Central nervous system pathology in fatal swine-origin influenza A H1N1 virus infection in patients with and without neurological symptoms: an autopsy study of 15 cases

Abstract

The first influenza pandemic of the twenty-first century was caused by a swine-origin, influenza A (H1N1) virus that contained genes from human, swine, and avian influenza A viruses [4]. It has long been recognized that a small subset of influenza patients develops neurologic complications [1]. Central nervous system (CNS) pathology in influenza virus infection is thought to be indirect and multifactorial [15] and whether H1N1 infects the brain or cerebrospinal fluid (CSF) remains controversial [2]. The current model is that H1N1 triggers a cytokine storm that disrupts the blood–brain barrier and activates glial cells. Subsequent disseminated intravascular coagulation (DIC) and liver and renal dysfunction triggered by hypercytokinemia may also contribute to CNS damage [15]. A number of clinical syndromes affecting the CNS have been described in the context of influenza infection. Although these syndromes have overlapping features and can be caused by other viruses and toxic agents, they have specific clinical, radiological, and laboratory criteria for their diagnosis and the pathogenesis and predisposing factors differ. Classical Reye’s syndrome is a non-inflammatory encephalopathy with associated hepatic microvesicular fatty change and hyperammonemia, and is usually precipitated by the use of salicylates [5]. Reye’slike syndrome occurs at a younger age and does not have the microvesicular fatty change and mitochondrial abnormality of classical Reye’s syndrome [13] and it is not associated with salicylate use. Hemorrhagic shock and encephalopathy syndrome (HSES) occurs in infants, and there is associated fever, shock, DIC, hepatic and renal dysfunction, and the brain shows edema with occasional intracranial hemorrhage [3]. Acute necrotizing encephalopathy (ANE) was first described in Japan in 1995 [8], and then subsequently in other countries [7, 16]. MRI and autopsy studies show bilateral symmetrical infarcts in the thalamus, basal ganglia, cerebellar and cerebral white matter, and brainstem tegmentum. CSF protein is typically elevated and the mortality rate is high. Some infants have complex febrile seizures at the onset, followed by delayed involvement of bilateral frontal lobes or the entire cerebral hemisphere [12]. Recently, familial and recurrent ANE has been described and is associated with mutation in the Ranbinding protein gene (RANBP2) [10]. Like earlier influenza pandemics, the recent pandemic of novel influenza A (H1N1) infection has resulted in a number of cases with neurological complications [2, 7, 16]. The purpose of the present study was to document the changes present in the brains of fatal H1N1 virus patients to determine if cases without documented neurologic A. Mukherjee and J.E.G. Peterson contributed equally to this work.