Differentials
West Nile virus infection
SIGNS / SYMPTOMS
No differentiating signs or symptoms, but lower case fatality rate.
West Nile virus neuroinvasive disease is rarely seen in children, unlike with EEEV infection.
INVESTIGATIONS
One of following: 4-fold increase in the anti-virus antibody titre between acute and convalescent serum; isolation of virus from tissue, blood, or cerebrospinal fluid (CSF); detectable IgM antibody to virus in single serum or CSF sample.
La Crosse virus infection
SIGNS / SYMPTOMS
No differentiating signs or symptoms, but fatalities are rare.
INVESTIGATIONS
One of following: 4-fold increase in the anti-virus antibody titre between acute and convalescent serum; isolation of virus from tissue, blood, or CSF; detectable IgM antibody to virus in single serum or CSF sample.
St Louis encephalitis
SIGNS / SYMPTOMS
No differentiating signs or symptoms, but symptoms are generally milder and lower case fatality rate.
INVESTIGATIONS
One of following: 4-fold increase in the anti-virus antibody titre between acute and convalescent serum; isolation of virus from tissue, blood, or CSF; detectable IgM antibody to virus in single serum or CSF sample.
Liver enzyme elevations may be seen.
Powassan encephalitis
SIGNS / SYMPTOMS
No differentiating signs or symptoms, but lower case fatality rate.
INVESTIGATIONS
One of following: 4-fold increase in the anti-virus antibody titre between acute and convalescent serum; isolation of virus from tissue, blood, or CSF; detectable IgM antibody to virus in single serum or CSF sample.
Reverse transcription-polymerase chain reaction (RT-PCR) or viral isolation from tissue, blood or CSF.
Western equine encephalitis (WEEV) infection
SIGNS / SYMPTOMS
No differentiating signs or symptoms, but lower case fatality rate.
WEEV infections occur mainly on the west coast of the US.
INVESTIGATIONS
One of following: 4-fold increase in the anti-virus antibody titre between acute and convalescent serum; isolation of virus from tissue, blood, or CSF; detectable IgM antibody to virus in single serum or CSF sample.
Herpes simplex virus encephalitis
SIGNS / SYMPTOMS
An oral or genital ulcer may be present, or the patient may have a recent history of such an ulcer.
While fever and headache are common, myalgias, arthralgias, and vomiting are less common.
INVESTIGATIONS
HSV PCR of CSF is diagnostic.
MRI often reveals hyperintensity of the temporal lobes on T2-weighted images.
Listeria monocytogenes (rhombo) encephalitis
SIGNS / SYMPTOMS
Systemic and central nervous system symptoms are very similar to EEEV infection, but may be accompanied by respiratory failure as well.
Meningoencephalitis is mostly seen in infants, pregnant women, or immunosuppressed individuals.
INVESTIGATIONS
CSF and/or blood cultures may grow Listeria.
MRI may show lesions in the brainstem.
Rabies encephalitis
SIGNS / SYMPTOMS
Classically, excessive salivation, dysphagia, and hydrophobia may accompany headache, fever, and altered mental status.
There may be a history or physical evidence of an animal bite.
Universally fatal.
INVESTIGATIONS
Multiple tissue samples are necessary for diagnosis (saliva, skin, serum, CSF).
PCR of skin biopsy, saliva.
Serology.
Paraneoplastic and autoimmune encephalitis
SIGNS / SYMPTOMS
Symptoms similar to EEEV infection.
Psychiatric symptoms, abnormal movements, seizures, autonomic instability, and hypoventilation are important hallmarks.
Underlying malignancy may be identified.
INVESTIGATIONS
Detection of paraneoplastic or autoimmune antibodies in CSF.
Toxoplasma encephalitis
SIGNS / SYMPTOMS
Tends to be more subacute.
Seen typically in immunocompromised individuals (especially HIV).
INVESTIGATIONS
CSF Toxoplasma gondii PCR.
MRI or CT often reveals central nervous system space-occupying lesions.
Toxoplasma serum IgG.
Cryptococcal meningitis
SIGNS / SYMPTOMS
Seen typically in immunocompromised individuals (especially HIV).
Advanced disease may present with lethargy and coma.
Increased intracranial pressure is a common finding, giving rise to seizures, coma, and death.
INVESTIGATIONS
Detection of CSF or serum cryptococcal antigen.
CSF Gram stain may reveal yeast forms.
CSF culture.
Increased opening pressure on lumbar puncture.
Bacterial meningitis
SIGNS / SYMPTOMS
May be no differentiating signs or symptoms, however a non-blanching petechial or purpuric rash can be present with bacterial meningitis.
