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Neurologic Complications Associated with Novel Influenza A (H1N1) Virus Infection in Children --- Dallas, Texas, May 2009

Neurologic complications, including seizures, encephalitis, encephalopathy, Reye syndrome, and other neurologic disorders, have been described previously in association with respiratory tract infection with seasonal influenza A or B viruses (1--2), but not with novel influenza A (H1N1) virus. On May 28, 2009, the Dallas County Department of Health and Human Services (DCHHS) notified CDC of four children with neurologic complications associated with novel influenza A (H1N1) virus infection admitted to hospitals in Dallas County, Texas, during May 18--28. This report summarizes the clinical characteristics of those four cases. Patients were aged 7--17 years and were admitted with signs of influenza-like illness (ILI) and seizures or altered mental status. Three of the four patients had abnormal electroencephalograms (EEGs). In all four patients, novel influenza A (H1N1) viral RNA was detected in nasopharyngeal specimens but not in cerebrospinal fluid (CSF). Antiviral therapy included oseltamivir (four patients) and rimantadine (three patients). All four patients recovered fully and had no neurologic sequelae at discharge. These findings indicate that, as with seasonal influenza, neurologic complications can occur after respiratory tract infection with novel influenza A (H1N1) virus. For children who have ILI accompanied by unexplained seizures or mental status changes, clinicians should consider acute seasonal influenza or novel influenza A (H1N1) virus infection in the differential diagnosis, send respiratory specimens for appropriate diagnostic testing, and promptly initiate empirical antiviral treatment, especially in hospitalized patients.

Case Identification

Since April 22, DCHHS has requested all hospitals in Dallas County to report details concerning patients admitted with novel influenza A (H1N1) virus infection. As of July 20, DCHHS had identified 405 persons with laboratory-confirmed novel influenza A (H1N1) virus infection in the greater Dallas area, including 44 hospitalized patients. No deaths had been reported. Of confirmed novel influenza A (H1N1) virus infections, 83% were in patients aged <18 years. Among these pediatric cases, 145 children, including 26 who were hospitalized, were identified through the Children's Medical Center of Dallas (CMCD) laboratory-based surveillance program. Medical records from admission and discharge for all hospitalized H1N1 patients are routinely screened by DCHHS epidemiology staff. Characteristics of hospitalized patients are compiled on an ongoing basis, with further investigation of cases noted to have unusual features and severe illness.

A patient with acute neurologic complications associated with novel influenza A (H1N1) virus infection was defined as having laboratory-confirmed novel influenza A (H1N1) virus infection of the respiratory tract associated with seizures, encephalopathy, or encephalitis within 5 days of ILI symptom onset, without evidence of an alternative etiology. Encephalopathy was defined as altered mental status lasting ≥24 hours. Encephalitis was defined as encephalopathy plus two or more of the following: fever ≥100.4°F (≥38.0°C), focal neurologic signs, CSF pleocytosis, EEG indicative of encephalitis, or abnormal neuroimaging indicative of infection or inflammation (1--2).

During April 22--July 20, seven possible cases of neurologic complications associated with novel A (H1N1) virus infection were identified. Three cases were excluded because the neurologic complications were determined to have alternative etiologies (e.g., hypocalcemia and apnea related to prematurity) or did not meet the case definition (e.g., altered mental status for <24 hours). Of the remaining four cases described in this report, one patient (patient A) was initially reported by a community hospital in Dallas on May 18. The three other cases were reported by CMCD to DCHHS during May 23--27. No additional cases had been reported in Dallas County through July 20.

Nasopharyngeal swab specimens collected from all three patients admitted to CMCD were tested for influenza A and B antigens by either Directigen EZ Flu A+B rapid enzyme immunoassay (EIA) (BD [Becton, Dickinson, and Company], Sparks, Maryland), QuickVue Influenza A+B test (EIA) (Quidel, San Diego, California), or D3 Ultra direct fluorescent assay (Diagnostic Hybrids, Athens, Ohio). All positive specimens were sent to DCHHS, and novel influenza A (H1N1) virus was identified by real-time reverse transcription--polymerase chain reaction (rRT-PCR) using CDC-approved primers and probe sets. All CSF samples were tested at CDC using rRT-PCR for influenza, enteroviruses, parechovirus, adenovirus, and human parainfluenza virus serotype 3. CSF for patients B and D were tested for additional viruses by a commercial laboratory (Viracor).*

