Neurological features related to influenza virus in the pediatric population: a 3-year monocentric retrospective study.

Influenza virus is generally characterized by fever, myalgia, and respiratory symptoms. Neurological entities have already been described, such as acute necrotizing encephalitis (ANE). We aimed to highlight the non-exceptional nature and explore the clinical spectrum and evolution of neurological features related to influenza virus in children. This monocentric observational study included patients under 18 years old, positive for influenza virus, between January 2017 and April 2019 in a pediatric university hospital. Patients were classified into two groups: those with or without a previous significant neurological or metabolic disorder. Two hundred eighty-nine children were identified with influenza infection. Thirty seven had a neurological manifestation: 14 patients who had previous significant neurological or metabolic disorder and 23 patients with no medical history. We identified several clinical patterns: 22 patients had seizures, 7 behavior disorders, 5 disturbances of consciousness, and 3 motor deficits. Four were diagnosed with a known influenza-associated neurological syndrome: 1 ANE, 1 cytotoxic lesion of the corpus callosum, 1 hemiconvulsion-hemiplegia-epilepsia syndrome, and 1 recurrent encephalitis in the context of a RANBP2 mutation. The neurological outcome was favorable in most cases. None of the patients with previous significant disorder retained sequalae or had a recurrence. Two patients had a fatal outcome, and both had a predisposing disorder. CONCLUSION: Various neurological manifestations can be associated with influenza virus. Certain entities led to a poor prognosis, but in most cases, symptoms improved within a few days. The severity of the neurological manifestations correlated with previous neurological or metabolic disorders. WHAT IS KNOWN: • Influenza viruses are well known pathogens with a seasonal epidemic evolution, particularly affecting children. These viruses cause acute fever with respiratory symptoms, associated with myalgia and headaches. Neurological presentation in influenza-virus infection is a well-established possibility as influenza virus is considered to be responsible for 27 to 36% of childhood encephalitis. Some specific and severe entity as acute necrotizing encephalitis, cytotoxic lesion of the corpus callosum, or Hemiconvulsion-hemiplegia-epilepsy syndrome are well described. WHAT IS NEW: • In a French monocentric cohort of 37 children with influenza-related neurologic manifestations, the majority of these manifestations, including seizure, drowsiness, motor deficiency, hallucination… are self limiting and do not lead to after-effects. In rare cases (4/37), they may reveal severe encephalitis requiring rapid and appropriate treatment. Otherwise, comparison of a group of 14 children with underlying neurological or metabolic disorder with a group of 23 children free of any significant disorder show that the severity of the neurological manifestations was largely related to previous neurological or metabolic disorders highlighting the importance of vaccination in this population.

Acute haemorrhagic leukoencephalitis (AHLE) - our experience and a short review.

BACKGROUND: Acute haemorrhagic leukoencephalitis (AHLE), a rare variant of acute disseminated encephalomyelitis (ADEM), often presents differently from classical ADEM, thereby posing a diagnostic challenge to the clinician. AIM: To report AHLE, its clinic-radiological manifestations, process of diagnosis and prognosis. METHOD AND RESULTS: Eight patients presented with altered sensorium, acute focal deficits with or without seizures. Initial workup showed evidence of haemorrhagic lobar or thalamic lesions in seven patients. All patients underwent extensive evaluation for collagen vascular disease and vasculitis profile, autoimmune encephalitis panel and aquaporin-4 antibody, which were found to be normal. Cerebrospinal fluid (CSF) biochemistry and microscopy was non-contributory and CSF viral PCRs, toxoplasma antibodies, cryptococcal antigen were also negative. All patients had progressively worsening sensorium and neurological deficits. Repeat MRIs showed increase in oedema in the lesions and appearance/expansion of haemorrhage in the thalamic/hemispherical lesions. All patients received intravenous methylprednisolone (IVMP) without any benefit. Four patients underwent plasmapheresis (PLEX), one received intravenous immunoglobulin (IVIG) and one received both second line immunotherapies, without significant improvement. Brain biopsy (performed in three patients) showed inflammatory demyelination and areas of haemorrhage, thus confirming the diagnosis. Six patients succumbed in 7-30 days of the illness, despite aggressive treatment and only two survived, albeit with a significant disability. CONCLUSION: AHLE is a rare, yet very severe variant of ADEM. MRI shows lesions with haemorrhages, oedema and mass effect and histology findings reveal inflammatory infiltrates, haemorrhagic foci and fibrinoid necrosis of vessel walls. Prognosis is worse as compared to the classic ADEM, with a high mortality rate. To the best of our knowledge, this is one of the largest series of AHLE to have been reported anywhere in the world. KEYMESSAGE: Acute encephalopathy, multifocal deficits accompanied by haemorrhagic CNS demyelinating lesions with oedema and mass effect are the key features of AHLE. It is a rare, yet very severe form of ADEM with very high morbidity and mortality.

