Acute Necrotizing Encephalopathy of Childhood with H1N1 Infection

Abstract

Acute necrotizing encephalopathy of childhood (ANEC) is an uncommon and fulminant complication of seasonal influenza infection associated with high mortality and poor neurological outcome. We report a 4.5-year-old female who had pneumonia, ANEC, and raised intracranial pressure (ICP) with polymerase chain reaction proven H1N1 infection. Management included mechanical ventilation, invasive monitoring and control of ICP, oseltamivir, methylprednisolone, and supportive care in pediatric intensive care unit. She survived with poor neurological status at discharge.

Introduction

Influenza infections can lead to various neurological complications in 10 to 18% of cases including febrile seizures, encephalopathy, encephalitis, acute necrotising encephalopathy of childhood (ANEC), and Guillain–Barre syndrome. ^{1 2 3} ANEC is a fulminant disorder characterized by rapid progressive encephalopathy, seizures, high mortality (10–40%), and poor neurological outcome (complete recovery is documented in only <10% cases). ^{4 5} The characteristic image findings of ANEC include bilateral symmetrical involvement of thalami, putamen, internal capsule, brainstem, cerebellum, and periventricular white matter. ⁵ The treatment is mainly supportive with care of airway, breathing, and circulation; management of raised ICP; and oseltamivir. Since cytokine storm has been implicated in pathogenesis of ANEC following viral infections, immunotherapy (steroids and intravenous immunoglobulin) may be beneficial. ⁵

Only few cases of ANEC or encephalitis in association with H1N1 infection have been reported from Indian subcontinent. ^{5 6 7} We present the clinical presentation, characteristic radioimaging findings, and management of ANEC in a 4½-year-old female child with H1N1 infection with poor neurological outcome.

Case Report

A 4.5-year-old female presented to the pediatric emergency with 7-day history of high-grade fever and cough. On day 6, she developed rapid breathing and altered sensorium. Two family members had history of fever and cough in preceding week. There was no history of recent travel and she did not receive influenza vaccine. There was no history of any neurological illness in the family. At that time, there was an outbreak of influenza (influenza A H1N1 pdm09) infection in community and in our hospital.

Examination revealed normal anthropometry; pallor; fever; pulse rate, 132/min; respiratory rate, 56/min; well palpable pulses; capillary refill time, 2 seconds; blood pressure, 86/50 mm Hg; and SpO2, 90%. Respiratory examination revealed subcostal retractions, bilateral crepitations, and bronchial breathing in right inframammary area. Neurological examination revealed Glasgow Coma Scale (GCS) score of 8, unequal pupils (right 4 mm and left 2 mm), bilateral hypertonia, up-going planter responses, and normal fundus.

She was started on invasive mechanical ventilation, antibiotics (ceftriaxone, 50 mg/kg/dose twice a day intravenously and azithromycin, 10 mg/kg/dose once a day), and antivirals (acyclovir, 500 mg/m ² /dose thrice a day intravenously and oseltamivir, 45 mg twice a day enterally). For raised ICP, first-tier measures, sedation and analgesia, and 3% saline infusion (0.5 mL/kg/h) was started. For monitoring ICP, intraparenchymal catheter was inserted and opening ICP was 24 mm Hg. To maintain cerebral perfusion pressure (ICP-mean arterial pressure) >50 mm Hg, norepinephrine infusion (0.1 µg/kg/min) was started.

Investigations showed blood glucose, 110 mg%; hemoglobin, 8.5 g%; platelet, 350,000/mm ³ ; and total leukocyte count, 11,800/mm ³ . Renal and liver functions were normal. Chest radiograph revealed right middle lobe consolidation ( Fig. 1A ). Nasopharyngeal swab tested positive for H1N1 by reverse-transcriptase polymerase chain reaction (RT-PCR). Contrast enhanced computerized tomography of brain showed ill-defined hypodensities involving white matter of bilateral cerebellar hemispheres, bilateral thalami, and brain stem ( Fig. 1B and 1C ).

Fig. 1.

( A ) Chest radiograph (anteroposterior) showing air space opacities in the right middle zone silhouetting right cardiac border suggestive of right middle lobe consolidation. ( B ) Contrast enhanced computerized tomography (CECT) brain showing ill-defined hypodensities in bilateral thalami and ( C ) bilateral cerebellar hemispheres.

