Neurological Complications of H1N1 Influenza in Children

Abstract & Commentary

By Sotirios Keros, MD, PhD, and Steven Weinstein, MD

Dr. Keros is Fellow, Child Neurology, Weill Cornell Medical College, New York Presbyterian Hospital; and Dr. Weinstein is Director, Pediatric Comprehensive Epilepsy Program, Weill Cornell Medical School, New York Presbyterian Hospital. Drs. Keros and Weinstein report no financial relationships relevant to this field of study.

Synopsis: Children with H1N1 influenza are more likely to have neurologic complications compared to those with non-N1H1 seasonal influenza.

Source: Ekstrand J, et al. Heightened neurological complications in children with pandemic H1N1 influenza. Ann Neurol DOI: 10.1002/ana.22184

Influenza long has been known to cause neurologic disorders, including encephalitis, encephalopathy, and seizures. Case reports of neurologic complications published during the 2009 H1N1 pandemic hinted at an increased incidence and severity of these complications when compared to previous years' non-H1N1 (seasonal) influenza A, particularly in children.

A single-center, retrospective study of children hospitalized at Primary Children's Hospital in Salt Lake City conducted by Ekstrand et al compared neurologic complications of H1N1 to seasonal influenza infections. Patients were all hospitalized, were younger than 19 years, had direct fluorescent antibody confirmed influenza A, and had new neurologic symptoms not attributable to another systemic problem. The 2009 H1N1 group was identified between April 1 and November 30, 2009, whereas the seasonal influenza group was admitted from summer 2004 to 2008. The H1N1 cases were further divided into two waves (April 1–July 31 and Aug 1–Nov 30). Qualifying neurologic disorders were seizures, including febrile seizures and status epilepticus, encephalopathy, encephalitis, headache, myositis, myalgia, aphasia, neuropathy, Guillain-Barré, and other focal neurologic signs.

In the 2004-2008 group, 234 hospitalized children were diagnosed with season influenza, with 16 meeting inclusion criteria. Of 303 children with 2009 H1N1, 18 met inclusion criteria, 9 in each wave. The H1N1 influenza group was older (mean 6.5 years vs. 2.4 years) and more likely to have an underlying medical or neurologic condition (83% vs. 25%) that included epilepsy, febrile seizures, neuromuscular disease, developmental delay, or a combination. The demographic characteristics were similar between wave 1 and wave 2.

The incidence of seizures (63% and 67%) and status epilepticus (39% and 37%) was similar between the groups. However, the H1N1 group had a statistically significant increased incidence of other neurologic symptoms including encephalopathy (n = 9), focal neurological findings (n = 5), and aphasia (n = 6).

Of those with lumbar punctures, none had CSF pleocytosis or significantly elevated protein, and one CSF sample tested for viral DNA by PCR was negative. The H1N1 group was more likely to be treated with antibiotics, antivirals, IVIG, and steroids, none with reported benefit. MRI was performed in seven children with H1N1 with three (17%) abnormal, and in five children with seasonal influenza, all of which were normal. EEG abnormalities were present in eight of 11 patients tested in the H1N1 group, compared to one of 12 in the seasonal group. Abnormal findings included burst-suppression, diffuse slowing, and spike-and-wave discharges. Four patients had persistent neurologic deficits, of which two of three for whom follow-up was available recovered after 6 months.

There was a trend toward increased severity of illness in wave 1 vs. wave 2 of the 2009 H1N1 pandemic, with longer hospital stay, more cases of encephalopathy, focal findings, persistent neurological symptoms, and MRI and EEG abnormalities.

Commentary

This is the largest study to date directly comparing the neurologic complications of the 2009 pandemic H1N1 influenza virus with non-H1N1 infections from previous years. A significant strength of the study is the large catchment area of Primary Children's Hospital that spans several states, but given the large distances to be traveled, may have led to an underestimate of complications with exclusion of milder cases not leading to hospitalization. The case ascertainment could have been alternatively skewed by the massive media coverage with multiple medical alerts for children with preexisting neurologic and other underlying medical conditions, leading to increased community awareness and hospital stays (median hospitalization stays were only 1-3 days). Although some conclusions are limited by the relatively small sample size and the retrospective design of the study, the data suggest that H1N1 infections are more likely to result in neurologic complications compared to seasonal influenza. But, are children with pre-existing neurologic conditions more likely to be infected and hospitalized with H1N1 in the first place, or of those hospitalized with influenza, is it those with neurologic and other illness who are more likely to have neurologic complications? The authors did not provide the baseline characteristics of the population of children hospitalized with influenza, and thus that question cannot be answered from the data provided.

This study emphasizes the potential severity of influenza infections in children, particularly the H1N1 subtype, and reinforces the need for vaccinations, especially in those with pre-existing medical and neurologic illness.