The major clinical syndromes of central nervous system infections include the following:
The classic triad of fever, headache and meningeal irritation (neck stiffness) sometimes do not occur altogether. Occasionally, patients may also have altered sensorium. Meningitis can be classified into acute, subacute, and chronic meningitis. Acute meningitis is characterized by onset of symptoms over the course of hours to up to several days. Subacute meningitis often has insidious onset. By definition, chronic meningitis would have compatible symptoms for at least 4 weeks.
The aetiological agents that can cause meningitis include bacteria, viruses, fungi, and even parasites. Patients in different age groups who have different underlying predispositions and environmental exposures would have different pathogens. In general, acute meningitis is usually caused by bacteria or viruses, while subacute or chronic meningitis are usually caused by mycobacteria, fungi, or atypical bacteria.
Common causes of acute pyogenic meningitis:
| Age 0 – 8 weeks | Escherichia coli (K1) |
| Streptococcus agalactiae (group B type III) | |
| Listeria monocytogenes | |
| Other Enterobacteriaceae eg. Salmonella sp. | |
| 3 months – 18 years | Haemophilus influenzae serotype b* |
| Neisseria meningitidis | |
| Streptococcus pneumoniae | |
| 18 years – 50 years | Streptococcus pneumoniae |
| Neisseria meningitidis | |
| > 50 years | Above 2 and aerobic Gram-negative bacilli (e.g. Klebsiella sp., Escherichia sp., Salmonella sp.) |
| Immunocompromised hosts | Above 3 and Listeria monocytogenes, Pseudomonas aeruginosa |
| Occupational / exposure to pigs | Streptococcus suis |
| Exposure to contaminated fresh water | Nagleria fowleri & other free-living amoeba (high mortality) |
| Ingestion of raw mollusk | Angiostrongylus cantonensis (eosinophilic meningitis) |
| Head trauma, intrathecal injection and post-neurosurgery | Staphylococcus aureus |
| Staphylococcus epidermidis | |
| Aerobic Gram-negative bacilli | |
| Aspergillus sp.; other molds | |
| Post-shunting | Above 3 and Proprionibacterium acne |
* Meningitis due to Haemophilus influenzae b has reduced markedly after routine immunization was introduced in some countires
The type of organism can be predicted by the route of acquisition of organisms and immune status. Common causes of viral meningitis is often the cause of acute encephalitis and include enteroviruses, Japanese encephalitis virus, mumps virus, herpes simplex types 1 & 2, varicella zoster virus and often as part of an infectious mononucleosis-like syndrome: human immunodeficiency virus (HIV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV).
Common etiological agents of subacute and chronic meningitis include:
1) Mycobacterium tuberculosis
2) Cryptococcus neoformans
3) Treponema pallidum (syphilis)
4) Borrelia burgdorferi (Lyme’s disease)
5) Nocardia sp. (most patients are immunosuppressed)
6) Others: dimorphic fungi, Candida sp., Acanthamoeba sp., Angiostrongylus sp., Brucella sp.
This often results from the rupture of a superficial infective granuloma on the pia mater into the subarachnoid space. Young patients often have concomitant progressive pulmonary / systemic disease whereas older patients may have no other clinically evident foci.
Patients with cryptococcal meningitis often present with a subacute onset of headache and dementia. 50% of these patients have an underlying immunodeficiency disorder, e.g. AIDS, lymphoma, receiving immunosuppressant therapy (such as steroids), had a history of transplantation etc.
The diagnosis of meningitis depends on the examination of the CSF. CSF should be sent for cell count and differential count, glucose and protein. Microbiological investigations including Gram smear, bacterial culture, Ziehl-Neelson smear, mycobacterial culture, Indian ink examination, fungal culture, rapid bacterial antigen detection (Group B Streptococcus, E. coli K1, Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b), VDRL for syphilis, PCR/RT-PCR for Mycobacterium tuberculosis, herpes simplex virus, and enterovirus, viral culture, and even wet mount should be considered depending on the clinical scenario. A minimal of 10 mL CSF should be collected (especially if various investigations are required).