Radiological manifestation of familial acute necrotizing encephalopathy with RANBP2 mutation in a Far-East Asian family: Case report.

RATIONALE: Acute necrotizing encephalopathy (ANE) is a specific type of encephalopathy usually followed by febrile infection. It has an aggressive clinical course; however, it usually does not recur after recovery in cases of spontaneous ANE. Nevertheless, there are several studies reporting recurrences in familial ANE with RAN-binding protein 2 (RANBP2) mutation. There are few cases of familial ANE with RANBP2 mutation in Asian populations. PATIENTS CONCERNS: A 21-month-old Korean boy who was previously healthy, presented with seizure following parainfluenza - a virus and bocavirus infection, followed by 2 recurrent seizure episodes and encephalitis after febrile respiratory illnesses. Meanwhile, his 3-year-old sister had focal brain lesions on neuroimaging studies when evaluated for head trauma. The siblings also had an older brother who presented status epilepticus after febrile respiratory illness at the age of 10 months old. DIAGNOSIS: Brain magnetic resonance imaging was performed to evaluate the seizure and neurologic symptoms. Imaging findings showed variable spectrum - from non-specific diffuse white matter injury pattern to typical "tricolor pattern" of the ANE on diffusion-weighted images. The other 2 siblings showed focal lesions in both external capsules and severe diffuse brain edema. Genetic tests identified a heterozygous missense mutation in the RANBP2 [c.1754C>T (p.Thr585Met)] in 2 siblings and their mother. INTERVENTIONS: Patients were treated conservatively with anticonvulsive agents, intravascular immunoglobulin, and steroids. OUTCOMES: Among the 3 siblings, 2 male siblings died from familial ANE, whereas the female sibling was asymptomatic. LESSONS: These cases highlight the radiological aspects of familial ANE with incomplete penetrance of the RANBP2 gene in 3 family members, showing variable involvements of the brain and natural history on magnetic resonance images. Radiologists should be aware of the typical and atypical imaging findings of familial ANE for prompt management of affected patients.

Acute Necrotizing Encephalopathy Associated with Influenza A.

A severe and unusual complication found in children with influenza is an acute necrotizing encephalopathy. A 20-month-old female with no significant past medical history was admitted to our facility, presenting with a 4-day history of worsening fever, upper respiratory symptoms, new-onset altered mental status and episodes of extensor posturing. The initial concern was a dystonic reaction secondary to promethazine following a recent diagnosis of influenza A virus. A head computed tomography scan indicated concern for widespread edema, and the video EEG revealed focal slowing in the frontocentral regions with no epileptiform activity during episodes of extensor posturing. The first magnetic resonance imaging results were consistent with acute hemorrhagic encephalitis or severe anoxic brain injury for which there is a broad differential. A second MRI five days later found new areas of restricted diffusion that were consistent with acute necrotizing encephalitis.

Acute Necrotizing Encephalopathy.

OBJECTIVE: To describe the clinical profile of pediatric patients with acute necrotizing encephalopathy (ANE). STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Aga Khan University Hospital, Karachi, Pakistan, from January 2014 to October 2017. METHODOLOGY: Retrospective review of medical records of all children aged 1 month to 16 years admitted with diagnosis of ANE was done. Diagnosis was based on the criteria of ANE described by Mizuguchi et al. the clinical profile, management and outcome were recorded. RESULTS: There were 17 patients. The mean age at presentation was 55.47 ± 59.13 months. The most common presentation was fever with altered consciousness and seizures. The mean length of stay was 11.7 ± 5.6 days. Viral etiology was established in three children. The managements of the patients were symptomatic and supportive; the combination of antibiotics, antivirals and anticonvulsants was the most frequently used regimen. Eleven out of seventeen (65%) patients required intensive care unit admission and mechanical ventilation; while others were managed in the special care unit. Three (17.6%) children died during the stay; while 10 (58.8%) children developed severe morbidity in the form of neurodevelopmental sequelae. CONCLUSION: The devastating outcome of ANE seemed to occur with increasing severity at the time of initial presentation; and the use of antivirals and immunomodulation did not alter the course of disease.

