Author: Anna Shekhdar / Editor: Michael John Stewart / Reviewers: Michael Perry, Amanda King / Codes: CAP14, CAP17, CAP21, CC5, CMP4, HAP14, HAP17, HAP33, PAP9 /
Published: 12/06/2020 / Review Date: 12/06/2023
Intracranial infections are also called central nervous system infections (CNS) infections. In this session, we will use the term CNS infection.
CNS infections are relatively rare, but form a very important differential diagnosis in the unwell patient presenting to the ED.
It is essential to suspect and expedite treatment in those at risk, as consequences of a missed CNS infection are severe.
CNS infection continues to have a high mortality rate, especially with opportunistic infections. Early diagnosis and treatment, regardless of pathogen, can reduce both mortality and morbidity.
The conditions considered in this session are:
- Cerebral abscess
- Cerebral malaria
- Cerebral tuberculosis
- Opportunistic infections in the immunocompromised host
The CNS and cerebrospinal fluid (CSF), are areas of relative immunodeficiency with lower levels of complement and immunoglobulin.
The choroid plexus is a common portal of entry for haematogenous spread into the CSF.
Malaria in returning travelers = 2% – 6%
Meningococcal meningitis = 5% 10%
Pneumococcal meningitis = 20%
Cerebral malaria in pregnancy = 50%
Herpes simplex encephalitis = 70%
Meningitis is characterised by inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges.
The key clinical discriminator of bacterial and viral causes of meningitis is the rate of onset and severity of symptoms.
Bacterial meningitis is, classically, an acute and rapid disease process.
The clinical outcome of acute bacterial meningitis is related to the severity of the inflammatory process in the subarachnoid space.
Inflammation is most pronounced in bacterial meningitis, with consequent increases in vascular and cell membrane permeability, leading to cerebral oedema.
If the host is able to mount an appropriate response, there is a marked increase in the number of polymorphonuclear leukocytes seen in the CSF.
If the infection persists, inflammation may spread throughout the subarachnoid space, leading to obstruction of CSF flow, oedema, vasculitis, focal deficits and death.
In acute bacterial meningitis, the bacteraemia that precedes meningitis is often associated with mild non-specific symptoms. The three principle organisms in patients aged 2 50 are:
- Neisseria meningitides
- Streptococcus pneumoniae
- Haemophilus influenzae
Meningitis secondary to a viral pathogen is a milder self-limiting disease.
More information on meningitis can be found on the Meningitis Research Foundation web site.
Meningococcal meningitis is usually caused by haematogenous spread of bacteria from an ear or throat infection. It is the commonest form of meningitis in the UK.
The meningococcus colonises, and infects, healthy individuals, and carriage rates in the throat are reported as 10-15%.
The disease is transmitted by close physical contact; probably by the exchange of upper respiratory secretions.
In the UK, meningococcal meningitis has a peak incidence in under-two-year olds, and a second peak in fifteen-to-twenty-four year olds. Mortality rates are highest in infants and adolescents.
Those patients who present with evidence of meningococcal septicaemia have the worst outcomes with 19-25% mortality.
However, meningococcal meningitis appears to have the lowest risk of major neurological sequelae compared with pneumococcal and H. influenzae meningitis.
The meningitis C vaccine was introduced in 2000. Approximately 85% of cases are now due to Meningitis B. There are currently no effective vaccines for Meningitis A or B.
Streptococcus pneumoniae is the second commonest form of meningitis in the UK.
The symptoms are indistinguishable from the other forms of bacterial meningitis. However, it is not associated with the purpuric rash seen in meningococcal disease.
The mortality rate is 20%. This is higher than the other forms of bacterial meningitis. It is also associated with the highest incidence of neurological sequelae. Approximately 40% have long-term sequelae such as:
- Functional impairment
It is most commonly seen in children under two years, the elderly and patients with significant co-morbidities.
Prior to the introduction of the haemophilus influenzae type B (HiB) vaccine in 1992, haemophilus influenzae was the commonest cause of meningitis in children under the age of five in the UK.
Since then, the number of cases has fallen by 90%.
Although the mortality rate is less than 5% in the UK, neurological sequelae occur in 20% of cases.
