Fatal Acute Necrotizing Encephalopathy in a 17-Year-Old Girl with COVID-19: A Case Report

Introduction

Neurological manifestations are increasingly recognized as significant complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Common symptoms include headache, anosmia, memory impairment [1], and, in some cases, more severe neuropsychiatric disturbances such as inattention, hallucinations, delusions, and behavioral changes [2]. Acute necrotizing encephalopathy (ANE) is a rare but devastating neurological condition characterized by rapid progression and high mortality. It typically occurs as a complication of systemic infections, including influenza, mycoplasma, and herpes simplex virus [3]. Notably, ANE associated with SARS-CoV-2 infection remains uncommon [4]. ANE has been predominantly reported in pediatric populations [5], and is exceedingly rare in adolescents and adults [6]. This report describes a fatal case of ANE in a 17-year-old girl following SARS-CoV-2 infection, aiming to highlight the importance of early recognition and aggressive intervention to improve outcomes in this life-threatening condition.

Case Report

A 17-year-old previously healthy Chinese girl presented with fever for 3 days before admission. She has a history of SARS-CoV-2 exposure, without an apparent family history. Although she was in poor spirits, she insisted on learning. Nine hours before admission, she had developed convulsions of the limbs, accompanied by upturned eyes, foaming at the mouth, and confusion, and was thus taken to a county hospital, where she tested positive for SARS-CoV-2 nucleic acid assay of pharyngeal swab, with real-time reverse transcriptase-polymerase chain reaction assay (RT-PCR). Five hours before admission, cranial computed tomography (CT) examination showed slightly hypodense foci in the thalamus, brainstem, and bilateral cerebellum, the fourth ventricle and the ring pool were poorly displayed, and the brain tissue was swollen (Figure 1). Half an hour later, cranial magnetic resonance imaging (MRI) showed symmetrical lesions in the bilateral cerebellar hemispheres and cerebellar vermis, brainstem, thalamus, basal ganglia, and medial temporal lobes, with edema and necrosis in the center of thalamic lesions (Figure 2). Considering the patient’s critical condition, she was then brought to our emergency department. The patient was comatose with respiratory distress, and oxygen saturation was less than 80% on high-flow oxygen. After endotracheal intubation with ventilator-assisted ventilation, she was admitted to the neurological intensive care unit. An examination revealed that she had a reduced level of consciousness (Glasgow Coma Scale score, E1/VT/M2), body temperature 37.5°C, heart rate 67 beats/min, and blood pressure 126/86 mmHg. Her pupils are 3 mm in diameter and sensitive to light, and she had cervical rigidity and positive Babinski signs. A few wet rhonchi were heard in the lungs bilaterally, the liver and spleen were not palpable, and she had urinary incontinence. The initial emergency blood tests revealed elevated ultrasensitive C-reactive protein (CRP) at 19.83 mg/L, lactate dehydrogenase levels 729 U/L, and triglycerides 7.03 mmol/L. Arterial blood gas analysis showed a persistently increasing lactate concentration and a decreasing potential hydrogen (PH) after admission (Table 1), with elevated alanine aminotransferase 352 U/L and aspartate aminotransferase 488 U/L. Her interleukin-6 (IL-6) was elevated (231.34 pg/ml), as was the level of protein in the cerebrospinal fluid (CSF) (2951.0 mg/L), with a normal cell count. SARS-CoV-2 nucleic acid in CSF was negative, but re-administration of the SARS-CoV-2 nucleic acid assay of pharyngeal swab was still positive with RT-PCR. A post-admission lung CT scan showed minor inflammation of bilateral lungs. To distinguish between encephalopathy from other pathogens, we performed blood immunoglobulin (Ig)M antibody tests for respiratory pathogens (Chlamydia pneumoniae, Mycoplasma pneumoniae, Influenza A Virus, Influenza B Virus, Parainfluenza virus, Coxsackie virus, Respiratory Syncytial Virus, Adenovirus, Legionella) were examined, and all were negative. Second-generation sequencing of pathogenic microorganisms was negative in CSF. The diagnosis of ANE was considered based on the patient’s seizures and progressive impaired consciousness after infectious fever, and head imaging showing symmetric edema and necrosis of bilateral thalamus. Soon after admission, we administered oral nirmatrelvir-ritonavir (300 mg/100 mg, every 12 hours) therapy for COVID-19, ganciclovir (0.5/d) antiviral, and intravenous immunoglobulin (IVIG) (0.4g/kg/d). Two hours later, after CSF results ruled out an intracranial infection, high-dose methylprednisolone (500 mg/d) was administered. The patient’s condition continued to deteriorate 9 hours after admission, she was hemodynamically unstable, and required maintenance with vasoactive drugs. Her pupils were dilated, without light reflexes, and other brainstem reflexes were absent. At 29 hours after admission, she had cardiac arrest and was pronounced dead after cardiopulmonary resuscitation.

