Sex: F
Vaccine: FLUX
Symptoms: Gene mutation identification test positive, Generalised tonic-clonic seizure, Heart rate increased, Hypotonia, Immunoglobulin therapy
Clinical narrative: Influenza-associated encephalopathy/encephalitis (IAE); Influenza B virus infection; status epilepticus; acute respiratory failure; fever/tactile fever; runny nose; generalised fatigue; bowel and bladder incontinence; bowel and bladder incontinence; recurrent, prolonged generalised tonic clonic seizures; respiratory failure; seizures; weak cough; gag reflexes; generalised hypotonia; decreased strength in all extremities; visual impairment; unresponsive; concerns about her vision/patient had no perception of bright light consistent with total blindness; This case was reported in a literature article and described the occurrence of encephalitis in a 4-year-old female patient who received Flu unspecified (Influenza vaccine) for prophylaxis.    On an unknown date, the patient received Influenza vaccine. On an unknown date, unknown after receiving Influenza vaccine and an unknown time after starting levetiracetam, the patient experienced encephalitis (serious criteria hospitalization and GSK medically significant), influenza b virus infection (serious criteria hospitalization), status epilepticus (serious criteria hospitalization and GSK medically significant), acute respiratory failure (serious criteria hospitalization and GSK medically significant), fever (serious criteria hospitalization), runny nose (serious criteria hospitalization), fatigability generalized (serious criteria hospitalization), unresponsive to stimuli (serious criteria GSK medically significant), bowel incontinence (serious criteria hospitalization), bladder incontinence (serious criteria hospitalization), generalized tonic-clonic seizure (serious criteria hospitalization and GSK medically significant), respiratory failure (serious criteria hospitalization and GSK medically significant), seizure (serious criteria GSK medically significant), blindness (serious criteria GSK medically significant), cough weak, retching, hypotonia, weakness in extremity and visual impairment. The patient was treated with ceftriaxone (Ceftriaxone Disodium), lorazepam, levetiracetam, ibuprofen, paracetamol (Acetaminophen), fosphenytoin, steroids nos (Steroids), immunoglobulins nos (Intravenous Immunoglobulin), oseltamivir, vancomycin and methylprednisolone. On an unknown date, the outcome of the encephalitis, influenza b virus infection, status epilepticus, acute respiratory failure, fever, runny nose, fatigability generalized, bowel incontinence, bladder incontinence, generalized tonic-clonic seizure, respiratory failure, cough weak, retching, hypotonia and weakness in extremity were recovering/resolving and the outcome of the unresponsive to stimuli, seizure, blindness and visual impairment were recovered/resolved.   It was unknown if the reporter considered the encephalitis, influenza b virus infection, status epilepticus, acute respiratory failure, fever, runny nose, fatigability generalized, unresponsive to stimuli, bowel incontinence, bladder incontinence, generalized tonic-clonic seizure, respiratory failure, seizure, blindness, cough weak, retching, hypotonia, weakness in extremity and visual impairment to be related to Influenza vaccine.  Additional details were provided as follows: This case was reported in a literature article and described the occurrence of influenza-associated encephalopathy/encephalitis (IAE) in a 4-years old female patient, who was vaccinated with unspecified influenza vaccine (manufacturer unknown) for prophylaxis.  The patient was girl. The patient's parents denied vomiting, diarrhoea, dysuria, rash or breathing difficulty. Three household contacts had similar complaints. No information on patient's medical history, family history, concurrent condition or concomitant medication was provided.  On an unspecified date, the patient received unspecified influenza vaccine (administration route and site unspecified, dosage unknown; batch number not provided) in the prior season. However, the patient had not received a vaccine for the current season [History revealed that she had an influenza vaccine in the prior season, but she had not received a vaccine for the current season].  On an unspecified date, an unknown period after the vaccination, the patient was transferred to paediatric intensive care unit (PICU) intubated due to status epilepticus and acute respiratory failure. Her symptoms started with fever, runny nose and generalised fatigue 6 days prior to admission. The patient was treated supportively at home with appropriate doses of ibuprofen and acetaminophen. The patient's parents put her to bed on the night before admission. Six hours later, the patient was rushed to the local emergency room (ER) after being found unresponsive with tactile fever, bowel and bladder incontinence. At the ER, the child was afebrile, with heart rate 136 beats per minute, blood pressure 95/57 mm Hg, respiratory rate 22 breaths per minute and oxygen saturation 88% on ambient air. The patient was noted to have recurrent, prolonged generalised tonic clonic seizures, and the patient was treated with multiple doses of intravenous lorazepam and a 20 mg/kg loading dose of levetiracetam. The patient required endotracheal intubation due to respiratory failure in the setting of these seizures and seizure treatments. Her laboratory workup, including electrolytes, liver function tests and complete blood count, was normal. The respiratory viral PCR panel via nasal swab was positive for influenza type B. The patient was transferred to PICU on a mechanical ventilator with propofol infusion for sedation. On arrival to the PICU, the child's vital signs were stable, but her Glasgow coma score was low off sedation, and her pupillary response was sluggish to light bilaterally. Fever and seizures recurred. The patient was treated with additional intravenous lorazepam and an intravenous loading dose of fosphenytoin with subsequent resolution of clinical seizures. The neurology consultation service recommended continuous electroencephalogram (EEG) and maintenance dosing of levetiracetam. EEG was consistent with moderate to severe encephalopathy. There were no seizures during the entirety of her 36-hour recording. Despite discontinuation of sedation on hospital day 1, the child remained unresponsive with weak cough and gag reflexes for the initial 4 days of her admission. The patient had generalised hypotonia and decreased strength in all extremities. Following receipt of steroids and intravenous immunoglobulin (IVIG), there was