The clinical assessment should focus on clues as to the likely pathogen. For example, the presence of non-CNS features and co-morbidities, as well as the consequences of the infection i.e. physiological and neurological derangement.
|Symptom||Sensitivity %||95% Confidence Interval (CI)|
|Nausea and vomiting||30||22-38|
|Neck Pain||28||One study only|
Classic symptoms of meningitis include headache, nausea or vomiting and neck pain.
Physical examination findings include fever, neck stiffness, altered mental status, focal neurological signs, rash, Kernigs sign and jolt accentuation of headache.
However, neck stiffness may be absent in up to 30% of cases of bacterial meningitis.
Similarly, the classic petechial/purpuric non-blanching rash seen in meningococcal septicaemia patients may be absent, or atypical, at presentation.
The image shows a non-blanching rash seen in septicaemic patients.
Symptom specificity and sensitivity
The sensitivity for the presence of two or more signs of fever, neck stiffness and altered mental status is 95%.
Kernigs sign and neck stiffness have very low sensitivities (9% and 15% respectively), but 100% specificity.
Patients with a positive Kernigs sign, or neck stiffness, almost certainly have meningitis. Patients in whom there is no fever, neck stiffness or altered mental status almost certainly do not.
Severity of the illness
|Sign on Clinical Examination|
|Poor peripheral perfusion||Capillary refill time >4s, or Systolic BP <90mmHg, or oliguria <0.5 ml/kg/hr|
|Signs of raised Intracranial pressure (ICP)||Bradycardia and Hypertension Papilloedema|
|Glasgow coma score (GCS)||<12, or decreased by >2, or fluctuating|
|Neurological signs||Focal neurology. Persistent seizures|
|Initial Investigation Results|
|Acidosis||pH <7.3 or base excess worse than -5|
The table demonstrates how the severity of the illness can be correlated with cardio-respiratory and neurological signs.
Glasgow meningococcal septicaemic prognostic score
|Hypotension (SBP <75mmHg under-4 years, SBP <85mmHg over-4 years)||3|
|Skin-rectal temperature difference >3oC||3|
|GCS <8 or fall of >3 within an hour||3|
|Deterioration in the hour prior to scoring||2|
|Absence of meningism||2|
|Extending purpuric rash or widespread ecchymoses||1|
|Base deficit >-8||1|
The table shows the Glasgow meningococcal septicaemic prognostic score validated for use in children only.
The maximum score is 15. A score of >8 predicts mortality, with 100% sensitivity
Viral Meningitis in The General Population
Most cases of viral meningitis are self-limiting and carry a good prognosis. However, the disease can cause considerable morbidity, with high fevers and severe headache.
Viral meningitis tends to be more common in the summer and presents with a subacute illness of 1-7 days.
It is most common in young children, and the incidence decreases with age. Until the introduction of the measles, mumps and rubella (MMR) vaccine, the commonest cause of viral meningitis in the UK was mumps. Enteroviruses are now the most common cause.
Herpes simplex virus (HSV) now ranks second among the causes of viral meningitis in adults and adolescents in developed countries.
HSV meningitis is a complication of primary genital herpes, especially with HSV-2. However, in many patients there is neither a history of genital herpes nor active genital lesions. In uncomplicated cases, the prognosis is usually good.
The danger is of progression to herpes simplex encephalitis, which presents with worsening fever and confusion over a few days, and is rapidly fatal.
In 50% of patients with viral meningitis, the causative organism is not isolated.
Clinical Assessment of Viral Meningitis in Immunocompromised Individuals
In immunocompromised individuals, HIV and Epstein-Barr Virus (EBV) are important causes of viral meningitis. Meningeal symptoms occur in 17% of patients undergoing HIV seroconversion.
Early diagnosis is important both for patients and partners, as the risk of transmission of HIV is greatest in the early stages of infection.
In addition to viral meningitis, patients with HIV are much more susceptible to tuberculous meningitis and cryptococcal meningitis.
Cryptococcal meningitis is an AIDS-defining illness. Patients may present with cerebellar signs such as ataxia, and involuntary movements.
Cryptococcal meningitis and encephalitis are usually seen in immunocompromised hosts.
The symptoms are usually chronic or subacute in nature. For example, fever of undetermined origin, chronic headaches, personality change and mental confusion. These progress gradually to lethargy and coma.
