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Neurological Manifestations of Influenza A (H1N1): Clinical Features, Intensive Care Needs, and Outcome

Objectives To describe neurological manifestations in children with Influenza A (H1N1). Methods This retrospective study was conducted in the Pediatric intensive care unit (PICU) and Pediatric Neurology unit of a tertiary care teaching hospital in North India involving children with PCR confirmed Influenza A (H1N1) with neurological manifestations during 2019 outbreak. Results Six children (5 females, 1 male) were enrolled. All presented with neurological symptoms (seizures and altered sensorium) accompanied with fever and respiratory symptoms with duration of illness of 2–7 d. The admission Glasgow Coma Scale ranged from 4 to 12. Only 2 cases showed cerebrospinal fluid pleocytosis. Neuroimaging was suggestive of diffuse cerebral edema, acute necrotizing encephalopathy of childhood, and acute disseminated encephalomyelitis. All were treated with Oseltamivir. Four cases had clinical features of raised intracranial pressure (ICP) and were managed in PICU, 3 of them needed mechanical ventilation, 3 needed vasoactive drugs, 3 received 3% saline infusion, 1 underwent invasive ICP monitoring, and 3 (cases 4, 5 and 6) received intravenous methylprednisolone (30 mg/kg) for 5 d. Total duration of hospital stay was 10–30 d. Case 2 expired due to refractory raised ICP. Among survivors, 3 children had residual neurological deficits and the remaining 2 had achieved premorbid condition. Conclusions Influenza A (H1N1) can present with isolated or predominant neurological manifestations which can contribute to poor outcome. The authors suggest to rule out H1N1 in any child who presents with unexplained neurological manifestations during seasonal outbreaks of H1N1.

The data about neurological manifestations in Influenza A (H1N1) in children from Indian subcontinent is limited to few case reports only [19,20]. In the present report, authors present 6 children (previously well) with Influenza A (H1N1) during 2019 outbreak with neurological manifestations in form of seizures, encephalopathy, encephalitis, raised ICP, ANEC and ADEM. The prominent radiological abnormalities are also demonstrated. Whenever any child presents with unexplained neurological manifestations during seasonal outbreak of H1N1, one should upfront start on empirical Oseltamivir after sending the investigations for the same.

Material and Methods
This retrospective study involves chart review of the children admitted in the Pediatric intensive care unit (PICU) and Pediatric Neurology unit of a tertiary care teaching hospital in North India over a period of 4 mo (January 2019 through April 2019). The authors identified 6 children with laboratory confirmed H1N1 infection with predominant neurological manifestations. The patients were diagnosed by the Centers for Disease Control recommended real time polymerase chain reaction (CDC-RT-PCR) from nasopharyngeal aspirations or swabs. The data was collected from the case records regarding demographic profile, clinical features, neurological signs and symptoms, laboratory investigations, neuroimaging, treatment details, intensive care needs, complications, and outcome. Since this was a retrospective study, patient consent was not obtained. The approval was obtained from the Departmental Review Board.

Results
During the influenza season of 2019 (January-April), 68 Influenza A (H1N1) cases were admitted to the hospital. Out of them, ten (14.7%) cases were admitted to PICU and Pediatric Neurology unit, and 6 (8.8%) had neurological manifestations due to Influenza A (H1N1). Five out of 6 cases were females with an age range of 6 mo to 10 y (median age 25 mo). All the cases were previously healthy. They had an illness duration of 2-7 d. All cases had fever and respiratory symptoms (cough, coryza, respiratory distress), and one had rash over extremities and face. All the cases had seizures and altered sensorium at admission with GCS ranging from 4 to 12. They had generalized tonicclonic seizures. Clinical signs of raised ICP (tachycardia, bradycardia, hypertension, unequal pupils, hypertonia, brisk deep tendon reflexes, pupillary inequality, or abnormal respiration) were noted in 4 cases. One case had focal deficit in form of left hemiparesis (Table 1).
Chest radiographs were abnormal in 3 cases (bilateral infiltrates in cases 1 and 6; right middle zone consolidation in case 4). Cerebrospinal fluid analysis revealed normal sugar and protein (n = 5) and pleocytosis in terms of 9-10 cells/ cumm with lymphocytic predominance (n = 2) ( Table 1). Patient 1 and 3 had normal contrast enhanced magnetic resonance imaging (CE MRI) brain and contrast enhanced computerized tomography (CECT) brain, respectively. Patient 2 had diffuse cerebral edema on CECT brain. MRI brain was suggestive of ANEC in Patient 4 and 5 (Figs. 1 and 2, respectively) and ADEM in patient 6 ( Fig. 3).
Cases 1-4 had respiratory failure at admission to Pediatric emergency, 3 cases had hemodynamic compromization, 1 had acute kidney injury (AKI), and 2 had transaminitis. All cases were treated with Oseltamivir for 5 d. Four cases with features of raised ICP were managed in PICU. Out of these 4 cases, 3 needed mechanical ventilation, and 3 cases with hemodynamic instability required vasoactive drugs, 3 received 3% saline infusion for raised ICP, and one case (case 4) underwent invasive ICP measurement by intraparenchymal ICP catheter ( Table 2). Three cases (cases 4, 5, and 6) received intravenous methylprednisolone (30 mg/kg) for 5 d followed by oral prednisolone for 4-6 wk for para-infectious immunological neuroimaging findings.
The clinical presentation of cases 1 and 3 were labelled as encephalopathy and raised ICP; case 2 as encephalitis, cerebral edema, and refractory raised ICP; case 4 as ANEC with raised ICP, case 5 as ANEC, and case 6 as ADEM. Case 2 expired on day 3 of admission in PICU due to diffuse cerebral edema, raised ICP, and brainstem herniation. The total duration of PICU stay was 10-21 d among PICU survivors (10, 14, and 21 d). Total duration of hospital stay was 10-30 d. Among survivors, 2 cases had residual neurological deficits and 3 were in premorbid condition (Table 2).

