Brain & Development xxx (2014) xxx–xxx www.elsevier.com/locate/braindev

Original article

Neurologic manifestations and complications of pandemic influenza A H1N1 in Malaysian children: What have we learnt from the ordeal? Hussain Imam Muhammad Ismail a, Chee Ming Teh b,⇑, Yin Leng Lee c, on behalf of National Paediatric H1N1 Study Group a

Institute of Paediatrics, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia b Department of Paediatrics, Hospital Pulau Pinang, Malaysia c Clinical Research Center, Ministry of Health, Malaysia

Received 7 January 2014; received in revised form 4 March 2014; accepted 7 March 2014

Abstract Introduction: In 2009, pandemic influenza A H1N1 emerged in Mexico and subsequently spread worldwide. In Malaysia, there were more than a thousand of confirmed cases among children. The general clinical characteristics of these children have been wellpublished. However, the description of neurologic complications is scarce. Objective: This study aims to describe the characteristics of neurologic manifestations and complications in a national paediatric cohort with pandemic influenza A H1N1. Methods: During the pandemic, children (12 years or less) admitted for novel influenza A H1N1 in 68 Malaysian public hospitals, were prospectively enrolled into national database. The clinical, laboratory and neuro-imaging data for children with neurologic manifestations, hospitalized from 15th June 2009 till 30th November 2009, was reviewed. Results: Of 1244 children with influenza A H1N1 during the study period, 103 (8.3%) presented with influenza-related neurological manifestations. The mean age of our study cohort was 4.2 years (SD: 3.3 years). Sixty percent of them were males. Sixty-nine (66.9%) were diagnosed as febrile seizures, 16 (15.5%) as breakthrough seizures with underlying epilepsy, 14 (13.6%) as influenza-associated encephalopathy or encephalitis (IAE) and 4 (3.9%) as acute necrotizing encephalopathy of childhood (ANEC). All 4 available CSF specimens were negative for influenza viral PCR. Among 14 children with brain-imaging done, 9 were abnormal (2: cerebral oedema, 4: ANEC and 3: other findings). There were four deaths and three cases with permanent neurological sequelae. Conclusion: About one-tenth of children with pandemic influenza A H1N1 presented with neurologic complications. The most common diagnosis was febrile seizures. One-fifth of those children with neurologic presentation had IAE or ANEC, which carried higher mortality and morbidity. This large national study provides us useful data to better manage children with neurologic complications in the future pandemic influenza outbreaks. Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Keywords: Pandemic; Influenza A; H1N1; Neurologic complications; Seizures; Encephalopathy; Children

1. Introduction ⇑ Corresponding author. Address: Department of Paediatrics, Hopsital Pulau Pinang, Jalan Residensi, 10990 Georgetown, Pulau Pinang, Malaysia. Tel.: +604 2225299; fax: +604 2281737. E-mail address: [email protected] (C.M. Teh).

In April 2009, a novel influenza A H1N1 was first identified in Mexican town of La Gloria, Veracruz [1]. Subsequently, it spread rapidly worldwide until World

http://dx.doi.org/10.1016/j.braindev.2014.03.008 0387-7604/Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: Muhammad Ismail HI et al. Neurologic manifestations and complications of pandemic influenza A H1N1 in Malaysian children: What have we learnt from the ordeal?. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.03.008

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H.I. Muhammad Ismail et al. / Brain & Development xxx (2014) xxx–xxx

