13th June 2023

Central Nervous System Infections

Meningitis

Bacterial meningitis

Meningitis is the inflammation of leptomeninges (arachnoid & pia matter) including subarachnoid space. Bacterial meningitis indicates life-threatening inflammation of the meninges caused by a bacterial pathogen.

Aetiology

Common organisms implicated in bacterial meningitis vary with age:

Presentation

Bacterial meningitis may present with the classic triad of fever, headache, and neck stiffness. There may also be more nonspecific symptoms of fever, nausea, vomiting, lethargy, irritability, headache, muscle ache or joint pain.

Symptoms and signs which can be more specific to meningitis include neck stiffness, altered mental state (confusion, drowsiness, impaired consciousness) or seizures, non-blanching rash (petechial or purpuric), back rigidity, photophobia, Kernig’s sign (patient unable to fully extend at the knee when hip is flexed), Brudzinski’s sign (patient’s knees and hips flex when neck is flexed), focal neurological deficit, e.g. isolated cranial nerve abnormalities (principally of cranial nerves III, IV, VI, and VII).

Pre-hospital settings

In cases of suspected bacterial meningitis with non-blanching rash (typical of meningococcal disease), intramuscular or intravenous benzylpenicillin should be given at the earliest opportunity, either in primary or secondary care. Benzylpenicillin should only be withheld in people who have a clear history of anaphylaxis after a previous first dose; history of rash following penicillin is not a contraindication. Cefotaxime may be an alternative if penicillin allergy. Chloramphenicol can be used if immediate hypersensitivity to penicillin and cephalosporins.

For suspected bacterial meningitis without non-blanching rash, patients should be transferred directly to secondary care without giving parenteral antibiotics unless urgent transfer is not possible.

Investigations

• Routine bloods, including CRP and coagulation screen
• Blood cultures
• Pneumococcal and meningococcal PCR
• Lumbar puncture for CSF analysis
• CT head if fluctuating level of consciousness or focal signs. If symptoms of raised intracranial pressure, CT head must be performed prior to performing lumbar puncture.

Cerebrospinal fluid analysis for different meningitis aetiologies:

Treatment

Empirical treatment (organism not confirmed):

Treatment (organism confirmed):

Steroids

NICE guidelines advise to start dexamethasone immediately if lumbar puncture shows any of the following:

• Purulent CSF
• CSF white cell count >1000/μL or raised white cell count with protein >1g/L
• Bacteria on gram stain.

Dexamethasone should not be started >12 hours after starting antibiotics, and high-dose dexamethasone should be avoided in meningococcal meningitis.

It is important to note that bacterial meningitis and meningococcal disease are notifiable diseases. Prophylaxis for close contacts, regardless of vaccination status, is advised for those with:

• Prolonged close contact in household setting during 7 days before the onset of illness.
• Transient close contact with case only if they have been exposed to large particle droplets/secretions from the respiratory tract.

Chemoprophylaxis for meningococcal disease should be given ideally within 24 hours of diagnosis of index case. Chemoprophylaxis in the UK is usually with either oral ciprofloxacin, rifampicin, or IM ceftriaxone (safe in pregnancy).

Complications

Immediate complications of bacterial meningitis include septic shock, seizures, cerebral oedema, septic arthritis, and pericardial effusion.

Delayed complications can include visual impairment, hearing impairment, motor deficits, epilepsy, cognitive impairment, hydrocephalus, Waterhouse Friedrichsen syndrome and septic thrombosis of dural venous sinuses.

Tuberculous meningitis

Meningitis can be caused by infection with Mycobacterium tuberculosis. This should be particularly considered in those with higher risk, including immigration from high endemic areas, healthcare professionals, and those residing in prisons or hostels etc.

Tuberculous meningitis can present acutely, however, it mostly presents as a subacute or chronic form. Clinical features include fever, malaise, intermittent headaches, and cranial nerve palsies.

CSF analysis usually shows a high protein, low glucose and raised lymphocytes. Acid-fast bacilli may be seen and Mycobacterium tuberculosis may be grown on culture.

Treatment active tuberculous meningitis (Recommended duration is 9-12 months) 

High dose steroids can be added at the start of treatment, with gradual withdrawal recommended over 4-8 weeks.

NICE recommends treating as tuberculous meningitis in cases of direct spinal cord involvement in TB (e.g.

spinal cord tuberculoma) and also in patients with miliary TB with signs and symptoms suggestive of CNS involvement.

Viral meningitis

In the UK, viral meningitis is the most common form of meningitis. Enteroviruses account for the majority, followed by herpes simplex and varicella zoster. It remains the most common cause of aseptic meningitis (i.e. no cause found after routine CSF stains and cultures). However, aseptic meningitis can also be caused by partially treated bacterial infections, fungi, parasites, drugs, and systemic disease, e.g. SLE, sarcoidosis, and Bechet’s disease.

Clinical features include acute onset meningism (i.e. neck stiffness, headache, photophobia) and fever. CSF shows a pleocytosis that is predominantly lymphocytic.

