Fatal Influenza A(H1N1)pdm09 Encephalopathy in Immunocompetent Man

Marie Simon¹, Romain Hernu¹, Martin Cour, Jean-Sébastien Casalegno, Bruno Lina, and Laurent Argaud

Author affiliations: Hospices Civils de Lyon, Lyon, France (M. Simon, R. Hernu, M. Cour, J.S. Casalegno, B. Lina, L. Argaud); Université Claude Bernard Lyon 1, Lyon (M. Cour, B. Lina, L. Argaud); Institut National de la Santé et de la Recherche Médicale, Lyon (M. Cour, L. Argaud); Centre National de Référence des Virus Influenza Région Sud France, Lyon (J.S. Casalegno, B. Lina)

Abstract

We report an immunocompetent patient who had fatal encephalopathy after mild influenza. He rapidly died after unusual symptoms related to intracerebral thrombosis and hemorrhage. A brain biopsy specimen was positive for influenza A(H1N1)pdm09 virus RNA, but a lung biopsy specimen and cerebrospinal spinal fluid samples were negative.

Influenza-related neurologic complications are rare, especially in immunocompetent adults. The clinical signs and severity of this pathology are variable. We report a life-threatening specific complication of influenza A(H1N1)pdm09 infection that was responsible for lethal central venous thrombosis.

The Study

A previously healthy 26-year-old man from northern Africa was admitted to our emergency department in Lyon, France, in November 2009, during the peak of influenza A(H1N1)pdm09 infection in France (1), because of cephalalgia, confusion, and lethargy. A Glasgow Coma Score was 12. He had no history of influenza vaccination. Initial symptoms (fever, cough, and myalgia) began a week before admission. Several members of his family had similar symptoms. There were no risk factors indicative of a complicated disease. Body temperature at admission was 36.8°C, and he had no respiratory distress or signs of shock. Results of a chest radiograph were normal.

Figure

Thumbnail of A) Noncontrast cranial computed tomographic (CT) scan of a 26-year-old immunocompetent man with influenza, showing diffuse cerebral edema (Ed) and bilateral parieto-occipital hematoma (H). B) Cranial CT scan with contrast injection, showing diffuse cerebral edema (Ed) and cord sign (arrow) related to a venous thrombosis (VT) of the superior sagittal sinus.

Figure. . . A) Noncontrast cranial computed tomographic (CT) scan of a 26-year-old immunocompetent man with influenza, showing diffuse cerebral edema (Ed) and bilateral parieto-occipital hematoma (H). B) Cranial CT scan with...

During the first hours after admission, the patient lost consciousness (Glasgow coma score 3), which was associated with a seizure. His pupils were anisocoric and nonreactive to light. Intubation was then required to protect the airways. A cranial computed tomographic (CT) scan showed thrombosis of the superior sagittal sinus associated with 3 cerebral hematomas (left frontal and bilateral parieto-occipital) and diffuse cerebral edema with signs of increased intracranial pressure (Figure).
Biologic results showed an increased neutrophil count (14.5 ×10⁹ cells/L), thrombocytopenia (25 × 10⁹ platelets/L), and an inflammatory syndrome (C-reactive protein level 49.7 mg/L). There was no renal dysfunction and no increases in levels of serum lactate or abnormalities in levels of cardiac, hepatic, and pancreatic enzymes. Toxicology screening showed no alcohol or drugs present. Results of thrombophilia screening (standard blood coagulation tests and tests for antibodies against thrombin III and phospholipid) were negative.
Real-time PCR for nasopharyngeal swab specimens rapidly confirmed influenza A(H1N1)pdm09 infection. Test results for cerebrospinal fluid (CSF) (312,000 erythrocytes/mm³, 1,000 leukocytes/mm³, glucose level 0.84 mmol/L, and protein level 2.7 g/dL) were not informative because of massive hemorrhaging. Results of real-time PCR for CSF were negative for influenza A(H1N1)pdm09 virus, herpes simplex virus (HSV1 and HSV2), and enterovirus. Results of serologic analyses for infectious agents often associated with encephalopathy (cytomegalovirus, Epstein-Barr virus, HSV, rubella virus, enterovirus, and Mycoplasma pneumoniae) were negative. The patient was also negative for HIV. Surgery was not considered because the neurologic condition was irreversible. Two electroencephalographic records showed no cerebral activity, confirming this poor prognosis. The patient died 72 hours after admission.
An autopsy was performed. Macroscopic examination showed a congested and edematous brain. Thrombosis of the superior sagittal sinus was caused by a platelet–fibrin thrombus. Acute subarachnoid hemorrhage was found with multiple intraparenchymal infarcts involving the frontal and parietal lobes. Cerebral tonsillar and bilateral uncal herniations were noted. Inflammatory infiltrates were scarce, and few perivascular lymphocytes were found. Immunohistochemical analysis showed no macrophagic infiltration, suggesting recent (<3 a="" and="" biopsy="" brain="" but="" by="" culture.="" days="" for="" infarcts.="" influenza="" lung="" negative="" p="" pcr="" pdm09="" positive="" real-time="" rna="" specimen="" virus="" was="">