Case Reports

Patient A. On May 17, a previously healthy black male aged 17 years visited a community hospital emergency department after 1 day of fever reaching 102.6°F (39.2°C), cough, headache, dizziness, and weakness. Influenza A was diagnosed by EIA, and the patient was discharged home with a prescription for oseltamivir. The patient was admitted the next day to another community hospital because of increased generalized weakness, disorientation to place, and markedly slow and intermittent responsiveness to questions. On physical examination, the patient was noted to be confused and unable to provide history of his own illness. He also was unable to lift his arms above his shoulders or stand. He had taken 1 dose of oseltamivir the morning of admission. A computed tomography (CT) head scan revealed pan-sinusitis, and CSF was normal (Table). The patient received ceftriaxone for 2 days, which was discontinued when CSF bacterial cultures indicated no growth. He received oseltamivir throughout his hospital admission. His mental status returned to normal on day three. He was discharged on day four with no apparent sequelae and completed a 5-day total course of oseltamivir.

Patient B. On May 23, a previously healthy Hispanic male aged 10 years was taken to a Dallas community hospital via emergency medical services after a 3-minute generalized tonic-clonic seizure and subsequent postictal mental state. The seizure occurred after 4 days of fever reaching 104.0°F (40.0°C), cough, decreased appetite, and fatigue. His family reported that the patient had contact with another child with ILI symptoms before the patient's illness onset. Upon initial evaluation in the emergency department, the patient was afebrile. A chest radiograph revealed a left lower lobe infiltrate, and a CT head scan was normal except for an incidentally noted single punctuate calcification in left frontal cortex. Influenza A was detected in a nasopharyngeal swab specimen by EIA. Three hours later, the patient had a second 3-minute generalized seizure. Intravenous (IV) lorazepam and ceftriaxone were administered, and the patient was transferred to a CMCD intensive-care unit.

On admission to CMCD, the patient was febrile, confused, and drowsy. He had difficulty answering questions and made frequent inappropriate attempts to get out of bed. CSF analysis was normal. He was administered IV fosphenytoin to prevent additional seizures, vancomycin and ceftriaxone for empirical treatment of bacterial pneumonia, supplemental oxygen via bilevel positive airway pressure for oxygen saturations <92%, and anticonvulsants. Over the ensuing 2 days, he had intermittent fevers reaching 102.0°F (38.9°C). On hospital day four, he had a prolonged partial complex seizure with focal onset (eye deviation to the right) and secondary generalization, lasting 30--40 minutes, which eventually was controlled by 4 doses of IV lorazepam and a bolus of IV fosphenytoin. Oseltamivir and rimantadine were initiated. Brain magnetic resonance imaging (MRI) with magnetic resonance angiography was normal, and an EEG was consistent with encephalopathy (Table). His mental status returned slowly to baseline by hospital day seven, when he was discharged without apparent sequelae to continue levetiracetam, amoxicillin, and clindamycin, and complete a 5-day course of oseltamivir.

Patient C. On May 26, a white male aged 7 years with a history of a simple febrile seizure 1 year previously was taken to a Dallas community hospital via emergency medical services after a seizure and 2 days of cough, nasal congestion, and fatigue. On the day of admission, he had been found at home on the floor, with tonic movements of his upper and lower extremities lasting at least 2 minutes. On admission to the community hospital, he was noted to have postictal drowsiness and a temperature of 100.8°F (38.2°C). A diagnosis of influenza A was made by EIA. Blood tests, CSF, and a CT head scan were normal (Table).

The patient was transferred the same day to CMCD, where he exhibited normal mental status and no fever or seizures. A brain MRI showed nonspecific white matter abnormalities not characteristic of infection or inflammation. Localized cerebral dysfunction was evident on EEG (Table). Oseltamivir and rimantadine were started on hospital day one, and the patient was discharged on hospital day three without any neurologic sequelae, to complete a 5-day course of both antivirals and to continue levetiracetam until reassessment by neurologists in 3 months.

Patient D. On May 27, a black male aged 11 years with a history of asthma was taken to CMCD because of 1 day of fever and vomiting. A household contact, his grandmother, had an upper respiratory infection 3 days before his illness. One day before admission, he had a fever of 102.0°F (38.9°C), fatigue, headache, abdominal pain, and vomiting, and was given bismuth subsalicylate twice and one 81 mg aspirin. At CMCD, he was febrile. Neurologic examination revealed ataxia. Soon after admission, the patient had a seizure consisting of episodic eye rolling and tongue thrusting. An EIA test for influenza A was positive, and oseltamivir, rimantadine, cefotaxime, and acyclovir were initiated.

