Journal of Medical Virology 84:1151–1156 (2012)
National Survey of Pandemic Influenza A (H1N1) 2009-Associated Encephalopathy in Japanese Children Hisashi Kawashima,1* Shinichiro Morichi,1 Akihisa Okumara,2 Satoshi Nakagawa,3 Tsuneo Morishima4 and the collaborating study group on influenza-associated encephalopathy in Japan 1
Department of Pediatrics, Tokyo Medical University, Tokyo, Japan Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan 3 Department of Intensive Care, National Center for Child Health and Development, Tokyo, Japan 4 Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan 2
The novel pandemic (pdm) influenza A (H1N1) 2009 virus caused an epidemic of critical illness, with some patients developing severe acute respiratory distress syndrome. Pdm H1N1 2009 infection has been reported to cause fatal encephalopathy and myocarditis as well as pneumonia. To investigate the actual characteristics of the encephalopathy associated with pdm H1N1 2009 infection in Japan, questionnaires were distributed and information collected on 207 cases of encephalopathy during one season. The results of the survey showed that encephalopathy was reported predominantly in males. The outcome was recorded in 188 of the 207 cases; 16 of 188 patients (8.5%) died, while 23 (12.2%) had sequelae. Serious cases were distributed across all age groups. Febrile convulsion was noted at a higher rate in medical pasthistory in cases without sequelae (40 of the 149 cases; 27%) than in serious cases. In contrast, pre-existing epilepsy and mental retardation were observed more frequently in serious cases. Twelve cases exhibited biphasic seizures; onehalf of these had sequelae, but none was fatal. Ten cases were accompanied by high cytokine levels, and three of these children died. Among the 149 cases with good outcomes, 29 of 116 cases (25%) showed abnormalities on MRI, and 14 of these demonstrated reversible splenial lesions. Abnormal behaviors, especially delirium and visual hallucinations, were observed more frequently in cases without sequelae. In conclusion, pdm H1N1 2009 infection-associated encephalopathy was a critical disease in children, with rapidly progressive characteristics similar to those of seasonal influenza-associated encephalopathy. J. Med. Virol. 84:1151–1156, 2012. ß 2012 Wiley Periodicals, Inc. ß 2012 WILEY PERIODICALS, INC.
KEY WORDS: MERS; EEG; abnormal behaviour; cytokine; MRI
INTRODUCTION The novel pandemic (pdm) influenza A (H1N1) 2009 virus caused an epidemic of severe illness, with some patients developing severe acute respiratory distress syndrome [Miroballi et al., 2010; Go´mez-Go´mez et al., 2010]. In addition to mortality due to pneumonia, pdm H1N1 2009 infection has also been reported worldwide to cause fatal or serious cases of encephalopathy and myocarditis [CDC, 2009; Kitcharoen et al., 2010; Zheng et al., 2010]. The WHO has stated that as of August 1, 2010, laboratory-confirmed cases of pdm influenza H1N1 2009, including over 18,449 deaths, have been reported in more than 214 countries and overseas territories or communities [WHO, 2010]. The incidence of seasonal influenza-associated encephalopathy has been increasing in Japan since 1998, and the mortality rate is high at approximately 30% [Yoshikawa et al., 2001; Morishima et al., 2002]. Despite critical care for seasonal influenza-associated encephalopathy, approximately one-half of Japanese patients experience sequelae. Pdm H1N1 2009 Grant sponsor: The Ministry of Health, Labour, and Welfare of Japan. *Correspondence to: Hisashi Kawashima, MD, PhD, Department of Paediatrics, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. E-mail:
[email protected] Accepted 29 March 2012 DOI 10.1002/jmv.23317 Published online in Wiley Online Library (wileyonlinelibrary.com).
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Kawashima et al. TABLE I. Profiles of Patients With Influenza-Associated Acute Encephalopathy According to Outcome
Neurological sequelae Cases (total: 188) Age (mean standard deviation) Sex (male:female) Past history Perinatal abnormality Underlying disease Febrile seizure Epilepsy Mental retardation Bronchial asthma Vaccination Seasonal New Antiviral therapy (Oseltamivir phosphate or Zanamivir hydrate) Symptoms Delirium Pneumonia
Fatal or with sequelae
No sequelae
Statistical analysis (chi-square test for independence)
39 6.2 4.03 21:18
149 7.8 3.16 98:50 (unknown: 1)
NS NS
3 6 4 5 5 5
5 33 40 1 5 28
NS NS P < 0.05 P < 0.05 P < 0.05 NS
4 5 33
40 28 147
P < 0.05 NS NS
13 7
82 23
P < 0.05 NS
Statistical significance was determined using the chi-square test for independence (sequelae vs. without sequelae). NS, not statistically significant.
