Twenty patients with influenza-associated encephalitis/encephalopathy treated during the 1997-2001 influenza A epidemics in Japan are reported from Niigata City General Hospital, Japan. The mean age was 3 years (range 1 to 12 years). No patient had been inoculated with influenza vaccine. None had received aspirin, but 16 patients had received antipyretics (diclofenac or acetaminophen) before onset of encephalopathy. Most had generalized tonic-clonic seizures, and most were treated with midazolam and corticosteroids intravenously. EEG showed high-voltage slow waves in 9 of 17 patients tested, flat records in 3, and focal discharges in 4. Five patients died, 8 had neurologic sequelae (mental retardation and epilepsy), and 7 recovered completely. Patients who died had hepatic involvement and disseminated intravascular coagulation; all had antipyretics but none had received acetaminophen alone. Patients who recovered had also received antipyretics. Five who died had acute necrotizing encephalopathy (with symmetric lesions in the thalami, brain stem, and cerebellum), 1 other had hemorrhagic shock and encephalopathy syndrome, and 2 had symptoms resembling Reye’s syndrome. In 2 deceased patients, plasma levels of cytokines were very high. Influenza vaccination to protect younger children from encephalitis/encephalopathy is recommended, especially those 5 years of age and under. 
COMMENT. The incidence of severe acute encephalitis/encephalopathy with influenza has increased in Japanese epidemics in recent years, and 80% of cases occur in children 0 to 5 years of age. The authors cite 202 cases in the nationwide surveillance, of whom 31% died, 26% had residual neurologic sequelae, and 43% recovered completely. Apart from the lack of vaccination, the reasons for the high incidence, mortality and morbidity were not clear. The above Niigata study shows that acute necrotizing encephalopathy with cerebral edema and thalamic lesions is the reason for the high mortality. The role of antipyretics, especially diclofenac, in the cause of influenza encephalopathy needs further investigation. Hypercytokinemia heralds a poor prognosis. Influenza vaccination is now promoted, especially in young children, and the use of antipyretics is discouraged.