During the first 2 hospital days, the patient was disoriented, had visual hallucinations, had difficulty responding to questions and following commands, had slow speech, and required supplemental oxygen via facemask for mild hypoxia and hypopnea attributed to decreased respiratory drive associated with encephalopathy. Chest radiograph was normal. An EEG was consistent with encephalopathy, and a CT head scan was normal (Table). The patient's mental status returned to normal by hospital day four. He completed a 5-day course of oseltamivir.

Reported by: AS Evans, MD, S Agadi, MD, JD Siegel, MD, Univ of Texas Southwestern Medical Center; WM Chung, MD, JT Carlo, MD, Dallas County Health and Human Svcs, Dallas, Texas. TM Uyeki, MD, J Sejvar, MD, S Lindstrom, PhD, D Erdman, DrPH, S Oberste, PhD, National Center for Immunization and Respiratory Diseases; SJ Olsen, PhD, Div of Emerging Infections and Surveillance Svcs, National Center for Preparedness, Detection, and Control of Infectious Diseases; F Dawood, MD, OW Morgan, PhD, EIS officers, CDC.

Editorial Note: Infection with seasonal influenza virus can be associated with neurologic complications (1--2), but the frequency with which these occur with novel influenza A (H1N1) virus infection is unknown. This is the first report describing patients with neurologic complications associated with novel influenza A (H1N1) virus infection. The severity of the neurologic disease in the four patients described in this report was less than the typical disease described in two studies of neurologic complications associated with seasonal influenza (1--2), which included reports of severe static encephalopathy and death. Only two of the four patients described in this report had seizures, and none died or had neurologic sequelae at discharge. Considering that clusters of influenza-associated encephalopathy in children have been reported during previous community outbreaks of seasonal influenza (1--2) and that children appear to be infected with novel influenza A (H1N1) virus more frequently than adults (3), additional neurologic complications in children are likely to be reported as the pandemic continues. Clinicians should consider influenza associated encephalopathy in the differential diagnosis of children with ILI and seizures or mental status changes, and remain aware of the potential for severe neurologic sequelae associated with seasonal or novel influenza A (H1N1) virus infection.

Neurologic complications in children associated with seasonal influenza have included acute cognitive and behavioral problems, focal neurologic deficits, and death from neurologic complications (4). Influenza-associated neurologic complications are estimated to account for up to 5% of cases of acute childhood encephalitis or encephalopathy (4) and were reported in 6% of influenza-associated deaths among children during one influenza season (2003--04) in the United States (5). The epidemiology of influenza-associated encephalopathy has been described extensively in Japan, where incidence has appeared to be higher than in other countries (1). In Japan, approximately 80% of influenza-associated encephalopathy cases occur in children aged <5 years (1,6), and neurologic signs typically develop within 1--2 days of influenza symptom onset (1,6). Manifestations have included seizures, altered consciousness, incoherence, irritability, and psychotic behaviors (1,6). Outcomes reported in one case-series from Japan ranged from complete resolution (in nearly 50% of cases), to mild (20%) or severe neurologic sequelae (10%), to death (20%) (6).

Neuroimaging results in influenza-associated encephalopathy might be normal, but in severe cases, abnormalities can include diffuse cerebral edema and bilateral thalamic lesions. EEG might show diffuse abnormalities (1,2,4). Only rarely is influenza virus detected in CSF, suggesting that neurologic manifestations might be an indirect effect of influenza respiratory tract infection (2,7).

For patients with respiratory illness and neurologic signs, diagnostic testing for possible etiologic pathogens associated with neurologic disease, including influenza viruses, is recommended (8). Health-care providers also should consider a diagnosis of Reye syndrome in patients with viral illness and altered mental status. Although one of the patients described in this report, patient D, received a salicylate-containing product and aspirin, no evidence of Reye syndrome was observed. Salicylates and salicylate-containing products should not be administered to children with influenza or other viral infections because of the increased risk for developing Reye syndrome (9).