infection differs from seasonal influenza in some virological characteristics, such as cell tropism and propagation in tissues [Nakajima et al., 2010]. Ekstrand et al. [2010] analyzed 18 cases of children with neurological complications and reported that patients with 2009 H1N1 influenza were significantly more likely to present with encephalopathy, aphasia, or focal neurological findings. Therefore, the characteristics of pdm 2009-associated encephalopathy might differ from those of seasonal influenza and therefore require a different treatment strategy. To investigate this hypothesis, all hospitals that provide medical treatment to children with encephalopathy were sent a questionnaire. The attending physicians were interviewed and the profiles and radiological findings of fatal cases collected. This survey included more than 200 patients, making it the largest and most reliable study of childhood encephalopathy cases resulting from the pdm H1N1 2009 infection performed till date worldwide. In addition, various patient characteristics were analyzed by outcomes in order to determine the predictors of poor prognosis in these patients. Subjects and Methods A questionnaire was provided to 824 pediatric and general hospitals that treat children with encephalopathy. The records of a total of 207 cases of pdm 2009associated encephalopathy in patients below 16 years of age from September 2009 to February 2010, including 14 fatal cases, were collected. The attending physicians at each hospital were interviewed to confirm that encephalopathy was the cause of death. The sequelae of encephalopathy were divided into three categories: mild (epilepsy and/or mild mental retardation), moderate, and severe (bedridden or died), in accordance with a previously reported classification J. Med. Virol. DOI 10.1002/jmv
scheme for the severity of sequelae of encephalopathy [Morishima et al., 2002]. Statistical significance was determined using the chi-square test for independence for significant differences in proportions of patients with sequelae or mortality and those without sequelae, Student’s t-test for differences in continuous variables (hours after onset) (Tables I and III), and the Mann–Whitney U-test/ rank sum test for differences in categorical variables such as outcome from fatal to no sequelae (Table II). RESULTS Data on 207 encephalopathy cases were collected from 143 institutes from July 2009 to January 2010. The patients were predominantly male (127 boys, 79 girls, 1 unrecorded). The pdm H1N1 2009 infection was confirmed by RT-PCR in 153 of 207 cases and by influenza A rapid tests and epidemiological data in the remaining cases (99.8% of the influenza viruses isolated in Japan during this time period were classified as pdm H1N1). The outcome at discharge was recorded in 188 cases. Sixteen of 188 cases (8.5%) died, 23 (12.2%) had sequelae (5 severe, 2 moderate, and 14 mild; the severity was not recorded in 2 cases), and the remainder (79.3%) had no sequelae. The age distributions of fatal cases and cases with severe sequelae are shown in Figure 1. There was only one case involving a patient less than 1 year of age. The serious cases were distributed among all ages. The greatest numbers of cases were in children ranging from 5 to 10 years in age. However, the proportion of serious cases was higher in children below 5 years of age than in older children. Table I shows the underlying disease and medical history for the cases for which the outcome is known. Forty of 149 cases (27%) with no sequelae had a
Pdm Influenza Encephalopathy in Japan
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TABLE II. Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) Imaging and Electroencephalogram (EEG) Findings According to Outcome Sequelae Outcome
Fatal
Severe
Mild or moderate
No sequelae
Statistical analysis
Brain MRI (abnormality/cases with diagnostic findings) MERS PRES Brain CT (abnormality/cases with diagnostic findings) Low density of brainstem Diffuse brain oedema EEG (abnormality/cases with diagnostic findings) HVS Low voltage Flat EEG
3/3 0/3 0/3 12/12 5/12 3/12
3/5 0/5 0/5 2/5 0/5 2/2
6/15 2/15 0/15 2/12 0/12 0/12
29/116 14/116 1/116 45/129 0/129 0/129
P < 0.05 NS NS P < 0.05 P < 0.05
1/8 2/8 4/8
1/4 0/4 3/4
5/14 1/14 0/14
92/125 0/125 0/125
P < 0.05 P < 0.05 P < 0.05
Statistical analysis was performed using Mann–Whitney’s U test/rank sum test for the categorical variable of outcome from death to no sequelae. NS, not statistically significant; MERS, mild encephalitis/encephalopathy with a reversible splenial lesion; PRES, posterior reversible encephalopathy syndrome; HVS. high-voltage slow activity.