Discussion
The experience of neurological manifestations in 6 children with Influenza A (H1N1) is being reported from a tertiary care teaching hospital in North India. The clinical presentations in these 6 children were encephalopathy, encephalitis, cerebral edema, raised ICP, ANEC, and ADEM. The authors also described clinical profile, neuroimaging findings, CSF abnormalities, treatment details, intensive care needs, and outcome.
The occurrence of neurological complications is uncommon with seasonal influenza where an estimated incidence of around 1.2 per 100,000 children per year is being observed [14,21]. The pathogenesis of influenza associated encephalitis and encephalopathy is postulated to be due to direct viral invasion of central nervous system, metabolic encephalopathy coexisting with severe influenza illness, and a dysregulated immune response [22].
Similar to above studies, the authors of present study also noted that 8.8% children with Influenza A (H1N1) developed neurological manifestations. As per available literature, 10-30% cases with Influenza A (H1N1) need intensive care [6,15,16], which is similar to the current study where 14.7% required PICU admission. Out of 6 children with neurological manifestations, 4 (66.7%) required ICU care and 50% required mechanical ventilation. This is at par with literature,  where in presence of neurological manifestations, 30% to 2/ 3rd needed ICU admission and 25%-50% cases required mechanical ventilation [16,17]. Patient 4 and 5 had ANEC and survived with significant sequelae. ANEC is special form of encephalopathy with higher mortality and sequelae [12,13].
Treatment of Influenza A (H1N1)-infected patients with neuraminidase inhibitors (Oseltamivir or Zanamivir) leads to reduction in duration of illness by 0.5 to 1.5 d, reduction in rate of complications, hospitalization, and mortality; and improved outcome [15,27]. There are no randomized, controlled studies examining the efficacy of antiviral treatment on influenza-related neurologic complications and it is not clear whether the prognosis is better following treatment. With the available literature, it is advisable to start the antiviral therapy in Influenza A (H1N1) patients with neurological symptoms or complications as soon as possible. Thus, patients (n = 6) in current study were administered oral Oseltamivir for 5 d.
The outcome associated with neurological complications in patients with Influenza A (H1N1) is highly variable ranging from self-limiting to severe complications. The mortality rate varied between 4 and 30% [16,22,28]. In the current study the mortality was 16.6% (1/6) whereas 40% (2/5) of survivors developed sequelae.

Conclusions
H1N1 infection may lead to neurological manifestations associated with poor outcome. During outbreaks season, high index of suspicion should be kept in children presenting with neurological symptoms with or without respiratory involvements and should be empirically started on Oseltamivir after sending the investigations for confirmation. Prompt diagnosis, early initiation of antiviral therapy, and supportive care are mainstay of preventing complications and early recovery.  • 78.6% were < 5 y of age.
• No mortality. 6 C u r r e n t s t u d y 6 • All had fever, respiratory symptoms, seizures and altered sensorium. • Admission GCS ranged from 4 to 12.
• Neuroimaging showed diffuse cerebral edema, ANEC and ADEM. • 4 cases had raised ICP and required PICU admission. • Duration of hospital stay was 10-30 d.
• One died and 3 cases had neurological deficits.
ADEM Acute disseminated encephalomyelitis, ANEC Acute necrotizing encephalopathy of childhood, GCS Glasgow coma scale, ICP Intracranial pressure, ICU Intensive care unit, MRI Magnetic resonance imaging, PICU Pediatric intensive care unit Indian J Pediatr 87(10): -(October 2020) diagnosis; KG: Helped in virological diagnosis; RKR: Helped in virological diagnosis and provided intellectual inputs for the manuscript; MJ: Supervised clinical management, reviewed the manuscript and will act as Guarantor for this paper.