Antiviral treatment should be initiated as soon as possible for any hospitalized patient with neurologic symptoms and suspected seasonal influenza or novel influenza A (H1N1) virus infection (2). Although respiratory specimens should be obtained for appropriate diagnostic testing before administering antiviral agents, clinicians should not wait for the results before beginning treatment. Antiviral medications have been shown to decrease the risk for complications from influenza (10); however, the effectiveness of antiviral treatment to prevent influenza-associated encephalopathy sequelae is unknown. Clinicians also should send respiratory specimens for appropriate diagnostic testing. Although no vaccination against novel influenza A (H1N1) virus is available currently, CDC recommends that all children aged >6 months receive annual seasonal influenza vaccination to prevent illness and complications from infection with seasonal influenza virus strains.§

Acknowledgments

The findings in this report are based, in part, on contributions by E Brock, A Varghese, Children's Medical Center Dallas; L Miller, Charleton Methodist Hospital; C Rowe, Las Colinas Medical Center; J Stringer, E Bannister, PhD, J Rodriguez, S Hughes, K Baumgart, MPH, A Friedman, Dallas County Health and Human Svcs; and N Pascoe, Texas Dept of State Health Svcs.

References

  1. Morishima T, Togashi T, Yokota S, et al. Encephalitis and encephalopathy associated with an influenza epidemic in Japan. Clin Infect Dis 2002;35:512--7.
  2. Maricich SM, Neul JL, Lotze TE, et al. Neurologic complications associated with influenza A in children during the 2003--2004 influenza season in Houston, Texas. Pediatrics 2004;114:e626--33.
  3. Dawood FS, Jain S, Finelli L, et al. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med 2009;360:2605--15.
  4. Amin R, Ford-Jones E, Richardson SE, et al. Acute childhood encephalitis and encephalopathy associated with influenza: a prospective 11-year review. Pediatr Infect Dis J 2008;27:390--5.
  5. Bhat N, Wright JG, Broder KR, et al. Influenza-associated deaths among children in the United States, 2003--2004. N Engl J Med 2005;353:2559--67.
  6. Wada T, Morishima T, Okumura A, et al. Differences in clinical manifestations of influenza-associated encephalopathy by age. Microbiol Immunol 2009;53:83--8.
  7. 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. J Med Virol 1999;58:420--5.
  8. Tunkel A, Glaser C, Bloch K, et al. Management of encephalitis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008;47:303--27.
  9. Belay ED, Bresee JS, Holman RC, Khan AS, Shahriari A, Schonberger LB. Reye's syndrome in the United States from 1981 through 1997. N Engl J Med 1999;340:1377--82.
  10. Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F. Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med 2003;163:1667--72.

* Viruses detected by the Luminex multiplex respiratory viral panel [xTAG] are influenza A and B; parainfluenza 1, 2, and 3; respiratory syncytial virus A and B; adenovirus; human metapneumovirus; and rhinovirus.

CDC guidance on antiviral therapy available at http://www.cdc.gov/h1n1flu/recommendations.htm.

§ CDC recommendations for seasonal influenza vaccination available at http://www.cdc.gov/mmwr/pdf/rr/rr5707.pdf.

TABLE. Selected characteristics and laboratory, radiologic, and neurodiagnostic results for four patients with neurologic complications associated with novel influenza A (H1N1) virus infection* --- Dallas, Texas, May 2009

Characteristic

Patient A

Patient B

Patient C

Patient D

Age (yrs)

17

10

7

11

Sex

Male

Male

Male

Male

Race/Ethnicity

Black, non-Hispanic

Hispanic

White, non-Hispanic

Black, non-Hispanic

Dates of hospitalization

May 18--21

May 23--29

May 26--28

May 27--30

Neurologic complication(s) diagnosed

Encephalopathy

Seizures, encephalopathy

Seizures

Encephalopathy

Interval from respiratory illness onset to neurologic symptoms (days)

1

4

2

1

Fever (maximum temperature)

102.6°F (39.2°C)

104.0°F (40.0°C)

100.8°F (38.2°C)

102.0°F (38.9°C)

Admission laboratory data

Serum electrolytes, chemistry

Normal (except initial creatinine 1.3 mg/dL [normal range for age: 0.3--1.0 mg/dL])

Normal

Normal (except sodium 131 mmol/L [normal range: 134--146 mmol/L])

Normal

Liver function tests (U/L)

ND

AST§ 28, ALT 51, GGT** 29

AST 36, ALT 12, GGT 29

AST 41, ALT 27, GGT <10, ammonia 28 mmol/L (repeat testing normal)

Blood bacterial culture

ND

S. epidermidis, Micrococcus (contaminants), no growth x2

No growth

No growth

Urine bacterial culture

ND

ND

ND

No growth

Other

Creatine kinase 75 U/L (normal range: 22--269 U/L)

Urine toxicology screen positive for benzodiazepines only

---

Urine toxicology screen positive for caffeine, salicylate, and acetaminophen; serum salicylate level <1 mg/dL