medical history of febrile convulsion and 28 (19%) had bronchial asthma. In addition, a family history of at least one of the conditions listed in Table I was recorded for 14 cases, nine of which had a family history of febrile convulsion. Pre-existing epilepsy and mental retardation were rare in contrast. The cases with no sequelae had a statistically higher rate of medical past history of febrile convulsion than did the cases with sequelae or fatal cases. The proportion of cases with pre-existing epilepsy or mental retardation was also significantly higher among the serious cases than among the cases with no sequelae. There was no difference in age or gender distribution between the serious cases and the cases without sequelae (Table I). Inoculation with the pdm 2009 vaccine had been performed in only ten cases (5.3%) (Table I). In the 188 cases for which the outcome was known, 12 patients experienced biphasic seizures (status
Fig. 1. Age distribution of influenza-associated acute encephalopathy (IAE) cases. [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/jmv]
convulsion followed a few days later by a cluster of seizures). One-half of those patients had sequelae, but none died. Ten cases were classified as acute encephalopathy accompanied by high cytokine levels; three of these children died. The MRI and CT imaging findings are summarized in Table II. In all of the fatal cases, abnormal findings such as generalized or brainstem oedema were seen by MRI and/or CT. Among the 149 cases with good outcomes, 29 of 116 cases (25%) showed abnormalities by MRI and 45 of 129 (35%) by CT. In cases with good outcomes, 14 showed MRI evidence of mild encephalitis/encephalopathy with a reversible splenial lesion (MERS), one posterior reversible encephalopathy syndrome, and one diffuse swelling of the cerebrum and high signal areas in several regions of white or gray matter by diffusion-weighted image (DWI) or fluid-attenuated inversion recovery (FALIR). The Mann– Whitney U-test/rank sum test for categorical variables (i.e., different outcomes from death to lack of sequelae) confirmed that the severity of the outcome was significantly correlated with the degree of abnormality of the MRI and CT findings (Table II). The EEG findings are shown in Table II. The fatal cases showed flat or low voltage. In contrast, 92 out of 125 cases (74%) showed high-voltage slow waves. The severity of outcome also correlated with the degree of abnormality (flat or low voltage) of the EEG results. There was no difference in the mean time of onset of neurological symptoms between patients with or without sequelae (23.75 hr vs. 20.43 hr). In contrast, among the patients with biphasic seizures, the time interval between the onset of fever and that of neurological signs was significantly longer for the cases with good outcomes (mean: 127 hr) than for those with poor outcomes (mean: 26.7 hr) by Student’s t-test. The presence of MERS had no significant effect on the outcome. Fatal cases showed a very short interval, approximately 24 hr (mean: 27.2 hr), between fever onset and the appearance of encephalopathy symptoms. J. Med. Virol. DOI 10.1002/jmv
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Kawashima et al. TABLE III. Abnormal Behaviors Observed According to Outcome
Neurological sequelae Delirium Oral tendency Visual hallucination Emotional hallucination Auditory hallucination Limbic system
Fatal or sequelae
No sequelae
Statistical analysis
13 1 1 2 0 7
82 1 23 20 4 23
P < 0.05 NS P < 0.05 NS NS NS
Statistical significance was determined using the chi-square test for independence (sequelae vs. without sequelae). The rates of delirium and visual abnormalities were significantly lower in patients with sequelae than in those without sequelae. NS, not statistically significant.
