Sandra S Chaves, MD, MSC

	In the United States, influenza epidemics occur every year, typically during the fall or winter months. Illness is often characterized by a combination of fever, myalgia, headache, malaise, nonproductive cough, sore throat, and rhinitis. Among children, diarrhea, nausea, and vomiting are not uncommon. In most cases, illness resolves within 3 to 7 days, although cough and malaise can persist for more than 2 weeks. However, influenza can be severe and lead to hospitalization and death.

	Children at increased risk for developing severe influenza and related complications include those aged younger than 5 years; children with certain medical conditions, especially those with chronic pulmonary (including asthma), cardiovascular, renal, hepatic, neurologic, hematologic, or metabolic disorders (including diabetes mellitus); children who are immunosuppressed (eg, from medications or human immunodeficiency virus); and children receiving long-term aspirin therapy and who therefore might be at risk for experiencing Reye syndrome after influenza virus infection.

	Common influenza-associated complications include primary influenza viral pneumonia, otitis media, and exacerbation of underlying medical conditions (eg, pulmonary, metabolic, or cardiac diseases). In addition, influenza may lead to secondary bacterial pneumonia or contribute to co-infections with other viral or bacterial pathogens.

 Neurologic complications associated with influenza virus infection also occur; most reports have been in children, possibly reflecting high influenza attack rates in this age group. Although neurologic complications of influenza are less common than other sequelae, familiarity with the clinical spectrum and features is important for clinicians to optimize clinical management.

Neurologic complications associated with influenza in children 

	Influenza has been associated with a variety of neurologic complications of varying severity (Table 1). The most common neurologic manifestations are seizures with and without fever and altered sensorium.

 More severe manifestations include Guillain-Barré syndrome (GBS),

 stroke, focal neurologic deficits, acute disseminated encephalomyelitis, encephalopathy, and transverse myelitis.

 In the 1980s, the use of salicylates in children with viral infections (including influenza) was found to be associated with Reye syndrome, a neurologic condition consisting of severe encephalopathy, hepatic microvesicular fatty change, and hyperammonemia. This syndrome is currently rare in the US, possibly because of public education on the dangers of salicylate use in children with an acute viral infection.

	Virus strain–specific associations with neurologic complications have been described in the literature. For example, some studies have associated encephalitis lethargica with the influenza A (H1N1) strain circulating during the pandemic of 1918-1919.

 In the 1990s, investigators in Japan reported many cases of encephalopathy/encephalitis with high mortality in children that were thought to be associated with the influenza A (H3N2) virus strain circulating at that time.

 It remains unclear, however, whether aspects of the clinical presentation and severity of neurologic manifestations truly vary with specific circulating strains.

	A number of recent reports have focused on neurologic manifestations associated with the pandemic influenza A (H1N1)pdm09 virus.

 Attempts to compare the neurologic manifestations described during the 2009 pandemic with those associated with seasonal influenza were mostly inconclusive due to the small number of observations and changes in case ascertainment (less sensitive influenza tests used before the 2009 influenza pandemic combined with heightened awareness of influenza-related complications during the pandemic).

Frequency of neurologic complications associated with influenza in children

	Based on a retrospective cohort study of US patients hospitalized with laboratory-confirmed influenza, from the 2000-2001 through 2003-2004 seasons, the incidence of neurologic complications associated with influenza was approximately 4 cases per 100,000 children-years; patients aged between 2 and 4 years and with preexisting neurologic or neuromuscular disease were at greatest risk.

	During the 2009 influenza pandemic, another population-based study looked at potential neurologic complications associated with laboratory-confirmed influenza in patients who were admitted to the intensive care unit (ICU) or died.

 Of all ICU and fatal cases, 3.7% were identified as having influenza-associated neurologic complications; the median age was 9 years. The researchers estimated that 1.2 severe neurologic complications occurred for every 100,000 persons with symptomatic influenza A (H1N1)pdm09 virus infection.

	Data on the clinical spectrum and epidemiology of the various neurologic manifestations associated with influenza virus infection are still limited. Because of varying case definitions and case ascertainment, the frequency of neurologic manifestations associated with influenza is likely to be underestimated.

	Seizures are the most frequently reported neurologic complication associated with influenza. Febrile seizures have been reported in up to 20% of children aged 6 months through 5 years hospitalized with influenza.

