Introduction

Influenza primarily affects the respiratory system [1,2,3]. It is the most frequent cause of acute upper respiratory tract infections, especially in the winter season. Neurological manifestations of influenza are rare, although well described. Most frequently reported complications are as follows: seizures [1, 4,5,6,7], encephalopathy [4, 5], Reye syndrome [8], acute disseminated encephalomyelitis (ADEM) [1], myelitis [9, 10], Guillain-Barre syndrome [11, 12], acute necrotizing encephalopathy (ANE) [1, 4, 5, 13, 14], and speech or motor disorders [5]. Although most of neurological complications are temporary, permanent sequel and death are not rare [5, 15, 16].

Knowledge is limited about the frequency, diagnosis, treatment, and prognosis of neurological manifestations of influenza in children [17]. Most available data are based on case reports or case series with limited numbers of patients [1, 5, 18, 19]. Neurological manifestations may be overlooked by clinicians in especially seasonal influenza infections or in areas that are not endemic for influenza related neurological complication.

In this study, we evaluated pediatric influenza cases exhibiting severe neurological complications (neuroinfluenza) from six hospitals which are considered as regional reference centers. The demographic and clinical characteristics of patients, their laboratory and neuroimaging findings, in addition applied treatments, outcomes, and factors affecting their prognosis, were evaluated.

Methods

Study population

The medical data of 14 patients from six hospitals in different regions of the country who had suffered neurological complications due to a confirmed influenza infection were retrospectively analyzed. All the centers included in the study were regional reference hospitals in pediatric intensive care unit (PICU), pediatric infectious diseases, and pediatric neurology. Five of the hospitals were university hospitals, one was a children’s hospital. The criteria for inclusion were patients aged 1 month–18 years who had contracted an influenza infection in the 2015–2016 flu season that resulted in severe neurological complications. Newborns, cases in which the relation between the influenza infection and neurological symptoms was uncertain, and patients who experienced isolated seizures (e.g., febrile convulsion) in the absence of other clinical, laboratory and/or imaging finding of neurological manifestation were excluded from the study.

The study was approved by the local ethics committee of Ondokuz Mayis University (Samsun, Turkey).

Data collection

The demographic and clinical characteristics of the patients, including comorbidities, were recorded. For each patient, the following data were collected: complete blood count, serum, and CSF biochemistry; acute phase reactants; CSF analysis; computed tomography (CT); magnetic resonance imaging (MRI); electroencephalography (EEG), electroneuromyography (ENMG) findings, and treatments, procedures, and outcomes. The patients’ data were obtained from hospital computer database system and patients’ medical cards. CT and MR imaging were evaluated by one neuroradiologist who had no knowledge of the patients’ clinical information. Main evaluation points included locations with abnormal signal, signal alteration, and enhancement.

The patients were divided into two groups according to their ages: <5 and >5 years.

Diagnosis and definitions

In all cases, influenza infection was confirmed by a real-time reverse transcription polymerase chain reaction (rRT-PCR) assay for influenza of nasal aspirates or combined nose and throat swabs. The assays were conducted at the National Health Ministry Laboratories. All the samples were tested for respiratory tract viruses other than influenza virus, including adenovirus, rhinovirus, respiratory syncytial virus, and parainfluenza virus. None of the patients were screened for viral agents in their CSF.

An influenza-associated neurological complication was defined as the emergence or worsening of a neurological symptom, which could not be explained otherwise, in a patient with laboratory proven influenza. Complications may be caused by central or peripheral nervous system involvement. Complications primarily include seizures, encephalopathy, encephalitis, Guillain-Barre syndrome, ADEM, ataxia, involuntary movements, and behavioral or personality disorders. A seizure was defined as clinical seizure with or without clinical or laboratory findings of encephalitis or meningitis [18]. Encephalopathy was defined as the presence of altered mental status starting within 5 days of the influenza infection and lasting longer than 24 h, together with lethargy, anxiety, and behavioral or personality changes [4, 20]. Encephalitis was defined as encephalopathy accompanied by two or more of the following findings: a fever or history of fever (>38.0 °C), a seizure and/or focal neurological finding indicative of brain parenchymal involvement, CSF pleocytosis, EEG consistent with encephalitis, or abnormal neuroradiological finding indicative of infection or inflammation [21, 22]. Meningitis was defined as CSF pleocytosis accompanied by meningeal symptoms such as headache, photophobia, nuchal rigidity, and altered state of consciousness. Hyponatremia was defined as serum sodium level lower than 135 mEq/L. Age-appropriate reference values were used in the consideration of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine phosphokinase (CPK) levels.