Influenza-Associated Acute Necrotizing Encephalopathy in Siblings.

Encephalopathy is an important complication associated with influenza, most frequently observed in young children, with a wide range of severity. The most severe category of influenza-associated encephalopathy (IAE) is acute necrotizing encephalopathy (ANE), characterized by high frequency of neurologic sequelae and fatal outcomes. We report two young siblings who developed fever and seizures with altered mental status. Influenza A(H1N1)pdm09 virus infection was identified in upper respiratory tract specimens from both patients, and neuroimaging revealed bilateral inflammatory lesions, consistent with acute necrotizing encephalopathy. Neither child had received influenza vaccination. Both children progressed to critical illness and required invasive mechanical ventilation. In addition to critical care management, both patients received high-dose corticosteroids, mannitol, anticonvulsants, and antiviral treatment of influenza. The older child recovered fully and was discharged 2 weeks after illness onset, but the younger sibling developed severe brainstem edema and cerebellar tonsillar herniation, and died on illness day 11. Both children tested positive for Ran Binding Protein 2 (RANBP2) gene mutations. RANBP2 is a genetic polymorphism associated with recurrent episodes of necrotizing encephalitis with respiratory viral infections. Annual influenza vaccination is especially important for ANE survivors, with or without RANBP2 mutations, their household contacts, and caregivers. During influenza season, close monitoring of any child with a history of neurological complications associated with respiratory illness is indicated, with prompt initiation of antiviral treatment with onset of acute respiratory illness, and influenza testing performed by molecular assay.

Acute disseminated encephalomyelitis presenting as a brainstem encephalitis.

Acute disseminated encephalomyelitis (ADEM) is a disease characterized by inflammation and destruction of myelin. Acute hemorrhagic leukoencephalitis (AHLE) is a severe form of ADEM known for its particularly poor outcome. We present a case of a young Caucasian female who presented with drowsiness and slurred speech followed by rapid brainstem involvement resembling rhomboencephalitis. Despite multiple diagnostic tests and empiric therapy with immunosuppressants, immunoglobulins, and antimicrobials, she lost most brainstem reflexes within a few weeks and ultimately passed away. Magnetic resonance imaging (MRI) showed progression of lesions from the brainstem to eventually involve bilateral cerebral hemispheres. Autopsy and microscopic examination of the brain revealed several hemorrhagic lesions throughout the brain and rendered a diagnosis of AHLE. AHLE was initially described in 1941 and is thought to be autoimmune related, possibly related to cross reactivity between the immune system and CNS tissues like myelin. While a definitive inciting pathogen was not discovered, this case emphasizes the importance of considering AHLE in the differential diagnosis of patients with rapid loss of neurologic function and highlights an atypical presentation of ADEM/AHLE.

Acute necrotising encephalopathy in a child with H1N1 influenza infection: a clinicoradiological diagnosis and follow-up.

Acute necrotising encephalopathy of childhood (ANEC) is a fulminant disorder with rapid progressive encephalopathy, seizures and poor outcome. It has been reported in association with various viral infections. We describe the clinicoradiological findings and short-term follow-up in a child with H1N1 influenza-associated ANEC. Laminar, target or tricolour pattern of involvement of the thalami was seen on apparent diffusion coefficient images. Our patient had significant morbidity at discharge despite early diagnosis and management with oseltamivir and immunoglobulin. Repeat imaging after 3 months had shown significant resolution of thalamic swelling, but there was persistence of cytotoxic oedema involving bilateral thalami. She was pulsed with intravenous steroids and maintained on a tapering schedule of oral steroids. This report emphasises the need for a high index of suspicion to establish early diagnosis, promotion of widespread immunisation strategies to prevent influenza outbreak, and more research to establish standard treatment protocols for this under-recognised entity.

Early and widespread injury of astrocytes in the absence of demyelination in acute haemorrhagic leukoencephalitis.