Abnormal behavior was divided into five categories: Oral tendency, visual, emotional, auditory, and limbic system encephalitis. Abnormal behaviors and visual abnormalities were observed significantly more frequently in cases with no sequelae (Table III). Approximately one-half of the cases were treated with oseltamivir (Tamiflu) or zanamivir before the appearance of any abnormal behavior (data not shown). Pneumonia was recorded in 2 of 16 fatal cases, 3 of 5 (60%) severe outcome cases, 2 of 13 mild-to-moderate cases (13%), and 23 of 149 sequelae-free cases. Encephalopathy was treated with a methylprednisolone pulse in almost all patients; 72 cases were also treated with gamma globulin. On the other hand, hypothermia and edaravone were used only in approximately 10 cases (data not shown). DISCUSSION This study presents a national survey of pdm 2009associated encephalopathy. The total number of patients hospitalized in Japan during the epidemic was 17,646, 79.2% of whom were children. During this time, 99% of influenza viruses isolated in Japan were identified as pdm H1N1 2009. At least 1.5% of the children hospitalized were admitted for encephalopathy [Ministry of Health, Labour, and Welfare, 2011]. Encephalopathy occurred predominantly in males, similarly to pneumonia associated with pdm flu in Japan [Nishiyama et al., 2010]. As the rate of H1N1 infection is similar in male and female patients, there must be some reason for the preponderance of males among encephalopathy patients. A history or family history of febrile convulsion appears to incur a susceptibility to encephalopathy in our cohort of patients presenting with H1N1, and as such may suggest genetic influences on responses to viral infections, as previously reported [Tardieu, 2010]. Seasonal influenza-associated encephalopathy has been increasing in Japan across the nation; the mortality rate is high, at approximately 30%, and there is no effective treatment. Seventy percent of patients with seasonal influenza-associated encephalopathy were under 5 years of age [Morishima et al., 2002]. The greatest number of patients that were treated by doctors and hospitalized due to pdm H1N1 2009 infection belonged to the 5–10 years age group. Therefore, J. Med. Virol. DOI 10.1002/jmv
the prevalence of encephalopathy in patients below 5 years of age was low only because the rate of infection was low in this age group. There have been few reports of pdm H1N1 2009-associated encephalopathy in other countries. In the United States, Baltagi et al. [2010] reported four cases of encephalopathy in patients aged 2–10 years, two of which were accompanied by sequelae. In Europe, two cases with acute necrotising encephalopathy and one with non-specific white matter changes were reported. However, neurological manifestations occurred more frequently than reports of encephalopathy [Surana et al., 2011]. Kedia et al. [2011] reported that among 307 children with pdm H1N1, 23 were suspected of having neurological complications. Of these 23, 15 (65%) required intensive-care monitoring. The most common manifestation was seizure with underlying neurological disease (in 62% of cases), followed by encephalopathy with or without neuroimaging changes (in 26% of cases). However, the overall incidence of encephalopathy was not high, and the number of fatal cases in the United States was extremely low. On the other hand, in Asia, Zheng et al. [2010] reported that 18 of 148 hospitalized children had neurological complications. Four (3%) previously healthy patients in China died, three of severe influenza-associated encephalopathy and one of secondary fungal meningitis. Surana et al. [2011] reported in Europe that 2–15% of admitted children presented with neurological problems, of which 69% had features of encephalopathy. With more than 200 cases, the present study is the largest survey worldwide of childhood encephalopathy cases resulting from pdm H1N1 2009 infection. Pdm H1N1 2009 infection is known to differ from seasonal influenza in some virological characteristics, such as cell tropism and propagation in tissue [Mauad et al., 2010; Nakajima et al., 2010]. Therefore, the characteristics of pdm 2009-associated encephalopathy might differ from those of seasonal influenza. The Ministry of Health, Labour, and Welfare research group and other groups have highlighted abnormal speech and behavior as important prodromal symptoms of influenza encephalopathy [Ryan et al., 1999; Nagao et al., 2008]. According to the survey on the clinical manifestations of seasonal influenza, abnormal speech and behavior were observed in 10.5% of
Pdm Influenza Encephalopathy in Japan