Health Organization (WHO) declared this novel virus as pandemic influenza in June 2009 [2,3]. Until March 2010, this pandemic influenza A H1N1 had been notified from almost all countries, infecting all ages and leading to more than 17,000 fatalities [4]. In Malaysia, there were more a thousand of confirmed cases among children during the pandemic. The demographic and general clinical characteristics of this cohort of children had been previously published [5]. However, there is scarce description of neurologic manifestations and complications. Other than its respiratory consequences, influenza infection has been associated with a wide spectrum of neurologic complications ranging from febrile seizures, influenza-associated encephalopathy or encephalitis, acute necrotizing encephalopathy of childhood (ANEC), Reye syndrome, acute disseminating encephalomyelitis (ADEM), Guillain–Barre syndrome, transverse myelitis etc. [6,7]. There were few articles on neurologic complications in children with pandemic influenza A H1N1. However, these articles were either case reports or series with small study samples of children [8–13]. In this study, we examined the characteristics of neurologic manifestations and complications associated with pandemic influenza A H1N1 in a large national paediatric cohort. 2. Methods We conducted a retrospective review of the national database by which the subjects were prospectively recruited during the pandemic influenza A H1N1, from 15th June 2009 till 30th November 2009. The demographic, clinical, laboratory, radiological and outcome data for all the children (12 years of age or less) diagnosed with novel influenza A H1N1 was entered into the national database by site investigators at 68 public hospitals in Malaysia. The database was managed and co-ordinated by Clinical Research Center, Malaysian Ministry of Health. The diagnosis of novel influenza A H1N1 infection were confirmed via real-time reverse transcription-PCR test using nasopharyngeal specimens or throat swabs. All children admitted with influenzalike illness (ILI) would have this test done. This study protocol was reviewed and approved by the Malaysian Research and Ethics Committee. Informed consent was obtained from all study participants. The first paediatric case was diagnosed in Malaysia during the third week of June 2009. Initially, Malaysian Ministry of Health mandated that all patients with influenza-like illness (ILI) were to be admitted to 68 public hospitals for management as the containment strategy. However, from August 2009, during the mitigation phase, only patients with moderate to severe cases of ILI were hospitalized to these public hospitals. These 68 Ministry-of-Health-affiliated public hospitals provide

total of 3757 beds for children and 101 pediatric intensive care beds. Annually, they serve approximately 7,900,000 children less than 12 years of age. All study subjects with novel influenza A H1N1 presenting with neurologic manifestations were reviewed. The two most important neurologic presentations used to identify this cohort of patients were seizures and altered consciousness (encephalopathy). The demographic, clinical, laboratory, neuro-imaging and outcome data for these children with neurologic complications was then analyzed. Subjects with incomplete data or neurologic manifestations related to aetiologies other than influenza (such as electrolytes imbalance, hypoglycaemia and hypoxia) were excluded for analysis. For those patients with encephalopathy without clinically-obvious aetiology prior to the diagnosis of influenza associated encephalopathy/encephalitis, routine metabolic tests including lactate, ammonia, blood spots for acyl-carnitine and amino acid profile as well as urine organic acid were also performed. The following definitions were used for this study [8,11]: (1) Neurologic manifestations associated with pandemic influenza – seizures or encephalopathy within 5 days from the onset of influenza symptoms. (2) Encephalopathy – altered mental status or consciousness or personality compared to premorbid state for 24 h or more. (3) Encephalitis – encephalopathy plus 2 or more: fever >38 °C, pleocytosis in cerebrospinal fluid (CSF) or neuro-imaging showing evidence of infection or inflammation. (4) Influenza associated encephalopathy/encephalitis – encephalopathy/encephalitis not caused by other aetiologies except influenza infection after fully investigated. To achieve the diagnoses of neurologic manifestations, the clinical, laboratory and neuro-imaging data of these subjects was thoroughly reviewed by the first 2 authors, as paediatric neurologists. The provisional diagnosis by the attending pediatrician was also taken into consideration. All the available neuro-imagings were reported by certified radiologists. The outcome of these children was defined as outcome on discharge from hospital, being either alive well, having neurological sequelae or death. We computed distribution of demographic data and characteristics of neurologic manifestations and complications. Chi-square or Fisher exact tests were applied to assess the level of significance for dichotomous variables. P-value < 0.05 was taken as significance. All the analyses were performed using SPSS version 18.

