Review
Influenza-associated central nervous system dysfunction: A literature review

https://doi.org/10.1016/j.tmaid.2008.03.003Get rights and content

Summary

Context

Influenza is a viral pathogen that imposes an under-recognized burden of central nervous system (CNS) disease.

Objective

To describe the epidemiology, clinical features and etiology of the CNS disease entities associated with influenza.

Data sources

English-language publications from MEDLINE.

Data extraction

Articles were identified using “influenza, human”[Mesh] AND “nervous system diseases”[Mesh] and screened for inclusion based on relevance and scientific rigor.

Results

Febrile seizure is the most frequently encountered influenza-associated CNS complication, with one in five children hospitalized with influenza experiencing one or more events. In most instances, symptoms resolve without neurological sequelae, although the risk for subsequent afebrile seizure may be increased. Influenza-associated encephalitis/encephalopathy is a less common but potentially more serious complication that is widely reported in Japanese populations, although cases from other East Asian countries, North America, and Europe have been described. Clinical manifestations are diverse, and typically involve febrile seizures and abnormal behaviors in mild cases, with rapid evolution through decreased consciousness to coma in severe forms. In cases of serious disease, the prognosis is often poor, with outcomes including death or severe neurological sequelae. Influenza is also a known trigger for a number of rarely encountered, yet often serious, CNS diseases, including the encephalopathic condition of Reye's syndrome, the peripheral neuropathy known as Guillain–Barré syndrome, and the lesser known complaints of Kleine–Levin syndrome and post-encephalitic Parkinson's disease.

Conclusions

Influenza imposes a sizeable burden of CNS disease. Increased awareness and monitoring of CNS function is indicated, especially in infants and young children.

Introduction

Influenza is a transmissible viral pathogen of the upper respiratory tract.1 In almost all cases, fever, cough, and myalgia present early in the course of infection1 and result in an extended period of debilitation and lost productivity through school and work absenteeism.2 In some individuals, complications may follow the primary viral infection. In adults, these usually take the form of bacterial or viral infections of the respiratory tract, such as pneumonia and bronchitis.3, 4 In young children, otitis media is the most common infective complication.5, 6 In combination with the initial symptoms of infection, these events account for substantial medical costs, which are incurred through excess physician consultations and emergency room visits, hospitalizations and prescriptions.7, 8, 9

Influenza is also an under-recognized cause of central nervous system (CNS) dysfunction. Febrile seizure is a common occurrence in infants and children with influenza and is an important cause of hospitalization.10, 11, 12, 13 Influenza infections in young individuals may also be associated with acute onset brain dysfunction, characterized by decreased consciousness and delirious or abnormal behaviors, such CNS dysfunction may be fatal or leave neurological sequelae.14, 15, 16, 17, 18, 19, 20 Such CNS dysfunction due to influenza has been reported worldwide, with most cases originating in Japan. Influenza infection is also an established trigger event for the encephalopathic condition known as Reye's syndrome.21, 22, 23 A link between influenza and the peripheral neuropathy, Guillain–Barré syndrome (GBS), has also been suggested.24, 25 Likewise, Kleine–Levin syndrome (KLS), a rare neurological disorder, characterized by periodic hypersomnia and cognitive and behavioral disturbances, has been noted following influenza infection.26 Some reports have also suggested a link between influenza A infection and post-encephalitic Parkinson's disease (PD).27, 28, 29

In this article, we describe the epidemiology and clinical features of the typical CNS complications that are linked with influenza infection through review and interpretation of historical reports and emerging data. Where available, etiological information is also presented.