patients [Okumura et al., 2005]. In this study of pdm H1N1 2009 infections, 99 of 188 cases (52.6%) demonstrated such abnormal behaviors. In particular, delirium and visual hallucinations were reported in the patients with good outcomes. This might have been because the serious cases, including those that were ultimately fatal, progressed rapidly, within 1–2 days. The high rate of behavioral disturbance is a characteristic of pdm H1N1 2009-associated encephalopathy. Regardless of the underlying cause, visual disturbance and abnormal speech are positive prognostic indicators. MRI showed reversible splenial lesions consistent with those of MERS in 14 cases. MERS has recently been reported as a new clinical entity of encephalitis and/or encephalopathy [Bulakbasi et al., 2006; Takanashi et al., 2009; Fluss et al., 2010]. Splenial lesions have been previously reported in viral infections, such as influenza and rotavirus infections, haemolytic uremic syndrome caused by O-157, and hyponatremia. Transient neurologic manifestations (most often altered levels of consciousness and convulsions) can occur but completely resolve without treatment in most cases. The MRI changes in MERS are also transient and disappear within a week. From the literature, the prognosis was reported to be favorable when the lesion was restricted to the splenium with no overall lesion or edema of the brain [Takanashi et al., 2009]. The mechanism of the regional specificity is not known. Pathologically, high-intensity signals in the white matter on diffusion-weighted images generally suggest edema and demyelination [Karaarslan and Arslan, 2008]. However, considering that fewer neurons are present in the splenial region and that the clinical symptoms are mild, edema in the medullary sheath and inflammatory cell infiltration, but not cytotoxic edema, should be assumed. Notably, one-half of cases with biphasic seizures, but very few of those with hypercytokinemia, experienced sequelae. Therefore, pdm H1N1-associated encephalopathy patients can largely be classified into two groups: Those who exhibited biphasic seizures and those with MERS and a good prognosis. In the present study, neurological symptoms appeared around 24 hr after the onset of fever in the fatal cases, and most other cases with poor outcomes exhibited neurological symptoms within 24 hr after the onset of fever. This correlation indicates that the rapidity of response is an important factor in determining the outcome of pdm H1N1-associated encephalopathy. The patients with biphasic seizures can be classified into two groups with different pathophysiologies. These results suggest that high-intensity-signal splenial lesions and abnormal behavior suggest a good prognosis. EEG findings of high-voltage slow waves were not poor prognostic indicators. The efficacy of anti-influenza virus treatment was not confirmed. One-third of the patients had received anti-influenza virus medication. Special treatments were used in many cases. However, no statistically
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significant effect could be verified because many of the fatal and serious cases progressed rapidly. Concerning treatment, it is possible that many cases were over-treated due to high number of patients who showed high-intensity signals corresponding to reversible splenial lesions, which represent mild encephalopathy. In contrast, the cases with biphasic seizures showed a high rate of sequelae and rapid progression. No effective treatment for this type of influenza-associated encephalopathy is known, although hypothermia and radical scavengers might be effective. A national survey should be performed to establish more useful treatments. Severe pneumonia was the most common reason for hospitalization in children without underlying disease, although encephalopathy associated with serious sequelae was seen in otherwise healthy children. Many aspects of the mechanisms by which these severe infections develop remain unclear. Encephalopathy may result in permanent neurological damage and thus significantly affect the quality of life of patients and their families. These cases indicate the importance of developing a uniform and efficient treatment protocol for pdm H1N1 2009-associated encephalopathy, with components such as steroid pulse and gamma-globulin, to reduce the mortality and sequelae of this disease. ACKNOWLEDGMENTS We wish to thank the physicians in medical institutions who participated in the survey despite their busy schedules. REFERENCES Baltagi SA, Shoykhet M, Felmet K, Kochanek PM, Bell MJ. 2010. Neurological sequelae of 2009 influenza A (H1N1) in children: A case series observed during a pandemic. Pediatr Crit Care Med 11:179–184. [PubMed: 20081552]. Bulakbasi N, Kocaoglu M, Tayfun C, Ucoz T. 2006. Transient splenial lesion of the corpus callosum in clinically mild influenzaassociated encephalitis/encephalopathy. AJNR Am J Neuroradiol 27:156–158. [PubMed: 17032879]. Centers for Disease Control and Prevention (CDC). 2009. Neurologic complications associated with novel influenza A (H1N1) virus infection in children - Dallas, Texas, May 2009. Morb Mortal Wkly Rep 58:773–778. [PubMed: 19629027]. Ekstrand JJ, Herbener A, Rawlings J, Turney B, Ampofo K, Korgenski EK, Bonkowsky JL. 2010. Heightened neurologic complications in children with pandemic H1N1 influenza. Ann Neurol 68:762–766. [PubMed: 20865762]. Fluss J, Ferey S, Menache-Starobinski C, Delavelle J, Van Bogaert P, Vargas MI. 2010. Mild influenza-associated encephalopathy/ encephalitis with a reversible splenial lesion in a Caucasian child with additional cerebellar features. Eur J Paediatr Neurol 14:97–100. [PubMed: 19819739]. Go´mez-Go´mez A, Magan˜a-Aquino M, Garcia-Sepu´lveda C, OchoaPe´rez UR, Falco´n-Escobedo R, Comas-Garcı´a A, Aranda-Romo S, Contreras-Trevin˜o HI, Jimene´z-Rico PV, Banda-Barbosa MA, Dominguez-Paulin F, Bernal-Blanco JM, Pere´z-Gonza´lez LF, Noyola DE. 2010. Severe pneumonia associated with pandemic (H1N1) 2009 outbreak, San Luis Potosı´, Mexico. Emerg Infect Dis 16:27–34. [PubMed: 20031039]. Karaarslan E, Arslan A. 2008. Diffusion weighted MR imaging in non-infarct lesions of the brain. Eur J Radiol 65:402–416. [PubMed: 17555903].
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