Cerebrospinal fluid (CSF) analysis

WBC†† (per mm3) (differential)

2 (differential ND)

2 (65%L 31%M)

4 (differential ND)

4 (95%L 5%M)

RBC§§ (per mm3)

18

0

2

1

Glucose (mg/dL) (normal range: 50--80 mg/dL)

39

63

58

65

Protein (mg/dL) (normal range: 10--45 mg/dL)

37

50

15

21

Bacterial culture

No growth

No growth

No growth

No growth

Neurodiagnostic testing

Computed tomography

No intra-parenchymal abnormality; pan-sinusitis

Single punctuate calcification in left frontal cortex

No intracranial abnormality

No intracranial abnormality; sphenoid sinusitis

Magnetic resonance imaging

ND

No parenchymal abnormality

Cortical nonspecific scattered T2 hyperintense foci within the cerebral white matter

No intracranial abnormality

Electroencephalogram

ND

Generalized continuous polymorphic delta slowing, without epileptogenic focus; consistent with mild/moderate encephalopathy

Midline parietal intermittent polymorphic delta slowing, without epileptogenic focus; consistent with localized cerebral dysfunction

Posterior background slowing, no epileptiform activity; consistent with mild encephalopathy

Viral testing and antiviral therapy

Influenza EIA¶¶

Positive***

Positive

Positive

Positive

Influenza DFA†††

ND

ND

ND

Positive

CSF influenza rRT-PCR§§§

Negative

Negative

Negative

Negative

rRT-PCR

Enteroviruses: negative

Parechovirus: negative

Adenovirus: negative

HPIV-3¶¶¶: negative

Enteroviruses: negative

Parechovirus: negative

Adenovirus: negative

HPIV-3: negative

Enteroviruses: negative

Parechovirus: negative

Adenovirus: negative

HPIV-3: negative

Enteroviruses: negative

Parechovirus: negative

Adenovirus: negative

HPIV-3: negative


TABLE. (Continued) Selected characteristics and laboratory, radiologic, and neurodiagnostic results for four patients with neurologic complications associated with novel influenza A (H1N1) virus infection --- Dallas, Texas, May 2009

Characteristic

Patient A

Patient B

Patient C

Patient D

Other testing

ND

CSF respiratory viral panel (RVP)****

ND

HSV†††† rRT-PCR: negative

Enterovirus rRT-PCR: negative

CSF RVP: negative

Antiviral therapy

Oseltamivir

Oseltamivir and rimantadine

Oseltamivir and rimantadine

Oseltamivir and rimantadine

* A patient with acute neurologic complications associated with novel influenza A (H1N1) virus infection was defined as having laboratory-confirmed novel influenza A (H1N1) virus infection of the respiratory tract associated with seizures, encephalopathy, or encephalitis within 5 days of influenza-like illness symptom onset, without evidence of an alternative etiology. Encephalopathy was defined as altered mental status lasting ≥24 hours. Encephalitis was defined as encephalopathy plus two or more of the following: fever ≥100.4°F (≥38.0°C), focal neurologic signs, cerebrospinal fluid pleocytosis, an electroencephalogram indicative of encephalitis, or abnormal neuroimaging indicative of infection or inflammation.

Not done.

§ Aspartate transaminases (normal range: 10--45 U/L).

Alanine aminotransferase (normal range: 10--50 U/L).

** Gamma glutamyltranspeptidase (normal range: 3--30 U/L).

†† White blood cell count.

§§ Red blood cell count.

¶¶ Enzyme immunoassay. All four patients had nasopharyngeal specimens obtained and tested for influenza A and B antigen by using Directigen EZ Flu A+B (EIA), QuickVue Influenza A+B test (EIA), or direct fluorescent assay using D3 Ultra.

*** All four patients' nasopharyngeal specimens were confirmed positive for novel influenza A (H1N1) virus by Dallas County Department of Health and Human Services, using CDC-approved primers and probes.

††† Direct fluorescent assay.

§§§ Real-time reverse--transcription polymerase chain reaction (performed at CDC).

¶¶¶ Human parainfluenza virus type 3.

**** CSF viral PCR testing was performed by Viracor, using the Luminex multiplex respiratory viral panel (xTAG), which tests for 10 different viruses (influenza A and B; parainfluenza 1, 2, and 3; respiratory synctial virus A and B; adenovirus; human metapneumovirus; and rhinovirus).

†††† Herpes simplex virus.

Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services.


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Date last reviewed: 7/23/2009

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