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Tick borne encephalitis without cerebrospinal fluid pleocytosis
© Stupica et al.; licensee BioMed Central Ltd. 2014
Received: 23 April 2014
Accepted: 5 November 2014
Published: 18 November 2014
Tick borne encephalitis is the most frequent vector-transmitted infectious disease of the central nervous system in Europe and Asia. The disease caused by European subtype of tick borne encephalitis virus has typically a biphasic clinical course with the second phase presenting as meningitis, meningoencephalitis, or meningoencephalomyelitis. Cerebrospinal fluid pleocytosis is considered a condition sine qua non for the diagnosis of neurologic involvement in tick borne encephalitis, which in routine clinical practice is confirmed by demonstration of serum IgM and IgG antibodies to tick borne encephalitis virus.
Here we present a patient from Slovenia, an area highly endemic for tick borne encephalitis, with encephalitis but without cerebrospinal fluid pleocytosis in whom tick borne encephalitis virus infection of the central nervous system was demonstrated.
Cerebrospinal fluid pleocytosis is not mandatory in encephalitis caused by tick borne encephalitis virus. In daily clinical practice, in patients with neurologic symptoms/signs compatible with tick borne encephalitis and the risk of exposure to ticks in a tick borne encephalitis endemic region, the search for central nervous system infection with tick borne encephalitis virus is warranted despite the lack of cerebrospinal fluid pleocytosis.
Tick borne encephalitis (TBE) is the most frequent vector-transmitted infectious disease of the central nervous system (CNS) in Europe and Asia and is considered an emerging disease due to its rising incidence and the spread of endemic areas in recent decades . TBE caused by European subtype of TBE virus (TBEV) has typically a biphasic clinical course with the second phase presenting as meningitis, meningoencephalitis, or meningoencephalomyelitis . Cerebrospinal fluid (CSF) pleocytosis is considered a condition sine qua non for the diagnosis of CNS involvement in TBE, which in routine clinical practice is confirmed by demonstration of serum IgM and IgG antibodies to TBEV -. Cases of TBE with neurologic involvement but without CSF pleocytosis have been published -, however, only the case recently reported by Pöschl et al. was convincingly substantiated . Here we present a patient from Slovenia, an area highly endemic for TBE , with clinical features of encephalitis, who fulfilled criteria for recent CNS infection with TBEV although he had no CSF pleocytosis.
Enzyme linked immunosorbent assay findings
IgM antibody index a
IgG antibody index a
IgM in serum
IgG in serum
IgM in CSF
IgG in CSF
Presenting symptoms and signs of TBE are nonspecific and similar as in acute aseptic meningoencephalitis of other etiologies with fever in 92%, vomiting in 38%, headache in 67-100%, altered consciousness in 12-35.5%, seizures in 0.3-3.3%, tremor in 7-78%, dysphasia in 0.7-3.8%, spinal nerve paralysis in 2.7-15%, and cranial nerve paralysis in 3.3-11% of cases ,. Accordingly, our patient with fever, altered consciousness and tremor of the hands and tongue had clinical indications of acute encephalitis.
In our patient, recent infection with TBEV was demonstrated by the presence of specific IgM and IgG antibodies in serum and further substantiated with the appropriate increase in antibody levels and IgG avidity in convalescent samples. Since detailed history revealed that he had not had TBE in the past, had not traveled outside Slovenia, nor was he vaccinated against TBE, yellow fever or Japanese encephalitis, and he had negative serum antibodies against West Nile virus, the only potential coinfecting flavivirus in Slovenia, the possibility of false positive serological results for TBE due to cross-reaction is highly improbable. In routine clinical practice the finding of specific IgM and IgG serum antibodies in a patient residing in endemic area, who has clinical signs/symptoms of meningitis/encephalitis associated with elevated CSF leukocyte count, is considered confirmatory for TBE ,. However, demonstration of recent infection with TBEV by itself does not attest for CNS involvement; in fact the majority of infections with TBEV are asymptomatic or without prominent morbidity . For a reliable diagnosis of unusual TBE cases such as ours without CSF pleocytosis, which is most likely rather rare and therefore associated with low pre-test probability, not only evidence of a recent infection, but also evidence of CNS infection with TBEV is needed. We were unable to demonstrate the presence of TBEV in CSF by PCR, which is not surprising in regard to earlier reports that the virus can be detected by PCR in blood during the initial phase of TBE, but extremely rarely in blood or CSF during the second phase of the disease . However, we ascertained CNS infection by demonstration of intrathecal synthesis of specific antibodies to TBEV, which is a much more sensitive approach for verifying CNS infection. The main source of CSF antibodies are lymphocytes B, but in patients with TBE lymphocytes B comprise only 3-5% of CSF lymphocyte population . Therefore, one may hypothesize, that the major source of CSF antibodies are lymphocytes B accumulated in the perivascular spaces of brain parenchyma .
In reports including large number of patients with proven TBE, CSF pleocytosis was established in all cases ,,,. This finding, however, might be due to a selection bias because in these studies CSF pleocytosis was one of the inclusion criteria for the diagnosis of TBE . Our case, together with the recently published case by Pöschl et al. , and some earlier less convincing reports ,, show that CSF pleocytosis is not mandatory in patients with encephalitis caused by TBEV. This is in accordance with the reports on encephalitis caused by some other viruses such as herpes simplex 1 in which about 3% of cases take place with normal CSF leukocyte count . The frequency of encephalitis without CSF pleocytosis caused by TBEV infection remains to be determined. However, the paucity of reports implies that such presentation is most probably very rare.
The findings in our patient suggest that in daily clinical practice, in patients with symptoms/signs of encephalitis compatible with TBE and the risk of exposure to ticks in a TBE endemic region, the search for infection with TBEV is warranted despite the lack of CSF pleocytosis. However, to reliably prove that the encephalitis with normal CSF white cell count is caused by TBEV, a proof of TBEV CNS infection is needed besides the usual diagnostic requirements i.e., the evidence of a recent infection with TBEV denoted by the presence of specific serum IgM and IgG antibodies.
Written informed consent was obtained from the patient for publication of this Case report. A copy of the written consent is available for review by the Editor of this journal.
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