Post-infectious encephalomyelitis (acute disseminated encephalomyelitis)
SIGNS / SYMPTOMS
May be triggered by a viral or bacterial infection, but is autoimmune in nature.
Symptoms similar to EEEV infection.
Mostly seen in children.
INVESTIGATIONS
Diagnosis is based on clinical and radiological features, and may be a diagnosis of exclusion.
MRI findings include deep and subcortical white matter lesions, as well as grey matter lesions in the basal ganglia and thalami.
Central nervous system tuberculosis
SIGNS / SYMPTOMS
Tends to be more subacute; associated with weeks of weight loss, low grade temperatures, night sweats.
There may be evidence of concurrent pulmonary tuberculosis.
INVESTIGATIONS
Extremely low glucose in CSF (<10 mg/dL).
Elevated protein in CSF (>200 mg/dL).
Mycobacterium tuberculosis may be isolated from CSF, but turnaround time is very slow and sensitivity is low.
Mycobacterium tuberculosis DNA may be detected by PCR of CSF, but sensitivity is low.
Amoebic meningoencephalitis
SIGNS / SYMPTOMS
Patient may have a history of exposure to freshwater or soil.
INVESTIGATIONS
Diagnosis is usually made postmortem.
PCR of brain tissue or CSF for Balamuthia mandrillaris, Acanthamoeba species, or Naegleria fowleri.
Malaria infection
SIGNS / SYMPTOMS
Differential diagnosis for South American EEEV/Madariaga virus infection; not considered a differential diagnosis for North American EEEV infection due to lack of geographical overlap.
Anaemia, jaundice, and persistent chills and fever are more common with malaria.
Residence in/travel from malaria-endemic region.
Inadequate or absent malaria chemoprophylaxis.
INVESTIGATIONS
Giemsa-stained thick and thin blood smears: positive for Plasmodium species.
Rapid diagnostic tests: positive for Plasmodium species.
Chikungunya virus
SIGNS / SYMPTOMS
Differential diagnosis for South American EEEV/Madariaga virus infection; not considered a differential diagnosis for North American EEEV infection due to lack of geographical overlap.
Polyarthralgia is common during the acute phase.
Carpal tunnel syndrome may also develop, but is less common than polyarthralgia.
Absence of bleeding tendency and circulatory failure.
INVESTIGATIONS
ELISA/indirect fluorescent antibody (IFA): positive for chikungunya antibodies.
RT-PCR: positive for chikungunya viral RNA.
Dengue fever
SIGNS / SYMPTOMS
Differential diagnosis for South American EEEV/Madariaga virus infection; not considered a differential diagnosis for North American EEEV infection due to lack of geographical overlap.
Biphasic fever and biphasic rash (transient generalised macular rash followed by a second morbilliform, maculopapular rash).
Bone pain.
INVESTIGATIONS
Detection of virus in serum, immunoglobulins (IgM and IgG), or both by ELISA antibody capture, monoclonal antibody, or haemagglutination.
FBC: thrombocytopenia, decreased total WCC and neutrophils, changing neutrophil-to-lymphocyte ratio, and elevated haematocrit may develop rapidly, particularly before the critical phase of infection.
Zika virus
SIGNS / SYMPTOMS
Zika is now found in the Americas and overlaps geographically with EEEV distribution.
Zika is a disease characterised by fever, rash, myalagias, arthralgias, headache, retro-orbital pain, conjunctivitis, and vomiting.
The disease is transmitted by Aedes mosquitoes and it has been reported in Mexico, South America, North America, Africa, and South East Asia.
INVESTIGATIONS
The diagnosis is confirmed by RT-PCR. Serology tests are available but they strongly cross-react with other flaviviruses, such as dengue and West Nile virus.
Yellow fever
SIGNS / SYMPTOMS
Differential diagnosis for South American EEEV/Madariaga virus infection; not considered a differential diagnosis for North American EEEV infection due to lack of geographical overlap.
The infection can be transmitted by Aedes aegypti.
Patients with yellow fever usually have a more toxic appearance and higher fever. The liver can be tender and enlarged on examination.
Elevated aminotransferases are more prominent.
Deterioration can occur with renal and liver failure and with haemorrhagic manifestations.
INVESTIGATIONS
The diagnosis is confirmed via detection of IgM by ELISA, molecular diagnosis, or direct virus isolation.
Mayaro virus infection
SIGNS / SYMPTOMS
Differential diagnosis for South American EEEV/Madariaga virus infection; not considered a differential diagnosis for North American EEEV infection due to lack of geographical overlap.
In Mayaro virus infection, similar to chikungunya, arthralgias and arthritis are prominent features.
Does not cause encephalitis, but systemic symptoms may be similar.
