One should also consider whether he has become septic, as
this will require rapid escalation and stabilisation to prevent further deterioration.

Investigations:

• Bedside: Blood gas, urinalysis, respiratory viral swab (PCR)
• Bloods: FBC, CRP, LFT, U&Es, Culture, and glucose (if not available on blood gas)
• CSF: glucose, protein, microscopy/culture, and virology (PCRs including enterovirus and HSV)
• Imaging: chest / abdominal radiographs are not currently indicated as there’s
  no suspicion of a source of infection here that an x-ray would reveal. Cranial imaging may be indicated if there were clinical concerns about raised intracranial pressure. This could include focal neurological findings on examination, seizures, vomiting or suggestions of postural headaches. Importantly, the NICE guideline advises using clinical assessment, as opposed to imaging, to decide whether to perform a lumbar puncture or not.

The critical investigation here will be a lumbar puncture. It is important this is
done as soon as possible, ideally before the administration of antibiotics.
The contraindications for performing a lumbar puncture are:

• Presence of purpura
• Infection at the lumbar puncture site
• New focal neurological findings
• Glasgow Coma Scale score ≤ 9 or a fall in the level of consciousness
• Abnormal pupillary reflexes

Empirical Treatment:

Given the suspicion of meningitis, antibiotic selection would need to be one with
good CNS penetration and cover for the commonest bacterial causes of meningitis
in this population. In most cases in the UK, a third-generation cephalosporin may
be used such as ceftriaxone of cefotaxime. However, it is important to consult
local antimicrobial guidelines which also take into account your local population’s
pathogen profiles and sensitivity. Cefotaxime or ceftriaxone also have a broad
enough spectrum to be used as empirical treatment to cover for sepsis secondary
to bacterial infections.

Clinically, this child is not floridly septic nor is unstable. With this in mind and given
the range of differentials, it would be reasonable to initially observe, commence
supportive measures and send off initial investigations (which could include a
lumbar puncture) and initially hold off antibiotics. If he doesn’t clinically improve
and concerns persist, antibiotics can be commenced. This would fall in line with
the latest international and national guidelines on sepsis, where clinicians have
3 hours within which to evaluate stable patients and commence antibiotics
(see below).

Figure 1 From the Society of Critical Care Medicine and the European Society
of Intensive Care Medicine. Endorsed by Pediatric Infectious Diseases Society
(PIDS) and UK Sepsis Trust.

Continuing with the previous case, now consider the following information…

Gram staining from the CSF sample shows gram negative diplococci which
subsequently is confirmed to be Neisseria meningitidis.

Next steps: Neisseria meningitidis is a causative organism for meningitis in
children. Importantly however is the fact that children are vaccinated against
multiple strains in their routine immunisation schedules. It is important to go over
their original history and confirm with the parents whether the child is up-to-date
with their immunisations. There may also need to be considerations for an
immunodeficiency work-up once the child is well, especially with a focus on complement dysfunction or impaired vaccine response (if vaccinated). To this end, it is also important to confirm the parents aren’t consanguineous if it has not been established already.

Meningococcal disease is a notifiable condition in the UK and the treating team
has a legal duty to notify the public health team to aid contact tracing and
chemoprophylaxis. It is worth establishing who lives in the household with the
child, what school they attend and any other places they regularly frequent to
aid the public health team.

Finally, with confirmation of bacterial meningitis, the patient should have an
audiology follow-up to check for sensorineural hearing loss and have paediatric
follow-up to monitor their ongoing development.

CSF Analyses:

CSF culture is the gold standard for diagnosing bacterial meningitis. It can not
only identify bacteria, but can also provide sensitivity profiles. It is for this reason
CSF sampling is ideally needed before administration of antibiotics to maximise
the likelihood of a culture diagnosis. Evidence from looking at paediatric CSF
yields indicate that CSF can be sterilised within 2 hours of antibiotic administration
with meningococcal disease and within 10 hours with streptococcal disease. CSF
cultures are usually negative if sampling is done after 24 hours of antibiotic therapy.

