96 • CID 2002:35 (1 July) • BRIEF REPORT BRIEF REPORT Hypophyseal Hemorrhage and Panhypopituitarism during Puumala Virus Infection: Magnetic Resonance Imaging and Detection of Viral Antigen in the Hypophysis Timo Hautala, 1 Tarja Sironen, 4 Olli Vapalahti, 4 Eija Pa ¨a ¨ kko ¨, 2 Terttu Sa ¨ rkioja, 3 Pasi I. Salmela, 1 Antti Vaheri, 4 Alexander Plyusnin, 4 and Heikki Kauma 1 Departments of 1 Internal Medicine, 2 Diagnostic Radiology, and 3 Forensic Medicine, University of Oulu, Oulu, and 4 Department of Virology, Haartman Institute, University of Helsinki, and Helsinki Central Hospital, Finland We describe 3 cases of nephropathia epidemica (NE) that confirm that Puumala virus infection may cause hypophyseal injury. Autopsy revealed a hemorrhagic hypophysis positive for Puumala virus antigen in both neuroendocrine stromal and vascular endothelial cells in 1 patient, and 2 patients developed hypophyseal hemorrhage (diagnosed with mag- netic resonance imaging) during or shortly after acute NE, both of whom developed panhypopituitarism. Puumala virus, a member of the Hantavirus genus in the Bunyaviridae family, causes a mild hemorrhagic fever with renal syndrome called “nephropathia epidemica” (NE). Along with the carrier rodent (the bank vole Clethrionomys glareo- lus), Puumala virus and NE are found in most of Europe (excluding the Mediterranean region), and they are highly endemic in areas of the Nordic countries and in many parts of eastern and central Europe. In Finland, there is a cyclic variation in the incidence of NE in proportion to the pop- ulation dynamics of bank voles, with peaks occurring in the autumns of every third to fourth year. An average of 1000 new cases of NE are diagnosed in Finland each year, and 5% of the Finnish population have antibodies to Puumala virus [1]. Transmission to humans is thought to occur by inhalation of aerosolized excreta of infected rodents, and, not surpris- Received 3 October 2001; revised 22 February 2002; electronically published 6 June 2002. Reprints or correspondence: Dr. Timo Hautala, Dept. of Internal Medicine, University of Oulu, PO Box 5000, FIN-90014, Oulu, Finland (thautala@sun3.oulu.fi). Clinical Infectious Diseases 2002; 35:96–101  2002 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2002/3501-0017$15.00 ingly, farmers have an increased occupational risk of infection with Puumala virus [2]. After an incubation period of 2–4 weeks, the clinical course of NE has a typical acute onset with fever, headache, abdominal pain, nausea, diarrhea, signs of renal involvement, and, in one- third of cases, acute myopia [3]. In addition to typical labo- ratory findings that include proteinuria, an elevated serum cre- atinine concentration, and thrombocytopenia, diagnosis is based on the detection of IgM antibodies or low-avidity IgG antibodies to Puumala virus in serum [4, 5]. Spontaneous re- covery is typical for patients with NE, although deaths have been sporadically reported [6–8]. Reviews of clinical aspects of NE reveal a variety of rare complications, including encepha- litis, seizures, Guillain-Barre ´ syndrome, hemorrhages in various organs, kidney rupture, and pancreatitis [3, 9, 10]. There is genetic susceptibility for severe courses of NE, with the oc- currence of shock and severe renal injury associated with hu- man leukocyte antigen B8 haplotype [11]. Hypophyseal hemorrhage and panhypopituitarism associ- ated with NE have been reported elsewhere [6, 8, 12]. The mechanism of the hemorrhage remains unclear, although han- taviruses have been shown to specifically infect endothelial cells and to interact with b-3 integrins present on platelets [13]. It is possible that the complications in the cases reported else- where may have been due to hypovolemic shock during the thrombocytopenic stage of the disease. We present what is, to our knowledge, the first report of evidence of direct Puumala virus invasion of the hypophysis. Furthermore, we report both the use of MRI for diagnosis of hypophyseal hemorrhage and the development of panhypopituitarism during or shortly after acute NE. Case reports. Patient 1 was a 58-year-old male farmer with previous hypertension who had a 4-day history of acute high fever (temperature, 39°C) and headache when he was admitted to the hospital in December 1999. He had a short period of nasal bleeding before admission. He was taking bisoprolol (5 mg/day) and hydrochlorthiazide (12.5 mg/day) for his blood pressure, which was in adequate control. At admission to the hospital, the patient was in stable condition and had a tem- perature of 38.3°C and no signs of edema, respiratory distress, or chest pain. His heart rate was 65 beats/min, and his blood pressure was 146/92 mm Hg. Constant t-wave inversions were noted in inferolateral electrocardiography leads. Laboratory studies revealed the following values: hemoglobin, 149 g/L; WBC count, cells/L; platelet count, platelets/ 9 9 6.9  10 69  10 Downloaded from https://academic.oup.com/cid/article/35/1/96/282574 by guest on 18 November 2021