| Cause | WBC (cells/mm3) | Cell type | Glucose (mg/dL) | Protein (mg/dL) |
| Viral | 50–1000 | Mononuclear | >45 | <200 |
| Bacterial | 1000–5000 | Polymorphonuclear | <40 | 100–500 |
| Tuberculosis | 50–300 | Mononuclear | <45 | 50–300 (or higher) |
| Cryptococcus | 20–500 | Mononuclear | <40 | >45 |
Figure 1. Presence of acid fast bacilli can be seen when the CSF is being stained with Zeihl-Neelsen stain
Figure 2. CSF microscopy findings of a patient with cryptoccocal meningitis. An area of ‘negative stain’ can be appreciated when the CSF is smeared with Indian ink. This corresponds to the large halo of capsular material which encloses the budding yeast.
The current management strategies consist of early use of empirical antibiotics +/- steroids. The antibiotic regimen should be able to penetrate the blood-brain barrier and therefore a high dose of antibiotics is usually necessary. The regimen can then be later guided by culture results when they are available. It is necessary to watch out for complications (e.g. hydrocephalus, stroke, and seizures). For conditions which are often associated with hydrocephalus (e.g. cryptococcal meningitis), repeated lumbar puncture +/- shunt insertion may be required.
The findings are currently inconclusive, as evidenced by 3 different recent meta-analyses:
The benefit of adjunctive dexamethasone for all or any subgroup of patients with bacterial meningitis thus remains unproven.
Tuberculous meningitis is associated with high mortality and disability among survivors. In a recent review, 7 trials involving 1140 patients (with 411 deaths) with tuberculosis meningitis were analyzed. All used dexamethasone or prednisolone. Overall, corticosteroids reduced the risk of death (RR 0.78, 95% CI 0.67 to 0.91; 1140 participants, 7 trials). Data on disabling residual neurological deficit from 3 trials revealed that corticosteroids reduce the risk of death or disabling residual neurological deficit (RR 0.82, 95% CI 0.70 to 0.97; 720 participants, 3 trials). Adverse events included gastrointestinal bleeding, bacterial and fungal infections and hyperglycaemia, but they were mild and treatable.
Corticosteroids should be routinely used in HIV-negative patients with tuberculous meningitis to reduce death and disabling residual neurological deficit amongst survivors. However, there is not enough evidence to support or refute a similar conclusion for those who are HIV-positive.
Close contacts of patients suffering from infection due to certain microorganisms such as Haemophilus influenzae type b and Neisseria meningitidis require chemoprophylaxis (e.g. rifampicin or ciprofloxacin).
The clinical manifestations of encephalitis may be similar to those of meningitis. However, altered level of consciousness is a predominant sign. It can range from mild lethargy to deep coma. Moreover, focal or generalized seizures occur in many patients with encephalitis, especially in severe disease. Virtually every possible type of focal neurological disturbances has been reported.
Encephalitis is most frequently due to viral infection. Herpes viruses (herpes simplex and varicella-zoster viruses) and enteroviruses are the commonest agents. Other viruses such as influenza virus, adenovirus, mumps virus, cytomegalovirus, Epstein-Barr virus, HIV, flaviviruses (e.g. Japanese encephalitis virus, West Nile virus) and rabies virus are potential causes.
Bacteria, fungi and parasites can also cause encephalitis – but these are far less common as a cause compared with viruses. Examples include Bartonella spp., Borrelia burgdorferi (Lyme disease), Listeria monocytogenes, Mycobacterium tuberculosis, Cryptococcus neoformans, and Toxoplasma gondii.
Examination of the CSF usually shows pleocytosis with predominantly mononuclear cells, mildly elevated protein and normal glucose. Since the commonest aetiological agents are viral in origin, CSF should be sent for viral culture; PCR/RT-PCR for herpesviruses, enteroviruses, and other suspected viruses. In cases of suspected Japanese B encephalitis, serum and CSF should also be sent for Japanese B virus specific IgM antibodies.
Imaging studies (CT or MRI) of the brain is useful as some of the viral encephalitis have specific imaging findings. For example, in Herpes simplex virus encephalitis, temporal lobe is the most commonly affected area (Figure 1) whereas in Japanese encephalitis, the basal ganglia and thalami (especially bilaterally) are more frequently involved (Figure 2). In addition, electroencephalograms (EEG) may also reveal features suggestive of viral encephalitis, e.g. periodic lateralising epileptiform discharges.