Aetiology

Herpes simplex virus (HSV-1) tends to cause encephalitis, whilst HSV-2 commonly causes meningitis. Mollaret syndrome is frequently associated with HSV-2, which is a recurrent and benign aseptic, lymphocytic meningitis.

Enterovirus infection can be suggested by a history of contact with small children with febrile illness, viral exanthema, symptoms of pericarditis, myocarditis, conjunctivitis, or pleurodynia (chest/abdominal pain associated with other viral prodrome), and symptoms of hand-foot-mouth disease.

Mumps infection may be indicated by meningeal symptoms following the onset of parotitis or orchitis. Epstein Barr Virus and Cytomegalovirus infection can be suggested by meningitis with mononucleosis syndrome. Varicella and CMV meningitis are more common in the immune-compromised host, e.g. transplant recipients.

Treatment

Treatment of viral meningitis is usually supportive only. If CSF analysis identifies a viral cause, antibiotics and steroids should be discontinued. Early treatment with aciclovir is found to be beneficial only in herpes encephalitis but not for meningitis. Ganciclovir for CMV is reserved for severe cases with positive CMV culture or when a congenital infection or an AIDS-related infection is suspected.

Encephalitis

Clinical presentation

Encephalopathy refers to altered consciousness persisting for longer than 24 hours, including lethargy, irritability or change in personality or behaviour. Encephalitis is defined as encephalopathy with evidence of CNS inflammation, demonstrated by at least two of:

• Fever
• Seizures or focal neurological findings attributable to the brain parenchyma
• CSF pleocytosis – more than 4 white cells/µL
• EEG findings suggestive of encephalitis
• Neuroimaging finding suggestive of encephalitis

Other clinical features include:

• Photophobia and neck stiffness
• Features of raised intracranial pressure including severe headache, nausea and vomiting
• Focal neurological deficits
• Non-specific viral prodrome symptoms (fever, myalgia, arthralgias)
• Rashes may be seen in varicella, hand-foot-mouth disease, rickettsia.
• Lymphadenopathy and hepatosplenomegaly may be seen in Ebstein Barr virus, varicella zoster virus, and cytomegalovirus infections.
• Features of parkinsonism if basal ganglia involvement in Japanese encephalitis.

The most common aetiology of encephalitis are viral causes, as outlined below, with Herpes Simplex Virus type 1 being the most common cause. More rarely, bacteria, fungi or parasites can cause encephalitis.

Aetiology

Viral causes of encephalitis

Non-viral cases of encephalitis

Investigations

Initial investigations consist of blood tests, imaging and CSF analysis.

Bloods

Routine bloods tests, including full blood count, urea and electrolytes, liver function tests, CRP, glucose and coagulation, can be useful in the first instance to investigate for a cause of the patient’s symptoms. A lymphocytosis may be seen in viral encephalitis. Serum microbiological cultures, serology and PCR may be useful in determining a causative organism.

In some cases, it may be necessary to rule out toxic causes, in which case bloods for paracetamol, salicylates, tricyclics and heavy metals may be required.

Specialist neurological blood tests may be required in some cases to rule out autoimmune or inflammatory causes. These may include complement levels, lupus anticoagulant, cardiolipin antibodies, thyroglobulin, thyroperoxidase antibodies, ferritin, fibrinogen, triglycerides, voltage-gated potassium channel complex and NMDA receptor antibodies.

Imaging

CT brain is normally the first neurological imaging performed as it is quick to arrange and can help to exclude other causes of symptoms such as brain tumour or abscess. CT brain may appear normal, although in some cases of herpes simplex encephalitis, a low attenuating area in the temporal lobes with surrounding oedema may be seen.

MRI brain is the imaging of choice in suspected viral encephalitis. Typical features of herpes simplex encephalitis include focal oedema of the temporal lobes, insular cortex, and inferolateral frontal lobes.

CSF analysis

Once brain imaging has ruled out evidence of raised intracranial pressure, a lumbar puncture to obtain CSF for analysis is important in supporting the diagnosis and ruling out other differentials, such as bacterial meningitis.

In viral causes of encephalitis, there is typically lymphocytic pleocytosis with a normal glucose and normal or mildly elevated protein. CSF culture and viral PCR can help identify a causative organism.

Other investigations

Electroencephalogram (EEG) can be useful in the diagnosis as well as monitoring of encephalitis and can be useful if distinguishing between encephalitis and metabolic encephalopathy.

In rare cases, brain biopsy may be performed.

Treatment

General management of encephalitis is supportive. In certain cases, treatment for seizures may be required, or in cases of severely raised intracranial pressure, therapy with steroids or mannitol may be required.

Specific treatment for encephalitis depends on the cause found and may include antivirals (e.g. IV acyclovir in the case of herpes simplex or varicella zoster encephalitis), antibiotics, antifungals, IV immunoglobulin or plasmapheresis (e.g. anti-NMDA encephalitis.