Classification of patient outcomes

The outcome was classified into four categories. These were as follows: (i) recovery without sequelae (good prognosis), (ii) minimal or mild sequelae that did not interfere with daily life, (iii) serious sequelae that resulted in need for assistance in daily life or the worsening of existing neurological state, and (iv) death [4].

Statistical analysis

Data was analyzed using descriptive statistics.

Results

Median age of the patients was 59 months (6 months–15 years and 5 months) and nine (64.3%) of the patients were male. Four (28.6%) patients had a comorbid disease, and all the other patients were previously healthy. Apart from one patient with Down syndrome and congenital heart disease, patients did not have immunodeficiency which would result in predisposition to infections. Median interval between the start of flu-like symptoms and the emergence of neurological findings was 2 days. None of the patients were vaccinated for influenza. The demographic and clinical characteristics of patients are shown in Table 1.

Table 1 Demographic and clinical characteristics of patients
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The most frequent complaints for hospital admission in order of frequency were the following: a fever, an altered state of consciousness, vomiting, and seizure. Six (42.9%) patients had been intubated prior to being admitted to the emergency room (ER) or were intubated in the ER. At admission to the ER, all the patients, except one, who had Guillain-Barre syndrome, had an altered mental status, which ranged from drowsiness to a coma. Five (35.7%) patients had a Glasgow Coma Scale (GCS) score lower than 8. One patient had facial paralysis and another displayed involuntary movements at admission. Only one patient had decorticated posture; the rest had normal posture. None of the patients had anisocoria, circulation problems, hypotension, or hypertension at admission. Four patients had lower respiratory involvement. One patient had hematologic system involvement, and one patient had simultaneous lower respiratory and hematologic involvement. The other patients had isolated nervous system involvement. The patients’ complaints at admission, together with the clinical findings, are shown in Table 2.

Table 2 Complaints and clinical findings at admission
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At admission, two patients had leukopenia, and five patients had leukocytosis. The thrombocyte count of four patients lower than 150,000/mm3, and two of these had a thrombocyte count lower than 50,000/mm3. Four patients had increases only in AST levels, and two patients had increases in both AST and ALT levels. In both cases, the levels were higher than twice the respective age-appropriate upper reference values. CPK values were determined in 12 patients. They were higher than normal for their age in five cases (368–1120 U/L). Laboratory findings are shown in Table 3.

Table 3 Laboratory findings
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The causative microorganism was H3N2 in two patients and influenza B in one patient. In all other patients, the causative agent was H1N1. CSF analysis was performed in 11 patients. The CSF sample was obtained by lumbar puncture in ten patients. External ventricular drainage was used to obtain the CSF sample from one patient who had increased intracranial pressure and hydrocephaly. Lumbar puncture and CSF analysis could not be performed in three patients because they were hemodynamically unstable. Only two patients showed CSF pleocytosis. CSF culture from one of these patients was positive for Streptococcus pneumonia. Neuroimaging was performed in 13 cases. In this series, the most common MRI findings were a symmetrical hyperintense T2 signal in the bilateral thalamus, basal ganglions, periventricular white matter, cerebellum, brainstem, and medulla spinalis (Fig. 1). In addition, two patients showed meningeal enhancement of the frontal, parietal, and occipital lobes. The results of influenza typing, CSF analysis and neuroradiological imaging findings are shown in Table 4.