Figure 1. Cerebral MRI of patient with HSV-2 encephalitis showing bilateral temporal lobe hyperintensity
Figure 2. Cerebral MRI of patient with Japanese B encephalitis, showing bilateral thalamic hyperintensity
Patients with encephalitis can deteriorate rapidly and so they should be closely monitored. Complications such as increased intra-cranial pressure, seizures, and autonomic dysfunction can occur.
Viral encephalitis, the most common cause, has limited antiviral drugs with proven efficacy. Acyclovir and related compounds are the most effective antiviral agents for herpes virus infection (HSV and VZV). Supportive measures are the mainstay of treatment for most encephalitis cases.
The clinical course of brain abscess ranges from indolent to fulminant. Most clinical manifestations are not due to the systemic signs of infection, but rather to the size and site of the abscess. Headache is the most common presenting symptom. Other symptoms and signs include changes in mental status, focal neurological deficits, fever, seizures, and increase intracranial pressure.
According to animal studies, four stages of brain abscess formation evolution were observed: early cerebritis (days 1–3), late cerebritis (days 4–9), early capsule formation (days 10–13) and late capsule formation (day 14 and later). The early cerebritis stage is characterized by an acute inflammatory infiltrate with visible bacteria on Gram stain and marked oedema surrounding the lesion. The centre of the lesion becomes necrotic during the late cerebritis stage. With early capsule formation, the necrotic centre begins to decrease in size with simultaneous development of a collagenous capsule in which it increased in density and thickness during the late capsule formation stage.
The aetiological agents of brain abscess depend on the underlying predisposition.
| Predisposing conditions | Micro-organisms |
| Otitis media, mastoiditis | Streptococci (aerobic and anaerobic), Bacteroides and Prevotella spp., Enterobacteriaceae. |
| Sinusitis | Streptococci (aerobic and anaerobic), Bacteroides, c, Staphylococcus aureus, Haemophilus spp. |
| Dental infection | Mixed anaerobes with Fusobacterium, Prevotella, Actinomyces, and Bacteroides spp., streptococci. |
| Penetrating trauma orpost-surgery | Staphylococcus aureus, streptococci, Enterobacteriaceae, Propionibacterium acnes. |
| Lung abscess, empyema, bronchiectasis, | Anaerobes such as Fusobacterium, Actinomyces, Bacteroides, also streptococci, Nocardia spp. |
| Infective endocarditis | Staphylococcus aureus, streptococci. |
| HIV infection | Toxoplasma gondii, Nocardia spp., Mycobacterium spp., Listeria monocytogenes, Cryptococcus neoformans. |
Imaging studies (CT and MRI) are the most important investigations in the diagnosis of brain abscess. The characteristic CT appearance of brain abscess is that of a hypodense centre with a peripheral uniform ring enhancement after the injection of contrast. This is surrounded by a variable hypodense area of brain oedema. However, CT may not be able to pick up the early cerebritis phase. MRI is superior and more sensitive than CT and offers significant advantages in the early detection of cerebritis. In T1-weighted images, the abscess capsule often appears as a discrete rim that is isointense to mild hyperintense, together with contrast enhancement with the paramagnetic agent (Figure 1).
Figure 1. Contrast enhanced T1 cerebral MRI showing left parietal brain abscess with a hyperintense, contrast enhancing rim.
Stereotactic CT-guided aspiration or incision and drainage (I & D) performed in the operating theatre are essential to aid microbiological diagnosis. Gram stain and culture of the abscess fluid can help identify the pathological organism and thus guide anti-microbial therapy.
Antibiotics with coverage of both aerobic and anaerobic bacteria (initially empirical, based on assessment of underlying predisposing factors) and measures for prevention of complications (e.g. use of anti-convulsants in patients with seizures, intravenous mannitol and intravenous steroids in patients with cerebral oedema) should be initiated as soon as possible. Occasionally, serological investigations such as serum cryptococcal antigen and Toxoplasma antibody might be helpful in identifying the causative pathogens.
Imaging modalities followed by aspiration or drainage of the empyema or abscess. Antibiotics should be guided initially by underlying predisposing factors and later by culture results.