Many hospitals now have commercial targeted PCR panels which can rapidly
(within 1-2 hours) produce results while cultures are awaited. These detect a
range of bacteria and viruses. However, one should be aware of false positive
and false negative profiles of these panels. Where possible, teams should
ideally confirm positive results by performing focused PCRs on the CSF sample.
It is important to ensure that enough CSF has been sampled to allow for these
additional tests to take place.

Alternatively, there are non-targeted 16S ribosomal PCR tests where traces of
bacterial ribosomal nucleic acid are detected and amplified in from the CSF.
This can help identify whether particular bacteria were present in the CSF.

In the UK, 16S PCR testing is currently only performed in a few specialist laboratories and requires samples to be sent away – this is usually following discussion with microbiology / paediatric infectious diseases team in cases where clinical concerns about meningitis exist while having culture-negative CSF. It is usually considered in complex or severe cases of meningitis where identifying a pathogen may help guide treatment duration, or to help predict or explain sequalae.

One advantage PCR offers is that it does not rely on live bacteria for detection,
whereas a culture does. This means a LP can still be useful diagnostically despite
having started therapy. While helpful in helping establishing a diagnosis, PCRs
are generally unable to provide antibiotic sensitivities as opposed to cultures
can. Conventional focused quantitative PCRs can provide cycle threshold values
(CT values) which can indicate the bacterial load present in the CSF, however
the targeted panels only produce a binary ‘detected’ or ‘not detected’ result.

A term baby was discharged home on day 2 of life following with an uneventful antenatal course and vaginal delivery. They were brought to the emergency department on day 6 of life with significantly increased work of breathing and were commenced empirically on cefotaxime. Bloods show CRP 9 mg/L, normal U&Es, and an ALT of 85 IU/L. Blood culture and CSF sampling is undertaken. They get progressively worse and are intubated and transferred to the regional paediatric intensive care unit.

Repeat bloods the next day show a CRP of 15 and other values are otherwise
unchanged. 24 hours later, little clinical progress is made and second-line antibiotics of tazocin and vancomycin are commenced . Later that day the CSF results return and show HSV-1 is detected.

What treatment should be started and for what duration?

When would you stop the acute treatment?

What are the next steps regarding longer-term management this diagnosis?

This is a case of neonatal herpes simplex CNS infection. It typically doesn’t declare
itself in the first few days of life, and usually presents between day 5 and 30 of
life. Importantly, many cases have no documented history of maternal lesions or
known maternal history. Thus the absence of maternal history of HSV infection
should not be a reason to downgrade vigilance. On a similar note, a neonate can
present with isolated HSV CNS infection the absence of skin and mucosal
lesions is not a reason to dismiss HSV CNS infection as a differential. HSV infection
should always be considered early in the presentation of a ‘flat’ (lethargic) neonate.

In this case, empirical treatment for HSV should have been considered when the
baby first presented to hospital. The current UK guidance to commence aciclovir
in neonates is as follows:

• ALT or AST >2x upper limit of normal
• Coagulopathy
• Presence of vesicles
• Seizure
• CSF pleocytosis
• Suspected meningitis/encephalitis
• Recent maternal herpes simplex disease OR postnatal contact with herpes
  simplex virus

In addition, it is recommended to strongly consider aciclovir if an unwell infant
presents at day 3-14 of life even if none of the above apply, should any of the following are present:

• No other obvious cause for their illness
• They are clinically not improving
• There was an unexplained maternal febrile illness in the peripartum window

Testing should also include swabs of the skin, eyes, mouth and rectal swabs help
diagnose neonatal HSV infection.