Using the Medline and Embase databases, the following search terms were used on July 15, 2007, to identify English-language publications for possible inclusion in the review: “influenza, influenza A, influenza B, flu, influenza-associated, influenza-like, flu-like, avian flu, H5N1, along with any one of the following terms: encephalopathy, encephalitis, neuropathy, central nervous system, psychosis, coma, loss or depressed level of consciousness, unconsciousness, delirium, convulsion, seizures, febrile convulsions, palsy, speech or language disorder, vision disorder, hyperactivity, hypoactivity, lethargy, encephalitis lethargica, hallucination, delusion, EEG (electro-encephalography) changes or abnormalities, neurologic complication, suicide, depression, anxiety, fear, abnormal behavior. The 338 abstracts identified by the search were then reviewed and full text versions of all possibly relevant articles were obtained for detailed inspection. The bibliographic content of these articles was also examined to ensure full coverage. The following six influenza-related topics were then identified for inclusion in the review: febrile seizures, acute encephalitis/encephalopathy, Reye's syndrome, GBS, KLS, and post-encephalitic PD: 94 publications considered most informative and scientifically rigorous were included in the review.

Febrile seizure is a common event in infancy or childhood that occurs in association with fever, but without evidence of intracranial infection or other defined cause.30 Two to five percent of children of North American or Western European origin will experience a febrile seizure before the age of 5 years.31, 32, 33 In Japanese populations, the incidence may be as high as 9%.34 Seizure events are classified as simple or complex. Simple febrile seizures are typical and characterized by single seizures that manifest as generalized tonic-clonic or clonic convulsions lasting no longer than 15 min. Simple febrile seizures are without recurrence within 24 h. Complex febrile seizures are atypical, and are characterized by partial or focal seizures, prolonged seizures, or multiple seizures within a short-time period. Simple and complex events are clinically distinguished, as complex seizures are associated with an increased risk of subsequent afebrile seizure.35, 36

Febrile seizures occur in approximately one in five hospitalized infants and young children with influenza. In a study described by Chiu et al.12 19.9% (54/272) and 18.8% (27/144) of children aged 6 months to 5 years hospitalized with influenza A infection in 1997 and 1998, respectively, had one or more febrile seizures. The incidence of febrile seizure (19.5%) was significantly higher than that in children hospitalized with parainfluenza or adenovirus infections (36/347, 10.4%; P=0.0004). A clear correlation between the seasonality of influenza A infection and the incidence of febrile seizure admissions was also evident (Figure 1). In another assessment, Kwong et al.10 found that febrile seizures occurred in 19.5% (34/177) of children aged 0–6 years hospitalized for influenza A infection. In a further study, Chung and Wong13 noted that 20.8% (163/785) of children ⩽15 years hospitalized with influenza had febrile seizures.

In recent studies, the clinical characteristics of febrile seizures in children with influenza have been examined. In the study described by Chiu et al.12 the mean age of the infected children with febrile seizures was 27 months in the 1997 patient group and 28 months in the 1998 patient group. In both populations, the mean maximum body temperature was 39.8 °C. A high incidence of repeat seizures during the same febrile episode was noted (22.2% in 1997 and 31.5% in 1998). In the Kwong assessment, children with febrile seizures had a mean age of 2.7 years, mean maximum body temperature of 40.4 °C and mean duration of fever prior to the onset of febrile seizure of 1.04 days.10 Complex febrile seizures were observed in 13/34 (38.2%) of these children (focal seizures, 6/34 patients (17.7%); multiple seizures, 10/34 patients (29.4%)). In a further study involving 47 children aged ⩾6 months who were hospitalized with febrile seizures and influenza infection, Hara et al.11 recorded a mean body temperature of 39.6 °C at seizure and median time from fever onset to seizure occurrence of 9 h. In this study, 11/47 patients (23.4%) had partial seizures, 2/47 (4.3%) had prolonged seizures and 6/47 (12.8%) had multiple seizures. Impairment of consciousness after seizure, manifested by drowsiness, lethargy, or coma, was prolonged for more than 30 min in 10 patients (21.3%).

In the Kwong study, significant risk factors for the development of febrile seizures in association with influenza infection were family history of seizure disorders, history of febrile seizure, and coexisting gastroenteritis; history of febrile seizure was an independent risk factor for febrile seizure.10 In the assessment by Chung and Wong,13 young age of onset, family history of febrile seizure, and complex febrile seizure at first presentation were identified as risk factors for the recurrence of febrile seizures.

