Acute febrile encephalopathy and seizures in children with diffusion restriction lesions on magnetic resonance imaging brain: A case series

Sai Divya Sasi Kumar; Venkat Sandeep Reddy; Bhakti Sarangi; Ajay Walimbe

doi:10.4103/JPCC.JPCC_132_20

CASE REPORT

Year : 2021 | Volume : 8 | Issue : 1 | Page : 42-46

Acute febrile encephalopathy and seizures in children with diffusion restriction lesions on magnetic resonance imaging brain: A case series

Sai Divya Sasi Kumar, Venkat Sandeep Reddy, Bhakti Sarangi, Ajay Walimbe
Department of Pediatrics, Bharati Vidyapeeth Medical College and Hospital, Pune, Maharashtra, India

Date of Submission	13-Aug-2020
Date of Decision	28-Aug-2020
Date of Acceptance	04-Sep-2020
Date of Web Publication	12-Dec-2020

Correspondence Address:
Dr. Bhakti Sarangi
3^rd Floor, Department of Pediatrics, Bharati Vidyapeeth Medical College and Hospital, Pune-Satara Road, Katraj-Dhankawadi, Pune - 411 043, Maharashtra
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JPCC.JPCC_132_20

Abstract

Over the last decade, several entities within the spectrum of acute febrile encephalopathy (AFE) including acute disseminated encephalomyelitis, acute necrotizing encephalitis, fever-induced refractory epilepsy syndrome, clinically mild encephalopathy with reversible splenial lesion, and autoimmune encephalitis have been recognized, all of which now have reasonably well-established clinicoradiological diagnostic criteria and therapeutic options. This case series highlights the clinical profile and outcome of seven children with the lesser-known entity of AFE with seizures and white matter diffusion restriction lesions on magnetic resonance imaging. All children had a history of acute onset fever, altered sensorium, and refractory seizures requiring multiple antiepileptic drugs and presented in shock requiring multiple organ support. All had extensive, diffusion-restricted lesions involving white matter. The infectious trigger was identified as influenza A (H3N2) in case 1, dengue virus in cases 2 and 6, and influenza B in case 4. Five children survived, each of whom had significant neurological sequelae.

Keywords: Acute febrile encephalopathy, diffusion restriction, pediatric, seizures

How to cite this article:
Sasi Kumar SD, Reddy VS, Sarangi B, Walimbe A. Acute febrile encephalopathy and seizures in children with diffusion restriction lesions on magnetic resonance imaging brain: A case series. J Pediatr Crit Care 2021;8:42-6

How to cite this URL:
Sasi Kumar SD, Reddy VS, Sarangi B, Walimbe A. Acute febrile encephalopathy and seizures in children with diffusion restriction lesions on magnetic resonance imaging brain: A case series. J Pediatr Crit Care [serial online] 2021 [cited 2021 Jan 26];8:42-6. Available from: http://www.jpcc.org.in/text.asp?2021/8/1/42/303266

Introduction

Encephalopathy associated with acute febrile illness is frequently encountered by pediatricians and is frequently attributed to infections including viral, bacterial, tubercular meningitis, and cerebral malaria. Noninfectious causes of acute encephalopathy include systemic disorders (dyselectrolytemia, hepatic/renal failure, and sepsis), hypoxic–ischemic encephalopathy, toxins, traumatic brain injury, and stroke. In recent times, newer entities causing acute encephalopathy in children have been described such as acute disseminated encephalomyelitis, acute necrotizing encephalitis (ANE), fever-induced refractory epilepsy syndrome (FIRES), clinically mild encephalopathy with reversible splenial lesion (MERS), and autoimmune encephalitis,^[1],[2] all of which have established clinicoradiological features. A short history of fever with acute-onset prolonged seizures with magnetic resonance imaging (MRI) showing variable lesions with restricted diffusion has been described in the literature. However, the precise clinical characteristics of children with acute encephalopathy with diffusion restriction on MRI are incompletely understood.

Case Report

We hereby report a series of seven children who presented with acute febrile encephalopathy (AFE) and seizures with features of diffusion restriction lesions on MRI brain in the span of 18 months. Informed consent was obtained from parents for usage and disclosure of MRI images. The age of the patients ranged from 3.5 years to 14 years, with a median of 7 years. Four (57.1%) were girls. All were previously neurologically normal. One child had aplastic anemia and was on regular transfusions. None had received age-appropriate immunization [Table 1]. Five of the seven children had fever, which was <24-h duration. Six children presented with refractory seizures lasting longer than 30 min. All seven patients had altered sensorium with signs of raised intracranial pressure (ICP) and received antiraised ICP measures. All of them had features of shock on admission and required mechanical ventilation and multiple vasoactive drugs. The average time of ventilation was 15.14 days. A comparison of the baseline investigations revealed elevated liver enzymes in all cases. Cerebrospinal fluid (CSF) examination done in five children was normal. Bedside continuous electroencephalogram (EEG) in all cases showed delta activity suggestive of encephalopathy. MRI brain for each of the seven cases done within 5 days of admission revealed extensive, asymmetric, multifocal diffusion-restricted lesions with frontoparietal region affection involving the white matter being common in all cases, with variable involvement of subcortical gray matter, brain stem, and cerebellum [Figure 1] and [Table 2]. Cases 1, 3, and 7 additionally showed evidence of hemorrhage (blooming in gradient-echo sequences). All children received the empirical combination of intravenous (IV) ceftriaxone, vancomycin, and acyclovir, and all required multiorgan support including fluids, vasoactive drugs, and mechanical ventilation. All the patients were given a trial of IV methylprednisolone pulse therapy (@30 mg/kg) for a duration of 5 days. Cases 5 and 6 additionally received IV immunoglobulin (IVIG) (@2 g/kg), whereas case 5 also received IV rituximab (@375 mg/m²). An infectious trigger was identified in four cases – influenza A (H3N2) in case 1, dengue virus in cases 2 and 6, and influenza B in case 4. Five children survived but developed significant neurological deficits with poor social interaction and significant tone changes and requiring feeding through nasogastric tube. All were entirely dependent on parents at the time of discharge, and only one showed partial recovery at a 6-month follow-up.