Initial treatment and duration

Initial treatment consists of IV aciclovir, which should be a 21 day course at minimum for neonatal HSV CNS disease. There is no role for oral treatment in the acute treatment. There’s no evidence of steroids being beneficial. Neonatal HSV CNS disease can be devastating. HSV can cause cerebral atrophy and particularly
affects the temporal lobes. Untreated neonatal CNS HSV disease has a mortality
rate of 50%. However the introduction of a high-dose, 21 day antiviral regimen
has led this to fall to 4%.

Given the length of treatment, it is worth siting a PICC line for the patient.

When to stop treatment

In terms of when to stop IV aciclovir treatment, some debate exists but a commonly
used approach is to repeat the LP and stop aciclovir after 21 days if the CSF HSV
PCR is negative. These decisions can be made following discussions with a paediatric infectious diseases team.

Management beyond the acute episode

For longer term management, the patient will need oral treatment for suppression
and prophylaxis for at least six months. This helps minimise morbidity: 30% have
normal neurodevelopment at 1 year of life following treatment with aciclovir for
21 days. This however rises to 70% with a subsequent six month course of oral
aciclovir. It is important to be vigilant about the need to regularly optimise dosing
as the child grows as well as monitor for renal dysfunction, hepatic dysfunction
and neutropaenia as a result of the treatment.

Long-term follow-up needs to take place to monitor for flares and additionally
evaluate the child’s development.

A 4 year old boy is brought to the emergency department following three days
of fever and becoming increasingly withdrawn. In the last 24 hours, his parents became especially concerned as he started vomiting and they noticed he struggled to balance when walking. He is previously fit and well with an unremarkable birth history and his immunisations are up to date.

His cardiovascular, abdominal and ENT examinations are normal. With regards to his neurology examination, he had an unsteady gait and struggled to coordinate his lower limbs.

What are you concerned about and what are your differentials?

His CT head shows the following.

Source: Radiopedia Creative Commons Attribution-Noncommercial-Share Alike
3.0 licence (http://creativecommons.org/licenses/by-nc-sa/3.0/)

What is your management?

What considerations are needed for finding potential causes?

Differentials

With this particular presentation, where there are some focal findings, one needs
to consider whether there is raised intracranial pressure. It may not be safe to
proceed to a lumbar puncture and cranial imaging is indicated.
Your differentials would include any sort of space-occupying lesion, including
abscesses, tumours or a haematoma.

Management

First steps in management would include IV antibiotics and ensuring the patient
is under a neurological observation protocol. A discussion with a neurosurgical
team is important and urgently required so they can help determine whether the
patient should be transferred to their centre.

Empirical antibiotic therapy would need the cover for the same pathogens as
bacterial meningitis, as well as additional cover for anaerobic species which
could originate from ENT sites. In the UK, in an otherwise healthy child (i.e., not
immunocompromised, post-neurosurgery etc.), ceftriaxone and metronidazole
would be appropriate. Importantly in children, it is important to remember that
gram negative infections are more common than in adults, and that lots of brain
abscesses are polymicrobial.

Treatment length will depend on whether the abscess was surgically managed
and would require joint input from neurosurgical and paediatric ID teams.
Typical antibiotic courses would be for approximately 6 weeks, with an IV-to-oral
switch being guided by the patient’s clinical status and specialist input. Even
following neurosurgical drainage, a high degree of vigilance is required going
forward as a new collection could form and cause a relapse of symptoms. This
may require further surgery and adjustment of duration of antibiotics.

Wider considerations

It is worth exploring whether there is an underlying reason why this patient got
this brain abscess. Teams should check if there are any obvious cranio-facial
abnormalities on inspection, or noted on imaging. This may require discussions
with ENT or maxillo-facial teams. Additionally, it is important to check the
patient’s dentition. Poor dentition is a risk factor for CNS abscess development.

An echocardiogram is needed to check for the presence of a patent foramen
ovale or atrial septal defect which could allow septic vegetations to bypass
pulmonary phagocytes and spread through the systemic circulation. And finally,
once the child is well, it may be worth evaluating them for an underlying
immunodeficiency, especially if they have a previous medical history of
recurrent infections.