Febrile seizure has a multifactorial etiology. Fever is an established trigger event for febrile seizure and a correlation with the height of fever rather than the rate of rise in body temperature exists.37, 38 Infectious agents also play a central role in the pathogenesis of febrile seizures,12, 13, 39 although their action has yet to be fully determined. Indirect involvement via the initiation of fever appears most likely, but direct neurological effects cannot be discounted. Infants and young children are most susceptible to febrile seizures, and this has been attributed to the immaturity of the brain in these individuals.40, 41, 42 A genetic predisposition to febrile seizure may also exist.43 Febrile seizure appears to resolve without neurological sequelae,44, 45 although prolonged febrile convulsions may be associated with impaired non-verbal intelligence.46

Encephalopathy refers to pathology of the CNS associated with reduced neurological function; encephalopathy is therefore a functional description. It is most commonly used to describe severe decreases or disturbances in CNS function, but may also be used to indicate milder disturbances. Encephalitis refers to inflammation of the CNS, which may or may not be due to the presence of micro-organisms. The two terms are often used in conjunction, in the form ‘encephalitis/encephalopathy’, to describe an uncommon neurological syndrome of childhood and adolescence that typically presents during the early phases of influenza infection. Influenza-associated encephalitis/encephalopathy is a distinct disease entity from post-influenza encephalopathy, in which the clinical manifestations of CNS dysfunction present with a delayed onset and only after the resolution of febrile illness and respiratory symptoms.47 Adenovirus co-infection may also contribute to the etiology of post-influenza encephalopathy.47

In Japan, the epidemiology of influenza-associated acute encephalopathy has been extensively evaluated, given the relatively high profile of the complication in this country. In an initial national cross-sectional survey commissioned by the Japanese Ministry of Health and Welfare, Kasai et al.48 identified 217 cases of clinically diagnosed influenza-associated encephalitis/encephalopathy in a nationwide study of Japanese medical facilities. A large majority of cases were in children <5 years (179 cases, 82.5%). In a second national survey, detailed information on all cases of influenza-associated encephalitis/encephalopathy diagnosed during the 1998–1999 influenza season was collected and assessed.14 In this instance, 148 confirmed cases of CNS dysfunction were identified by Morishima et al. Most were children (78 boys, 70 girls) aged <5 years (81.8%) (Figure 2). Togashi et al.15 also explored the incidence of influenza-associated CNS dysfunction at a local level in Hokkaido, the northernmost island of Japan. In this assessment, 89 cases of acute onset brain dysfunction in association with influenza were identified between 1994 and 2002; patients were aged between 9 months and 12 years (mean age: 3.8 years; 51 males, 38 females). In each season, the peak of event reporting was coincidental with the peak of the annual influenza epidemic.

Acute encephalopathy, in association with influenza infection, has been reported in a number of areas worldwide, including North America, Europe, and Taiwan.18, 19, 20, 47, 49, 50, 51, 52, 53, 54, 55 However, the epidemiology of the condition is less well established outside Japan, possibly due to the lower profile of acute encephalopathy in these countries. It is noteworthy that none of the US pediatric cases described by Maricich et al.19 were of Asian descent.

Influenza-associated acute encephalopathy is associated with a diverse spectrum of clinical symptoms. Outcomes are also highly variable. In the national surveys described by Kasai et al.48 and Morishima et al.14 symptoms of CNS dysfunction generally presented within 2 days of the onset of the first signs of influenza. In the Kasai report, typical symptoms were described as seizures and unconsciousness.48 Morishima et al.14 also cited seizures and altered consciousness (e.g., somnolence) or loss of consciousness as common CNS manifestations, but also reported hallucinations, abnormal or delirious behaviors, motor paralysis, and sensory loss (Table 1). In both studies, outcomes were highly variable. In the Kasai series, persistent neurological sequelae were reported in 56/217 cases (25.8%), and death in 58/217 cases (26.7%).48 Morishima et al.14 reported symptom resolution in 59/147 cases (40.1%), mild sequelae in 28/147 cases (19.0%), severe sequelae in 13/147 cases (8.8%), and death in 47/147 cases (32.0%). In the study described by Togashi et al., the most commonly reported symptoms were rising fever in 89/89 patients (100%), disturbance of consciousness in 88/89 patients (98.9%), and convulsions in 68/89 patients (76.4%)15; EEG abnormalities were present in 56/66 cases (84.8%). Brain imaging abnormalities were also evident by CT scan (60/81 cases assessed (74.1%)) and MRI scan (17/30 cases assessed (56.7%)), and typified by the presence of symmetrical, low-density lesions in the thalamus, pons, and brain stem. In a further study, Yoshikawa et al.56 demonstrated that the presence of symmetric brain lesions and/or diffuse brain edema was indicative of a poor prognosis. Similar clinical characteristics are described in case reports and case series originating from Taiwan49 and North America.51, 52, 53