Fig. 1
figure 1

MRI in a 15-year-old girl, 4 days after neurological symptom onset. a Axial T2-weighted image illustrates symmetrical hyperintensities in the bilateral thalamus. b Fluid-attenuated inversion recovery coronal image shows hyperintense signal in bilateral cerebellar hemisferes. c Axial T2-weighted image shows hyperintense signal in the pons. d Diffusion-weighted axial image shows the lesions in the pons with restricted diffusion

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Table 4 Influenza typing, CSF analysis, and neuroradiological imaging findings
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Nine (64.3%) of the 14 patients had suffered epileptic seizures. Seven patients had seizures before being admitted to the hospital. Five (55.6%) of these nine patients had repeated seizures during hospitalization. Two patients who had previously been diagnosed with epilepsy each had one seizure during hospitalization. Two patients had focal seizures, while the rest had generalized seizures. Two patients developed status epilepticus during the follow-up: a 40-month-old patient who was previously healthy and was diagnosed with influenza-associated ADEM, and a 36-month-old patient who had citrullinemia (Table 5).

Table 5 Demographic and clinical characteristics, treatments, and prognosis of patients included in the study
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Two patients presented with influenza-associated late complication. Both patients were <5 years old. In one case, 9 days had elapsed between the start of flu-like symptoms and the emergence of neurological findings. This patient was diagnosed with Guillain-Barre syndrome. In the other case, 14 days had elapsed between the onset of influenza-like symptoms and emergence of neurological findings. This patient was diagnosed with ADEM. All the other patients presented with acute complications of influenza.

The most frequent diagnoses in order of frequency were as follows: encephalopathy (n = 4), encephalitis (n = 3), meningitis (n = 3), and ANE (n = 2). The patient numbered as two, who was diagnosed with meningitis, had findings consistent with mild encephalopathy with reversible splenial lesion (MERS) and had S. pneumonia growth in CSF culture.

All patients except one, who died prior to PCR-confirmed influenza, received oseltamivir treatment. In six (42.9%) patients, the treatment was commenced immediately after admission to hospital empirically. The median time between hospital admission and commencement of oseltamivir treatment was 24 (1–96) h. None of the patients showed any oseltamivir-related neurological side effect. Eight patients received hypertonic saline and/or mannitol as an antiedematous treatment. In addition to antiviral regimen, six patients received intravenous immunoglobulin (IVIG) treatment, and one patient received IVIG plus corticosteroid treatment. Two of these patients were the Guillain-Barre syndrome and ADEM patients; the remaining were diagnosed with influenza-associated encephalitis.

Seven of the 14 patients received mechanical ventilation. The median duration of mechanical ventilation was 7 (2–14) days. In one patient, external ventricular drainage was implemented in the early stage and a ventriculoperitoneal shunt was placed during follow-up. No other patients received neurosurgical intervention.

The median length of stay in the PICU and hospital was 8 (1–21) and 20 (5–62) days, respectively.

Seven (50.0%) of the 14 patients with influenza-related neurological manifestations made, a full recovery, without sequelae. Both patients with influenza-related late complications recovered without sequelae. Three (21.4%) patients were discharged with mild sequelae, and another three (21.4%) were discharged with severe neurological sequelea. One (7.1%) patient died. One patient who was discharged with severe neurological sequelea had a neurodevelopmental disorder and was diagnosed with ANE and myelitis. The other two patients were previously healthy and were diagnosed with ANE and meningitis. The patient who died had a history of citrullinemia, and admitted with severe hyponatremia (admission sodium level 125 mEq/L), and developed status epilepticus during hospitalization. Demographic and clinical characteristics, treatments, and outcomes of patients included in the study are shown in Table 5.

The patients were divided into two groups according to their previous health status. All four patients with comorbid disease needed mechanical ventilation support and were admitted to the PICU. In the previous healthy group, 30% required mechanical ventilator support and 80% were admitted to the PICU. The duration of mechanical ventilation and length of PICU/hospital stay of the patients with comorbid diseases were longer than those of the previously healthy group.