 This is higher than the background rate of febrile seizure of 2% to 5% estimated for this age group.

	The majority of children with influenza-associated febrile seizures will have a single uncomplicated partial or generalized seizure.

 However, as many as one-third of these children may have prolonged seizures of more than 15 minutes or multiple seizures within 24 hours, and some can require ICU support and/or mechanical ventilation.

 Beyond the typical age at which febrile seizures are common, older children who have seizures associated with influenza are more likely to have a previous diagnosis of epilepsy or encephalopathy/encephalitis.

	Although most patients with influenza-associated seizures do not have abnormalities on the electroencephalogram (EEG) or on neuroimaging,

 those with EEG abnormalities may have diffuse slowing, spike and wave discharges, or a burst suppression pattern.

 In rare instances, magnetic resonance imaging (MRI) of the brain has shown increased T2 signal changes in the hippocampus and splenium or mild gyral swelling consistent with meningoencephalitis. However, cerebrospinal fluid (CSF) cell counts, glucose level, and protein level are usually within normal limits. In most case reports, patients with influenza-associated seizures survived with no residual neurologic sequelae.

 When seizures are associated with severe neurologic complications, such as encephalopathy or encephalitis, the prognosis can be somber.

ENCEPHALOPATHY (WITH OR WITHOUT SEIZURES)

	Encephalopathy/encephalitis appears to be the second most common neurologic complication associated with influenza. It is usually defined as altered mental status lasting for more than 24 hours, but its clinical spectrum can vary from mild confusion to behavioral changes, delirium/hallucination, meaningless speech, mutism/aphasia, lethargy, somnolence, and coma. Neuropsychiatric behaviors have been associated with influenza as part of the clinical spectrum of encephalopathy/encephalitis.

 Children or adolescents may present within the first 3 days of influenza with delirium characterized by visual hallucinations, inappropriate laughing or smiling, meaningless words, incoherent speech, and restlessness, and the MRI scan and EEG are often normal.

	There have been attempts to separate encephalopathy from encephalitis based on the presence of central nervous system (CNS) inflammation. For instance, only a few patients with influenza-associated encephalopathy have elevated protein or mild pleocytosis in the CSF; in most cases CSF is normal.

 Neuroimaging abnormalities have been described and include focal or generalized cerebral edema.

 Nonetheless, it is difficult to assess accurately the level of CNS inflammation or the patient’s prognosis based on neuroimaging results.

	Most case series of encephalopathy come from Japan, Taiwan, and Korea, which suggests that the disease could be more common in these areas, although there is no clear explanation for a geographic predisposition. The cases of encephalopathy in Japan have been described as severe, with a high fatality rate.

 Morishima and colleagues described 148 cases of encephalitis or encephalopathy identified in Japan during the 1999 influenza season, and more than 80% of those cases occurred in children aged younger than 5 years.

 Approximately 10% of those cases had imaging studies consistent with acute necrotizing encephalopathy. Of the total 148 patients, 32% died and 28% had long-term sequelae.

	Acute necrotizing encephalopathy is a severe type of encephalopathy associated with influenza and other viral infections such as mycoplasma, herpes simplex virus, and human herpesvirus 6. The condition causes bilateral necrosis of the thalami and other regions, including the cerebral white matter, cerebellum, and brain stem.

 The patient’s mental status can deteriorate rapidly to coma; permanent neurologic sequelae or death is not uncommon.

	A population-based study from California found 29 patients with encephalopathy/encephalitis out of 77 with neurologic complications associated with influenza A (H1N1)pdm09; 55% were pediatric patients.

 In these patients, CSF was generally unremarkable and only 3 patients had abnormal neuroimaging (2 had significant edema and 1 had bilateral frontal, temporal, and thalamic signal abnormalities consistent with acute necrotizing encephalitis). In contrast to the reports from Japan, most patients had good clinical outcomes and returned to their baseline status before hospital discharge.

	A study from Australia described neurologic complications associated with influenza A (H1N1)pdm09 in 49 children; 55% had preexisting comorbid conditions.

 Among all cases with influenza infection (N=506), 7 (1.4%) had encephalitis/encephalopathy and 5 of them needed ICU treatment; 1 died. In both studies, encephalopathy/encephalitis generally occurred shortly after the onset of respiratory symptoms and was rapidly progressive.