In the reporting of the above studies, only limited coverage was given to those patients in whom CNS symptoms resolved without neurological sequelae. In recent reports, the clinical characteristics of these patients have been described in detail. In one report, Okumura et al.57 described a case series of 15 children (10 boys, 5 girls; mean age: 6.5 years) who were hospitalized with delirious behavior in association with influenza infection. In almost all cases (14/15), the delirious behavior presented on the day, or the day after, the onset of febrile illness. Manifestations included disorientation, hallucinations, meaningless speech, fearfulness, unresponsiveness, irritability, laughing, shouting, and crying (Table 2).57 Somnolence was also observed in 10 children and seizures in 5 children. Brain imaging revealed no abnormalities, while EEG was mildly abnormal in 13 children. EEG abnormalities included mild slowing of the background activity, insertion of semirhythmic, high-voltage, slow waves, and the appearance of relatively high-voltage semirhythmic theta waves; no patients exhibited generalized or predominantly unilateral slowing (Figure 3). Resolution of symptoms occurred in all patients and all follow-up EEGs were normal (Figure 3). Another report by Fukumoto et al.17 described the clinical features of 10 children (9 boys, one girl, median age: 4.3 years) in whom delirious behavior closely followed the onset of influenza infection (median interval: 20.6 h). In this case series, the clinical manifestations of delirium included meaningless speech, periodic crying without an apparent trigger, ‘blank eyes’, and hallucinations. EEG abnormalities, including focal and generalized slowing, were detected in five patients. Symptom resolution occurred in all patients. In addition to the more severe forms of neurological disease, mild cases of acute onset encephalopathy have also been reported in Taiwan20, 50 and North America.18, 19

Physical degeneration of the CNS is rarely observed in children with mild forms of influenza-associated CNS dysfunction.16, 18 In more severe cases, however, diffuse cerebral edema is often evident.14, 15 Vascular damage, plasma protein leakage, thrombosis, altered blood coagulation, reduced platelet counts, and liver dysfunction may also be present.14, 15 Cases of acute necrotizing encephalopathy are characterized by the presence of multiple focal lesions of edematous necrosis that are symmetrically distributed among the bilateral thalami, putamina, cerebral and cerebellar medulla, and brainstem tegmentum.58 Neuropathalogically, the lesions show edema, petechial hemorrhage and necrosis, which is suggestive of a local breakdown of the blood-brain barrier (BBB).

In autopsied individuals, influenza virus or genetic material is rarely isolated from brain tissue.14, 15 Detection of viral antigen or genome in cerebrospinal fluid is also uncommon.14, 59 In many cases, however, hypercytokinemia in serum, plasma, and/or CSF is evident. Typically, this involves the pro-inflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF) alpha and soluble TNF receptor 1.17, 60, 61, 62, 63, 64 Increased cytokine transcription has also been detected,64 with blood monocytes the proposed site of cytokine over-production.65 In some patients, elevated concentrations of soluble E-selectin, a marker of vascular endothelial injury, and cytochrome C, a marker of apoptosis, may also be present.60, 66, 67, 68