Table 1: Epidemiology, clinical features, laboratory, and radiology findings

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Figure 1: Lesions on magnetic resonance imaging (a) diffusion restriction in thalami and periventricular region seen in case 1, (b) diffusion restriction in bilateral cerebellar regions in case 2, (c) diffusion restriction in thalami and periventricular region seen in case 3, (d) diffusion restriction in frontal, parietal, and occipital region seen in case 6, (e) diffusion restriction in basal ganglia and temporal region seen in case 7

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Table 2: Areas of lesions seen on magnetic resonance imaging

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Discussion

The most common etiology of AFE in India is central nervous system (CNS) infections.^[3] The most prominent feature of the clinical profile of our cases was an overlap of symptoms on presentation including fever and change in sensorium, followed by refractory seizures requiring multiple antiepileptic drugs. All the children had also presented with features of shock requiring ventilation and multiple vasoactive drugs. Shock, severe anemia, bradycardia, low Glasgow Coma Scale, longer duration of coma, and refractory seizures are known to be associated with higher mortality rates in these children.^[4],[5] The proposed mechanisms of CNS injury in AFE include direct insult by the viruses, cytokine-mediated injury, excitotoxic injury with delayed (or apoptotic) cell death, and nitrous oxide-mediated activation of glial cells and excessive release of glutamate.^[6] In influenza-associated encephalitis/encephalopathy, increased concentrations of cytokines, such as soluble tumor necrosis factor receptor-1, interleukin (IL)-1 β, and IL-6, have been observed in serum and CSF.^[7] Apart from cytokine-mediated injury, studies in dengue have also shown virus crossing the blood–brain barrier passively, secondary to endothelial inflammatory damage, or actively due to its supposed neurotropism.^[8]

MRI is the preferred modality in diagnosing the lesion in febrile encephalopathy.^[9] MRI brain in all of the seven cases showed white matter lesions with characteristic bilateral symmetrical areas of T2- and fluid-attenuated inversion recovery hyperintensities that were hyperintense in diffusion-weighted images with loss of signal in apparent diffusion coefficient (ADC) sequences (suggestive of diffusion restriction). Takanashi et al. have reported a series of 17 cases who presented with prolonged febrile seizures and later revealed subcortical white matter lesions on MRI with different viruses isolated in ten of these 17 cases.^[10] Patients with similar lesions on MRI were associated with poor neurologic sequelae.^[11],[12] Features on MRI brain help distinguish between the various parainfectious febrile encephalopathies. While MRI in FIRES is normal, autoimmune encephalitis shows involvement of limbic structures, striatum/ diencephalon/ rhobencephalon. Similarly imaging in MERS shows characterisitic splenial lesion while ANE involves necrotic or hemorrhagic thalamic changes apart from possible brain stem, cerebellum, and white matter involvement. Diagnostic MRI features in the clinical-radiological syndrome of Acute Leukoencephalopathy with Restricted Diffusion (ALERD) include restricted diffusion areas in white matter with edematous changes in cortical and subcortical areas which promptly revert on ADC maps.

Twenty-four hour EEG in all the cases uniformly showed diffuse delta activity suggestive of encephalopathy with case 5 also showing periodic lateralized epileptiform discharges, the presence of which has shown a correlation with seizures and poor prognosis.^[13],[14] Keeping with the current understanding of immune-mediated CNS injury, all four cases were given pulse methylprednisolone. Case 5 had persistent, refractory seizures and additionally received IVIG and 2 weekly doses of rituximab.^[15] Cases 1 and 4 were also given a course of oral oseltamivir^[16] for the treatment of influenza to reduce the viremia and thereby reduce the stimulation of host inflammatory response. Survival in some cases has been achieved with aggressive neuro-intensive management with other therapies including administration of antivirals, corticosteroids, IG, hyperosmolar therapy, plasmapheresis, and hypothermia in some cases.^[17] Postencephalopathy neurological sequelae including epilepsy were prominent in all the cases.

Conclusion

AFE with seizures and restricted diffusion lesions on MRI forms an integral part of the spectrum of AFE. MRI brain is crucial in distinguishing the entity from other components of the AFE spectrum.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understands that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgments

We acknowledge our pediatric neurology team led by Dr. Kavita Srivastava for providing their valuable insights in the management of the patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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