We report our experience of neurological complications seen in hospitalized children with pH1N1. We found that 7.5% of hospitalized children presented with neurological manifestations. To our knowledge, this is the largest and most comprehensive report of the incidence of neurological complications in hospitalized children infected with pH1N1. It is consistent with reports for pH1N17
and other strains of influenza viruses.1
Currently, there are a number of case reports and case series documenting the neurological manifestations and complications of pH1N1 infection in children.7–15
In a brief report,8
4 pediatric cases presenting with seizures and or encephalopathy were described. All 4 had minimal CSF pleocytosis, EEG abnormalities occurred in 3, and MRI abnormalities were found in 1 of the 3 patients who underwent imaging. In another case series, 3 children had AMS, EEG abnormalities consistent with acute encephalopathy, and lack of other organ dysfunction.11
Two of these 4 patients showed imaging abnormalities, 1 with thalamic swelling and diffusion-weighted changes, and the second with initial normal MRI results and volume loss on subsequent MRI scans. In 2 other case series including adults, the children similarly presented with seizures and AMS with no abnormalities on CSF analysis and neuro-imaging except for 1 child diagnosed as having brain atrophy.13,14
Other case reports and series have demonstrated children with pH1N1 presenting with complex febrile seizure,16
In our study, the most common neurological manifestation in hospitalized children with pH1N1 was seizures. All of these patients were febrile, and all but 1 had known underlying epilepsy. Febrile seizures are a common event for children with influenza and may result in hospitalization.18,19
We had a low incidence of simple febrile seizures, likely because children with simple febrile seizures are not routinely admitted to the hospital at our institution. Because of this, the overall incidence of central nervous system manifestations of pH1N1 influenza may be higher than 7.5%. There were no children hospitalized for seizures without a fever. It is not clear whether seizures in the pH1N1 population are a nonspecific effect of a viral infection, cytokine release, or fever by lowering seizure threshold, or a more specific neurotropic effect of pH1N1 virus.19–21
The second most common neurological manifestation was encephalopathy. Our findings support previous observations that encephalopathy in influenza has a wide spectrum of presentations and is associated with poor neurological outcomes. Several reports,22,23
most from Japan, have documented influenza-associated ANE, which was originally defined by Mizuguchi23
according to the following criteria: (1) acute encephalopathy following a viral febrile illness with rapid deterioration in the level of consciousness and convulsions; (2) lack of CSF pleocytosis, but increased CSF protein commonly observed; (3) CT or MRI evidence of symmetric, multifocal brain lesions involving the bilateral thalami; (4) elevation of serum aminotransferases with no increase in blood ammonia; and (5) exclusion of other resembling diseases. The pathogenesis of ANE has not been clearly defined but is thought to be related to increased cytokine and macrophage activation.22–25
Both cases 1 and 3 presented with an acute encephalopathy, fever, and seizures with bilateral thalamic T2 changes. By Mizuguchi’s23
original diagnostic criteria for ANE, case 1 would favor a diagnosis of ADEM over ANE based on the presence of a mild pleocytosis and absence of a transaminitis or thrombocytopenia. Symmetric basal ganglia and thalamic gray matter lesions have been commonly reported in ADEM and are among the 4 patterns used to describe MRI findings in ADEM.26,27
As seen in this patient, the onset of ADEM is acute and typically occurs 2 days to 1 month after infection or vaccination.26,27
Histologically, there is a paucity of inflammatory cells in ANE, whereas ADEM demonstrates perivenule macrophages and T cells associated with demyelination.27
Some studies have used the complete resolution of MRI brain changes (ie, cavitary lesions) or a biphasic course in which bilateral thalamic lesions were not found at relapse as evidence supporting an ADEM diagnosis.26
Results from histological and repeated MRI studies, however, were not available for case 1.
Case 3 exemplified a CSF profile more typical of ANE with a significantly elevated protein level and absence of WBCs. A similar, but less dramatic, CSF profile (1 WBC/ µL, 0 RBCs, normal glucose level, and protein level of 135 mg/dL) was present with this patient’s prior presentation of encephalopathy and seizures that was initially presumed to be viral encephalitis. During his prior episode, the results from his MRI scan were normal, his aspartate transaminase level was mildly elevated at 73 U/L (1.22 µkat/L), but he showed no other evidence of an insult characteristic of ANE or ADEM. The patient was not treated with steroids, and he clinically recovered with little impairment. In retrospect, however, based on autopsy findings, there was likely some white matter insult at that time. The patient’s second presentation demonstrated bilateral thalamic lesions on MRI. However, he did not show other abnormalities common to ANE, including throm-bocytopenia or transaminitis. Nevertheless, his 2 clinical presentations of encephalopathy with CSF albumino-cytologic dissociation in conjunction with a postmortem diagnosis of ANE may reflect the clinical spectrum of ANE or the possibility of a biphasic course.
Although most of our patients with encephalopathy presented with symptoms of somnolence, decreased level of consciousness, or loss of consciousness, 1 patient presented with abnormal behaviors and hallucinations (case 2). Fevers have been associated with similar mental status changes, but this patient was afebrile. Although unusual, acute psychosis was reported in 6 of 148 patients with influenza (4%) during the 2002 epidemic in Japan and was reported in 1 case report of a patient with pH1N1.12,21
Six of our 7 patients with LPs had no clinically significant pleocytosis. Interestingly, 3 children, all of whom had poor outcomes, presented with elevated CSF protein levels. Concordant with previous reports that influenza RNA is rarely present in CSF,7,28,29
results from influenza PCR on our 2 CSF samples were negative for influenza RNA. In a third patient, a brain biopsy specimen was negative for influenza. It continues to be unclear whether the CNS manifestations of influenza are from a direct effect of the virus or a secondary inflammatory effect.
Similar to other reports of influenza-related CNS illnesses,21,30
children with pH1N1 who had neurological manifestations had a severe disease course. This was evidenced by the fact that approximately two-thirds of our cohort required ICU care. In addition, this subset of patients had an overall mortality of 13% compared with 2.1% in all of the hospitalized children with pH1N1 at our institution (Bagdure et al31
). Furthermore, 74% of the children who presented with a neurological manifestation had a preexisting neurological diagnosis. Of note, none of our patients had an underlying neuromuscular disorder, and all of our patients in our neuromuscular clinic who acquired pH1N1 influenza had a mild disease course (J.P., unpublished observation, 2010), suggesting that muscle weakness or dysfunction did not predispose to neurological complications or severe disease. This highlights what others have reported1
: that children with underlying neurological disease have increased risk of a neurological complication and a more severe disease course from influenza.
Vaccines for pH1N1 were not available in our region during most of the pandemic in 2009; therefore, a majority of our patients were unvaccinated. It is possible that timely vaccination could have prevented some of these complications.
In conclusion, neurological manifestations were seen in approximately 7.5% of hospitalized patients with pH1N1 and primarily in patients with underlying neurological conditions. The most common neurological manifestations seen were seizures and encephalopathy. In general, these patients had a severe disease course requiring prolonged hospital stays and ICU support, with a high percentage of deaths and neurological disability. Children with underlying neurological conditions should be particularly targeted for influenza prevention and aggressive supportive treatment at the onset of influenzalike symptoms.