In numerous investigations, concentrations of pro-inflammatory cytokines have been correlated with the severity of CNS dysfunction.17, 62 A similar association with patient outcomes has been reported.64 These findings are supported by laboratory studies showing the deleterious effects of TNF-alpha on vascular endothelium,69 spinal cord nerves,70 and the BBB.71, 72, 73 IL-6 is also known to disrupt the BBB71, 72, 73 and is toxic to rat hippocampal cells.73 During the early stages of CNS dysfunction, serum concentrations of cytochrome C are a sensitive and specific marker for severe encephalopathy.67 The presence of lactate, a known product of anaerobic metabolism, in the basal ganglia of Patient 8 in the Maricich series is indicative of oxidative stress and mitochondrial dysfunction.19

Although the process is yet to be fully elucidated, the above evidence suggests that hypercytokinemia and apoptosis play a central role in the pathogenesis of acute encephalopathy. Disruption of the BBB also appears likely, which may possibly allow cytokines to enter the brain and directly damage tissues. A genetic component may also be evident that may predispose certain individuals to infection-associated encephalopathy. For example, by comparing 11 members of a US family who were affected by acute necrotizing encephalopathy with unaffected relatives, Neilson et al.74, 75 identified an autosomal dominant form of this disease, which was always triggered by a febrile illness. Although some family members were obligate carriers, they were unaffected clinically, demonstrating incomplete penetrance of the condition. The condition was later mapped to chromosome 2 using whole genome linkage analysis.74, 75

Reye's syndrome is a serious disease that manifests clinically as acute encephalopathy with fatty hepatic involvement. Its symptoms are thought to be caused by mitochondrial injury, often associated with drug or toxin exposure in the presence of acute viral infection, including influenza and varicella.76 In the liver, this results in metabolic failure, leading to hypoglycemia, hyperammonia, and the onset of CNS dysfunction. During the 1980s, Reye's syndrome was reported with a low overall incidence in children and adolescents (0.2–4.0 cases per annum/100,000 children aged <18 years).77 However, in recent years, reports of Reye's syndrome have been even less frequent. This is thought to be due to a decrease in the use of acetylsalicylic acid in children with febrile illnesses78 and the improved diagnosis of underlying metabolic disorders with similar symptoms.79 Infection is usually followed by a short disease free-interval of 3–5 days. Abrupt deterioration then occurs, with persistent vomiting and convulsions marking the onset of encephalopathy and hepatic fatty infiltration. Patients with Reye's syndrome have a poor prognosis; death or symptom resolution with neurological sequelae are common outcomes.21, 22

Influenza A and B infection is an established trigger event for Reye's syndrome. In a review of national surveillance data performed in the USA, Hurwitz et al. identified >2000 cases of Reye's syndrome in the periods 1973–1974 and 1976–1980.21 In all years, outbreaks of Reye's syndrome were temporally and geographically associated with outbreaks of influenza A and B infections. In this study, >90% of the cases reported within each year were in persons aged <15 years. In another US study, Rogers et al.22 identified 213 cases of Reye's syndrome between December 1981 and November 2003. During this surveillance period, 127 (64%) of the 197 cases with a known month of hospitalization occurred between January 1 and May 31, the same period in which isolates of influenza B were identified by the World Health Organization influenza surveillance system. In a further epidemiological study, Ruben et al.23 identified 97 cases of Reye's syndrome in southwestern Pennsylvania, USA, between January 1970 and December 1980. In 44 patients (45%), the onset of Reye's syndrome occurred during periods of documented influenza activity (Table 3).23 The mean age of this patient group was 9.8 years and 15 patients (34%) died.

GBS is a post-infectious auto-immune radiculopathy that is an important cause of acute flaccid paralysis in young adults and the elderly.80 Males are more commonly affected than females (ratio: ∼1.25:1) and an overall incidence of 1.3 cases per 100,000 population has recently been calculated.81 Antecedent illnesses are reported in approximately two-thirds of patients prior to the onset of GBS. Respiratory and gastrointestinal infections are the most commonly linked trigger illnesses, with Campylobacter jejuni infection being the most common precursor infection.81 Acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN) forms of GBS are now evident. AIDP is considered the classical form of the disease, and is characterized by segmental demyelination of peripheral nerves with variable levels of lymphocytic infiltration. In contrast, AMAN involves peripheral motor axon dysfunction in the absence of demyelination. In many cases, the onset of AMAN is preceded by C. jejuni infection, which results in the development of autoantibodies against gangliosides, such as GM1 and GD1a. Molecular mimicry between the terminal tetrasaccharide of GM1 and lipo-oligosaccharide of C. jejuni is thought to cause the autoimmune attack.82 In most patients, GBS is a self-limiting disease, although a mortality rate of ∼10% and requirement for artificial ventilation of ∼25% has been reported in population-based studies. Symptoms usually present 1–3 weeks after infection, with limb weakness reaching a nadir within 4 weeks. Partial or complete resolution of symptoms over weeks or months is the usual clinical course. The temporal pattern of symptom evolution and decay is suggestive of a pathophysiology centered on a primary humoral response.

