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Chapter 10: Diagnosis

Antibody testing of CSF difficulties in the serological diagnosis of
flavivirus infections.
Both IgM and IgG anti-TBEV antibodies can be
Structural test formats like ELISA are
detectable in CSF at the onset of CNS especially prone to serological cross reactions,
symptoms, and their detection can be however also hemagglutination inhibition and
important in special circumstances or for indirect immune-fluorescence test systems
supporting the diagnosis of a TBEV infection.
show varying degrees of cross-reactions
IgM is produced locally within the CNS but is
between flavivirus infections or flavivirus
not passively transferred into the CSF to a vaccinations. The test with the highest
great extent. IgG is transferred passively, specificity against other flaviviruses is the
however, especially during inflammatory
neutralization test, which is believed to be
processes in the CNS that disturb the blood–
highly specific for the respective flavivirus.
brain barrier. The detection of IgG in the CSF
is therefore not primarily indicative of an But besides the test systems also the different
acute TBEV infection. IgM can be detectable immunoglobulin classes exhibit varying
within the CSF during the first days of CNS degrees of cross-reactivity. While different
symptoms in only 50% of patients and may IgG-class antibodies show high cross-reactions
only become detectable in the remainder among the members of the flaviviruses, anti-
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during the next 10 days. Therefore, the bodies of the IgM-class are highly specific and
detection of IgM in serum samples is superior usually exhibit low or no cross-reactions.
to the detection of IgM in CSF for the
diagnosis of TBE. The detection of IgM in CSF The degree of cross-reactions between
may help to distinguish an acute TBEV different flavivirus antibodies is also depend-
infection from the antibody response induced ent on the serological status of the patient
by a recent vaccination; an ‘IgM index’ can be resp. vaccinee. In patients exhibiting a primary
calculated for this purpose (Figure 3). immune response due to the first contact of
his immune system with a flavivirus a
The production of IgG antibodies within the monospecific immune response can be mainly
CSF must be demonstrated in order to prove seen with only low and mainly short-lived
that a patient has a neurologic TBEV cross-reactions against other flaviviruses. The
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infection, and this can be evaluated by titer difference, which can be usually found is
calculating the CSF serum index according to significant, which means there is a signifi-
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Reiber et al. There are different options for cantly higher titer to the infecting resp.
the calculation, with the most commonly used vaccinating flavivirus in comparison to other
shown in Figure 4. related, but non-applied flaviviruses.

Serological cross reactions with other If the patient resp. vaccinee was already
flaviviruses infected or vaccinated with a flavivirus, a
second flavivirus infection or vaccination
Due to the close genetic relationship between might cause a serological response of the
the members of the genus Flavivirus within secondary type. Here high antibodies against
the family Flaviviridae some cross-reactions in a different number of flaviviruses can be seen.
the available serological tests might be The titers are high against all flaviviruses and
expected. These serological cross-reactions the infecting resp. vaccinated flavivirus cannot
are mainly directed against the E protein of be distinguished anymore. Sometimes the
the flaviviruses and known for most of the second flavivirus induces a strong serological
available serological tests and they may cause answer of the IgG antibodies against the

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