The patients were divided into two groups according to their age: <5 and >5 years. There were no difference between the groups regarding the comorbid disease and presence of previous seizure. Two patients developed influenza-related late complications. Both patients were <5 years old. In patients <5 years old, elapsed time between the start of flu-like symptoms and presentation of the first neurological finding was shorter, clinical findings were more severe and outcome was worse. Length of PICU/hospital stay was longer in patients >5 years old. The only patient who died was <5 years old. Comparisons of the groups are shown in Table 6.

Table 6 Comparisons of the clinical characteristics and outcomes according to age groups
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Discussion

The results showed that seasonal influenza infections may cause severe neurological complications in children. Neurological complications may present early during infection or late after the infection. Clinical course is variable. According to results, a history of good health is not protective against to occurrence of influenza-related neurological complication.

Influenza is a common infectious agent worldwide. It primarily affects the respiratory system [1,2,3]. However, in some cases, neurological symptoms may be predominant or even the initial finding [12, 23].

The actual frequency of neurological complications due to influenza infection in children is unknown. However, it is more often compared to adults and is reported as 1.7–15% among children who are hospitalized because of an influenza infection [1, 3, 12, 18, 22, 24, 25].

There are no markers to predict the development of neurological complications in patients with flu-like symptoms. Young age was reported to be the most important risk factor for influenza-associated neurological complication [1, 3, 4, 12, 18, 25]. The risk is the highest in children under 5 years age [4, 12, 18, 25, 26].

Some researchers reported that having a comorbid or preexisting disease, especially neurodevelopmental disorder, was associated with increased risk [1, 3, 12, 25, 27, 28]. However, other studies suggest that influenza may be an important mortality and morbidity cause in previously healthy children [4, 18, 29]. The results of present study support the idea that a history of good health is not a protective factor against the development of neurological complication in influenza infections.

The rate and nature of protection provided by seasonal vaccines against neurological complications is unknown. According to some studies, patients who developed neurological complications were mostly children who had no received the influenza vaccination [1, 25]. None of the children in present study were vaccinated for influenza. These findings may indicate the potential importance of seasonal flu vaccines in children.

The interval between occurrence of fever and the appearance of first neurological findings is usually shorter than 48 h [3, 4, 25]. In this study, two patients, one with Guillain-Barre syndrome and the other with ADEM, were hospitalized due to influenza-associated late neurological complications. We found median time between flu-like symptoms and the presentation of neurological findings as 2 days.

Influenza-associated neurological complications are various, also their severity and outcomes are variable [2]. Altered state of consciousness and seizure are the most frequently reported neurological findings [3,4,5, 12, 18, 25, 30]. Previously healthy children may experience their first seizure as a consequence of influenza or the frequency of seizures may increase in epileptic patients [3, 25, 31]. These seizures may be focal, generalized, or in the form of status epilepticus [2, 3, 14, 31]. The most frequent seizure type is febrile convulsion [3]. Seizure frequency is reported as 53–87.5% in patients with neurological complications [1, 4, 5, 18]. In the present study, seizure occurred in 50% of the patients prior to admission and 64.3% had seizures during hospitalization. Two patients had seizures in the form of status epilepticus, and one of these patients later died. Other neurological findings that are less frequent are personality changes, speech disorders, and hallucinations [3, 25]. Our findings were in agreement with literature.

Although altered state of consciousness is frequent in influenza-associated neurological involvement; presence of meningeal irritation findings such as nuchal rigidity, positive Kerning, and Brudzinski’s sign are not common [1, 18]. In accordance with the literature, the rate of positive sign indicative of meningeal irritation was found to be low in this study.

Encephalopathy characterized with sudden onset of fever, convulsion, and rapidly progressive coma is a severe form of influenza-associated neurological manifestation [4]. Encephalitis and ANE are less frequent forms of serious encephalopathy. They are characterized with the addition of typical clinical, laboratory, and neuroradiological findings to encephalopathy [1, 3, 4]. In our study, most of the patients with acute neurological manifestations were diagnosed with encephalopathy. The clinical and radiological findings of one patient were consistent with mild encephalopathy with reversible splenial lesion (MERS). Interestingly, this patient also had CSF pleocytosis and S. pneumonia growth in CSF culture. MERS as a new type of acute encephalopathy, characterized by transient splenial lesions with high-signal intensity on diffusion-weighed MRI, a mild clinical course, and good outcome [2, 32]. Patient was discharged without sequelae.