Sporadic case reports have suggested a direct link between GBS and influenza infection.83, 84, 85, 86 Recent studies have confirmed this association. In an initial study, which was performed in UK and used time-series methods, Tam et al.24 observed a positive association between the numbers of reports of laboratory-confirmed influenza A in any given week and GBS hospitalizations in the same week. A follow-up, nested, case-control study by the same group supported this outcome. In this assessment, a positive association between GBS and infection with influenza-like illness in the previous 2 months was identified in data derived from the United Kingdom General Practice Research Database (1991–2001).25

An increased frequency of GBS was associated with the 1976 swine influenza vaccine,87, 88 with an incidence of one case per 10,0000 persons vaccinated estimated. Adults aged ⩾25 years were at higher risk for influenza vaccine-associated GBS than younger individuals (aged <25 years).89 Evidence for a causal relationship between influenza vaccines subsequent to the 1976 swine influenza vaccine has not been consistent. In fact, no studies other than those involving the 1976 swine influenza vaccine have shown sizeable increases in influenza vaccine-associated GBS.87, 90, 91, 92 Moreover, recent data from VAERS (Vaccine Adverse Events Reporting System) demonstrate a decrease in the reporting of GBS after vaccination over time.93 These findings are supportive of a low risk for influenza vaccine-associated GBS with present-day influenza vaccines, for which the risk:benefit ratio remains clearly positive.

KLS is a rare neurological disorder characterized by recurrent episodes of hypersomnia and various degrees of cognitive and behavioral disturbance, compulsive eating disorder, and hypersexuality.26 Although its etiology is largely unknown, it has been suggested that KLS represents a viral or post-infectious autoimmune encephalitis with primary impact on the hypothalamus. An association with (HLA) subtype DQB1*02 has been noted in patients who developed post-infection KLS,94 further suggesting an autoimmune etiology precipitated by infection. In a systematic literature review of 168 primary KLS cases, Arnulf et al.26 noted that the disease occurred sporadically worldwide, mostly in men (114 patients, 68%), with a median age of onset of 15 years (range 4–82 years). Typically, the syndrome lasted 8 years, with seven episodes of 10 days, recurring every 3.5 months (median values). KLS lasted longer in women and in patients with less frequent episodes during the first year.

In the Arnulf series,26 KLS was precipitated most frequently by infections (64 cases, 38.2%). Infection or fever was reported in 72/168 patients (43%), of whom 42 (25%) displayed a non-specific or influenza-like fever and 20 (12%) had an upper respiratory tract infection, tonsillitis, sore throat, or cough. The pathogens responsible for infection were only identified in five cases (3%), but did include Asian influenza virus, as well as Streptococcus, chicken pox and mononucleosis, enterovirus, and post-typhoid vaccine fever.

Sporadic case reports suggest a link between influenza A infection and the subsequent development of post-encephalitic PD.27, 28, 29 In a contemporary report, Ghaemi et al.28 described a 74-year-old women who developed akinetic-rigid PD following acute viral encephalitis. The patient exhibited tremor, hypokinesia, hypomimia, rigidity, and cogwheel phenomenon in all four extremities. Brady-dysdiadochokinesia and myoclonic jerks of the arms were also evident. Analysis of cerebral spinal fluid showed evidence of viral encephalitis, while serological assessments revealed an influenza A antibody titer of >1:160. A link between post-encephalitic PD in Guam, an island in the Western Pacific Ocean, and the influenza pandemic of 1918 has also been reported.29 Takahashi and Yamada27 have suggested an etiology for PD that involves the infection of neurons in the substantia nigra, cerebellum, and hippocampus by neurovirulent viruses, including influenza A. In this proposal, viral infection instigates the development of Lewy body dementia, the later death of nigral neurons, and the subsequent development of PD. Oxidative stress and permissive tissue antigens may also be important in the pathology of post-infectious PD.29

