Central nervous system manifestations in Puumala hantavirus infection

Puumala hantavirus causes hemorrhagic fever with renal syndrome, which is endemic and common in Finland. Among adults, 5% present with Puumala antibodies in laboratory test as a marker for previous Puumala hantavirus infection. Hallmarks for the disease include fever, abdominal and back pain, impaired vision and acute kidney insufficiency. Besides typical findings, Puumala hantavirus infected patients often exhibit central nervous system related symptoms i.e., headache, nausea, or light sensitivity. Even though clinical course is mostly mild, serious consequences are possible. Central nervous system complications such as pituitary hemorrhage or encephalitis have been reported in severe cases of Puumala hantavirus infected patients.
We re-evaluated patients from our recent cohort of Puumala hantavirus patients, who had volunteered to be examined for central nervous system and hormonal properties during an acute Puumala hantavirus infection which had taken place 4 to 8 years earlier. Pituitary magnetic resonance imaging was performed. Pituitary size had diminished in all of the patients by the time the acute phase and a control magnetic resonance imaging was considered. One patient with acute phase pituitary hemorrhage suffered from long-lasting panhypopituitarism. Some patients presented with hormonal laboratory abnormalities, which were not caused by their previous Puumala hantavirus infection.
We also explored the possibility that genetic defects in innate host defence, such as in Toll-like receptor 3 (TLR3), could explain Puumala hantavirus encephalitis. Patients with Puumala hantavirus encephalitis were studied. Genetic testing revealed heterozygosity for TLR3 p.L742F novel variant in two patients. This variant was shown to compromise the host defence activity.
Neopterin is a marker for activation of the cellular immune system. Cerebrospinal fluid neopterin was measured from acute-phase PUUV patients and compared to markers of clinical severity. The neopterin levels were elevated in Puumala hantavirus patients. In patients with intrathecal Puumala-IgM-antibody production and those with elevated cerebrospinal fluid protein concentration, cerebrospinal fluid neopterin was especially high.
In conclusion, no late-onset pituitary dysfunction had developed after Puumala hantavirus infection among our patient population. Novel variant of TLR3 p.L742F might predispose to Puumala encephalitis. Elevated central nervous system neopterin concentration is associated with disease severity in acute Puumala hantavirus infection.