WARNING : A patient who tested positive for COVID-19 developed acute necrotizing encephalitis (ANE)


Henry Ford Health System is reporting an unusual case of encephalitis associated with COVID-19.

In a case report published online Tuesday in the journal Radiology, a team of doctors say a patient who tested positive for the coronavirus developed a case of acute necrotizing encephalitis, or ANE, a central nervous infection that mostly afflicts young children.

The 58-year-old female patient is hospitalized in serious condition.

This case report is believed to be the first published case highlighting the association between encephalitis and COVID-19.

Diagnosed via Neuroimaging

The 58-year-old woman presented with a 3-day history of fever, cough, and muscle aches ― symptoms consistent with COVID-19.

She was transported by ambulance to the emergency department and showed signs of confusion, lethargy, and disorientation.

The woman tested negative for influenza, but a rapid COVID-19 test confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) infection.

She was later diagnosed with acute hemorrhagic necrotizing encephalopathy.

“The team had suspected encephalitis at the outset, but then back-to-back CT and MRI scans made the diagnosis,” Fory said in the statement.

Noncontrast head CT revealed “symmetric hypoattenuation within the bilateral medial thalami with a normal CT angiogram and CT venogram,” the team reports in their article. Brain MRI showed “hemorrhagic rim enhancing lesions within the bilateral thalami, medial temporal lobes, and subinsular regions.”

The patient was started on intravenous immunoglobulin but not high-dose steroids, because of concern for respiratory compromise.

As of April 1, the patient was hospitalized in serious condition. Henry Ford Hospital has not provided an update.

Acute necrotizing encephalopathy (ANE) is a rare complication of viral infections, but until now, it has not been known to have occurred as a result of COVID-19 infection.

ANE has been associated with intracranial “cytokine storms,” and a recent report in the Lancet suggested that a subgroup of patients with severe COVID-19 might develop a cytokine storm syndrome.

Commenting for Medscape Medical News, Cyrus A. Raji, MD, PhD, assistant professor of radiology and neurology, Washington University in St. Louis, Missoui, said, “Since this is just one report of one patient, the findings are the most preliminary we can conceive, and more research is needed to determine the extent to which COVID-19 may affect the central nervous system.”

Encephalopathy is a severe influenza-associated complication and has been described most frequently in young children, particularly in Japan [1–3].

The onset of influenza-associated encephalopathy (IAE) typically occurs within a few days of the onset of influenza signs and symptoms, and the outcomes range from full recovery to neurologic sequelae in survivors or to fulminant progression and brain death [1–3].

IAE is distinct from Reye syndrome and not associated with salicylate exposure; although the transaminase level can be elevated, hypoglycemia and hyperammonemia are uncommon [1, 2].

Acute necrotizing encephalopathy (ANE) of childhood, the most severe form of IAE, first described in Japan in 1995, is characterized by sudden onset of fever, convulsions, coma, and sometimes death; symmetric inflammatory brain lesions are noted on neuroimaging [4].

IAE has been reportedly associated with influenza A, B, and C virus infections of the respiratory tract that can trigger a dys-regulated host cytokine response [5–9].

Before the 2009 H1N1 pandemic, sporadic cases of IAE, including ANE with fatal outcome, were reported infrequently in the United States [10–13]. During the 2009 pandemic, a large increase in pediatric IAE cases associated with influenza A(H1N1)pdm09 virus infection was noted in Japan [3]. Sporadic cases of influenza A(H1N1) pdm09–associated IAE in children have been reported in the United States and worldwide [14–17].

Here, we report cases of IAE with ANE that occurred concurrently in 2 young siblings, from nonconsanguineous parentage, who were heterozygous for a missense mutation in the nuclear pore protein Ran-binding protein 2 gene (RANBP2); mutations in RANBP2 have been linked to infection-triggered familial and recurrent ANE [18]

Case 1

A 5-year-old boy in Mexico with a history of complex febrile seizures since the age of 2 years developed fever up to 39.4°C and cough in January 2017, and he received outpatient treatment with oral antibiotics for pharyngitis and ibuprofen for fever. He experienced nausea, emesis, and nonbloody diarrhea over the following 2 days.

On illness day 4, he developed seizures and altered mental status and was admitted to the pediatric intensive care unit (PICU) of hospital A. Two prolonged generalized tonic-clonic seizures were observed, and anticonvulsant therapy with intravenous (IV) levetiracetam and IV midazolam was started. Electroencephalography results were reportedly abnormal. Computed tomography (CT) of his head revealed cerebral edema. Brain magnetic resonance imaging (MRI), performed 2 days later, revealed bilateral temporal lobe lesions with sub-cortical white matter lesions, consistent with encephalitis. Mannitol and methylprednisolone (1 g/24 hours) were administered.

A lumbar puncture yielded no white blood cells, and Gram-staining results were negative. An upper respiratory tract specimen tested positive for influenza A viral antigen, and oral oseltamivir treatment was started on illness day 4. Other admission laboratory testing results are listed in Table 1. The patient had received all recommended routine childhood immunizations except for the influenza vaccine.