Section snippets

Conclusions

Influenza infection elicits a sizeable burden of CNS disease in infants, children, and young adolescents. Febrile seizure is the most commonly encountered neurological complaint in young individuals, but the prognosis is good in most cases. Acute encephalopathy is a less common, but potentially more serious, complication of influenza infection. Although widely reported in Japanese populations, case series from around the globe have also been described. Clinical symptoms are diverse and range

Acknowledgments

The author would like to thank Scott Malkin (Medical Writer) for assisting the development of this manuscript, funding for which was provided by F. Hoffmann-La Roche Ltd.

References (94)

  • E.M. Ouellette

    The child who convulses with fever

    Pediatr Clin North Am

    (1974)
  • T. Kasai et al.

    Encephalopathy associated with influenza epidemics

    Lancet

    (2000)
  • M. Sazgar et al.

    Influenza B acute necrotizing encephalopathy: a case report and literature review

    Pediatr Neurol

    (2003)
  • M.H. Smidt et al.

    Encephalopathy associated with influenza A

    Eur J Paediatr Neurol

    (2004)
  • A. Okumura et al.

    Delirious behavior in children with influenza: its clinical features and EEG findings

    Brain Dev

    (2005)
  • T. Ichiyama et al.

    Analysis of cytokine levels and NF-kappaB activation in peripheral blood mononuclear cells in influenza virus-associated encephalopathy

    Cytokine

    (2004)
  • G. Farkas et al.

    Experimental acute pancreatitis results in increased blood-brain barrier permeability in the rat: a potential role for tumor necrosis factor and interleukin 6

    Neurosci Lett

    (1998)
  • H.E. de Vries et al.

    The influence of cytokines on the integrity of the blood-brain barrier in vitro

    J Neuroimmunol

    (1996)
  • R.A. Hughes et al.

    Guillain–Barre syndrome

    Lancet

    (2005)
  • N. Yuki

    Carbohydrate mimicry: a new paradigm of autoimmune diseases

    Curr Opin Immunol

    (2005)
  • M. Migita et al.

    Two cases of influenza with impaired ocular movement

    Eur J Paediatr Neurol

    (2001)
  • K.G. Nicholson et al.

    Textbook of influenza

    (1998)
  • T. Szucs

    The socio-economic burden of influenza

    J Antimicrob Chemother

    (1999)
  • C.R. Meier et al.

    Population-based study on incidence, risk factors, clinical complications and drug utilisation associated with influenza in the United Kingdom

    Eur J Clin Microbiol Infect Dis

    (2000)
  • A. Sessa et al.

    The incidence, natural history and associated outcomes of influenza-like illness and clinical influenza in Italy

    Fam Pract

    (2001)
  • R.B. Belshe et al.

    The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children

    N Engl J Med

    (1998)
  • V.H. Menec et al.

    The impact of influenza-associated respiratory illnesses on hospitalizations, physician visits, emergency room visits, and mortality

    Can J Public Health

    (2003)
  • W.W. Thompson et al.

    Influenza-associated hospitalizations in the United States

    JAMA

    (2004)
  • K.M. Neuzil et al.

    The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children

    N Engl J Med

    (2000)
  • S.S. Chiu et al.

    Influenza A infection is an important cause of febrile seizures

    Pediatrics

    (2001)
  • B. Chung et al.

    Relationship between five common viruses and febrile seizure in children

    Arch Dis Child

    (2007)
  • T. Morishima et al.

    Encephalitis and encephalopathy associated with an influenza epidemic in Japan

    Clin Infect Dis

    (2002)
  • A. Okumura et al.