Cryptococcus neoformans is a fungal infection acquired by inhaling dust containing the fungus. The result can range from harmless colonisation of airways to disseminated disease or meningitis.
The key determinant of disease progression is the immune status of the host.
Patients with HIV
HIV patients may have minimal or non-specific symptoms at presentation, and may be afebrile.
Alternatively, they may have a low-grade fever only and no neck stiffness.
Patients with AIDS
In patients with AIDS and other causes of immunosuppression, it is not possible to effect a cure of cryptococcal infection.
Patients require lifelong suppressive therapy. Even with treatment, the mortality rate is 25-30%.
Relapse occurs in 20-25% of patients.
Of those who survive, 40% have significant neurological deficits including.
- Loss of vision
- Decreased mental function
- Cranial nerve palsies
Patients with no immunosuppression
In patients with no immunosuppression, early diagnosis and treatment is effective in controlling, or terminating, the infection in 70-75% of patients.
Tuberculous meningitis presents with a more indolent course than bacterial meningitides. It is usually seen in immunocompromised hosts.
In the UK, there are around 150 – 200 cases of terculous meningitis reported each year.
Tuberculosis tends to prevail under certain host conditions, with the immunocompromised being particularly susceptible.
It is a common secondary infection in patients with HIV infection, and is associated with a particularly high mortality.
A high index of suspicion is paramount because symptoms are rarely obvious. Patients most at risk are those who have not received the bacillus Calmette-Gurin (BCG) vaccination.
Usually, the prodrome is non-specific, including:
Drowsiness and confusion are typical.
Symptoms of meningism seldom occur in the immunocompromised.
Most cases present within 2 weeks of symptom onset, but some patients will report several months of symptoms preceding presentation.
Headache and mental status changes are much more common in elderly persons.
Encephalitis is inflammation of the brain, caused either by infection or autoimmune disease and has a mortality rate between 10 30%.
Viruses are the most common cause of infectious encephalitis (e.g. herpes virus, enterovirus, West Nile and Japanese encephalitis), and only rarely are bacteria, fungus or parasites found to be the causative organism.
Autoimmune encephalitis causes are vast and can be associated with specific antibodies; VGKC, NMDA receptor, GAD, AMPAR and GABA, or none at all. Some cancers may produce an antibody, for example Anti NMDA-receptor encephalitis is linked with ovarian teratomas in over 50% of women of child-bearing age.
In about 50% of cases no cause can be confirmed via imaging or laboratory tests.
Autoimmune encephalitis often has a longer duration of symptoms and can present in a more atypical manner. Symptoms can include: confusion, memory loss, altered behaviours or personality, psychosis and hallucinations which may progress to seizures or reduced consciousness. Treatment for autoimmune encephalitis should be commenced with expert advice, and in most cases patients should receive empirical antibiotics and/or anti-viral therapy in the first instance.
Brain abscesses usually arise as a consequence of the direct spread of infection from chronic sinusitis, otitis media, dental abscess, neurosurgical procedures, or penetrating head injury.
They can also occur via haematogenous seeding from remote sources.
Studies show that strep. viridans is the commonest pathogen
The localised collection of pus is surrounded by inflammation and oedema. This mass effect leads to the typical presenting symptoms, and signs, of cerebral abscess i.e. features of a space-occupying lesion.
The host inflammatory response attempts to contain the localised infection. Classically, this leads to an encapsulated collection of pus surrounded by an inflamed area.
Of the physical symptoms associated with a brain abscess, the classic triad is fever, headache and focal neurological signs.
However, this is seen in only a minority of patients.
A sudden worsening of the headache, and reduced level of consciousness, may indicate rupture of the abscess into the ventricular system.
Mortality ranges widely, and is most influenced by the patient’s conscious level at presentation. If the patient is fully conscious, the mortality rate is very low. In patients in coma, it rises to 75%.
Malaria is transmitted by the female anopheline mosquito and leads to a protozoan infection of red blood cells.
As a result of increased travel and tourism, tropical infections such as cerebral malaria now present more frequently to UK hospitals.
In the map above, the red areas indicate where malaria is prevalent.
The most severe form of malaria is caused by plasmodium falciparum, and this can lead to cerebral malaria.