On illness day 8, the patient was transferred to the emergency department of hospital B, where he was noted to have a Glasgow Coma Scale score of 7; he was placed on invasive mechanical ventilation. Radiography of his chest revealed bilateral infiltrates.

A head CT scan revealed bilateral decreased attenuation involving the capsule area. Later that day, he was transferred to the PICU of hospital C, where a neurological examination revealed intact pupillary light and gag reflex. Inotropic support was required for his bradycardia and occasional hypotension. He was started on IV vancomycin, IV ceftriaxone, and oral oseltamivir.

His hepatic transaminase levels and results of his coagulation studies were all within their reference range (Table 1). His initial white blood cell count was 7500/μL with 70% neutrophils and 22% lymphocytes.

A repeat head CT scan performed after his admission to hospital C revealed symmetric areas of decreased attenuation in the external capsules and inferior temporal lobes bilaterally, with partial effacement of the cortical sulci. Electroencephalography revealed bilateral parietal spike activity.

A nasopharyngeal swab tested positive for influenza A(H1N1)pdm09 viral RNA in a multiplex respiratory pathogen panel (BioFire Diagnostics, Salt Lake City, Utah). Results of brain MRI performed on illness day 9 were significant for bilaterally symmetric restricted diffusion and extensive diffuse signal abnormalities along the external capsules, medial temporal lobes, and pons, consistent with ischemia/infarction (Figure 1).

Levetiracetam was continued for the necrotizing encephalitis diagnosis. Oral oseltamivir was discontinued, and IV peramivir was started.

Antibiotics were discontinued, and he received 1 dose of IV immunoglobulin (1 g/kg) and was started on methylprednisolone (30 mg/kg per day); after 4 days, he was switched to prednisolone (2 mg/kg per day) for an additional 3 days. The results of bacterial cultures of blood, urine, and tracheal aspirate specimens obtained on admission were negative.

His neurological status improved, and he was extubated on illness day 10 and transferred to the general inpatient floor on room air for additional monitoring and physical therapy and to complete a 5-day course of IV peramivir.

On illness day 14, his neurological examination was normal, quadrivalent inactivated influenza vaccine was administered, and the patient was discharged to his home on levetiracetam anticonvulsant therapy. Blood obtained for genetic testing (Fulgent Diagnostics, Temple City, California) revealed a missense mutation (c.1754C→T p.Thr585MET) heterozygous for RANBP2.

Case 2

A previously healthy 17-month-old girl, the sister of the boy described in case 1, had fever onset of 40°C, eye deviation, and several episodes of focal seizure-like activity in January 2017. The patient had received all recommended routine childhood immunizations except for the influenza vaccine. Her parents denied that the child had any antecedent respiratory symptoms. She was admitted to hospital A on the same day as her brother and was transferred to the PICU with a clinical diagnosis of encephalitis and influenza, despite negative influenza antigen testing results on an upper respiratory specimen; she was started on empiric oseltamivir treatment. Diarrhea and vomiting were noted. Twelve hours after admission, her seizures reoccurred and IV levetiracetam was administered.

Brain MRI revealed multiple hypodense lesions in the limbic region, hippocampus, and frontal lobe with severe brainstem edema. Methylprednisolone (1 g/24 hours) and mannitol were administered. The patient was intubated for respiratory failure with associated anisocoria and decerebrate posturing.

On illness day 5, the patient was transferred to hospital B and then transferred to hospital C later that day. The physical examination on admission was significant for mechanical ventilation without sedation and absent pupillary, corneal, and gag reflexes, but withdrawal to pain was noted.

A head CT scan revealed diffuse effacement of the sulci and basilar cisterns. A chest CT scan revealed atelectasis or infiltrate in the left lingula. Empiric acyclovir, oseltamivir, vancomycin, and ceftriaxone were administered. Laboratory study results were remarkable for a serum sodium level of 170 mmol/L (Table 2).

Immediate management of diabetes insipidus with vasopressin was started, and levetiracetam was continued for seizure management. A nasopharyngeal swab tested positive for influenza A(H1N1)pdm09 viral RNA via a multiplex respiratory pathogen panel (BioFire Diagnostics), and peramivir was continued in place of oseltamivir.

Brain MRI results were markedly abnormal; severe brainstem edema and cerebellar tonsillar herniation, bilateral severe hemorrhagic and edematous thalami, bilateral signal abnormalities in the external capsules and medial temporal lobes, and increased signal in the left parietal lobe were seen (Figures 2 and 3).

The results of bacterial cultures of blood, urine, and tracheal aspirate specimens obtained on admission were negative. The child died on illness day 11. Genetic testing of her blood revealed a missense mutation (c.1754C→T p.Thr585MET) heterozygous for RANBP2.

Figure 1.
T2-weighted sagittal magnetic resonance image showing bilateral enhancement of the external capsules in a 5-year-old boy with acute necrotizing encephalopathy.
Figure 2.
T2-weighted sagittal magnetic resonance image showing enhancement of the bilateral thalami and external capsule in a 17-month-old girl with necrotizing encephalitis.
Figure 3.
T2-weighted coronal magnetic resonance image showing enhancement and edema of the brainstem in a 17-month-old girl with necrotizing encephalopathy.


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