The mechanism underlying the development of influenza-associated neurological manifestation is not clear. It may develop due to immune or inflammatory injury or direct viral invasion. Previous studies report a low rate of CSF pleocytosis [3, 5, 12, 16, 18, 25]. In this study, pleocytosis was detected in only two of 11 (18.2%) patients in whom CSF analysis was performed. The lack of pleocytosis in most of the patients who had neuroradiological evidence of central nervous system manifestation suggests that nervous system injury may be immune-mediated or due to direct viral invasion or vascular inflammation, rather than inflammatory response [2, 33, 34]. Our results show that the absence of CSF pleocytosis does not exclude the presence of neurological manifestation, which is in agreement with previous studies.

Studies report that the infectious agent is usually influenza type A and less frequently influenza type B [16]. In the current study, only one patient had influenza type B, whereas the rest had influenza type A. Thus, it was not possible to make comparisons between subtypes.

Previous studies reported positive bacterial culture during influenza-associated neurological manifestation [17, 18, 35]. Dawood et al. [17] report that S. aureus and S. pneumonia are the two most frequently isolated bacterial agents in children hospitalized due to influenza infection. In the present study, CSF culture from one patient was positive for S. pneumonia.

Neuroradiological studies may assist in confirming a diagnosis, evaluating the severity of clinical state, and making the decision regarding the initial treatment [32]. A neuroradiological study was performed at least once on all the patients except one who was diagnosed with Guillain-Barre syndrome. The most frequently reported neuroradiological abnormalities detected in patients with neurological complications of influenza are as follows: localized or generalized edema, cortical and subcortical white matter signal alterations, and bilateral symmetrical multifocal lesions on the thalamus and cerebellar medulla [2, 5, 18]. Serious radiological abnormalities were also detected in control images obtained from patients who had normal radiology findings at presentation [5, 32]. In the present study, the most frequently affected regions of nervous system were the cerebellum, brainstem, thalamus, basal ganglions, periventricular white matter, and medulla spinalis.

Patients who are diagnosed with influenza-associated neurological manifestation should be monitored in ICU due to the risk of rapid progression and multiple-organ failure [18, 32]. Intensive care unit requirement were reported as 30.6–65.0% in previous studies [12, 25]. In the present study, 83.3% of patients were monitored in ICUs.

There is no specific treatment for influenza-associated neurological manifestation [12]. Various treatment options suggested to date include antiviral medications, corticosteroids, IVIG, hypothermia, therapeutic plasma exchange, cyclosporine, and surgical intervention [2, 36]. Which option is more effective is not clear. However, early diagnosis and intervention were crucial. Neurocritical care treatments such as hemodynamic monitorization and support, fever control, sedo-analgesia, mechanical ventilation support, anticonvulsive and hyperosmolar antiedematous therapy may have positive effect on the prognosis, independent of the severity of neurological manifestation [2, 37, 38].

The positive effect of antiviral therapy, including oseltamivir, on decreasing neurological complications and improving outcome is unknown [5]. However, early intervention with antiviral therapy may suppress viral expression, thus reducing the inflammatory response, which has an important role in neurological injury [2]. All the patients in this study, except the patient who died, received oseltamivir phosphate treatment for 5 days. Neurological side effects due to the use of oseltamivir phosphate are reported in literature [39]. However, neurological deterioration due to oseltamivir use is not reported in studies evaluating pediatric patients who had influenza-associated neurological manifestation, as was the case in present study [1, 12, 25].

Median length of stay in the hospital is reported as 4–6 days [18, 25]. However, this duration may be prolonged, especially in cases of encephalitis and ANE [18]. In the current study, the length of stay in the PICU and hospital were found to be longer than that reported in previous studies. This may be explained by the severity of our patients.

