Differentials
Herpes simplex encephalitis
SIGNS / SYMPTOMS
No differentiating signs and symptoms.
St. Louis encephalitis
SIGNS / SYMPTOMS
No differentiating signs and symptoms.
INVESTIGATIONS
Serology: 4-fold increase in virus antibody titre between acute and convalescent serum; detectable IgM antibodies to virus in a single serum or cerebrospinal fluid (CSF) sample. Plaque reduction neutralisation test (PRNT) can delineate West Nile virus from other zoonoform viral infections.
Virus isolation: virus can be isolated from tissue, blood, or CSF.[60][61]
Eastern equine encephalitis
SIGNS / SYMPTOMS
No differentiating signs and symptoms.
INVESTIGATIONS
Serology: 4-fold increase in virus antibody titre between acute and convalescent serum; detectable IgM antibodies to virus in a single serum or CSF sample.
Virus isolation: virus can be isolated from tissue, blood, or CSF.[61]
Western equine encephalitis
SIGNS / SYMPTOMS
No differentiating signs and symptoms.
INVESTIGATIONS
Serology: 4-fold increase in virus antibody titre between acute and convalescent serum; detectable IgM antibodies to virus in a single serum or CSF sample.
Virus isolation: virus can be isolated from tissue, blood, or CSF.[61]
Viral meningitis (other aetiology)
SIGNS / SYMPTOMS
No differentiating signs and symptoms.
INVESTIGATIONS
CSF PCR or viral culture: positive for the causative virus and negative for West Nile virus. However, a negative PCR does not necessarily exclude viral meningitis.
Bacterial meningitis
SIGNS / SYMPTOMS
No differentiating signs and symptoms.
INVESTIGATIONS
CSF analysis: high protein, low glucose, CSF Gram stain positive for specific organisms.[62]
Cryptococcal meningitis
SIGNS / SYMPTOMS
Always suspect in people with a compromised immune system (e.g., AIDS, lymphoma).
INVESTIGATIONS
Cryptococcal polysaccharide antigen: positive in serum or CSF.
Culture: positive for Cryptococcus neoformans in serum or CSF.
CSF microscopy: India ink stain detects the organism.[63]
Tuberculous meningitis
SIGNS / SYMPTOMS
No clear differentiating signs and symptoms.
INVESTIGATIONS
CSF PCR: detection of acid-fast bacilli.
CT/MRI head: can show cerebral tuberculomas or basilar arachnoiditis.[64]
Guillain-Barre syndrome
SIGNS / SYMPTOMS
Typically presents 1 to 8 weeks following acute viral infection.
There is no fever or leukocytosis.
Ascending symmetrical weakness.
No bowel or bladder dysfunction.
No concurrent encephalopathy.
INVESTIGATIONS
Diagnosis is usually clinical.[65]
CSF analysis: shows elevated protein, no elevated cell count.
Poliovirus-associated poliomyelitis
SIGNS / SYMPTOMS
Residence or travel in endemic area.
Unimmunised status.
Usually clinically and pathologically identical to West Nile poliomyelitis.
INVESTIGATIONS
Virus culture (stool, CSF, or pharynx): positive for poliovirus.
Diagnosis is usually clinical.
Zika virus infection
SIGNS / SYMPTOMS
Residence in or travel to an endemic region.
Widespread maculopapular (sometimes morbilliform) rash is common; it is often itchy.
Non-purulent conjunctivitis or conjunctival hyperaemia may be present.
Not associated with neuroinvasive disease but has been associated with Guillain-Barre syndrome (GBS).
INVESTIGATIONS
Reverse transcriptase PCR: positive for Zika virus RNA.
Serology: positive for Zika virus antibodies.
Dengue fever
SIGNS / SYMPTOMS
Residence in or travel to an endemic region.
Biphasic fever and biphasic rash (transient generalised macular rash, followed by a second morbilliform, maculopapular rash).
Bone pain.
INVESTIGATIONS
Serology: positive for dengue virus antibodies.
Chikungunya virus infection
SIGNS / SYMPTOMS
Residence in or travel to an endemic region.
Prominent joint symptoms.
Absence of signs of neuroinvasive disease.
INVESTIGATIONS
Reverse transcriptase PCR: positive for Chikungunya virus RNA.
Serology: positive for Chikungunya virus antibodies.
Leptospirosis
SIGNS / SYMPTOMS
There is usually a history of exposure to contaminated water or soil, or contact with infected animals or their depositions.
Neurological involvement is less common.
Biphasic presentation.
Bilateral conjunctival suffusion is pathognomonic.
Muscle tenderness is localised in calves.
Pulmonary signs and symptoms (e.g., cough, dyspnoea).
In severe cases, jaundice, renal failure, and bleeding can occur.
INVESTIGATIONS
PCR: positive for Leptospira RNA.
Serology (microscopic agglutination test): positive for Leptospira antibodies.
Blood or urine culture: positive for Leptospira.
Malaria
SIGNS / SYMPTOMS
Residence in or travel to an endemic region.
Inadequate or absent malaria chemoprophylaxis.
Neurological involvement is less common.
INVESTIGATIONS
Full blood count: may show anaemia and/or thrombocytopaenia.
Giemsa-stained thick and thin blood smears: detection of asexual or sexual forms of the parasites inside erythrocytes.
Rapid diagnostic tests: detection of parasite antigen or enzymes.
Lyme disease
SIGNS / SYMPTOMS
History of tick bite.
More chronic course and gradual onset.
Erythema chronicum migrans.
Lyme arthritis.
Chronic radicular paraesthesias.
Rocky Mountain spotted fever
SIGNS / SYMPTOMS
Characteristic rash appears 2 to 6 days after fever onset.
Initially maculopapular eruption that begins on wrists and ankles and spreads to trunk and extremities, involving palms and soles. Later becomes petechial in appearance.[68]
INVESTIGATIONS
Serology: positive for Rickettsia rickettsii.[69]
Legionnaire's disease
SIGNS / SYMPTOMS
Respiratory symptoms and signs, such as cough, chest tightness, crackles, rhonchi, chest tightness.[70]
Brain tumour
SIGNS / SYMPTOMS
Neurological deficit usually focal.
Symptom onset more gradual.
INVESTIGATIONS
CT/MRI head: shows mass.[71]
Brain abscess
SIGNS / SYMPTOMS
Neurological deficit usually focal.
Symptom onset more gradual.
INVESTIGATIONS
CT/MRI head: shows abscess.[72]
Stroke
SIGNS / SYMPTOMS
Neurological deficit usually focal.
Progression of signs/symptoms occurs over a few hours, not days or weeks.
INVESTIGATIONS
CT/MRI head: shows infarction and/or haemorrhage.[73]
Sub-acute bacterial endocarditis
SIGNS / SYMPTOMS
Cardiac murmur and signs of congestive heart failure present.
Characteristic but less common features include splinter haemorrhages, Osler's nodes, Janeway lesions, and Roth's spots.
INVESTIGATIONS
Bacterial blood cultures: positive.
Echocardiogram: shows vegetations.
Coronavirus disease 2019 (COVID-19)
SIGNS / SYMPTOMS
Important to consider the current epidemiological situation. May give history of unwell contacts.
Respiratory symptoms may be prominent.
INVESTIGATIONS
Real-time reverse transcription polymerase chain reaction (RT-PCR): positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA. Rapid antigen tests may also be used.
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