    Oseltamivir and delirious behavior in children with influenza

    Pediatr Infect Dis J

    (2006)
  • S.M. Maricich et al.

    Neurologic complications associated with influenza A in children during the 2003–2004 influenza season in Houston, Texas

    Pediatrics

    (2004)
  • C.H. Lin et al.

    Neurologic manifestations in children with influenza B virus infection

    Pediatr Infect Dis J

    (2006)
  • E.S. Hurwitz et al.

    National surveillance for Reye syndrome: a five-year review

    Pediatrics

    (1982)
  • M.F. Rogers et al.

    National Reye syndrome surveillance, 1982

    Pediatrics

    (1985)
  • F. Ruben et al.

    Epidemiologic features of Reye syndrome seen in southwestern Pennsylvania 1970–1980

    Am J Public Health

    (1983)
  • C.C. Tam et al.

    Influenza, Campylobacter and Mycoplasma infections, and hospital admissions for Guillain–Barre syndrome, UK

    Emerg Infect Dis

    (2006)
  • C.C. Tam et al.

    Guillain–Barre syndrome and preceding infection with campylobacter, influenza and Epstein–Barr virus in the general practice research database

    PLoS ONE

    (2007)
  • I. Arnulf et al.

    Kleine–Levin syndrome: a systematic review of 186 cases in the literature

    Brain

    (2005)
  • M. Takahashi et al.

    Viral etiology for Parkinson's disease—a possible role of influenza A virus infection

    Jpn J Infect Dis

    (1999)
  • M. Ghaemi et al.

    FDG- and Dopa-PET in postencephalitic parkinsonism

    J Neural Transm

    (2000)
  • Practice parameter: the neurodiagnostic evaluation of the child with a first simple febrile seizure. American Academy of Pediatrics. Provisional Committee on Quality Improvement, Subcommittee on Febrile Seizures

    Pediatrics

    (1996)
  • C.M. Verity et al.

    Febrile convulsions in a national cohort followed up from birth. I. Prevalence and recurrence in the first five years of life

    Br Med J (Clin Res Ed)

    (1985)
  • K.B. Nelson et al.

    Predictors of epilepsy in children who have experienced febrile seizures

    N Engl J Med

    (1976)
  • M. Offringa et al.

    Prevalence of febrile seizures in Dutch schoolchildren

    Paediatr Perinat Epidemiol

    (1991)
  • Cited by (130)

    • The effect of influenza A (H1N1) pdm09 virus infection on cytokine production and gene expression in BV2 microglial cells

      2022, Virus Research
      Citation Excerpt :

      Some researchers have suggested that neuroinflammation upon infection with influenza virus could play a role in the pathogenesis in patients with encephalopathy (Ito et al., 2011; Zeng et al., 2013; Nakai et al., 2003). In some patients, viruses can infect the central nervous system (CNS) through the peripheral nerves or damage the blood-brain barrier (BBB), inducing a CNS cytokine storm and directly damaging and promoting the apoptosis of neurons and glial cells (Mastrolia et al., 2019; Toovey,2008). A previous study showed that proinflammatory cytokines were increased in the cerebrospinal fluid (CSF) and plasma of patients with IAE.

    • Suicidal behaviors and ideation during emerging viral disease outbreaks before the COVID-19 pandemic: A systematic rapid review

      2020, Preventive Medicine
      Citation Excerpt :

      EVDOs also result in economic downturns, causing unemployment and general instability that has been associated with numerous health problems, including increased deaths by suicide (Oyesanya et al., 2015). Second, viruses exhibit neurotrophic properties and can cause severe neurological damage and nervous diseases (e.g., toxic infectious encephalopathy) that cause mental disorders (Toovey, 2008; Wu et al., 2020). In some cases, viral infections can cause disorientation, dysphoria, confusion, and delirium, which in turn lead to suicidal ideation and behaviors (Chevance et al., 2020; Reger et al., 2020; Severance et al., 2011).

    • Neurological and Neuropsychiatric Impacts of COVID-19 Pandemic

      2021, Canadian Journal of Neurological Sciences
    View all citing articles on Scopus
    View full text