The prognosis of patients with influenza-associated neurological complications are varies [12, 32]. The prognosis in cases of encephalopathy and ANE is usually poor [3, 4, 16], with a mortality rate of 0–31.8% reported [1, 3, 4, 12, 16, 18, 23, 25, 30, 35, 38, 40]. Death is mostly due to multiple organ failure and is usually occurs within 2 days after the appearance of neurological findings [16].

To date, there are no markers that can help in predicting clinical course and prognosis in case of neurological complications of influenza. Some previous studies identified existing neurological disease as an independent risk factor for increased mortality [12, 41]. In study by Khander et al. [12], two children who died both had preexisting chronic health conditions. Coma usually presents within 24 h of the occurrence of fever. Serious coma is associated with high mortality.

The prognostic significance of various factors, such as high leukocyte count, C-reactive protein and sedimentation rate, thrombocytopenia, impaired liver function and coagulation tests, increased LDH and CPK values, hypo-hyperglycemia and hyperammonemia, has been investigated especially in patients who develop encephalopathy and ANE [4, 40]. Nagao et al. [40] report four factors affected the prognosis in influenza-associated encephalopathy: increased AST, hyperglycemia, hematuria or proteinuria, and use of diclofenac sodium. Tsuneo et al. [4] report that a low thrombocyte count, severely elevated transaminase, lactate dehydrogenase and CPK levels, in addition to prolonged coagulation test times, were related to poor prognosis. In present study, none of the patients, including the patient who died, had severely elevated levels of transaminase. In the patient who died, the most significant laboratory abnormality was severe hyponatremia.

Neuromotor deficit persists in some patients who developed neurological complications of influenza [16]. Previous studies report sequelae rate as 3.1–27.7% [4, 23, 25, 30, 38, 42]. The fundamental cause of sequel is cerebral atrophy [5, 16]. Research showed that MRI findings at presentation are not useful in predicting permanent sequelae development. However, Mizuguchi et al. [36] report that ANE patients with bilateral thalamic involvement on MRI had a poor prognosis. In the present study, two of four patients (nos. 1 and 13) who had bilateral thalamic involvement were discharged with severe neurologic sequelae. One patient (no. 9) had mild neurological sequelae, and one (no. 7) was discharged without sequelae.

The present study included only patients who had severe neurological manifestation. Those with isolated seizures, such as febrile convulsion which have relatively better prognosis, were excluded from the study. Despite this, the rate of mortality and severe neurological sequelae were low. Early commencement of oseltamivir treatment and ICU monitorization of patients may have influenced these results. Studies designed to investigate the effects of antiviral therapy on the development of neurological complications and patients’ outcome are required.

This study provides useful information on influenza-related complications in pediatric patients. However, it has some limitations. These are the retrospective nature of the study, relatively low number of cases, and the lack of long-term evaluation of the patients. Retrospective studies like ours and case reports or series comprise a high proportion of the studies investigating influenza-associated neurological complications in children. This study, conducted on patients from six regional reference centers, is the largest case series study investigating neurological complications due to seasonal influenza infection in Turkey. The main differences between the present study and similar studies in the literature are the inclusion of patients with severe complications, and the availability of neurological imaging findings for almost all the patients. In addition, we did not include patients who had isolated seizures without clinical, laboratory or imaging findings suggesting nervous system involvement. These patients comprised most of the cases in previous studies. However, studies based on larger numbers of patients are needed to enhance the reliability of the findings.

In conclusion, influenza-associated neurological complications are not rare in children. The diagnosis may be difficult in patients who have existing neurological disease or in patients whose respiratory involvement are not dominant. Healthy children are as much risk as patients who have comorbid conditions. All children who are admitted with neurological findings, especially during the influenza season, should be evaluated for influenza-associated neurological complications even if their respiratory complaints are mild or nonexistent. The lack of CSF pleocytosis does not exclude nervous system involvement. Further studies with a larger population are required for the evaluation of vaccination programs, identification of markers for the prediction of neurological involvement and prognosis, and investigation of long-term results.