Further, norepinephrine was given for 24 hours, 3% saline infusion for 48 hours, and oseltamivir for 14 days. By day 5, ICP was controlled and catheter was then removed. Cerebrospinal fluid (CSF) analysis showed 9 cells/mm ³ (all lymphocytes), normal sugar and proteins, and negative gram stain and culture. The PCR for H1N1, herpes simplex virus, and Japanese encephalitis were negative. Magnetic resonance imaging (MRI) of brain was suggestive of ANEC ( Fig. 2 ). Methylprednisolone pulse (30 mg/kg/day) was given for 5 days and prednisolone (2 mg/kg/day in two divided doses enterally) for another 4 weeks. There was gradual improvement in sensorium and respiratory status and she was extubated on day 13. She developed dystonia for which trihexyphenidyl and baclofen were given. She was discharged at day 18 with significant neurological sequelae (not able to walk with support, not able to feed self, and not able to talk). Three months after follow-up, there was improvement in her neurological status (able to walk with support, feed self, and talk) and she was continued on physical rehabilitation.

Fig. 2.

( A ) MRI brain showing T2 hyperintensities involving bilateral medial thalami and right occipital cortex ( B ) midbrain and ( C ) white matter of bilateral cerebellar hemispheres. The corresponding areas showed patchy contrast enhancement and diffusion restriction (not in image). MRI, magnetic resonance imaging.

Discussion

ANEC is a rare underrecognized parainfectious disorder associated with various viral infections including influenza and is characterized by fulminant clinical course with rapid onset of seizures, altered sensorium, raised ICP, and hepatic dysfunction with high mortality and profound neurologic sequelae. ^{1 2 3 5} The pathogenesis of brain damage in ANEC is suggested to be caused by indirect rather than direct injury due to wide spread activation of cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-1, and IL-6) and cell-mediated immune response leading to cerebral edema, petechial hemorrhages, and necrosi. ⁵ The characteristic absence of cells and elevated proteins in CSF differentiates ANEC from more common conditions like acute disseminated encephalomyelitis (ADEM) and acute hemorrhagic encephalitis. However, ANEC, ADEM, and acute hemorrhagic encephalitis are not discrete disease entities per se and develop as a result of parainfectious immunemediated inflammatory involvement of central nervous system from many viral etiologies. The characteristic imaging findings in ANEC are bilaterally symmetrical involvement of thalami, putamen, internal capsule, brainstem, periventricular, and cortical white matter, and cerebellum, ⁵ as in index case. Most of the cases of ANEC are sporadic. The familial or recurrent ANEC has been reported in patients with genetic susceptibility to ANEC due to a mutation in RAN binding protein 2 (RANBP2). ^{8 9 10}

Outcome in severe ANEC is generally poor, with high mortality (30%) and survivors used to have moderate to severe disability. There are no definitive treatment guidelines for the management of ANEC. It is important to have high index of suspicion of ANEC in such cases; timely and aggressive intensive care, monitoring and management of raised ICP, and early use of hyperosmolar therapy (hypertonic saline) are measures to prevent and treat brain edema and herniation; rationale antiviral treatment and downregulation of immune response by early use of pulse intravenous methylprednisolone ± gamma globulins or plasma exchange may improve the outcome. ^{11 12} Okumura et al ¹³ demonstrated that the early administration (within 24 hours) of intravenous steroids showed better correlation with better outcome (no or mild cognitive impairment) in children with ANEC without brain stem involvement. The negative H1N1 PCR in CSF may be due to the fact that ANEC is a cytokine storm mediated brain injury ¹¹ and the lumber puncture was performed late in the course of disease when she had already received oseltamivir for 6 days. There are reports of benefits of therapeutic hypothermia in children with ANEC. ^{14 15} As increased blood IL-6 level correlates with poor outcome, there has been reports that showed that the use of anti-IL-6 blocker (tocilizumab) is safe and lead to improved outcomes and prevented disability in children with ANEC. ¹⁶

Conclusion

ANEC is dreadful and uncommonly reported complication of H1N1 infection. MRI brain aids in diagnosis. High index of suspicion for ANEC, aggressive intensive care management, monitoring and treatment of raised ICP, rationale antivirals, and early use of pulse intravenous methylprednisolone ± gamma globulins or plasma exchange may improve the outcome.