Please cite this article in press as: Muhammad Ismail HI et al. Neurologic manifestations and complications of pandemic influenza A H1N1 in Malaysian children: What have we learnt from the ordeal?. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.03.008

H.I. Muhammad Ismail et al. / Brain & Development xxx (2014) xxx–xxx

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3. Results

Acute necrotizing encephalopathy of childhood (ANEC)

A total of 1254 children (12 years or less) were diagnosed with pandemic influenza A H1N1 during the study period. Ten patients were excluded due to incomplete data. One-hundred-and-eight children presented with neurologic manifestations. However, the neurologic presentation in five of them was caused by the aetiologies other than influenza infection (such as hypoxia, hypoglycaemia and electrolytes imbalance). Onehundred-and-three (8.3%) children presented with influenza-related neurologic complications and their characteristics were described in Table 1. The most common presentation was seizures (89.3%). Altered mental status was present in 17.5% of these children.

Complications ICU admission Ventilation Acute respiratory distress syndrome (ARDS) Shock (with vasopressin) Renal impairment Liver impairment Disseminated intravascular coagulation (DIVC)

20 (19.4) 15 (15) 4 (3.9) 6 (5.8) 5 (4.9) 4 (3.9) 0

Outcome Alive Death Neurological sequelae Unknown

93 (90.3) 4 (3.9) 3 (2.9) 3 (2.9)

Neuro-imaging (N = 14) Normal Diffuse cerebral oedema ANEC Intracranial haemorrhages and cerebral oedema Cerebral atrophy

5 2 4 1 2

Table 1 Characteristics of neurologic manifestations and complications associated with pandemic influenza A H1N1 in Malaysian children. Characteristics (N = 103)

n (%)

Age, years (mean, SD) Gender, male

4.2 (3.3) 62 (60.2)

Ethnic group Malay Chinese Indian Others

74 (71.8) 6 (5.8) 6 (5.8) 17 (16.5)

Concurrent clinical symptoms Documented fever History of fever Sore throat Cough Shortness of breath Diarrhea Nausea and vomiting Poor feeding Headache

66 (64.1) 38 (36.9) 6 (5.8) 77 (74.8) 12 (11.7) 16 (15.5) 27 (26.2) 19 (18.4) 3 (2.9)

Past medical conditions No previous medical history Genetic disorder Epilepsy or seizures Cerebral palsy Neuro-muscular Asthma Chronic lung disease Congenital heart disease Others

70 (68) 3 (2.9) 17 (16.5) 7 (6.8) 2 (1.9) 9 (8.7) 8 (7.8) 2 (1.9) 2 (1.9)

Neurologic manifestations Seizures only Encephalopathy only Both seizures and encephalopathy

85 (82.5) 11 (10.7) 7 (6.8)

Neurologic diagnosis Febrile seizures Breakthrough or exacerbation of seizures with underlying epilepsy Influenza associated encephalopathy or encephalitis

69 (67) 16 (15.5) 14 (13.6)

4 (3.9)

(4.9) (1.9) (13.8) (0.97) (1.9)

Seven percent presented with both seizures and altered mental status. The mean age for this cohort of children with neurologic manifestations was 4.2 years (SD: 3.3 years). Sixtytwo (60%) of them were boys. There were 3 major races in Malaysia, with the proportion of 50.4% Malay, 23.7% Chinese and 11% Indian. However, we observed an increase in neurologic presentation in Malay ethnic group (71.8%), followed by Chinese (5.8%) and Indian (5.8%). All the children in this cohort had either documented or history of fever. Other than neurological symptoms (seizures and altered consciousness), the most frequent concurrent symptom was cough, followed by nausea, vomiting, poor feeding, diarrhea and shortness of breath. Sixty-eight percent of the children with neurologic manifestations were premorbid well. However, about 28% of them had pre-existing neurological illnesses: 16.5% epilepsy or seizure disorders, 6.8% cerebral palsy, 2.9% neuro-genetic disorders and 1.9% neuro-muscular disorders. A small proportion of them (less than 10%) of them had asthma, chronic lung disease or congenital heart disease. With regards to the diagnoses of neurologic manifestations, 67% of them were diagnosed with febrile seizures. Besides, 15.5% of them were considered to have breakthrough or exacerbation of seizures with the underlying epilepsy. Influenza associated encephalopathy or encephalitis was present in 14 (13.6%) and there were 4 cases (3.9%) of acute necrotizing encephalopathy of childhood (ANEC). Four cerebrospinal fluid (CSF) specimens were available for review. All of the samples were biochemically or microscopically normal with negative influenza PCR test. We also did not find