Acute hemorrhagic leukoencephalitis (AHL) is a fulminant demyelinating disease of unknown etiology. Most cases are fatal within one week from onset. AHL pathology varies with the acuteness of disease. Hemorrhages, vessel fibrinoid necrosis, perivascular fibrin exudation, edema and neutrophilic inflammation are early features, while perivascular demyelination, microglial foci and myelin-laden macrophages appear later. Reactive astrocytosis is not present in early hemorrhagic non-demyelinated lesions, but is seen in older lesions. This case report presents the pathology of an AHL case with fulminant course and fatal outcome within 48 hours from presentation. Severe hemorrhages, edema and neutrophilic inflammation in the absence of circumscribed perivascular demyelination affected the temporal neocortex and white matter, hippocampus, cerebellar cortex and white matter, optic chiasm, mammillary bodies, brainstem, cranial nerve roots and leptomeninges. Perivascular end-feet and parenchymal processes of astrocytes exhibited impressive swelling in haemorrhagic but non-demyelinated white matter regions. Astrocytes were dystrophic and displayed degenerating processes. Astrocytic swellings and remnants were immunoreactive for aquaporin-4, aquaporin-1 and glial fibrillary acidic protein. These morphological changes of astrocytes consistent with injury were also observed in haemorrhagic and normal appearing cortex. Our findings reinforce that perivascular demyelination is not present early in AHL. This is the first study that highlights the early and widespread astrocytic injury in the absence of demyelination in AHL, suggesting that, similarly to neuromyelitis optica and central pontine myelinolysis, demyelination in AHL is secondary to astrocyte injury.

Acute necrotizing encephalopathy (ANE1): rare autosomal-dominant disorder presenting as acute transverse myelitis.

The term "acute transverse myelitis (ATM)" comprises various non-traumatic disorders that eventually can be associated with a focal myelopathy. Patients characteristically present with an acutely occurring paraparesis/plegia and require a comprehensive and timely diagnostic work up for the initiation of an appropriate treatment. We present a case of a 36-year-old female patient with a rare genetic disorder (ANE1: Acute Necrotizing Encephalopathy due to a RANBP2 mutation) who presented with an acute quadriplegia. Following an acute pulmonal infection, she rapidly (< 24 h) developed a severe quadriplegia (total motor score 38) with some facial sensory symptoms (perioral hypoesthesia). Magnetic resonance imaging (MRI) revealed a combination of longitudinal extensive transverse myelitis and symmetrical thalamic lesions. A work-up for infectious and systemic diseases was negative; specifically, no findings related to multiple sclerosis, neuromyelitis optica or vascular disorders. After empirical high dose steroid treatment and rehabilitation therapy, the patient gained almost normal gait and upper limb function. She was found to carry an autosomal-dominant missense mutation in the RANBP2 gene predisposing for ANE. Gene segregation was confirmed in other family members that had been affected by other episodes of acute steroid-responsive encephalopathies. We propose that a redefined diagnostic workup of ATM might include ANE1, as the frequency of this rare disorder might be underestimated.

Acute necrotizing encephalopathy associated with enterovirus infection.

Acute necrotizing encephalopathy is a rare, clinically distinct entity of acute encephalopathy triggered by acute febrile diseases, mostly viral infections. It is postulated to arise from uncontrolled cytokine release during a febrile illness, and is most often seen in East Asia. We describe a rare Saudi patient of acute necrotizing encephalopathy attributable to enterovirus in a 4 years and 6 months old girl. A work-up revealed elevations in serum and cerebrospinal fluid interleukin-6 and tumor necrosis factor-α. The outcome on intravenous pulse methylprednisolone was good. This case is the first, to the best of our knowledge, of acute necrotizing encephalopathy reported from Saudi Arabia with a good outcome despite severe magnetic resonance imaging findings and delay in the steroid treatment.

Caso de neurorradiología presentado en la Sesión General de Lectura de Casos del XXX Congreso Nacional de la SERAM, A Coruña. Mayo 2010 / No disponible

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Acute necrotizing encephalopathy progressing to brain death in a pediatric patient with novel influenza A (H1N1) infection.

We report a case of encephalopathy progressing to brain death in a pediatric patient with confirmed infection with novel influenza H1N1. Although neurologic dysfunction associated with H1N1 has been described, we believe this to be the first published report of brain death associated with H1N1 infection.

Acute necrotizing encephalopathy in a child with H1N1 influenza infection.

Since the World Health Organization declared a global pandemic of novel influenza A H1N1 in June 2009, there has been a sustained rise in the number of cases of this strain of influenza. Although most cases are mild with complete and uneventful recovery, multiple cases of severe infection with complications including death have been reported. To the best of our knowledge, the majority of fatal outcomes in the United States have been related to pulmonary complications. We report a 12-year-old girl infected with influenza A H1N1 whose clinical course was complicated by rapid progressive neurologic deterioration and striking CT and MRI findings consistent with acute necrotizing encephalopathy (ANE). To our knowledge this has not been reported in the pediatric radiology literature. We hope this case will alert radiologists to this complication and familiarize radiologists with imaging findings that herald ANE.