a gradual improvement in her neurological status starting with spontaneous eye opening and an improved cough/gag reflex. At the time of her extubation on hospital day 12, there were already concerns about her vision. Subsequent ophthalmology exam was significant for minimal pupillary response to light and diffuse visual field restriction in total superior temporal, inferior temporal, superior nasal, inferior nasal fields. The patient had no perception of bright light consistent with total blindness. Perimetry and visual evoked potentials were attempted but not completed as child was younger and not cooperative. By the time of discharge on hospital day 16, she was walking, talking and eating food by mouth; however, the patient still had visual impairment and could not track or reach objects. Blood glucose and serum electrolytes were within normal limits throughout her hospitalisation. Liver and renal function tests were within normal limits. C-reactive protein (CRP) was less than 0.5 mg/dL on admission. CRP was as high as 5.3 mg/dL on hospital day 2, which trended down to normal from hospital day 3. Antinuclear antibody screen was negative, complement levels (C3 and C4) were within normal limits. Chest X-ray showed right upper lobe and left lobe atelectasis, with resolution within few days while intubated. Neuromyelitis optica (NMO)/aquaporin-4-IgG in serum and cerebrospinal fluid (CSF) were negative, and myelin oligodendrocyte glycoprotein (MOG) antibody assay in serum was negative. CSF analysis was normal with nucleated cells of 3/cubic mm, mildly elevated protein at 85 mg/dL and normal glucose at 66 mg/dL. The CSF meningitis/encephalitis PCR panel was negative. A CT scan of her brain on admission showed mild hypodensities in the left temporal and parietal lobes. Subsequent MRI of the brain showed bilateral, symmetric diffusion restriction of the amygdala, hippocampus, putamen, thalami, pons and regions of the peripheral cortex. [MRI brain findings in a patient with influenza-associated encephalitis/encephalopathy showing the involvement of bilateral putamen and thalami. It showed diffusion restriction in diffusion weighted image. It showed diffusion restriction in apparent diffusion coefficient image]. Faint enhancement of the posterior optic nerves was observed bilaterally on the post-contrast images. [MRI brain with and without contrast findings in a patient with influenza-associated encephalitis/encephalopathy showing enhancement of the posterior optic nerves bilaterally]. MRI C-spine was normal without any demyelinating changes. She was also found to be heterozygous for RAN binding protein 2 (RANBP2) gene mutation on further diagnostic investigation. The working diagnosis at this point was acute necrotizing encephalopathy (ANE) secondary to influenza B infection. The differential diagnosis included NMO, MOG antibody associated encephalopathy, vasculitis and bacterial meningitis. Appropriate workup for these alternative diagnoses was negative. The patient was treated for influenza B infection with oseltamivir for 5 days. The patient was also empirically treated with ceftriaxone and vancomycin until blood, urine and CSF cultures returned negative. Given the working diagnosis of ANE, the patient was given pulse dose steroid therapy with methylprednisolone 30 mg/kg/day from hospital days 3-7 followed by a steroid taper over 3 weeks. The patient was also treated with 0.5 g/kg/day IVIG from hospital days 7-10. The patient continued to improve after the hospital discharge, and within a month, The patient had subjectively regained full vision. At her follow-up visit with neurology, The patient was able to identify colours, and The patient could track objects. Visual acuity testing in neurology clinic was limited as the patient did not cooperate with age appropriate visual acuity testing using the tumbling E vision chart. The patient's parents expressed concerns at that appointment for her learning, stating that it seemed difficult for her to retain new information. Neuropsychology evaluation was scheduled. Patient was scheduled to have an ophthalmology appointment the following week but was then lost to follow-up. The child and her family members were referred to genetics clinic, pending additional genetic testing at the time of this case report. This case has been considered as serious due to hospitalization.  The author commented, "Influenza-associated neurological manifestations vary from encephalitis/encephalopathy, myelitis, Guillain-Barre syndrome and Reye's syndrome, to ANE. Influenza type A is the predominant cause of IAE in children. IAE is more frequently reported in country than the rest of the world. The incidence of influenza-related neurological complications was 4 cases per 100 000 child-years in the country. Abrupt onset of seizures and loss of consciousness following a short duration of fever are the most common manifestations of IAE. CSF analysis may reveal pleocytosis and/or increased protein; however, normal CSF analysis and negative RT-PCR do not rule out IAE. CT and/or MRI may show diffuse cerebral oedema. Neuroimaging in ANE further shows symmetric necrosis of thalami, cortex, internal capsule and brain stem structures. MRI findings in our index patient were consistent with ANE. Cytokine-mediated vascular inflammation and parenchymal cell apoptosis are the most proposed pathophysiological mechanisms for IAE. While our patient's neurological improvement correlated with receipt of these treatments, it is difficult to interpret whether the treatments caused the improvement or if her improvement was due to the natural course of the illness. Larger studies are needed to determine the efficacy of steroids and IVIG in IAE. Our index case was also found to be heterozygous for RANBP2 gene mutation. This genetic mutation was well studied and was found to be associated with recurrent and familial cases of ANE. Visual defects such as uveitis, optic neuritis, neuroretinitis, retinal infarction and lateral geniculate body (visual pathway relay centre in thalamus) infarction have been reported in paediatric patients with influenza. Blindness in our patient is likely explained by the combination of optic nerve enhancement and ANE affecting the lateral geniculate bodies. Presence of isolated optic nerve enhancement without optic disc oedema in our index case was not reported in previous studies. It was described a child diagnosed with IAE due to influenza B virus infection who developed temporary visual impairment as a sequela." This article corresponding to this case is not available for regulatory submission due to copyright restriction.