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First Case Report of Acute Necrotizing Encephalopathy Associated with COVID-19

The first case of COVID-19-associated acute necrotizing encephalopathy was diagnosed in a 58-year old airline worker, according to a neurointensivist and neurohospitalist at Henry Ford Health System in Detroit, who was called in on the case.

Elissa Fory, MD, who shared the details of the case with Neurology Today, said the patient was transported by emergency medical services to the emergency department in the Henry Ford Health System on March 19th with a fever, cough, and altered mental status. She was awake but not able to answer any questions outside of saying her name. She had been having symptoms at home for four days. Her condition has worsened over the two-week period, and she remains in critical condition.

The patient's first CT scan showed bi-thalamic hypointensities; a CT angiogram of the head and neck were normal, Dr. Fory said. A CT-venogram showed normal flow in her deep and superficial veins. Due to fever and confusion, she had a lumbar puncture. The cerebrospinal fluid (CSF) was traumatic (showing evidence of some blood), and there were high proteins. The patient was growing more lethargic each day.  

Henry Ford was one of the first hospitals to do onsite testing for the coronavirus, and the woman's nasal swab came back positive on the second day of her hospitalization. Around this same time, a repeat CT scan showed worsening hypointensities in the thalami and new hypodensities spreading into the temporal lobes. Finally, MRI scans with and without contrast confirmed the diagnosis.

Dr. Fory said that the woman had gone from being mildly hemiparetic to quadriparetic and remained nonverbal. Today, she seemed to have some brief moments of improvement and was more alert.

After the coronavirus PCR was positive, the patient was treated for five days with a COVID-19 protocol of hydroxychloroquine. When she continued to worsen neurologically, intravenous immunoglobulin infusion therapy and high dose intravenous steroids were given, said Dr. Fory. The staff requested but were not able to obtain the antiviral remdesivir for treating the patient, she added

"It is devastating," said Dr. Fory, adding that this is the first case of acute necrotizing encephalitis she has seen. "I think it outlines the seriousness of what we are dealing with [in COVID-19]."

She said that there have been case reports of acute necrotizing encephalitis associated with H1N1 influenza and other viruses. "We just do not know what treatment will work for our patient. We have been trying treatments without having good data about what may or may not help. We have to take things day by day."

Radiologists from Henry Ford who are also working on the patient published a brief report of their findings March 31 in the journal, Radiology. The radiologists wrote in the paper that "acute necrotizing encephalopathy is a rare complication of influenza and other viral infections and has been related to intracranial cytokine storms, which result in blood-brain-barrier breakdown."

They added: "As the number of patients with COVID-19 increases worldwide, doctors should be alert for patients presenting with COVID-19 and altered mental status."

Commenting on the study, Avindra Nath, MD, MBBS, FAAN, senior investigator in the section of infections of the nervous system and clinical director of the National Institute of Neurological Disorders and Stroke, said: "This is a case report of a parainfectious acute necrotizing hemorrhagic encephalopathy (ANHE) in a patient with COVID-19 due to SARS-CoV-2 infection. 

The neurological symptoms were present early in the course of the illness and were associated with acute respiratory distress syndrome (ARDS). The radiological features were typical of ANHE showing bilateral thalamic lesions and other symmetric multifocal lesions in white and grey matter with hemorrhages and contrast enhancement but no demyelination."         

"Although not commented upon by the authors, there may be a high signal intensity lesion in the upper brainstem on the T2 weighted image, which is also typically seen with ANHE," Dr. Nath said. "DWI and ADC [MRI] sequences would have been useful in this setting," he added.

"This case report is particularly important since alteration in level of consciousness is common in patients with COVID-19-associated ARDS and is often attributed to hypoxia or multiorgan failure," Dr. Nath continued. "MRI of the brain should be considered in these patients to look for the possibility of brain lesions. ANHE can be seen with a wide variety of viral infections and does not suggest direct involvement of the brain by the virus but is thought to be mediated by massive cytokine dysregulation or 'cytokine storm.'"

"Most often corticosteroids are used for treatment. However, appropriately, in this patient corticosteroids were not used out of concern for 'respiratory compromise,'" Dr. Nath said, and presumably ongoing viral replication.

Dr. Nath said an alternative might be the use of plasmaphoresis, however, this may not be easily feasible in this setting where patients are in isolation in the ICU. Anti-IL6 and anti-TNF-alpha antibodies are also being considered for treatment of the cytokine storm and could potentially be useful for patients with ANHE if diagnosed early, he said

"An important distinction needs to be made between ANHE and acute disseminated encephalomyelitis (ADEM), which is often post-viral, and MRI shows multifocal lesions associated with demyelination and CSF may show pleocytosis," Dr. Nath said.

"In patients with ANHE the CSF may show increased protein but there is no pleocytosis. ADEM has been reported with other coronaviruses such as MERS and HCoV-OC43 and one needs to be on the lookout for the possibility that it may occur with SARS-CoV-2 as well. Mouse coronaviruses have been shown to spread trans-neuronally from the olfactory pathways to the brainstem and from the lung retrogradely to the lower brainstem. Anosmia is a very common symptom in COVID19 suggesting the invasion of the olfactory nerve. However, autopsy studies will be necessary to determine if SARS-CoV2 is in fact neuroinvasive."

Dr. Nath said his colleagues at the NINDS are developing protocols for monitoring COVID-19 patients in ICU settings and non-ICU settings for neurological complications. They are also assisting with autopsy studies to define the neuropathology of the infection.

"This [case] certainly is very concerning. We are very interested in getting to understand this better and develop treatments that would enter the brain. There is currently a lot of talk and planning."

Link Up for More Information:

·      Poyiadji N, Shahin G, Noujaim, et al. COVID 19-associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features. Radiology 2020; Epub 2020 Mar 31.