	Guillain-Barré syndrome may be described as a collection of clinical syndromes manifesting as an acute inflammatory polyradiculoneuropathy and resulting in weakness and diminished reflexes. Children usually complain of difficulty in climbing stairs. The child may complain of paresthesia of the feet followed by leg, buttock, or back pain, which likely result from nerve root and peripheral nerve inflammation.

	Clinical GBS is characterized by muscle pain and symmetric, ascending paresis with minor sensory abnormality. The neurologic deficit of GBS progresses over several days to a month. In most cases, GBS develops 2 to 4 weeks after a prodromal gastrointestinal or respiratory illness or immunization. The history may include antecedent trauma or surgery. The contribution of influenza to GBS rates is not fully understood. Epidemiologic data suggest that there is a temporal association between influenza and developing GBS within 30 to 60 days.

 The pathophysiology of GBS is not completely understood either; autoimmune phenomena can lead to damage of peripheral nerves causing muscle weakness.

 There is no confirmatory laboratory test for GBS.

Diagnosis of influenza-associated neurologic complications

	Despite extensive testing, it is not easy to establish causality between influenza virus infection and many of these neurologic conditions. Some of the conditions described here have similar clinical presentations, so the physician must differentiate among infectious, postinfectious (mediated by immunologic response), or noninfectious (eg, vasculitis) origin to guide patient management. Identifying an etiologic agent early in the course of the disease can be important for prognosis, potential prophylaxis, counseling of patients and family, and public interventions. Direct diagnostic workups help to rule in or exclude the most common etiologies.

	Because CSF and neuroimaging findings are often unremarkable in patients with influenza-associated neurologic disease, the final diagnosis is based on clinical assessment of the neurologic manifestations and laboratory confirmation of acute influenza virus infection. During influenza outbreaks in the community, physicians should consider influenza in the differential diagnosis of patients with seizures and altered mental status, especially if patients developed respiratory signs and symptoms shortly before the onset of neurologic manifestations and even if a rapid influenza diagnostic test is negative. Rapid influenza tests provide results within 15 minutes or less, but the low sensitivity of these tests precludes the exclusion of influenza based on a negative result.

	Respiratory signs and symptoms caused by influenza virus infection overlap with those caused by other respiratory pathogens.

 Moreover, young children are less likely to experience “typical” influenza symptoms (eg, fever and cough).

 The best way to diagnose influenza is by the detection of viral RNA by reverse transcriptase polymerase chain reaction (RT-PCR) or by viral culture from upper respiratory tract specimens collected as close to illness onset as possible.

 Serologic testing (antibody detection) is not recommended for routine diagnosis. Preferred respiratory samples for influenza testing include nasopharyngeal or nasal swab, and nasal wash or aspirate, depending on which type of test is used (Table 2).

 Early diagnosis of influenza in patients with neurologic complications provide the option of using influenza antiviral therapy.

Treatment of influenza-associated neurologic complications

	In general, immediate medical care is aimed at appropriate management of the airway, bladder function, fluid and electrolyte balance, nutrition, secondary pulmonary infection, and hyperpyrexia. Care in an ICU setting may be required, especially if seizure activity is sustained or intracranial pressure is increased. Encephalopathy/encephalitis is a neurologic emergency for which consultation with a neurologist is recommended; consultation with an infectious disease specialist is also appropriate. Guidelines on the management of encephalitis have been published recently and offer etiology-specific treatment recommendations.

	No study has evaluated whether treatment with influenza antiviral drugs can influence the course of influenza-associated neurologic complications. However, randomized, controlled trials have shown a reduction in the duration and severity of uncomplicated influenza in otherwise healthy children treated with neuraminidase inhibitors, and observational studies have shown a reduction in hospital stay among treated children admitted to the ICU with influenza.

 Based on currently available data, prompt antiviral treatment is recommended for persons with severe influenza or those at risk of complications.

 Although antiviral drugs work best when given within 48 hours of illness onset, observational studies have shown that treatment up to 5 days after illness onset was associated with reduced morbidity and mortality among hospitalized patients. Current treatment guidelines are applicable to children.

	The neuraminidase inhibitors oseltamivir (Tamiflu; Roche Laboratories; Nutley, New Jersey) and zanamivir (Relenza; GlaxoSmithKline; Research Triangle Park, North Carolina) are the only antiviral medications routinely recommended for treatment of influenza virus infection.