INVESTIGATIONS
The diagnosis, similar to other arboviruses, can be made via serology, RT-PCR, or direct virus isolation.
Typhoid fever
SIGNS / SYMPTOMS
Differential diagnosis for South American EEEV/Madariaga virus infection; not considered a differential diagnosis for North American EEEV infection due to lack of geographical overlap.
Pulse-temperature dissociation may occur in typhoid fever. The rash is macular and has a preference for the abdominal area.
Hepatosplenomegaly, gastrointestinal bleeding, abnormal mental status, and frank sepsis may occur after the third week of infection.
INVESTIGATIONS
Diagnosis is confirmed by isolation of Salmonella enterica in blood, urine, stool, or bone marrow cultures. Serological antibody titres measured during acute and convalescing periods may also be used for diagnosis.
Serological antibody titres measured during acute and convalescing periods may also be used for diagnosis.
Leptospirosis
SIGNS / SYMPTOMS
Differential diagnosis for South American EEEV/Madariaga virus infection; not considered a differential diagnosis for North American EEEV infection due to lack of geographical overlap.
Neurological involvement is less common with leptospirosis.
In severe cases, jaundice, renal failure, and bleeding can occur.
There is usually a history of exposure to contaminated water or soil, or contact with infected animals or their depositions.
INVESTIGATIONS
Diagnosis depends on detection of antibodies, real-time PCR, or, less commonly, cultures of blood or urine.
Serology (microscopic agglutination test): positive for leptospirosis.
Rubella
SIGNS / SYMPTOMS
Differential diagnosis for South American EEEV/Madariaga virus infection; not considered a differential diagnosis for North American EEEV infection due to lack of geographical overlap.
Prominent lymphadenopathy affecting posterior cervical, posterior auricular, and suboccipital lymph nodes is common.
Enanthema on the soft palate (Forchheimer spots) can occur.
Orchitis can be a complication.
INVESTIGATIONS
Diagnosis is made by antibody detection or rarely via viral culture.
Rocky Mountain spotted fever
SIGNS / SYMPTOMS
The rash tends to evolve into a purpuric appearance. It classically affects palms and soles.
Common complications include: encephalitis, adult respiratory distress syndrome, cardiac arrhythmias, coagulopathy, gastrointestinal bleeding, and skin necrosis.
INVESTIGATIONS
The diagnosis is made by detection of antibodies, direct immunofluorescence, or immunoperoxidase staining in skin biopsies. PCR could be used, but sensitivity is low early in the course of the disease.
Epstein-Barr virus (EBV) infection
SIGNS / SYMPTOMS
Encephalitis is very rare.
Maculopapular and pruritic rash may follow administration of ampicillin or amoxicillin.
Complications such as airway obstruction from massive adenopathy and spleen rupture may occur.
Course tends to be more prolonged (weeks) for EBV compared with EEEV (days).
INVESTIGATIONS
Diagnosis is made by detection of heterophile antibodies or EBV-specific antibodies and by DNA detection.
Acute retroviral syndrome following HIV infection
SIGNS / SYMPTOMS
A history of recent sexual contact is usually obtained.
During the acute retroviral syndrome, pharyngitis can be prominent.
Rash may affect the palms and soles.
INVESTIGATIONS
The best diagnosis method for acute retroviral syndrome is quantitative plasma HIV RNA level (viral load) by RT-PCR and antigen/antibody immunoassay.
Venezuelan equine encephalitis virus (VEEV) infection
SIGNS / SYMPTOMS
No differentiating signs or symptoms, although neurological sequelae may be less severe.
INVESTIGATIONS
ELISA with plaque reduction neutralisation test: positive for VEEV antibodies (IgG or IgM).
South American haemorrhagic fever
SIGNS / SYMPTOMS
Signs and symptoms on presentation may be similar to EEEV infection.
Progression to severe disease with bleeding from mucosas, and the relatively narrow geographical location of cases helps in the differential diagnosis.
INVESTIGATIONS
Diagnosis is based on RT-PCR, or ELISA if RT-PCR is unavailable.
Diagnostic testing requires a biosafety level 4 laboratory.
Tuberculous meningitis
SIGNS / SYMPTOMS
No differentiating signs or symptoms.
Birth in tuberculosis-prevalent countries.
INVESTIGATIONS
Detection of acid-fast bacilli in CSF using PCR.
CT/MRI: can show cerebral tuberculomas or basilar arachnoiditis.[40]
Viral meningitis
SIGNS / SYMPTOMS
A non-blanching petechial or purpuric rash is typical of viral meningitis.
INVESTIGATIONS
CSF: PCR positive for specific viruses.
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