Please cite this article in press as: Muhammad Ismail HI et al. Neurologic manifestations and complications of pandemic influenza A H1N1 in Malaysian children: What have we learnt from the ordeal?. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.03.008

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H.I. Muhammad Ismail et al. / Brain & Development xxx (2014) xxx–xxx

any significant result for the metabolic tests done for patients with encephalopathy. There were only 14 neuro-imagings (10 CT and 4 MRI brain) done for this cohort. The major indication of neuro-imaging was for alteration of consciousness. Five of the brain scans were normal. Two of the scans showed diffuse cerebral oedema. The typical radiologic features of ANEC (bilateral and almost symmetrical thalamic lesions) were present in 4 patients. One patient had intracranial haemorrhages likely related to sepsis or heamorrhagic shock and encephalopathy syndrome. On the other hand, two brain scans demonstrated cerebral atrophy; however, these two scans were done 1–2 weeks after acute event. One-fifth of the children with neurologic complications were admitted to paediatric intensive care unit. Fifteen percent of them required assisted ventilation, particularly for airway protection due to altered mental status. Four to six percent of them had other complications namely acute respiratory distress syndrome (ARDS), shock needing vasopressor, renal impairment or hepatic impairment. Among the cohort with neurological manifestation, 90.3% were discharged well. There were 4 deaths: two caused by ANEC, one caused by influenza associated encephalopathy/encephalitis with diffuse cerebral oedema and one due to concomitant ARDS. Besides, three of them ended with permanent neurological sequelae. Among these three patients, two had ANEC and the other one had intracranial haemorrhage. The mean age for patients with influenza associated encephalitis or encephalopathy (IAE) and acute necrotizing encephalopathy of childhood (ANEC) was 5.7 years (SD: 4.1 years). However, the subset of patients with ANEC was younger (mean age: 3.8 years, SD: 0.9 years) compared with patients with IAE (mean age: 6.4 years, SD: 4.5 years). There were more patients who were diagnosed with IAE or ANEC needing ICU admission and ventilation as well as suffering from other complications (shock, renal and liver impairment). More deaths and cases with neurological sequelae were also observed among those with IAE/ANEC (Table 2). 4. Discussion Influenza virus either seasonal or pandemic causes predominantly respiratory presentations and consequences. However, it is well-documented that a broad spectrum of neurologic manifestations is associated with influenza infection as well, particularly in children [14]. During the pandemic influenza A H1N1 in 2009–2010, young people seemed more susceptible to the infection [15,16]. With a surge of paediatric patients during the pandemic, numerous cases with neurologic complications in children had been recognized and published [6,8–13]. However, all these articles were mainly case

Table 2 Characteristics of children with influenza associated encephalitis/ encephalopathy (IAE) or acute necrotizing encephalopathy of childhood (ANEC). Characteristics

Without IAE/ ANEC (n = 85)

With IAE/ ANEC (n = 18)

p-valuea

Age, mean years (SD) Gender, male Premorbid healthy

3.9 (3.1) 50 57

5.7 (4.1) 12 13

0.021 0.54 0.67

Complications ICU admission Ventilation Shock with vasopressor Liver impairment Renal impairment ARDS

10 8 1 2 1 3

10 7 5 3 2 1

Neurologic manifestations and complications of pandemic influenza A H1N1 in Malaysian children: what have we learnt from the ordeal?

In 2009, pandemic influenza A H1N1 emerged in Mexico and subsequently spread worldwide. In Malaysia, there were more than a thousand of confirmed case...
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