6th August 2024

Infective and inflammatory causes

Overview of infective and inflammatory causes

Infective and inflammatory processes within the CNS are notable causes of alteration in consciousness level or seizures and may be accompanied by other symptoms, including fever, headache, focal neurology and behavioural change.

The majorly encountered causes, both in clinical practice and MRCP exams, include the following:

Infective pathologies

A wide range of pathogens can cause CNS infection – this section will focus on a selection of viral and bacterial agents which commonly cause meningitis, encephalitis, and abscesses. Some of these are more classically associated with diseases in the immunocompromised or with a returning traveller, for example cerebral toxoplasmosis or malaria respectively. They remain, however, important differentials and so should be kept in mind when considering patients with the appropriate risk factors – it is important to elicit a broad history, including travel, sexual, and immunosuppressive risk, when assessing these patients.

A broad, but by no means exhaustive, sample of commonly encountered infective causes is given in the table below. Microscopy findings are indicated for common pathogens identifiable in this way (though it is important to note that stain microscopy is not a definitive test for the presence of organisms in the CSF).

Encephalitis and meningitis

Encephalitis occurs when there is inflammation of the brain parenchyma, whereas meningitis refers specifically to inflammation of the meninges. There may be overlap in the clinical syndrome, and they may indeed coexist (meningoencephalitis). A brief comparison is shown below.

Special considerations

Some patients presenting with a clinical picture of meningitis and/or encephalitis may have features in the history requiring further assessment, as well as follow on actions that may need to be considered:

• Immunosuppression: those with HIV and other immunodeficiencies are at risk of opportunistic infections with atypical organisms and if they present with features of meningitis and/or encephalitis, should be assessed for these. Cryptococcus neoformans is an invasive fungus for which having a CD4 count of <100 is a risk factor, and may present initially with pulmonary disease with progression to the CNS. Classically, Indian ink staining has been used to detect it in the CSF, but cryptococcal antigen is more sensitive. If suspected, it should be empirically treated until ruled out. Patients with a relative immunodeficiency, for example as a result of age or diabetes, are more at risk of less common organisms, including Listeria, for which cover with ampicillin is required.
• Travel history: patients with recent travel or migration who present with altered consciousness levels and/or seizures should be evaluated for potential imported or rare pathologies. TB meningitis can occur even in the absence of active pulmonary TB and should be considered in patients from a high prevalence area with suggestive symptoms and signs. Those who have travelled to areas with mosquitos must have malaria considered and have blood smears carried out for this. More temperate areas with mosquitos, especially in the US, may have a higher incidence of West Nile virus. Potential tick exposure should prompt consideration of tick-borne encephalitis or Lyme disease. If there is a history of travel to areas with an increased prevalence of penicillin-resistant pneumococci, then rifampicin should be added to the initial treatment regimen.
• Malignancy: some solid malignancies, namely melanoma, non-small cell lung cancer, and breast cancer, as well as haematological malignancies including lymphomas, can spread to the leptomeninges, causing a range of symptoms. This is usually as a result of haematogenous spread but may also be direct invasion or (rarely) a primary tumour. Patients may complain of headache, nausea, or lower limb weakness, but signs may be subtle, including cerebellar dysfunction and meningeal irritation. There may also be signs and symptoms of an obstructive hydrocephalus. Investigation is via cytology for malignant cells in the CSF, which may also have a raised protein.
• Other epidemiological factors: unusual causes can be associated with exposure to carriers of pathogens, human or animal, in those susceptible to severe disease. For example, cat scratch disease, caused by Bartonella henselae, can cause encephalitis in a small minority of cases. Those unvaccinated against measles, mumps and rubella (MMR) may be at risk of encephalitis from these causes if exposed.
• Contacts of confirmed meningococcal disease: meningitis and encephalitis are notifiable diseases in the UK. Those who are contacts of patients with confirmed N. meningitidis meningitis should be offered prophylaxis: single dose ciprofloxacin or rifampicin for 2 days as second line. For non-B serotypes, an ACWY vaccine should be offered.

Autoimmune and paraneoplastic encephalitis

These are rarer but clinically extremely significant causes of encephalitis. Paraneoplastic encephalitis refers to an autoimmune process that is associated specifically with a malignancy, whilst autoimmune encephalitis may happen in the absence of a malignant process. Several important causes are summarised below.

Anti-NMDA receptor encephalitis

This is a rapidly progressing encephalitis that affects predominantly young women and presents with a prominent psychiatric component, motor features, seizures, autonomic dysfunction, and occasionally severe hypoventilation. It can be preceded by a mild viral-type illness. It has a strong association with ovarian teratomas and should prompt a search for such a tumour. It may also be associated with small-cell lung cancer and testicular teratoma. Formal diagnosis is by anti-NMDA receptor antibodies in blood and CSF (with the latter being more specific), though these may take time, so diagnosis is frequently made on clinical grounds. Treatment is with immunomodulation (e.g. methylprednisolone ± IVIg or rituximab), as well as management of any neoplasm found.

Paraneoplastic encephalitis

Some malignancies are associated with autoimmune processes that target the central and/or peripheral nervous system. Classically, this is a limbic encephalitis, presenting with prominent behavioural or mood components but also with seizures and cognitive dysfunction. There may also be involvement of the brainstem or descending CNS tracts. One of the most frequent associations is with small-cell lung cancer by way of anti-Hu antibodies, though there is a wide range of autoantibodies and cancer types associated with CNS involvement. Treatment, again, utilises immunomodulatory agents in combination with management of the underlying malignancy.

References

• Dalmau J, Rosenfeld M. Paraneoplastic and autoimmune encephalitis. UpToDate [Internet]. Eds: Wen P, Eichler A. 2021 [cited 6 January 2022]. Available from: https://www.uptodate.com/contents/paraneoplastic-and-autoimmune-encephalitis
• Demopoulos A. Clinical features and diagnosis of leptomeningeal metastases from solid tumours. UpToDate [Internet]. Eds: Wen P, Loeffler J, Eichler A. 2020 [cited 13 April 2022). Available from: https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-leptomeningeal-metastases-from-solid-tumors
• Gluckmann S. Viral encephalitis in adults. UpToDate [Internet]. Eds: Hirsch M, Mitty J. 2021 [cited 6 January 2022]. Available from: https://www.uptodate.com/contents/viral-encephalitis-in-adults
• Hasbun R. Clinical features and diagnosis of bacterial meningitis in adults. UpToDate [Internet]. Eds: Tunkel A, Mitty J. 2021 [cited 6 January 2022]. Available from: https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-acute-bacterial-meningitis-in-adults
• Manji H, Connolly S, Kitchen N, Lambert C, Mehta A. Oxford Handbook of Neurology [Internet]. 2nd ed. Oxford: Oxford University Press; 2014 [cited 29 November 2021]. Available from: https://oxfordmedicine.com/view/10.1093/med/9780199601172.001.0001/med-9780199601172
• Patel P. Encephalitis. BMJ Best Practice [Internet]. 2020 [cited 6 January 2022]. Available from: https://bestpractice.bmj.com/topics/en-gb/436
• Tunkel A. Aseptic meningitis in adults. UpToDate [Internet]. Eds: Hirsch M, Mitty J. 2021 [cited 6 January 2022]. Available from: https://www.uptodate.com/contents/aseptic-meningitis-in-adults