The definition of cerebral malaria is coma in a patient infected with plasmodium falciparum, with no other cause for the coma.
In cerebral malaria, plasmodium falciparum-infected red blood cells bind to the blood-brain barrier endothelium, and in so doing, significantly decrease blood-brain barrier resistance to invasion by the parasite.
Altered consciousness may occur as a direct result of cerebral infection, or as a consequence of convulsions, hypoglycaemia or acidosis.
Patients with malaria usually present with:
Non-specific and irregular fever
- Malaise with tachycardia
Vomiting occurs in approximately 20% of patients.
- Drowsiness or confusion
- Decorticate rigidity
- Decerebrate rigidity
- Pupillary changes
- Absent corneal reflexes
- Abnormal respiratory patterns
- Gaze abnormalities
Seizures are particularly common in children.
Most deaths occur within 24 hours of diagnosis, and most of those who survive recover fully within 48 hours of starting treatment. Only 10% of survivors have neurological sequelae.
Profound coma, repeated or prolonged seizures, metabolic acidosis and hypoglycaemia are associated with poor outcomes.
Priority investigations in suspected CNS infection are:
Venous blood for FBC, U&Es, glucose, LFTs, and clotting profile. However, a normal white blood count (WBC) does not exclude CNS infection. Cryptococcal infection, in particular, is often extensive despite normal haematological indices.
Blood gases to determine whether the patient has a significant acidaemia.
Microbiology including blood cultures, throat swab, clotted blood for serology, EDTA blood for polymerase chain reaction (PCR).
In cases of suspected viral meningitis, PCR is used to test the cerebrospinal fluid for:
- Herpes simplex virus
- Varicella zoster
This is estimated to be up to 1,000-fold more sensitive than routine viral culture.
Lumbar puncture and cerebrospinal fluid analysis
Lumbar puncture and cerebrospinal fluid analysis CSF microscopy, culture and PCR.
A lumbar puncture is the diagnostic test for meningitis and should be done, unless it is contraindicated. In all cases of suspected CNS infection, CSF glucose concentration should be compared with serum glucose measurements. CSF opening pressures can also be measured in suspected cases of CNS infection as a prognostic indicator. In cryptococcal meningitis, an elevated opening pressure indicates a particularly poor prognosis.
Analysis of cerebrospinal fluid is needed whenever meningitis of any aetiology is suspected, to confirm or refute the diagnosis as well as to identify the causative organism.
Cause of meningitis
|WBC/mm3/106 cells/l||Predominant cell type||
CSF:serum glucose ratio
|Protein (g/l) (N = 0.2-0.4)|
Even if CSF microscopy is normal, it is essential to culture the CSF as some infections, including Cryptococcus, may be present even when the CSF profile is normal.
The question of whether prior CT imaging is needed is controversial.
In patients with focal neurological signs, a CT scan is thought necessary. However, CT scans cannot predict the likelihood of cerebral herniation following an LP.
A normal CT scan does not rule out raised ICP, and even in the presence of raised ICP, it is uncertain as to whether an LP increases the risk of cerebral herniation.
Therefore, if there are no clinical contraindications to an LP (e.g. a coagulopathy), a CT scan is not essential prior to the procedure.
Subsequently, a CT may be useful in identifying dural defects predisposing to meningitis. A CT scan may also be useful because certain pathogens have classic findings on CT. For example, in herpes simplex encephalitis, there may be an area of low attenuation in the temporo-parietal lobe, and with toxoplasmosis, classically, multiple ring enhancing lesions are seen in the area surrounding the basal ganglia.
A differentiation between bacterial meningitis, viral meningoencephalitis, HSV encephalitis and a brain abscess must be made presumptively. The treatments for each are distinctly different, and must be initiated promptly
Cases of cerebral malaria are normally more easily distinguishable by the history.
In all cases, general management of airway, breathing and circulation (ABC) are the initial priority.
Hypoglycaemia is an important differential diagnosis in the patient presenting with an altered conscious level, but many CNS infections also cause blood glucose levels to fall. Always check the blood glucose and give dextrose, if required.
If bacterial meningitis is suspected, treatment with antibiotics must be initiated as soon as possible. Empirical treatment is based on the most probable pathogens, and this, in turn, depends on host factors, especially age and immune status.