 Antiviral resistance to oseltamivir and zanamivir among strains of influenza viruses expected to circulate during the 2013-2014 season is likely low. However, clinicians should monitor susceptibility information throughout the season either at the American Academy of Pediatrics Web site (

http://aapredbook.aappublications.org/flu

) or the Centers for Disease Control and Prevention (CDC) Web site (

	Oseltamivir is available in capsule and oral-suspension formulations. The manufactured liquid formulation has a concentration of 6 mg/mL. If the commercially manufactured oral suspension is not available, retail pharmacies may open the capsule and mix the contents with a sweetened liquid to a final concentration of 15 mg/mL. Table 3 shows the recommended dosage and schedule for the treatment of influenza in children.

 Information on influenza antiviral dosages and formulations is available at the CDC Web site: 

http://www.cdc.gov/flu/professionals/antivirals/index.htm.

	Influenza remains a major cause of medically attended respiratory illness in young children. The most effective way to prevent influenza-associated neurologic complications is to prevent influenza. Annual influenza vaccination for children aged 6 months or older is recommended.

 To protect children aged younger than 6 months, annual influenza vaccination of pregnant women and of those in close contact with young infants should be emphasized.

	Multiple influenza vaccines are expected to be available during the 2013-2014 influenza season. In general, there will be trivalent and quadrivalent inactivated influenza vaccines (IIV3/IIV4) that are available in an intramuscular formulation and an intradermal formulation licensed for those aged 18 years and older; and a quadrivalent live attenuated influenza vaccine (LAIV4), which is given as an intranasal spray and can be used in healthy people aged 2 to 49 years.

	Influenza has been associated with a variety of neurologic complications of varying severity in children, such as febrile seizures, encephalopathy/encephalitis, and GBS. Pediatricians must be aware of the appropriate diagnosis and treatment of influenza-associated neurologic findings and administer influenza vaccine according to current guidelines.

	1. Fiore AE, Shay DK, Broder K, et al; Centers for Disease Control and Prevention. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. 

	2. Blyth CC, Webb SA, Kok J, et al; ANZIC Influenza Investigators; COSI Microbiological Investigators. The impact of bacterial and viral co-infection in severe influenza. 

	3. Chung B, Wong V. Relationship between five common viruses and febrile seizure in children. 

	4. Glaser CA, Winter K, DuBray K, et al. A population-based study of neurologic manifestations of severe influenza A(H1N1)pdm09 in California. 

	5. Surana P, Tang S, McDougall M, Tong CY, Menson E, Lim M. Neurological complications of pandemic influenza A H1N1 2009 infection: European case series and review. 

	6. Ekstrand JJ. Neurologic complications of influenza. 

	7. Sivadon-Tardy V, Orlikowski D, Porcher R, et al. Guillain-Barré syndrome and influenza virus infection. 

	8. Newland JG, Laurich VM, Rosenquist AW, et al. Neurologic complications in children hospitalized with influenza: characteristics, incidence, and risk factors. 

	9. Landau YE, Grisaru-Soen G, Reif S, Fattal-Valevski A. Pediatric neurologic complications associated with influenza A H1N1. 

	10. Belay ED, Bresee JS, Holman RC, Khan AS, Shahriari A, Schonberger LB. Reye's syndrome in the United States from 1981 through 1997. 

	11. Foley PB. Encephalitis lethargica and the influenza virus. II. The influenza pandemic of 1918/19 and encephalitis lethargica: epidemiology and symptoms. 

	12. Morishima T, Togashi T, Yokota S, et al; Collaborative Study Group on Influenza-Associated Encephalopathy in Japan. Encephalitis and encephalopathy associated with an influenza epidemic in Japan. 

	13. Fujimoto S, Kobayashi M, Uemura O, et al. PCR on cerebrospinal fluid to show influenza-associated acute encephalopathy or encephalitis. 

	14. Ekstrand JJ, Herbener A, Rawlings J, et al. Heightened neurologic complications in children with pandemic H1N1 influenza. 

	15. Okumura A, Nakagawa S, Kawashima H, et al. Severe form of encephalopathy associated with 2009 pandemic influenza A (H1N1) in Japan. 