Discussion

ANE is a severe neurological complication characterized by rapid progression and high mortality. Clinically, ANE typically manifests as acute encephalopathy, including altered mental status and seizures, within 3 days of a febrile viral illness such as influenza or SARS-CoV-2 infection. Neuroimaging often reveals symmetrical, multifocal lesions in the thalamus, brainstem, and/or cerebral white matter, accompanied by necrosis, edema, or hemorrhage. Laboratory findings may include elevated CSF protein levels without pleocytosis, increased serum aminotransferases without hyperammonemia, and the exclusion of other similar conditions such as acute disseminated encephalomyelitis (ADEM) or Leigh syndrome [7]. Poyiadji first reported a presumptive case of COVID-19-associated ANE in a 50-year-old woman with fever, altered mental status, and cough, treated with IVIG [8]. Similarly, Ritwik described a woman with cognitive decline, seizures, and coma, treated unsuccessfully with steroids [9]. Xia conducted a study on 12 pediatric cases of COVID-19-associated ANE, revealing that fever and impaired consciousness were present in 100% of cases, while seizures occurred in 75% [5]. A systematic review of adult cases (n=30) showed nonspecific symptoms (fever: 66.7%) and 53.3% mortality [6]. Our case involved a 17-year-old girl with SARS-CoV-2-associated ANE, who presented with fever, convulsions, and progressive consciousness impairment, consistent with prior reports. Laboratory findings revealed elevated aminotransferases and interleukin-6, elevated CSF protein levels without pleocytosis, and bilateral thalamic edema and necrosis on imaging, fulfilling the diagnostic criteria for ANE while excluding ADEM and Leigh syndrome. ADEM typically presents with round or ovoid high-signal lesions in the white matter, rarely involving the basal nuclei or thalamus, without necrosis. Leigh syndrome, a hereditary mitochondrial disorder, usually manifests in infancy or childhood with chronic progressive symptoms and elevated lactate levels in blood or CSF. Our patient had no prior history of genetic disorders or developmental abnormalities, and the elevated lactate was attributed to systemic infection rather than a mitochondrial disorder. Brainstem involvement, particularly cerebellar vermis necrosis compressing the anterior brainstem, contributed to the rapid clinical deterioration. Although early administration of high-dose methylprednisolone (within 24 hours of symptom onset) has been associated with improved outcomes in brainstem-predominant ANE [10], delayed hospital admission (3 days after onset) precluded timely intervention in this case. Despite immediate immunomodulatory therapy with IVIG and steroids, the patient’s condition deteriorated rapidly, resulting in death [10], consistent with Noora’s report of a treatment-refractory pediatric ANE case [11]. Notably, elevated CSF protein and serum procalcitonin proposed as early ANE indicators in influenza-related cases [12]. Elevated arterial lactate and shock hypotension were observed in our patient, which indicates severe systemic inflammation and a poor prognosis. This case highlights the critical importance of early recognition and intervention in COVID-19-associated ANE. Patients presenting with seizures and decreased consciousness following a febrile illness should raise suspicion for ANE. Emergency neuroimaging, including MRI to identify symmetrical thalamic lesions, and lumbar puncture to exclude intracranial infection, are essential diagnostic steps. Early initiation of immunomodulatory therapy, such as glucocorticoids, may improve survival chances in this devastating condition.

The exact pathogenesis of ANE is still unknown. Recent studies on the effects of COVID-19 infection on the central nervous system have reported that the observed injuries are primarily the result of inflammation rather than direct viral damage [13]. Proposed mechanisms include cytokine storm, activation of prothrombotic pathways, and endothelial dysfunction mediated by angiotensin-converting enzyme 2 (ACE2). Additional factors such as hypoxia, systemic disorders, and medications may also contribute to encephalopathy in critically ill COVID-19 patients [14,15].

Although various treatments for ANE have been proposed, evidence supporting individualized therapeutic strategies remains limited. Given the central role of pro-inflammatory cytokines in disease progression, immunomodulatory therapies such as corticosteroids and IVIG are commonly employed [10]. IL-6, a cytokine significantly elevated in ANE, was markedly increased in our patient. Tocilizumab, an IL-6 receptor antagonist, has shown promise in improving symptoms in similar patients [16].

Despite aggressive antiviral therapy, symptomatic support, and early administration of IVIG and high-dose glucocorticoids, our patient died due to the disease the following day. The poor prognosis may be attributed to an overwhelming immune response and severe intracranial lesions, particularly in the cerebellum, brainstem, and thalamus. This case highlights the rapidly progressive course of COVID-19-associated ANE with brainstem lesions and underscores the need for early recognition, aggressive neuroimaging, and timely immunomodulation to optimize the prognosis.

Conclusions

ANE is a rare and devastating condition following SARS-CoV-2 infection. Rapid neuroimaging and lumbar puncture play a vital role in diagnosing adolescents who suddenly present with neurological symptoms and signs following infection. Early diagnosis, immunotherapy, and assertive management are essential to decrease the high mortality associated with this severe neurological disorder.