There is good evidence, from the Meningitis Research Foundation that all patients with suspected bacterial meningitis should receive a third-generation cephalosporin (ceftriaxone/cefotaxime), with additional therapies, depending on their age and most likely pathogen.
Antimicrobial therapy can be refined as soon as culture results from blood and CSF are known
Additional Treatment of Cerebral Abscess
- Patients exhibit evidence of mass effect
- The abscess lies in close proximity to the ventricular system
- There is secondary hydrocephalus
Treatments Comparisons for CNS Infections
All patients should receive a 3rd generation cephalosporin.
|Suspected Diagnosis||Host Factors||Additional Organism to cover||3rd Generation Cephalosporin plus|
|High risk of abscess||Recent surgery/VP shunt||Strep. epidermidis||
|Suspected pneumococcal penicillin resistance||
|TB meningitis||Immunocompromised alcoholics||Cryptococcus neoformans var. neoformans||
|Without HIV||Cryptococcus neoformans var. neoformans||
|Viral encephalitis||If immunocompromised or non-HSV suspected will need discussion with local microbiology department||Herpes Simplex Virus||AciclovirPatients are often treated for HSV encephalitis in addition to meningitis where the diagnosis is unclear|
Check your local microbiology guidelines as these may vary in different regions.
In addition to antimicrobial agents, studies have looked at adjunct therapies to improve patient outcome.
Diuretics are indicated only in patients with raised ICP/decompensated hydrocephalus whereby head elevation alone has not been sufficient, and should be managed in conjunction with advanced neuroprotective measures.
Mannitol and frusemide are both recommended by the Meningitis Research Foundation for their diuretic properties.
Mannitol should be administered intravenously at a dose of 0.25g/kg, followed by furosemide at 1mg/kg.
Mannitol is effective in lowering ICP, whatever the underlying pathological process, and this may buy time.
The Meningitis Research Foundation recommends administration of corticosteroids to:
- Adults with pneumococcal meningitis
- Non-immunised children with suspected haemophilus influenzae infection
It is also thought that steroids may be of benefit in TB meningitis.
A Cochrane review also recommended steroid therapy for the same groups, and found that adverse events were not increased significantly with the use of adjuvant corticosteroids.
The recommended agent and dose is dexamethasone 0.15mg/kg/q.d.s. for four days starting with, or just before, the first dose of antibiotics.
There is insufficient evidence to recommend the use of steroids in cerebral malaria.
The occurrence of seizures exacerbates the problem of raised ICP, and it is postulated that this in turn worsens the prognosis for all causes of CNS infection.
However, in a Cochrane review of trials comparing phenobarbitone with placebo, or no treatment, death rates were doubled in the anticonvulsant group despite significant reductions in the number of seizures.
Fluid and electrolyte balance
Careful management of fluid and electrolyte balance has a crucial role in minimising mortality in acute bacterial meningitis, as well as other causes of CNS infection. Both over- and under-hydration can rapidly occur.
Acutely unwell patients are prone to Syndrome of Inappropriate ADH Secretion (SIADH). Normal fluid excretion is reduced exacerbating cerebral oedema.
In the UK, patients are often given restricted fluids (70%) for the first 24 hours. However, in patients who present late, or have evidence of haemodynamic compromise, fluids should not be restricted.
Patients with cerebral malaria often have a marked metabolic acidosis. Rapid intravenous fluid therapy combined with antimalarial therapy is essential.
Hypoglycaemia may complicate any case of CNS infection, particularly in children, and particularly with cerebral malaria. Hypoglycaemia requires prompt and aggressive management.
The following areas require particular consideration when managing a case of CNS infection:
- The diagnosis of bacterial meningitis needs to be considered, even if a child is up-to-date with their immunisations. There is currently no effective vaccination against Meningitis B
- The classic triad of fever, neck stiffness and altered mental status, typical of meningitis, occurs in less than 50% of cases
- Viral meningitis is most commonly a self-limiting disease. However, if caused by HSV, herpes simplex encephalitis can ensue, which is rapidly fatal
- Normal C-reactive protein (CRP) and low peripheral white blood cell count, in isolation, do not rule out the possibility of intracranial infection
- In cases of suspected bacterial meningitis, neither CT scanning nor an LP is necessary before commencing IV antibiotics
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