	16. Davis LE. Neurologic and muscular complications of the 2009 influenza A (H1N1) pandemic. 

	17. Baltagi SA, Shoykhet M, Felmet K, Kochanek PM, Bell MJ. Neurological sequelae of 2009 influenza A (H1N1) in children: a case series observed during a pandemic. 

	18. Chiu SS, Tse CY, Lau YL, Peiris M. Influenza A infection is an important cause of febrile seizures. 

	19. Steering Committee on Quality Improvement and Management, Subcommittee on Febrile Seizures American Academy of Pediatrics. Febrile seizures: clinical practice guideline for the long-term management of the child with simple febrile seizures. 

	20. Huang YC, Lin TY, Wu SL, Tsao KC. Influenza A-associated central nervous system dysfunction in children presenting as transient visual hallucination. 

	21. Takanashi J, Tada H, Kuroki H, Barkovich AJ. Delirious behavior in influenza is associated with a reversible splenial lesion. 

	22. Ito Y, Ichiyama T, Kimura H, et al. Detection of influenza virus RNA by reverse transcription-PCR and proinflammatory cytokines in influenza-virus-associated encephalopathy. 

	23. Mizuguchi M. Acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in Japan and Taiwan. 

	24. Olgar S, Ertugrul T, Nisli K, Aydin K, Caliskan M. Influenza A-associated acute necrotizing encephalopathy. 

	25. Khandaker G, Zurynski Y, Buttery J, et al. Neurologic complications of influenza A(H1N1)pdm09: surveillance in 6 pediatric hospitals. 

	26. Tam CC, O'Brien SJ, Petersen I, Islam A, Hayward A, Rodrigues LC. Guillain-Barré syndrome and preceding infection with campylobacter, influenza and Epstein-Barr virus in the general practice research database. 

	27. Ryan MM. Guillain-Barré syndrome in childhood. 

	28. Centers for Disease Control and Prevention. Evaluation of 11 commercially available rapid influenza diagnostic testsâUnited States, 2011-2012. 

	29. Ohmit SE, Monto AS. Symptomatic predictors of influenza virus positivity in children during the influenza season. 

	30. Glezen WP, Taber LH, Frank AL, Gruber WC, Piedra PA. Influenza virus infections in infants. 

	31. Centers for Disease Control and Prevention (CDC). Seasonal influenza (flu). Guidance for clinicians on the use of RT-PCR and other molecular assays for diagnosis of influenza virus infection. CDC Web site. 

http://www.cdc.gov/flu/professionals/diagnosis/molecular-assays.htm

. Updated May 25, 2012. Accessed July 10, 2013.

	32. Centers for Disease Control and Prevention (CDC). Seasonal influenza (flu). Guidance for clinicians on the use of rapid influenza diagnostic tests. CDC Web site. 

http://www.cdc.gov/flu/professionals/diagnosis/clinician_guidance_ridt.htm#Table1

. Updated November 13, 2012. Accessed July 10, 2013.

	33. Leland DS, Ginocchio CC. Role of cell culture for virus detection in the age of technology. 

	34. Tunkel AR, Glaser CA, Bloch KC, et al; Infectious Diseases Society of America. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. 

	35. Garg S, Fry AM, Patton M, Fiore AE, Finelli L. Antiviral treatment of influenza in children. 

	36. Coffin SE, Leckerman K, Keren R, Hall M, Localio R, Zaoutis TE. Oseltamivir shortens hospital stays of critically ill children hospitalized with seasonal influenza: a retrospective cohort study. 

	37. Fiore AE, Fry A, Shay D, Gubareva L, Bresee JS, Uyeki TM; Centers for Disease Control and Prevention (CDC). Antiviral agents for the treatment and chemoprophylaxis of influenzaârecommendations of the Advisory Committee on Immunization Practices (ACIP). 

	38. US Food and Drug Administration (FDA). Drugs. Influenza (flu) antiviral drugs and related information. FDA Web site. 

http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm100228.htm

. Updated January 17, 2013. Accessed July 10, 2013.

Articles

Influenza-associated neurologic complications in children are rare but can be severe. Familiarity with the clinical presentation and frequency of specific neurologic findings can help pediatricians with early diagnosis and treatment.

Sandra S Chaves, MD, MSC

Articles

Neurologic complications of influenza in children